Project description:Our knowledge of metabolism can be represented as a network comprising several thousands of nodes (compounds and reactions). Several groups applied graph theory to analyse the topological properties of this network and to infer metabolic pathways by path finding. This is, however, not straightforward, with a major problem caused by traversing irrelevant shortcuts through highly connected nodes, which correspond to pool metabolites and co-factors (e.g. H2O, NADP and H+). In this study, we present a web server implementing two simple approaches, which circumvent this problem, thereby improving the relevance of the inferred pathways. In the simplest approach, the shortest path is computed, while filtering out the selection of highly connected compounds. In the second approach, the shortest path is computed on the weighted metabolic graph where each compound is assigned a weight equal to its connectivity in the network. This approach significantly increases the accuracy of the inferred pathways, enabling the correct inference of relatively long pathways (e.g. with as many as eight intermediate reactions). Available options include the calculation of the k-shortest paths between two specified seed nodes (either compounds or reactions). Multiple requests can be submitted in a queue. Results are returned by email, in textual as well as graphical formats (available in http://www.scmbb.ulb.ac.be/pathfinding/).
Project description:This study builds conceptual explanations and empirical examinations of the vulnerability response of networks under attack. Two quantities of "vulnerability" and "uncertainty in vulnerability" are defined by scrutinizing the performance loss trajectory of networks experiencing attacks. Both vulnerability and uncertainty in vulnerability quantities are a function of the network topology and size. This is tested on 16 distinct topologies appearing in infrastructure, social, and biological networks with 8 to 26 nodes under two percolation scenarios exemplifying benign and malicious attacks. The findings imply (i) crossing path, tree, and diverging tail are the most vulnerable topologies, (ii) complete and matching pairs are the least vulnerable topologies, (iii) complete grid and complete topologies show the most uncertainty for vulnerability, and (iv) hub-and-spoke and double u exhibit the least uncertainty in vulnerability. The findings also imply that both vulnerability and uncertainty in vulnerability increase with an increase in the size of the network. It is argued that in networks with no undirected cycle and one undirected cycle, the uncertainty in vulnerability is maximal earlier in the percolation process. With an increase in the number of cycles, the uncertainty in vulnerability is accumulated at the end of the percolation process. This emphasizes the role of tailoring preparedness, response, and recovery phases for networks with different topologies when they might experience disruption.
Project description:Pathway databases are becoming increasingly important and almost omnipresent in most types of biological and translational research. However, little is known about the quality and completeness of pathways stored in these databases. The present study conducts a comprehensive assessment of transcriptional regulatory pathways in humans for seven well-studied transcription factors: MYC, NOTCH1, BCL6, TP53, AR, STAT1, and RELA. The employed benchmarking methodology first involves integrating genome-wide binding with functional gene expression data to derive direct targets of transcription factors. Then the lists of experimentally obtained direct targets are compared with relevant lists of transcriptional targets from 10 commonly used pathway databases.The results of this study show that for the majority of pathway databases, the overlap between experimentally obtained target genes and targets reported in transcriptional regulatory pathway databases is surprisingly small and often is not statistically significant. The only exception is MetaCore pathway database which yields statistically significant intersection with experimental results in 84% cases. Additionally, we suggest that the lists of experimentally derived direct targets obtained in this study can be used to reveal new biological insight in transcriptional regulation and suggest novel putative therapeutic targets in cancer.Our study opens a debate on validity of using many popular pathway databases to obtain transcriptional regulatory targets. We conclude that the choice of pathway databases should be informed by solid scientific evidence and rigorous empirical evaluation.This article was reviewed by Prof. Wing Hung Wong, Dr. Thiago Motta Venancio (nominated by Dr. L Aravind), and Prof. Geoff J McLachlan.
Project description:Gene regulatory networks (GRNs) provide a transformation function between the static genomic sequence and the primary spatial specification processes operating development. The regulatory information encompassed in developmental GRNs thus goes far beyond the control of individual genes. We here address regulatory information at different levels of network organization, from single node to subcircuit to large-scale GRNs and discuss how regulatory design features such as network architecture, hierarchical organization, and cis-regulatory logic contribute to the developmental function of network circuits. Using specific subcircuits from the sea urchin endomesoderm GRN, for which both circuit design and biological function have been described, we evaluate by Boolean modeling and in silico perturbations the import of given circuit features on developmental function. The examples include subcircuits encoding positive feedback, mutual repression, and coherent feedforward, as well as signaling interaction circuitry. Within the hierarchy of the endomesoderm GRN, these subcircuits are organized in an intertwined and overlapping manner. Thus, we begin to see how regulatory information encoded at individual nodes is integrated at all levels of network organization to control developmental process.
Project description:Assessing the vulnerability and adaptive capacity of species, communities, and ecosystems is essential for successful conservation. Climate change, however, induces extreme uncertainty in various pathways of assessments, which hampers robust decision-making for conservation. Here, we developed a framework that allows us to quantify the level of acceptable uncertainty as a metric of ecosystem robustness, considering the uncertainty due to climate change. Under the framework, utilizing a key concept from info-gap decision theory, vulnerability is measured as the inverse of maximum acceptable uncertainty to fulfill the minimum required goal for conservation. We applied the framework to 42 natural forest ecosystems and assessed their acceptable uncertainties in terms of maintenance of species richness and forest functional type. Based on best-guess estimate of future temperature in various GCM models and RCP scenarios, and assuming that tree species survival is primarily determined by mean annual temperature, we performed simulations with increasing deviation from the best-guess temperature. Our simulations indicated that the acceptable uncertainty varied greatly among the forest plots, presumably reflecting the distribution of ecological traits and niches among species within the communities. Our framework provides acceptable uncertainty as an operational metric of ecosystem robustness under uncertainty, while incorporating both system properties and socioeconomic conditions. We argue that our framework can enhance social consensus building and decision-making in the face of the extreme uncertainty induced by global climate change.
