Convergence behaviour and Control in Non-Linear Biological Networks.
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ABSTRACT:
SUBMITTER: Karl S
PROVIDER: S-EPMC4464179 | biostudies-literature | 2015 Jun
REPOSITORIES: biostudies-literature
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Project description:BackgroundSystems wide modeling and analysis of signaling networks is essential for understanding complex cellular behaviors, such as the biphasic responses to different combinations of cytokines and growth factors. For example, tumor necrosis factor (TNF) can act as a proapoptotic or prosurvival factor depending on its concentration, the current state of signaling network and the presence of other cytokines. To understand combinatorial regulation in such systems, new computational approaches are required that can take into account non-linear interactions in signaling networks and provide tools for clustering, visualization and predictive modeling.ResultsHere we extended and applied an unsupervised non-linear dimensionality reduction approach, Isomap, to find clusters of similar treatment conditions in two cell signaling networks: (I) apoptosis signaling network in human epithelial cancer cells treated with different combinations of TNF, epidermal growth factor (EGF) and insulin and (II) combination of signal transduction pathways stimulated by 21 different ligands based on AfCS double ligand screen data. For the analysis of the apoptosis signaling network we used the Cytokine compendium dataset where activity and concentration of 19 intracellular signaling molecules were measured to characterise apoptotic response to TNF, EGF and insulin. By projecting the original 19-dimensional space of intracellular signals into a low-dimensional space, Isomap was able to reconstruct clusters corresponding to different cytokine treatments that were identified with graph-based clustering. In comparison, Principal Component Analysis (PCA) and Partial Least Squares - Discriminant analysis (PLS-DA) were unable to find biologically meaningful clusters. We also showed that by using Isomap components for supervised classification with k-nearest neighbor (k-NN) and quadratic discriminant analysis (QDA), apoptosis intensity can be predicted for different combinations of TNF, EGF and insulin. Prediction accuracy was highest when early activation time points in the apoptosis signaling network were used to predict apoptosis rates at later time points. Extended Isomap also outperformed PCA on the AfCS double ligand screen data. Isomap identified more functionally coherent clusters than PCA and captured more information in the first two-components. The Isomap projection performs slightly worse when more signaling networks are analyzed; suggesting that the mapping function between cues and responses becomes increasingly non-linear when large signaling pathways are considered.ConclusionWe developed and applied extended Isomap approach for the analysis of cell signaling networks. Potential biological applications of this method include characterization, visualization and clustering of different treatment conditions (i.e. low and high doses of TNF) in terms of changes in intracellular signaling they induce.
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Project description:BackgroundThe alignment of protein-protein interaction networks was recently formulated as an integer quadratic programming problem, along with a linearization that can be solved by integer linear programming software tools. However, the resulting integer linear program has a huge number of variables and constraints, rendering it of no practical use.ResultsWe present a compact integer linear programming reformulation of the protein-protein interaction network alignment problem, which can be solved using state-of-the-art mathematical modeling and integer linear programming software tools, along with empirical results showing that small biological networks, such as virus-host protein-protein interaction networks, can be aligned in a reasonable amount of time on a personal computer and the resulting alignments are structurally coherent and biologically meaningful.ConclusionsThe implementation of the integer linear programming reformulation using current mathematical modeling and integer linear programming software tools provided biologically meaningful alignments of virus-host protein-protein interaction networks.
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Project description:BackgroundThe current challenge of Systems Biology is to integrate high throughput data sets for simulating the complexity of biological networks, exploit the evolution of nature-designed networks that maintain the robustness of a biological system, and thereby generate novel, experimentally testable hypotheses. In order to simulate non-linear biological complexities, we have previously developed an Enzyme-Centric mechanistic modeling approach and validated it using metabolic network in E. coli. The idea is to use prior knowledge of catalytic and regulatory mechanisms of each enzyme within the metabolic network to build a dynamic model for investigating the network level regulation and thus understand the nature design principle behind the network.ResultsIn this paper, we further demonstrate the application of complex enzyme catalytic and regulatory modules to simulate nonlinear network regulatory patterns vs. simple linear conversion model. We learned and validated that it is essential to incorporate prior knowledge from the literature to simulate non-linear biological complexities. The network expandability is demonstrated and validated with the complex amino acid biosynthetic network with multi-regulations. Also, we demonstrated the compatibility of mechanistic models within close species. Furthermore, the eukaryotic protein factory model for insuring steady mRNA production is simulated and the coupling of RNA transcription and splicing is validated by both mathematical simulation and experimental analysis.ConclusionWe demonstrated the importance of modeling complex enzyme catalytic and regulatory mechanisms to further understand nonlinear network regulatory patterns. The simulations presented in this paper reveal how a living system maintains homeostasis and its robustness to continue functioning while facing environmental stresses or genetic mutations.
