Properties Of Biological Networks Research Articles

Predicting p53-dependent cell transitions from thermodynamic models.

A cell's fate involves transitions among its various states, each defined by a distinct gene expression profile governed by the topology of gene regulatory networks, which are affected by 3D genome organization. Here, we develop thermodynamic models to determine the fate of a malignant cell as governed by the tumor suppressor p53 signaling network, taking into account long-range chromatin interactions in the mean-field approximation. The tumor suppressor p53 responds to stress by selectively triggering one of the potential transcription programs that influence many layers of cell signaling. These range from p53 phosphorylation to modulation of its DNA binding affinity, phase separation phenomena, and internal connectivity among cell fate genes. We use the minimum free energy of the system as a fundamental property of biological networks that influences the connection between the gene network topology and the state of the cell. We constructed models based on network topology and equilibrium thermodynamics. Our modeling shows that the binding of phosphorylated p53 to promoters of target genes can have properties of a first order phase transition. We apply our model to cancer cell lines ranging from breast cancer (MCF-7), colon cancer (HCT116), and leukemia (K562), with each one characterized by a specific network topology that determines the cell fate. Our results clarify the biological relevance of these mechanisms and suggest that they represent flexible network designs for switching between developmental decisions.

Total-activity conservation of probabilistic Boolean networks and its applications

Conservation law is a basic property of biological networks, which exhibits the total-activity conservation in Boolean networks (BNs). This article analyzes the total-activity conservation of probabilistic Boolean networks (PBNs) based on the algebraic state space representation approach. The concept of total-activity conservation is proposed for PBNs, and a vector-based criterion is presented to verify the total-activity conservation of PBNs. Moreover, the impact of deterministic function perturbation on the total-activity conservation of PBNs is analyzed. Finally, as an application of total-activity conservation for PBNs, the robust total-activity conservation of BNs subject to stochastic function perturbation is explored.

Total-Activity Conservation Analysis and Design of Boolean Networks.

The law of conservation of mass, represented in Boolean networks (BNs) as total-activity conservation, is one of the typical properties of biological networks. This article analyzes the total-activity conservation of BNs based on the algebraic state-space representation (ASSR) approach. First, the total-activity-conservative matrix is defined and a matrix-based criterion is proposed to verify the total-activity conservation of BNs. Meanwhile, when function perturbation is considered, robust total-activity conservation is investigated. Second, by means of the pseudo-Boolean function generated by total-activity conservation, a constructive design procedure of the Boolean dynamics is given to achieve the total-activity conservation. Third, the total-activity conservation of switched Boolean networks (SBNs) under arbitrary switching signal is studied, which together with network aggregation achieves the total-activity conservation of large-scale BNs.

Identification of cell subpopulations associated with disease phenotypes from scRNA-seq data using PACSI

BackgroundSingle-cell RNA sequencing (scRNA-seq) has revolutionized the transcriptomics field by advancing analyses from tissue-level to cell-level resolution. Despite the great advances in the development of computational methods for various steps of scRNA-seq analyses, one major bottleneck of the existing technologies remains in identifying the molecular relationship between disease phenotype and cell subpopulations, where “disease phenotype” refers to the clinical characteristics of each patient sample, and subpopulation refer to groups of single cells, which often do not correspond to clusters identified by standard single-cell clustering analysis. Here, we present PACSI, a method aimed at distinguishing cell subpopulations associated with disease phenotypes at the single-cell level.ResultsPACSI takes advantage of the topological properties of biological networks to introduce a proximity-based measure that quantifies the correlation between each cell and the disease phenotype of interest. Applied to simulated data and four case studies, PACSI accurately identified cells associated with disease phenotypes such as diagnosis, prognosis, and response to immunotherapy. In addition, we demonstrated that PACSI can also be applied to spatial transcriptomics data and successfully label spots that are associated with poor survival of breast carcinoma.ConclusionsPACSI is an efficient method to identify cell subpopulations associated with disease phenotypes. Our research shows that it has a broad range of applications in revealing mechanistic and clinical insights of diseases.

