RNDEtree: Regulatory Network With Differential Equation Based on Flexible Neural Tree With Novel Criterion Function

It is crucial to establish accurate models for the identification of genes interactions. In our study, the ensemble model (EM) of flexible neural tree (FNT) and ordinary differential equations (ODEs) is used to infer gene regulatory networks (GRNs) more precisely. During the train of FNT, probabilistic incremental program evolution (PIPE) is employed to optimize the architecture, and particle swarm optimization (PSO) is employed to evolve the parameters. Similarly, the ODEs also use this method to optimize. Finally, the experimental results show that the model can be more accurate compared with some earlier methods. The mean squared error (MSE) of gene expression time series forecasting in this paper is smaller than prior work.

Ordinary differential equation (ODE) models are quite popular for modelling complex dynamic processes in many scientific fields, and the parameters in these models are usually unknown, and we need to estimate them using statistical methods. When some observations are contaminated, regular estimation methods, such as nonlinear least-square estimation, will bring large bias. In this paper, robust estimations of both constant and time-varying parameters in ODE models using M-estimators are proposed, and their asymptotic properties are obtained under some mild conditions. We focus on Huber M-estimator, and also provide a method to adjust the Huber parameter automatically to the observations. The proposed method is compared to existing methods in numerical simulations and CD8+ T cell data analysis. It is demonstrated that our method gain substantial efficiency as well as robust properties.

Recursive prediction error identification and scaling of non-linear state space models using a restricted black box parameterization

Modeling and analysis of complex systems are important aspects of understanding systemic behavior. In the lack of detailed knowledge about a system, we often choose modeling equations out of convenience and search the (high-dimensional) parameter space randomly to learn about model properties. Qualitative modeling sidesteps the issue of choosing specific modeling equations and frees the inference from specific properties of the equations. We consider classes of ordinary differential equation (ODE) models arising from interactions of species/entities, such as (bio)chemical reaction networks or ecosystems. A class is defined by imposing mild assumptions on the interaction rates. In this framework, we investigate whether there can be multiple positive steady states in some ODE models in a given class. We have developed and implemented a method to decide whether any ODE model in a given class cannot have multiple steady states. The method runs efficiently on models of moderate size. We tested the method on a large set of models for gene silencing by sRNA interference and on two publicly available databases of biological models, KEGG and Biomodels. We recommend that this method is used as (i) a pre-screening step for selecting an appropriate model and (ii) for investigating the robustness of non-existence of multiple steady state for a given ODE model with respect to variation in interaction rates. Scripts and examples in Maple are available in the Supplementary Information. wiuf@math.ku.dk Supplementary data are available at Bioinformatics online.

ABSTRACTSeveral approaches exist for estimating the derivatives of observed data for model exploration purposes, including functional data analysis (FDA; Ramsay & Silverman, 2005), generalized local linear approximation (GLLA; Boker, Deboeck, Edler, & Peel, 2010), and generalized orthogonal local derivative approximation (GOLD; Deboeck, 2010). These derivative estimation procedures can be used in a two-stage process to fit mixed effects ordinary differential equation (ODE) models. While the performance and utility of these routines for estimating linear ODEs have been established, they have not yet been evaluated in the context of nonlinear ODEs with mixed effects. We compared properties of the GLLA and GOLD to an FDA-based two-stage approach denoted herein as functional ordinary differential equation with mixed effects (FODEmixed) in a Monte Carlo (MC) study using a nonlinear coupled oscillators model with mixed effects. Simulation results showed that overall, the FODEmixed outperformed both the GLLA and GOLD across all the embedding dimensions considered, but a novel use of a fourth-order GLLA approach combined with very high embedding dimensions yielded estimation results that almost paralleled those from the FODEmixed. We discuss the strengths and limitations of each approach and demonstrate how output from each stage of FODEmixed may be used to inform empirical modeling of young children’s self-regulation.

A common approach to the modeling of gene regulatory networks is to represent activating or repressing interactions using ordinary differential equations for target gene concentrations that include Hill function dependences on regulator gene concentrations. An alternative formulation represents the same interactions using Boolean logic with time delays associated with each network link. We consider the attractors that emerge from the two types of models in the case of a simple but nontrivial network: a figure-8 network with one positive and one negative feedback loop. We show that the different modeling approaches give rise to the same qualitative set of attractors with the exception of a possible fixed point in the ordinary differential equation model in which concentrations sit at intermediate values. The properties of the attractors are most easily understood from the Boolean perspective, suggesting that time-delay Boolean modeling is a useful tool for understanding the logic of regulatory networks.

