Science.gov

Sample records for expression-based network biology

  1. Significant Deregulated Pathways in Diabetes Type II Complications Identified through Expression Based Network Biology

    NASA Astrophysics Data System (ADS)

    Ukil, Sanchaita; Sinha, Meenakshee; Varshney, Lavneesh; Agrawal, Shipra

    Type 2 Diabetes is a complex multifactorial disease, which alters several signaling cascades giving rise to serious complications. It is one of the major risk factors for cardiovascular diseases. The present research work describes an integrated functional network biology approach to identify pathways that get transcriptionally altered and lead to complex complications thereby amplifying the phenotypic effect of the impaired disease state. We have identified two sub-network modules, which could be activated under abnormal circumstances in diabetes. Present work describes key proteins such as P85A and SRC serving as important nodes to mediate alternate signaling routes during diseased condition. P85A has been shown to be an important link between stress responsive MAPK and CVD markers involved in fibrosis. MAPK8 has been shown to interact with P85A and further activate CTGF through VEGF signaling. We have traced a novel and unique route correlating inflammation and fibrosis by considering P85A as a key mediator of signals. The next sub-network module shows SRC as a junction for various signaling processes, which results in interaction between NF-kB and beta catenin to cause cell death. The powerful interaction between these important genes in response to transcriptionally altered lipid metabolism and impaired inflammatory response via SRC causes apoptosis of cells. The crosstalk between inflammation, lipid homeostasis and stress, and their serious effects downstream have been explained in the present analyses.

  2. Research on Individualized Product Requirement Expression Based on Semantic Network

    NASA Astrophysics Data System (ADS)

    Yang, Qin; Pan, Xiuqin; Wei, Daozhu; Wu, Ke

    In order to establish an effective platform for individualized product development, the individualized product requirement expression forms were put forward. The diversity Semantic Network of product knowledge representation was researched based on the dualistic semantic network, and the product requirement framework model was established. Thereby the validity, reliability and consistency of the requirement expression process were ensured. Finally an example of customer requirement expression model about differential mechanism based on semantic network was described to satisfy with the individualized product design system.

  3. Networks in Cell Biology

    NASA Astrophysics Data System (ADS)

    Buchanan, Mark; Caldarelli, Guido; De Los Rios, Paolo; Rao, Francesco; Vendruscolo, Michele

    2010-05-01

    Introduction; 1. Network views of the cell Paolo De Los Rios and Michele Vendruscolo; 2. Transcriptional regulatory networks Sarath Chandra Janga and M. Madan Babu; 3. Transcription factors and gene regulatory networks Matteo Brilli, Elissa Calistri and Pietro Lió; 4. Experimental methods for protein interaction identification Peter Uetz, Björn Titz, Seesandra V. Rajagopala and Gerard Cagney; 5. Modeling protein interaction networks Francesco Rao; 6. Dynamics and evolution of metabolic networks Daniel Segré; 7. Hierarchical modularity in biological networks: the case of metabolic networks Erzsébet Ravasz Regan; 8. Signalling networks Gian Paolo Rossini; Appendix 1. Complex networks: from local to global properties D. Garlaschelli and G. Caldarelli; Appendix 2. Modelling the local structure of networks D. Garlaschelli and G. Caldarelli; Appendix 3. Higher-order topological properties S. Ahnert, T. Fink and G. Caldarelli; Appendix 4. Elementary mathematical concepts A. Gabrielli and G. Caldarelli; References.

  4. Querying Large Biological Network Datasets

    ERIC Educational Resources Information Center

    Gulsoy, Gunhan

    2013-01-01

    New experimental methods has resulted in increasing amount of genetic interaction data to be generated every day. Biological networks are used to store genetic interaction data gathered. Increasing amount of data available requires fast large scale analysis methods. Therefore, we address the problem of querying large biological network datasets.…

  5. Functional Aspects of Biological Networks

    NASA Astrophysics Data System (ADS)