Cascade Deep Forest With Heterogeneous Similarity Measures for Drug-Target Interaction Prediction.

Drug repositioning is a method of systematically identifying potential molecular targets that known drugs may act on. Compared with traditional methods, drug repositioning has been extensively studied due to the development of multi-omics technology and system biology methods. Because of its biological network properties, it is possible to apply machine learning related algorithms for prediction. Based on various heterogeneous network model, this paper proposes a method named THNCDF for predicting drug–target interactions. Various heterogeneous networks are integrated to build a tripartite network, and similarity calculation methods are used to obtain similarity matrix. Then, the cascade deep forest method is used to make prediction. Results indicate that THNCDF outperforms the previously reported methods based on the 10-fold cross-validation on the benchmark data sets proposed by Y. Yamanishi. The area under Precision Recall curve (AUPR) value on the Enzyme, GPCR, Ion Channel, and Nuclear Receptor data sets is 0.988, 0.980, 0.938, and 0.906 separately. The experimental results well illustrate the feasibility of this method.

Identifying Disease Related Genes by Network Representation and Convolutional Neural Network.

The identification of disease related genes plays essential roles in bioinformatics. To achieve this, many powerful machine learning methods have been proposed from various computational aspects, such as biological network analysis, classification, regression, deep learning, etc. Among them, deep learning based methods have gained big success in identifying disease related genes in terms of higher accuracy and efficiency. However, these methods rarely handle the following two issues very well, which are (1) the multifunctions of many genes; and (2) the scale-free property of biological networks. To overcome these, we propose a novel network representation method to transfer individual vertices together with their surrounding topological structures into image-like datasets. It takes each node-induced sub-network as a represented candidate, and adds its environmental characteristics to generate a low-dimensional space as its representation. This image-like datasets can be applied directly in a Convolutional Neural Network-based method for identifying cancer-related genes. The numerical experiments show that the proposed method can achieve the AUC value at 0.9256 in a single network and at 0.9452 in multiple networks, which outperforms many existing methods.

Self assembly of model polymers into biological random networks

The properties of biological networks, such as those found in the ocular lens capsule, are difficult to study without simplified models. Model polymers are developed, inspired by “worm-like” curve models, that are shown to spontaneously self assemble to form networks similar to those observed experimentally in biological systems. These highly simplified coarse-grained models allow the self assembly process to be studied on near-realistic time-scales. Metrics are developed (using a polygon-based framework) which are useful for describing simulated networks and can also be applied to images of real networks. These metrics are used to show the range of control that the computational polymer model has over the networks, including the polygon structure and short range order. The structure of the simulated networks are compared to previous simulation work and microscope images of real networks. The network structure is shown to be a function of the interaction strengths, cooling rates and external pressure. In addition, “pre-tangled” network structures are introduced and shown to significantly influence the subsequent network structure. The network structures obtained fit into a region of the network landscape effectively inaccessible to random (entropically-driven) networks but which are occupied by experimentally-derived configurations.

Biyolojik ve Biyolojik Olmayan Ağlar Üzerine

With a general classification, there are two types of networks in the world: Biological and non-biological networks. We are unable to change the structure of biological networks. However, for networks such as social networks, technological networks and transportation networks, the architectures of non-biological networks are designed and can be changed by people. Networks can be classified as random networks, small-world networks and scale-free networks. However, we have problems with small-world networks and scale free networks. As some authors ask, “how small is a small-world network and how does it compare to other models?” Even the issue of scale-free networks are whether abundant or rare is still debated. Our main goal in this study is to investigate whether biological and non-biological networks have basic defining features. Especially if we can determine the properties of biological networks in a detailed way, then we may have the chance to design more robust and efficient non-biological networks. However, this research results shows that discussions on the properties of biological networks are not yet complete.

Review of tools and algorithms for network motif discovery in biological networks.

