Target Control in Logical Models Using the Domain of Influence of Nodes.
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ABSTRACT:
SUBMITTER: Yang G
PROVIDER: S-EPMC5951947 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A variety of biological networks can be modeled as logical or Boolean networks. However, a simplification of the reality to binary states of the nodes does not ease the difficulty of analyzing the dynamics of large, complex networks, such as signal transduction networks, due to the exponential dependence of the state space on the number of nodes. This paper considers a recently introduced method for finding a fairly small subnetwork, representing a collection of nodes that determine the states of most other nodes with a reasonable level of entropy. The subnetwork contains the most determinative nodes that yield the highest information gain. One of the goals of this paper is to propose an algorithm for finding a suitable subnetwork size. The information gain is quantified by the so-called determinative power of the nodes, which is obtained via the mutual information, a concept originating in information theory. We find the most determinative nodes for 36 network models available in the online database Cell Collective (http://cellcollective.org). We provide statistical information that indicates a weak correlation between the subnetwork size and other variables, such as network size, or maximum and average determinative power of nodes. We observe that the proportion represented by the subnetwork in comparison to the whole network shows a weak tendency to decrease for larger networks. The determinative power of nodes is weakly correlated to the number of outputs of a node, and it appears to be independent of other topological measures such as closeness or betweenness centrality. Once the subnetwork of the most determinative nodes is identified, we generate a biological function analysis of its nodes for some of the 36 networks. The analysis shows that a large fraction of the most determinative nodes are essential and involved in crucial biological functions. The biological pathway analysis of the most determinative nodes shows that they are involved in important disease pathways.
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Project description:Substantial effort in recent years has been devoted to constructing and analyzing large-scale gene and protein networks on the basis of "omic" data and literature mining. These interaction graphs provide valuable insight into the topologies of complex biological networks but are rarely context specific and cannot be used to predict the responses of cell signaling proteins to specific ligands or drugs. Conversely, traditional approaches to analyzing cell signaling are narrow in scope and cannot easily make use of network-level data. Here, we combine network analysis and functional experimentation by using a hybrid approach in which graphs are converted into simple mathematical models that can be trained against biochemical data. Specifically, we created Boolean logic models of immediate-early signaling in liver cells by training a literature-based prior knowledge network against biochemical data obtained from primary human hepatocytes and 4 hepatocellular carcinoma cell lines exposed to combinations of cytokines and small-molecule kinase inhibitors. Distinct families of models were recovered for each cell type, and these families clustered topologically into normal and diseased sets.
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Project description:BackgroundBoolean models of biological signalling-regulatory networks are increasingly used to formally describe and understand complex biological processes. These models may become inconsistent as new data become available and need to be repaired. In the past, the focus has been shed on the inference of (classes of) models given an interaction network and time-series data sets. However, repair of existing models against new data is still in its infancy, where the process is still manually performed and therefore slow and prone to errors.ResultsIn this work, we propose a method with an associated tool to suggest repairs over inconsistent Boolean models, based on a set of atomic repair operations. Answer Set Programming is used to encode the minimal repair problem as a combinatorial optimization problem. In particular, given an inconsistent model, the tool provides the minimal repairs that render the model capable of generating dynamics coherent with a (set of) time-series data set(s), considering either a synchronous or an asynchronous updating scheme.ConclusionsThe method was validated using known biological models from different species, as well as synthetic models obtained from randomly generated networks. We discuss the method's limitations regarding each of the updating schemes and the considered minimization algorithm.
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Project description:The investigation of vulnerable components in a signaling pathway can contribute to development of drug therapy addressing aberrations in that pathway. Here, an original signaling pathway is derived from the published literature on breast cancer models. New stochastic logical models are then developed to analyze the vulnerability of the components in multiple signalling sub-pathways involved in this signaling cascade. The computational results are consistent with the experimental results, where the selected proteins were silenced using specific siRNAs and the viability of the cells were analyzed 72 hours after silencing. The genes elF4E and NFkB are found to have nearly no effect on the relative cell viability and the genes JAK2, Stat3, S6K, JUN, FOS, Myc, and Mcl1 are effective candidates to influence the relative cell growth. The vulnerabilities of some targets such as Myc and S6K are found to vary significantly depending on the weights of the sub-pathways; this will be indicative of the chosen target to require customization for therapy. When these targets are utilized, the response of breast cancers from different patients will be highly variable because of the known heterogeneities in signaling pathways among the patients. The targets whose vulnerabilities are invariably high might be more universally acceptable targets.