    Sneppen, Kim

    2007-03-01

    We discuss biological networks with respect to 1) relative positioning and importance of high degree nodes, 2) function and signaling, 3) logic and dynamics of regulation. Visually the soft modularity of many real world networks can be characterized in terms of number of high and low degrees nodes positioned relative to each other in a landscape analogue with mountains (high-degree nodes) and valleys (low-degree nodes). In these terms biological networks looks like rugged landscapes with separated peaks, hub proteins, which each are roughly as essential as any of the individual proteins on the periphery of the hub. Within each sup-domain of a molecular network one can often identify dynamical feedback mechanisms that falls into combinations of positive and negative feedback circuits. We will illustrate this with examples taken from phage regulation and bacterial uptake and regulation of small molecules. In particular we find that a double negative regulation often are replaced by a single positive link in unrelated organisms with same functional requirements. Overall we argue that network topology primarily reflects functional constraints. References: S. Maslov and K. Sneppen. ``Computational architecture of the yeast regulatory network." Phys. Biol. 2:94 (2005) A. Trusina et al. ``Functional alignment of regulatory networks: A study of temerate phages". Plos Computational Biology 1:7 (2005). J.B. Axelsen et al. ``Degree Landscapes in Scale-Free Networks" physics/0512075 (2005). A. Trusina et al. ``Hierarchy and Anti-Hierarchy in Real and Scale Free networks." PRL 92:178702 (2004) S. Semsey et al. ``Genetic Regulation of Fluxes: Iron Homeostasis of Escherichia coli". (2006) q-bio.MN/0609042

  6. Design principles in biological networks

    NASA Astrophysics Data System (ADS)

    Goyal, Sidhartha

    Much of biology emerges from networks of interactions. Even in a single bacterium such as Escherichia coli, there are hundreds of coexisting gene and protein networks. Although biological networks are the outcome of evolution, various physical and biological constraints limit their functional capacity. The focus of this thesis is to understand how functional constraints such as optimal growth in mircoorganisms and information flow in signaling pathways shape the metabolic network of bacterium E. coli and the quorum sensing network of marine bacterium Vibrio harveyi, respectively. Metabolic networks convert basic elemental sources into complex building-blocks eventually leading to cell's growth. Therefore, typically, metabolic pathways are often coupled both by the use of a common substrate and by stoichiometric utilization of their products for cell growth. We showed that such a coupled network with product-feedback inhibition may exhibit limit-cycle oscillations which arise via a Hopf bifurcation. Furthermore, we analyzed several representative metabolic modules and find that, in all cases, simple product-feedback inhibition allows nearly optimal growth, in agreement with the predicted growth-rate by the flux-balance analysis (FBA). Bacteria have fascinating and diverse social lives. They display coordinated group behaviors regulated by quorum sensing (QS) systems. The QS circuit of V. harveyi integrates and funnels different ecological information through a common phosphorelay cascade to a set of small regulatory RNAs (sRNAs) that enables collective behavior. We analyzed the signaling properties and information flow in the QS circuit, which provides a model for information flow in signaling networks more generally. A comparative study of post-transcriptional and conventional transcriptional regulation suggest a niche for sRNAs in allowing cells to transition quickly yet reliably between distinct states. Furthermore, we develop a new framework for analyzing signal

  7. Reputation-based collaborative network biology.

    PubMed

    Binder, Jean; Boue, Stephanie; Di Fabio, Anselmo; Fields, R Brett; Hayes, William; Hoeng, Julia; Park, Jennifer S; Peitsch, Manuel C

    2015-01-01

    A pilot reputation-based collaborative network biology platform, Bionet, was developed for use in the sbv IMPROVER Network Verification Challenge to verify and enhance previously developed networks describing key aspects of lung biology. Bionet was successful in capturing a more comprehensive view of the biology associated with each network using the collective intelligence and knowledge of the crowd. One key learning point from the pilot was that using a standardized biological knowledge representation language such as BEL is critical to the success of a collaborative network biology platform. Overall, Bionet demonstrated that this approach to collaborative network biology is highly viable. Improving this platform for de novo creation of biological networks and network curation with the suggested enhancements for scalability will serve both academic and industry systems biology communities. PMID:25592588