Network motifs are recurrent and over‐represented patterns having biological relevance. This is one of the important local properties of biological networks. Network motif discovery finds important applications in many areas such as functional analysis of biological components, the validity of network composition, classification of networks, disease discovery, identification of unique subunits etc. The discovery of network motifs is a computationally challenging task due to the large size of real networks, and the exponential increase of search space with respect to network size and motif size. This problem also includes the subgraph isomorphism check, which is Nondeterministic Polynomial (NP)‐complete. Several tools and algorithms have been designed in the last few years to address this problem with encouraging results. These tools and algorithms can be classified into various categories based on exact census, mapping, pattern growth, and so on. In this study, critical aspects of network motif discovery, design principles of background algorithms, and their functionality have been reviewed with their strengths and limitations. The performances of state‐of‐art algorithms are discussed in terms of runtime efficiency, scalability, and space requirement. The future scope, research direction, and challenges of the existing algorithms are presented at the end of the study.

Association analysis of loci implied in "buffering" epistasis.

The existence of buffering mechanisms is an emerging property of biological networks, and this results in the buildup of robustness through evolution. So far, there are no explicit methods to find loci implied in buffering mechanisms. However, buffering can be seen as interaction with genetic background. Here we develop this idea into a tractable model for quantitative genetics, in which the buffering effect of one locus with many other loci is condensed into a single statistical effect, multiplicative on the total additive genetic effect. This allows easier interpretation of the results and simplifies the problem of detecting epistasis from quadratic to linear in the number of loci. Using this formulation, we construct a linear model for genome-wide association studies that estimates and declares the significance of multiplicative epistatic effects at single loci. The model has the form of a variance components, norm reaction model and likelihood ratio tests are used for significance. This model is a generalization and explanation of previous ones. We test our model using bovine data: Brahman and Tropical Composite animals, phenotyped for body weight at yearling and genotyped at high density. After association analysis, we find a number of loci with buffering action in one, the other, or both breeds; these loci do not have a significant statistical additive effect. Most of these loci have been reported in previous studies, either with an additive effect or as footprints of selection. We identify buffering epistatic SNPs present in or near genes reported in the context of signatures of selection in multi-breed cattle population studies. Prominent among these genes are those associated with fertility (INHBA, TSHR, ESRRG, PRLR, and PPARG), growth (MSTN, GHR), coat characteristics (KIT, MITF, PRLR), and heat resistance (HSPA6 and HSPA1A). In these populations, we found loci that have a nonsignificant statistical additive effect but a significant epistatic effect. We argue that the discovery and study of loci associated with buffering effects allow attacking the difficult problems, among others, of the release of maintenance variance in artificial and natural selection, of quick adaptation to the environment, and of opposite signs of marker effects in different backgrounds. We conclude that our method and our results generate promising new perspectives for research in evolutionary and quantitative genetics based on the study of loci that buffer effect of other loci.

A comprehensive statistical study of metabolic and protein–protein interaction network properties

Understanding the mathematical properties of graphs underlying biological systems could give hints on the evolutionary mechanisms behind these structures. In this article we perform a complete statistical analysis over thousands of graphs representing metabolic and protein–protein interaction (PPI) networks. First, we investigate the quality of fits obtained for the nodes degree distributions to power-law functions. This analysis suggests that a power-law distribution poorly describes the data except for the far right tail in the case of PPI networks. Next we obtain descriptive statistics for the main graph parameters and try to identify the properties that deviate from the expected values had the networks been built by randomly linking nodes with the same degree distribution. This survey identifies the properties of biological networks which are not solely the result of their degree distribution, but emerge from yet unidentified mechanisms other than those that drive these distributions. The findings suggest that, while PPI networks have properties that differ from their expected values in their randomized versions with great statistical significance, the differences for metabolic networks have a smaller statistical significance, though it is possible to identify some drift.

Omics Data Integration and Analysis for Systems Pharmacology.

Systems pharmacology aims to understand drug actions on a multi-scale from atomic details of drug-target interactions to emergent properties of biological network and rationally design drugs targeting an interacting network instead of a single gene. Multifaceted data-driven studies, including machine learning-based predictions, play a key role in systems pharmacology. In such works, the integration of multiple omics data is the key initial step, followed by optimization and prediction. Here, we describe the overall procedures for drug-target association prediction using REMAP, a large-scale off-target prediction tool. The method introduced here can be applied to other relation inference problems in systems pharmacology.