Bistability arises within a wide range of biological systems from the lambda phage switch in bacteria to cellular signal transduction pathways in mammalian cells. Changes in regulatory mechanisms may result in genetic switching in a bistable system. Recently, more and more experimental evidence in the form of bimodal population distributions indicates that noise plays a very important role in the switching of bistable systems. Although deterministic models have been used for studying the existence of bistability properties under various system conditions, these models cannot realize cell-to-cell fluctuations in genetic switching. However, there is a lag in the development of stochastic models for studying the impact of noise in bistable systems because of the lack of detailed knowledge of biochemical reactions, kinetic rates, and molecular numbers. In this work, we develop a previously undescribed general technique for developing quantitative stochastic models for large-scale genetic regulatory networks by introducing Poisson random variables into deterministic models described by ordinary differential equations. Two stochastic models have been proposed for the genetic toggle switch interfaced with either the SOS signaling pathway or a quorum-sensing signaling pathway, and we have successfully realized experimental results showing bimodal population distributions. Because the introduced stochastic models are based on widely used ordinary differential equation models, the success of this work suggests that this approach is a very promising one for studying noise in large-scale genetic regulatory networks.

In some patients with myeloproliferative neoplasms (MPN), two genetic mutations are often found, JAK2 V617F and one in the TET2 gene. Whether or not one mutation is present will influence how the other subsequent mutation affects the regulation of gene expression. When both mutations are present, the order of their occurrence has been shown to influence disease progression and prognosis. We propose a nonlinear ordinary differential equation (ODE) model and a Moran process models to explain the non-additive and non-commutative mutation effects on recent clinical observations of gene expression patterns, proportions of cells with different mutations, and ages at diagnosis of MPN. These observations consistently shape our modeling framework. Our key proposal is that bistability in gene expression provides a natural explanation for many observed order-of-mutation effects. We also propose potential experimental measurements that can be used to confirm or refute predictions of our models. Citation Format: Yue Wang, Tom Chou, Blerta Shtylla. Order-of-mutation effects on cancer progression: Models for myeloproliferative neoplasm [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B034.

US high school (HS) students are lagging behind their foreign peers in math performance. It is thus necessary to design teaching modules that motivate US HS students to learn more math and to improve their math skills. Our study set out to test two different software programs designed for the development of such skills. MATLAB Simulink provides a friendly interface with which HS students can build ordinary differential equation (ODE) models. An alternative programming language, the R language is free and extensively used in the field of statistical learning and engineering. In this study, a group of HS students first got trained in both Simulink and R and then solved an ODE model of a microbial fuel cell (MFC), which can convert the organic compounds found in waste water into electricity, using both Simulink and R. Three anonymous surveys were conducted for: 1) students’ feedback on the module-based teaching approaches with R and Simulink training, 2) students’ self-evaluation in the improvement of their skills in solving ODE models following their training in R and Simulink, and 3) students’ comparison of R and Simulink in their learning and modeling experience. The instructor also evaluated students’ modeling skills with R and Simulink based on their performance in developing the MFC ODE model. Both students’ self-evaluation and the instructor’s direct evaluation indicate that students’ skills in solving ODE models with both R and Simulink were significantly improved after this R-Simulink modeling project. The surveys show that students generally enjoyed the module-based teaching format and that they would recommended this project to their peers. It was shown in the surveys that students preferred Simulink over R in solving ODE models and that they preferred learning Simulink first and then following up by learning R. Students’ comments for opening questions indicate that the major hurdle in this project was their limited background knowledge in biology and electrochemistry for microbial fuel cells.

Revealing gene regulation-based neural network computing in bacteria

We find concrete evidence for a recently discovered form of intermittency, referred to as in–out intermittency, in both partial differential equation (PDE) and ordinary differential equation (ODE) models of mean field dynamos. This type of intermittency [introduced in P. Ashwin, E. Covas, and R. Tavakol, Nonlinearity 9, 563 (1999)] occurs in systems with invariant submanifolds and, as opposed to on–off intermittency which can also occur in skew product systems, it requires an absence of skew product structure. By this we mean that the dynamics on the attractor intermittent to the invariant manifold cannot be expressed simply as the dynamics on the invariant subspace forcing the transverse dynamics; the transverse dynamics will alter that tangential to the invariant subspace when one is far enough away from the invariant manifold. Since general systems with invariant submanifolds are not likely to have skew product structure, this type of behavior may be of physical relevance in a variety of dynamical settings. The models employed here to demonstrate in–out intermittency are axisymmetric mean-field dynamo models which are often used to study the observed large-scale magnetic variability in the Sun and solar-type stars. The occurrence of this type of intermittency in such models may be of interest in understanding some aspects of such variabilities.