Project description:BackgroundAn accurate understanding of interactions among genes plays a major role in developing therapeutic intervention methods. Gene regulatory networks often contain a significant amount of uncertainty. The process of prioritizing biological experiments to reduce the uncertainty of gene regulatory networks is called experimental design. Under such a strategy, the experiments with high priority are suggested to be conducted first.ResultsThe authors have already proposed an optimal experimental design method based upon the objective for modeling gene regulatory networks, such as deriving therapeutic interventions. The experimental design method utilizes the concept of mean objective cost of uncertainty (MOCU). MOCU quantifies the expected increase of cost resulting from uncertainty. The optimal experiment to be conducted first is the one which leads to the minimum expected remaining MOCU subsequent to the experiment. In the process, one must find the optimal intervention for every gene regulatory network compatible with the prior knowledge, which can be prohibitively expensive when the size of the network is large. In this paper, we propose a computationally efficient experimental design method. This method incorporates a network reduction scheme by introducing a novel cost function that takes into account the disruption in the ranking of potential experiments. We then estimate the approximate expected remaining MOCU at a lower computational cost using the reduced networks.ConclusionsSimulation results based on synthetic and real gene regulatory networks show that the proposed approximate method has close performance to that of the optimal method but at lower computational cost. The proposed approximate method also outperforms the random selection policy significantly. A MATLAB software implementing the proposed experimental design method is available at http://gsp.tamu.edu/Publications/supplementary/roozbeh15a/.
Project description:To gain insights into complex biological processes, genome-scale data (e.g., RNA-Seq) are often overlaid on biochemical networks. However, many networks do not have a one-to-one relationship between genes and network edges, due to the existence of isozymes and protein complexes. Therefore, decisions must be made on how to overlay data onto networks. For example, for metabolic networks, these decisions include (1) how to integrate gene expression levels using gene-protein-reaction rules, (2) the approach used for selection of thresholds on expression data to consider the associated gene as "active", and (3) the order in which these steps are imposed. However, the influence of these decisions has not been systematically tested. We compared 20 decision combinations using a transcriptomic dataset across 32 tissues and showed that definition of which reaction may be considered as active (i.e., reactions of the genome-scale metabolic network with a non-zero expression level after overlaying the data) is mainly influenced by thresholding approach used. To determine the most appropriate decisions, we evaluated how these decisions impact the acquisition of tissue-specific active reaction lists that recapitulate organ-system tissue groups. These results will provide guidelines to improve data analyses with biochemical networks and facilitate the construction of context-specific metabolic models.
Project description:Information about the enzyme kinetics in a metabolic network will enable understanding of the function of the network and quantitative prediction of the network responses to genetic and environmental perturbations. Despite recent advances in experimental techniques, such information is limited and existing experimental data show extensive variation and they are based on in vitro experiments. In this article, we present a computational framework based on the well-established (log)linear formalism of metabolic control analysis. The framework employs a Monte Carlo sampling procedure to simulate the uncertainty in the kinetic data and applies statistical tools for the identification of the rate-limiting steps in metabolic networks. We applied the proposed framework to a branched biosynthetic pathway and the yeast glycolysis pathway. Analysis of the results allowed us to interpret and predict the responses of metabolic networks to genetic and environmental changes, and to gain insights on how uncertainty in the kinetic mechanisms and kinetic parameters propagate into the uncertainty in predicting network responses. Some of the practical applications of the proposed approach include the identification of drug targets for metabolic diseases and the guidance for design strategies in metabolic engineering for the purposeful manipulation of the metabolism of industrial organisms.
Project description:Integrated real-time control (RTC) of urban wastewater systems, which can automatically adjust system operation to environmental changes, has been found in previous studies to be a cost-effective strategy to strike a balance between good surface water quality and low greenhouse gas emissions. However, its regulatory implications have not been examined. To investigate the effective regulation of wastewater systems with this technology, two permitting approaches are developed and assessed in this work: upstream-based permitting (i.e., environmental outcomes as a function of upstream conditions) and means-based permitting (i.e., prescription of an optimal RTC strategy). An analytical framework is proposed for permit development and assessment using a diverse set of high performing integrated RTC strategies and environmental scenarios (rainfall, river flow rate, and water quality). Results from a case study show that by applying means-based permitting, the best achievable, locally suitable environmental outcomes (subject to 10% deviation) are obtained in over 80% of testing scenarios (or all testing scenarios if 19% of performance deviation is allowed) regardless of the uncertain upstream conditions. Upstream-based permitting is less effective as it is difficult to set reasonable performance targets for a highly complex and stochastic environment.
Project description:Floridean starch and floridoside are the main storage carbohydrates of red algae. However, their complete metabolic pathways and the origin, function, and regulatory mechanism of their pathway genes have not been fully elucidated. In this study, we identified their metabolic pathway genes and analyzed the changes in related gene expression and metabolite content in Neoporphyra haitanensis under continuous dark conditions. Our results showed that genes from different sources, including eukaryotic hosts, cyanobacteria, and bacteria, were combined to construct floridean starch and floridoside metabolic pathways in N. haitanensis. Moreover, compared with those in the control, under continuous dark conditions, floridean starch biosynthesis genes and some degradation genes were significantly upregulated with no significant change in floridean starch content, whereas floridoside degradation genes were significantly upregulated with a significant decrease in floridoside content. This implies that floridean starch content is maintained but floridoside is consumed in N. haitanensis under dark conditions. This study elucidates the "floridean starch-floridoside" metabolic network and its gene origins in N. haitanensis for the first time.