Gene Regulatory Networks: A Primer in Biological Processes and Statistical Modelling.

Modelling gene regulatory networks requires not only a thorough understanding of the biological system depicted, but also the ability to accurately represent this system from a mathematical perspective. Throughout this chapter, we aim to familiarize the reader with the biological processes and molecular factors at play in the process of gene expression regulation. We first describe the different interactions controlling each step of the expression process, from transcription to mRNA and protein decay. In the second section, we provide statistical tools to accurately represent this biological complexity in the form of mathematical models. Among other considerations, we discuss the topological properties of biological networks, the application of deterministic and stochastic frameworks, and the quantitative modelling of regulation. We particularly focus on the use of such models for the simulation of expression data that can serve as a benchmark for the testing of network inference algorithms.

CRISPR-Based Editing Reveals Edge-Specific Effects in Biological Networks.

Unraveling the properties of biological networks is central to understanding both normal and disease cellular phenotypes. Networks consist of functional elements (nodes) that form a variety of diverse connections (edges), with each node being a hub for multiple edges. Herein, in contrast to node-centric network perturbation and analysis approaches, we present a high-throughput CRISPR-based methodology for delineating the role of network edges. Ablation of network edges using a library targeting 93 miRNA target sites in 71 genes reveals numerous edges that control, with variable importance, cellular growth and survival under stress. To compare the impact of removing nodes versus edges in a biological network, we dissect a specific p53-microRNA pathway. We show that removal of the miR-34a target site from the anti-apoptotic gene BCL2 desensitizes the cell to ectopic delivery of miR-34a in a p53-dependent manner. In summary, we demonstrate that network edges are critical to the function and stability of biological networks. Our results introduce a novel genetic screening opportunity via edge ablation and highlight a new dimension in biological network analysis.

An integrative approach to develop computational pipeline for drug-target interaction network analysis

Understanding the general principles governing the functioning of biological networks is a major challenge of the current era. Functionality of biological networks can be observed from drug and target interaction perspective. All possible modes of operations of biological networks are confined by the interaction analysis. Several of the existing approaches in this direction, however, are data-driven and thus lack potential to be generalized and extrapolated to different species. In this paper, we demonstrate a systems pharmacology pipeline and discuss how the network theory, along with gene ontology (GO) analysis, co-expression analysis, module re-construction, pathway mapping and structure level analysis can be used to decipher important properties of biological networks with the aim to propose lead molecule for the therapeutic interventions of various diseases.

A new approach to solving the feature-binding problem in primate vision.

We discuss a recently proposed approach to solve the classic feature-binding problem in primate vision that uses neural dynamics known to be present within the visual cortex. Broadly, the feature-binding problem in the visual context concerns not only how a hierarchy of features such as edges and objects within a scene are represented, but also the hierarchical relationships between these features at every spatial scale across the visual field. This is necessary for the visual brain to be able to make sense of its visuospatial world. Solving this problem is an important step towards the development of artificial general intelligence. In neural network simulation studies, it has been found that neurons encoding the binding relations between visual features, known as binding neurons, emerge during visual training when key properties of the visual cortex are incorporated into the models. These biological network properties include (i) bottom-up, lateral and top-down synaptic connections, (ii) spiking neuronal dynamics, (iii) spike timing-dependent plasticity, and (iv) a random distribution of axonal transmission delays (of the order of several milliseconds) in the propagation of spikes between neurons. After training the network on a set of visual stimuli, modelling studies have reported observing the gradual emergence of polychronization through successive layers of the network, in which subpopulations of neurons have learned to emit their spikes in regularly repeating spatio-temporal patterns in response to specific visual stimuli. Such a subpopulation of neurons is known as a polychronous neuronal group (PNG). Some neurons embedded within these PNGs receive convergent inputs from neurons representing lower- and higher-level visual features, and thus appear to encode the hierarchical binding relationship between features. Neural activity with this kind of spatio-temporal structure robustly emerges in the higher network layers even when neurons in the input layer represent visual stimuli with spike timings that are randomized according to a Poisson distribution. The resulting hierarchical representation of visual scenes in such models, including the representation of hierarchical binding relations between lower- and higher-level visual features, is consistent with the hierarchical phenomenology or subjective experience of primate vision and is distinct from approaches interested in segmenting a visual scene into a finite set of objects.