For system identification, the ordinary differential equations (ODEs) model is popular for its accuracy and effectiveness. Consequently, the ODEs model is extended to the stochastic differential equations (SDEs) model to tackle the stochastic case intuitively. But the existence of stochastic integral is a rigid barrier. We simply transform the SDEs to their corresponding stochastic difference equations (SDCEs) to eliminate stochastic integrals and propose an easy but effective solution to stochastic system identification. In this solution, the maximum likelihood estimation can be applied and the evolutionary algorithms are used to determine structures and parameters of the unknown system.

Experimental results have shown that anti-cancer therapies, such as radiotherapy and chemotherapy, can modulate the cell cycle and generate cell cycle phase-dependent responses. As a result, obtaining a detailed understanding of the cell cycle is one possible path towards improving the efficacy of many of these therapies. Here, we consider a basic structured partial differential equation (PDE) model for cell progression through the cell cycle, and derive expressions for key quantities, such as the population growth rate and cell phase proportions. These quantities are shown to be periodic and, as such, we compare the PDE model to a corresponding ordinary differential equation (ODE) model in which the parameters are linked by ensuring that the long-term ODE behaviour agrees with the average PDE behaviour. By design, we find that the ODE model does an excellent job of representing the mean dynamics of the PDE model within just a few cell cycles. However, by probing the parameter space we find cases in which this mean behaviour is not a good measure of the PDE population growth. Our analytical comparison of two caricature models (one PDE and one ODE system) provides insight into cases in which the simple ODE model is an appropriate approximation to the PDE model.

BackgroundThe emergent dynamics of complex gene regulatory networks govern various cellular processes. However, understanding these dynamics is challenging due to the difficulty of parameterizing the computational models for these networks, especially as the network size increases. Here, we introduce a simulation library, Gene Regulatory Interaction Network Simulator (GRiNS), to address these challenges.ResultsGRiNS integrates popular parameter-agnostic simulation frameworks, RACIPE and Boolean Ising formalism, into a single Python library capable of leveraging GPU acceleration for efficient and scalable simulations. GRiNS extends the ordinary differential equations (ODE) based RACIPE framework with a more modular design, allowing users to choose parameters, initial conditions, and time-series outputs for greater customisability and accuracy in simulations. For large networks, where ODE-based simulation formalisms do not scale well, GRiNS implements Boolean Ising formalism, providing a simplified, coarse-grained alternative, significantly reducing the computational cost while capturing key dynamical behaviours of large regulatory networks.ConclusionGRiNS enables parameter-agnostic modeling of gene regulatory networks to study their dynamic and steady-state behaviors in a scalable and efficient manner. The documentation and installation instructions for GRiNS can be found at https://moltenecdysone09.github.io/GRiNS/.

This study developed a 6-dimensional nonlinear ordinary differential equation model to investigate the criminal activity associated with narcotic drug abuse in Nigeria. The model was structured around the dynamics of disease transmission, with the goal of limiting and potentially eliminating the threat posed by drug abuse crimes. The analysis of the basic reproduction number, R0, revealed that narcotic drug abuse will die out when R0<1, and become endemic when R0>1. The model’s stability analysis showed that the narcotic drug abuse-free equilibrium is asymptotically stable when the Routh-Hurwitz criteria are satisfied. The study emphasizes the importance of consistent law enforcement, effective rehabilitation programs, and a coordinated, multi-sectoral approach to addressing the escalating narcotic drug abuse crisis in Nigeria. The findings of this research are recommended for consideration by policymakers, public health professionals, and community stakeholders to mitigate the far-reaching consequences of this pressing issue. The use and trafficking of narcotic drugs have emerged as a growing public health and social concern in Nigeria in recent years. The misuse of narcotics, including substances such as opioids, cannabis, and cocaine which is alarming in the preval_ence of narcotic drug abuse across the country, with profound implications for individual well-being, public safety, and socioeconomic development.