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Project description:MotivationFull-order partial correlation, a fundamental approach for network reconstruction, e.g. in the context of gene regulation, relies on the precision matrix (the inverse of the covariance matrix) as an indicator of which variables are directly associated. The precision matrix assumes Gaussian linear data and its entries are zero for pairs of variables that are independent given all other variables. However, there is still very little theory on network reconstruction under the assumption of non-linear interactions among variables.ResultsWe propose Distance Precision Matrix, a network reconstruction method aimed at both linear and non-linear data. Like partial distance correlation, it builds on distance covariance, a measure of possibly non-linear association, and on the idea of full-order partial correlation, which allows to discard indirect associations. We provide evidence that the Distance Precision Matrix method can successfully compute networks from linear and non-linear data, and consistently so across different datasets, even if sample size is low. The method is fast enough to compute networks on hundreds of nodes.Availability and implementationAn R package DPM is available at https://github.molgen.mpg.de/ghanbari/DPM.Supplementary informationSupplementary data are available at Bioinformatics online.
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Project description:Gene expression profiling has identified cancer prognostic and predictive signatures with superior performance to conventional histopathological or clinical parameters. Consequently, signatures are being incorporated into clinical practice and will soon influence everyday decisions in oncology. However, the slight overlap in the gene identity between signatures for the same cancer type or condition raises questions about their biological and clinical implications. To clarify these issues, better understanding of the molecular properties and possible interactions underlying apparently dissimilar signatures is needed. Here, we evaluated whether the signatures of 24 independent studies are related at the genome, transcriptome or proteome levels. Significant associations were consistently observed across these molecular layers, which suggest the existence of a common cancer cell phenotype. Convergence on cell proliferation and death supports the pivotal involvement of these processes in prognosis, metastasis and treatment response. In addition, functional and molecular associations were identified with the immune response in different cancer types and conditions that complement the contribution of cell proliferation and death. Examination of additional, independent, cancer datasets corroborated our observations. This study proposes a comprehensive strategy for interpreting cancer signatures that reveals common design principles and systems-level properties.
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Project description:Hematopoiesis is a highly complex developmental process that produces various types of blood cells. This process is regulated by different genetic networks that control the proliferation, differentiation, and maturation of hematopoietic stem cells (HSCs). Although substantial progress has been made for understanding hematopoiesis, the detailed regulatory mechanisms for the fate determination of HSCs are still unraveled. In this study, we propose a novel approach to infer the detailed regulatory mechanisms. This work is designed to develop a mathematical framework that is able to realize nonlinear gene expression dynamics accurately. In particular, we intended to investigate the effect of possible protein heterodimers and/or synergistic effect in genetic regulation. This approach includes the Extended Forward Search Algorithm to infer network structure (top-down approach) and a non-linear mathematical model to infer dynamical property (bottom-up approach). Based on the published experimental data, we study two regulatory networks of 11 genes for regulating the erythrocyte differentiation pathway and the neutrophil differentiation pathway. The proposed algorithm is first applied to predict the network topologies among 11 genes and 55 non-linear terms which may be for heterodimers and/or synergistic effect. Then, the unknown model parameters are estimated by fitting simulations to the expression data of two different differentiation pathways. In addition, the edge deletion test is conducted to remove possible insignificant regulations from the inferred networks. Furthermore, the robustness property of the mathematical model is employed as an additional criterion to choose better network reconstruction results. Our simulation results successfully realized experimental data for two different differentiation pathways, which suggests that the proposed approach is an effective method to infer the topological structure and dynamic property of genetic regulations.
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Project description:IntroductionThe relationship between human capital, health spending, and economic growth is frequently neglected in the literature. However, one of the main determinants of human capital is health expenditures, where human capital is one of the driving forces of growth. Consequently, health expenditures affect growth through this link.MethodsIn the study, these findings have been attempted to be empirically tested. Along this axis, health expenditure per qualified worker was chosen as an indicator of health expenditure, and output per qualified worker was chosen as an indicator of economic growth. The variables were treated with the convergence hypothesis. Due to the non-linear nature of the variables, the convergence hypothesis was carried out with non-linear unit root tests.ResultsThe analysis of 22 OECD countries from 1976 to 2020 showed that health expenditure converged for all countries, and there was a significant degree of growth convergence (except for two countries). These findings show that health expenditure convergence has significantly contributed to growth convergence.DiscussionPolicymakers should consider the inclusiveness and effectiveness of health policies while making their economic policies, as health expenditure convergence can significantly impact growth convergence. Further research is needed to understand the mechanisms behind this relationship and identify specific health policies most effective in promoting economic growth.