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Project description:The energy needed in controlling a complex network is a problem of practical importance. Recent works have focused on the reduction of control energy either via strategic placement of driver nodes, or by decreasing the cardinality of nodes to be controlled. However, optimizing control energy with respect to target nodes selection has yet been considered. In this work, we propose an iterative method based on Stiefel manifold optimization of selectable target node matrix to reduce control energy. We derive the matrix derivative gradient needed for the search algorithm in a general way, and search for target nodes which result in reduced control energy, assuming that driver nodes placement is fixed. Our findings reveal that the control energy is optimal when the path distances from driver nodes to target nodes are minimized. We corroborate our algorithm with extensive simulations on elementary network topologies, random and scale-free networks, as well as various real networks. The simulation results show that the control energy found using our algorithm outperforms heuristic selection strategies for choosing target nodes by a few orders of magnitude. Our work may be applicable to opinion networks, where one is interested in identifying the optimal group of individuals that the driver nodes can influence.
| S-EPMC7581767 | biostudies-literature
Project description:Systems biology studies the structure and dynamics of biological systems using mathematical approaches. Bottom-up approaches create models from prior knowledge but usually cannot cope with uncertainty, whereas top-down approaches infer models directly from data using statistical methods but mostly neglect valuable known information from former studies. Here, we want to present a workflow that includes prior knowledge while allowing for uncertainty in the modeling process. We build not one but all possible models that arise from the uncertainty using logical modeling and subsequently filter for those models in agreement with data in a top-down manner. This approach enables us to investigate new and more complex biological research questions, however, the encoding in such a framework is often not obvious and thus not easily accessible for researcher from life sciences. To mitigate this problem, we formulate a pipeline with specific templates to address some research questions common in signaling network analysis. To illustrate the potential of this approach, we applied the pipeline to growth factor signaling processes in two renal cancer cell lines. These two cell lines originate from similar tissue, but surprisingly showed a very different behavior toward the cancer drug Sorafenib. Thus our aim was to explore differences between these cell lines regarding three sources of uncertainty in one analysis: possible targets of Sorafenib, crosstalk between involved pathways, and the effect of a mutation in mammalian target of Rapamycin (mTOR) in one of the cell lines. We were able to show that the model pools from the cell lines are disjoint, thus the discrepancies in behavior originate from differences in the cellular wiring. Also the mutation in mTOR is not affecting its activity in the pathway. The results on Sorafenib, while not fully clarifying the mechanisms involved, illustrate the potential of this analysis for generating new hypotheses.
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Project description:A central debate in the exercise sciences is the cause of the fatigue that develops especially during high intensity exercise of short duration. The most popular theory holds that this form of exercise is limited by a peripherally based, metabolite induced failure of skeletal muscle contractile function, independent of reduced muscle activation by the central nervous system; so-called peripheral fatigue. This theory arose originally from studies undertaken by Nobel Laureate Sir Archibald Vivian Hill and colleagues in Manchester, UK in the 1920s. In turn, their interpretations were crucially influenced by the earlier 1907 findings of Sir Frederick Gowland Hopkins, Nobel Laureate for his discovery of the vitamins, and Walter Morley Fletcher. The original model of Hill and his colleagues proposed that performance during exercise of high intensity was limited by skeletal muscle anaerobiosis that developed as the result of a limiting skeletal muscle blood flow, following the onset of myocardial ischaemia. Such skeletal muscle anaerobiosis ultimately prevented the neutralization of the lactic acid that, Hill believed, initiated muscle contraction. The resulting lactic acid accumulation impaired skeletal muscle relaxation, causing the (involuntary) termination of exercise. The evolutionary progression of this model led to the "catastrophe theory" of Richard Edwards, which posits that exercise terminates when the physiological and biochemical limits of the body are exceeded, causing a catastrophic failure of intracellular homeostasis. This paper addresses six hallmark physiological requirements that must be correct if Hill's cardiovascular/ anaerobic/catastrophic model is the exclusive explanation for the fatigue that develops during maximum exercise to exhaustion. This leads to a review of the evidence supporting other, related "catastrophe" models that have been developed to explain fatigue during exercise of lower intensities and longer durations. It is concluded that there is little published evidence supporting the theory that fatigue occurs only after physiological homeostasis fails according to the prediction of these catastrophe models. Rather, it is proposed that fatigue in any form of exercise may form part of a regulated, anticipatory response co-ordinated in the subconscious brain. The ultimate goal of this regulation is to preserve homeostasis in all physiological systems during exercise, regardless of intensity or duration or the environmental conditions in which it is undertaken.
| S-EPMC1724943 | biostudies-literature
Project description:BackgroundThe analysis of biochemical networks using a logical (Boolean) description is an important approach in Systems Biology. Recently, new methods have been proposed to analyze large signaling and regulatory networks using this formalism. Even though there is a large number of tools to set up models describing biological networks using a biochemical (kinetic) formalism, however, they do not support logical models.ResultsHerein we present a flexible framework for setting up large logical models in a visual manner with the software tool ProMoT. An easily extendible library, ProMoT's inherent modularity and object-oriented concept as well as adaptive visualization techniques provide a versatile environment. Both the graphical and the textual description of the logical model can be exported to different formats.ConclusionNew features of ProMoT facilitate an efficient set-up of large Boolean models of biochemical interaction networks. The modeling environment is flexible; it can easily be adapted to specific requirements, and new extensions can be introduced. ProMoT is freely available from http://www.mpi-magdeburg.mpg.de/projects/promot/.
| S-EPMC1665465 | biostudies-literature