Combinatorial Algorithms for Control of Biological Regulatory Networks

Biological processes, including cell differentiation, organism development, and disease progression, can be interpreted as attractors (fixed points or limit cycles) of an underlying networked dynamical system. In this paper, we study the problem of computing a minimum-size subset of control nodes that can be used to steer a given biological network toward a desired attractor, when the networked system has Boolean dynamics. We first prove that this problem cannot be approximated to any nontrivial factor unless P = NP. We then formulate a sufficient condition and prove that the sufficient condition is equivalent to a target set selection problem, which can be solved using integer linear programming. Furthermore, we show that structural properties of biological networks can be exploited to reduce computational complexity. We prove that when the network nodes have threshold dynamics and certain topological structures, such as block cactus topology and hierarchical organization, the input selection problem can be solved or approximated in polynomial time. For networks with nested canalyzing dynamics, we propose polynomial-time algorithms that are within a polylogarithmic bound of the global optimum. We validate our approach through numerical study on real-world gene regulatory networks.

Learning Nonlinear Dynamics in Efficient, Balanced Spiking Networks Using Local Plasticity Rules

The brain uses spikes in neural circuits to perform many dynamical computations. The computations are performed with properties such as spiking efficiency, i.e. minimal number of spikes, and robustness to noise. A major obstacle for learning computations in artificial spiking neural networks with such desired biological properties is due to lack of our understanding of how biological spiking neural networks learn computations. Here, we consider the credit assignment problem, i.e. determining the local contribution of each synapse to the network's global output error, for learning nonlinear dynamical computations in a spiking network with the desired properties of biological networks. We approach this problem by fusing the theory of efficient, balanced neural networks (EBN) with nonlinear adaptive control theory to propose a local learning rule. Locality of learning rules are ensured by feeding back into the network its own error, resulting in a learning rule depending solely on presynaptic inputs and error feedbacks. The spiking efficiency and robustness of the network are guaranteed by maintaining a tight excitatory/inhibitory balance, ensuring that each spike represents a local projection of the global output error and minimizes a loss function. The resulting networks can learn to implement complex dynamics with very small numbers of neurons and spikes, exhibit the same spike train variability as observed experimentally, and are extremely robust to noise and neuronal loss.

Reduction of Qualitative Models of Biological Networks for Transient Dynamics Analysis.

Qualitative models of dynamics of signalling pathways and gene regulatory networks allow for the capturing of temporal properties of biological networks while requiring few parameters. However, these discrete models typically suffer from the so-called state space explosion problem which makes the formal assessment of their potential behaviors very challenging. In this paper, we describe a method to reduce a qualitative model for enhancing the tractability of analysis of transient reachability properties. The reduction does not change the dimension of the model, but instead limits its degree of freedom, therefore reducing the set of states and transitions to consider. We rely on a transition-centered specification of qualitative models by the mean of automata networks. Our framework encompasses the usual asynchronous Boolean and multi-valued network, as well as 1-bounded Petri nets. Applied to different large-scale biological networks from the litterature, we show that the reduction can lead to a drastic improvement for the scalability of verification methods.

Network analyses in systems biology: new strategies for dealing with biological complexity

The increasing application of network models to interpret biological systems raises a number of important methodological and epistemological questions. What novel insights can network analysis provide in biology? Are network approaches an extension of or in conflict with mechanistic research strategies? When and how can network and mechanistic approaches interact in productive ways? In this paper we address these questions by focusing on how biological networks are represented and analyzed in a diverse class of case studies. Our examples span from the investigation of organizational properties of biological networks using tools from graph theory to the application of dynamical systems theory to understand the behavior of complex biological systems. We show how network approaches support and extend traditional mechanistic strategies but also offer novel strategies for dealing with biological complexity.