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Project description:Synchronization constitutes one of the most fundamental collective dynamics across networked systems and often underlies their function. Whether a system may synchronize depends on the internal unit dynamics as well as the topology and strength of their interactions. For chaotic units with certain interaction topologies synchronization might be impossible across all interaction strengths, meaning that these networks are non-synchronizable. Here we propose the concept of interaction control, generalizing transient uncoupling, to induce desired collective dynamics in complex networks and apply it to synchronize even such non-synchronizable systems. After highlighting that non-synchronizability prevails for a wide range of networks of arbitrary size, we explain how a simple binary control may localize interactions in state space and thereby synchronize networks. Intriguingly, localizing interactions by a fixed control scheme enables stable synchronization across all connected networks regardless of topological constraints. Interaction control may thus ease the design of desired collective dynamics even without knowledge of the networks' exact interaction topology and consequently have implications for biological and self-organizing technical systems.
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Project description:Spiking neural networks (SNNs) are a computational tool in which the information is coded into spikes, as in some parts of the brain, differently from conventional neural networks (NNs) that compute over real-numbers. Therefore, SNNs can implement intelligent information extraction in real-time at the edge of data acquisition and correspond to a complementary solution to conventional NNs working for cloud-computing. Both NN classes face hardware constraints due to limited computing parallelism and separation of logic and memory. Emerging memory devices, like resistive switching memories, phase change memories, or memristive devices in general are strong candidates to remove these hurdles for NN applications. The well-established training procedures of conventional NNs helped in defining the desiderata for memristive device dynamics implementing synaptic units. The generally agreed requirements are a linear evolution of memristive conductance upon stimulation with train of identical pulses and a symmetric conductance change for conductance increase and decrease. Conversely, little work has been done to understand the main properties of memristive devices supporting efficient SNN operation. The reason lies in the lack of a background theory for their training. As a consequence, requirements for NNs have been taken as a reference to develop memristive devices for SNNs. In the present work, we show that, for efficient CMOS/memristive SNNs, the requirements for synaptic memristive dynamics are very different from the needs of a conventional NN. System-level simulations of a SNN trained to classify hand-written digit images through a spike timing dependent plasticity protocol are performed considering various linear and non-linear plausible synaptic memristive dynamics. We consider memristive dynamics bounded by artificial hard conductance values and limited by the natural dynamics evolution toward asymptotic values (soft-boundaries). We quantitatively analyze the impact of resolution and non-linearity properties of the synapses on the network training and classification performance. Finally, we demonstrate that the non-linear synapses with hard boundary values enable higher classification performance and realize the best trade-off between classification accuracy and required training time. With reference to the obtained results, we discuss how memristive devices with non-linear dynamics constitute a technologically convenient solution for the development of on-line SNN training.
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Project description:BackgroundReverse engineering gene networks and identifying regulatory interactions are integral to understanding cellular decision making processes. Advancement in high throughput experimental techniques has initiated innovative data driven analysis of gene regulatory networks. However, inherent noise associated with biological systems requires numerous experimental replicates for reliable conclusions. Furthermore, evidence of robust algorithms directly exploiting basic biological traits are few. Such algorithms are expected to be efficient in their performance and robust in their prediction.ResultsWe have developed a network identification algorithm to accurately infer both the topology and strength of regulatory interactions from time series gene expression data in the presence of significant experimental noise and non-linear behavior. In this novel formulism, we have addressed data variability in biological systems by integrating network identification with the bootstrap resampling technique, hence predicting robust interactions from limited experimental replicates subjected to noise. Furthermore, we have incorporated non-linearity in gene dynamics using the S-system formulation. The basic network identification formulation exploits the trait of sparsity of biological interactions. Towards that, the identification algorithm is formulated as an integer-programming problem by introducing binary variables for each network component. The objective function is targeted to minimize the network connections subjected to the constraint of maximal agreement between the experimental and predicted gene dynamics. The developed algorithm is validated using both in silico and experimental data-sets. These studies show that the algorithm can accurately predict the topology and connection strength of the in silico networks, as quantified by high precision and recall, and small discrepancy between the actual and predicted kinetic parameters. Furthermore, in both the in silico and experimental case studies, the predicted gene expression profiles are in very close agreement with the dynamics of the input data.ConclusionsOur integer programming algorithm effectively utilizes bootstrapping to identify robust gene regulatory networks from noisy, non-linear time-series gene expression data. With significant noise and non-linearities being inherent to biological systems, the present formulism, with the incorporation of network sparsity, is extremely relevant to gene regulatory networks, and while the formulation has been validated against in silico and E. Coli data, it can be applied to any biological system.
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