  8. Mining Functional Modules in Heterogeneous Biological Networks Using Multiplex PageRank Approach.

    PubMed

    Li, Jun; Zhao, Patrick X

    2016-01-01

    Identification of functional modules/sub-networks in large-scale biological networks is one of the important research challenges in current bioinformatics and systems biology. Approaches have been developed to identify functional modules in single-class biological networks; however, methods for systematically and interactively mining multiple classes of heterogeneous biological networks are lacking. In this paper, we present a novel algorithm (called mPageRank) that utilizes the Multiplex PageRank approach to mine functional modules from two classes of biological networks. We demonstrate the capabilities of our approach by successfully mining functional biological modules through integrating expression-based gene-gene association networks and protein-protein interaction networks. We first compared the performance of our method with that of other methods using simulated data. We then applied our method to identify the cell division cycle related functional module and plant signaling defense-related functional module in the model plant Arabidopsis thaliana. Our results demonstrated that the mPageRank method is effective for mining sub-networks in both expression-based gene-gene association networks and protein-protein interaction networks, and has the potential to be adapted for the discovery of functional modules/sub-networks in other heterogeneous biological networks. The mPageRank executable program, source code, the datasets and results of the presented two case studies are publicly and freely available at http://plantgrn.noble.org/MPageRank/. PMID:27446133

  9. Mining Functional Modules in Heterogeneous Biological Networks Using Multiplex PageRank Approach

    PubMed Central

    Li, Jun; Zhao, Patrick X.

    2016-01-01

    Identification of functional modules/sub-networks in large-scale biological networks is one of the important research challenges in current bioinformatics and systems biology. Approaches have been developed to identify functional modules in single-class biological networks; however, methods for systematically and interactively mining multiple classes of heterogeneous biological networks are lacking. In this paper, we present a novel algorithm (called mPageRank) that utilizes the Multiplex PageRank approach to mine functional modules from two classes of biological networks. We demonstrate the capabilities of our approach by successfully mining functional biological modules through integrating expression-based gene-gene association networks and protein-protein interaction networks. We first compared the performance of our method with that of other methods using simulated data. We then applied our method to identify the cell division cycle related functional module and plant signaling defense-related functional module in the model plant Arabidopsis thaliana. Our results demonstrated that the mPageRank method is effective for mining sub-networks in both expression-based gene-gene association networks and protein-protein interaction networks, and has the potential to be adapted for the discovery of functional modules/sub-networks in other heterogeneous biological networks. The mPageRank executable program, source code, the datasets and results of the presented two case studies are publicly and freely available at http://plantgrn.noble.org/MPageRank/. PMID:27446133

  10. Introduction to Network Analysis in Systems Biology

    PubMed Central

    Ma’ayan, Avi

    2011-01-01

    This Teaching Resource provides lecture notes, slides, and a problem set for a set of three lectures from a course entitled “Systems Biology: Biomedical Modeling.” The materials are from three separate lectures introducing applications of graph theory and network analysis in systems biology. The first lecture describes different types of intracellular networks, methods for constructing biological networks, and different types of graphs used to represent regulatory intracellular networks. The second lecture surveys milestones and key concepts in network analysis by introducing topological measures, random networks, growing network models, and topological observations from molecular biological systems abstracted to networks. The third lecture discusses methods for analyzing lists of genes and experimental data in the context of prior knowledge networks to make predictions. PMID:21917719

  11. A model of gene expression based on random dynamical systems reveals modularity properties of gene regulatory networks.

    PubMed

    Antoneli, Fernando; Ferreira, Renata C; Briones, Marcelo R S

    2016-06-01

    Here we propose a new approach to modeling gene expression based on the theory of random dynamical systems (RDS) that provides a general coupling prescription between the nodes of any given regulatory network given the dynamics of each node is modeled by a RDS. The main virtues of this approach are the following: (i) it provides a natural way to obtain arbitrarily large networks by coupling together simple basic pieces, thus revealing the modularity of regulatory networks; (ii) the assumptions about the stochastic processes used in the modeling are fairly general, in the sense that the only requirement is stationarity; (iii) there is a well developed mathematical theory, which is a blend of smooth dynamical systems theory, ergodic theory and stochastic analysis that allows one to extract relevant dynamical and statistical information without solving the system; (iv) one may obtain the classical rate equations form the corresponding stochastic version by averaging the dynamic random variables (small noise limit). It is important to emphasize that unlike the deterministic case, where coupling two equations is a trivial matter, coupling two RDS is non-trivial, specially in our case, where the coupling is performed between a state variable of one gene and the switching stochastic process of another gene and, hence, it is not a priori true that the resulting coupled system will satisfy the definition of a random dynamical system. We shall provide the necessary arguments that ensure that our coupling prescription does indeed furnish a coupled regulatory network of random dynamical systems. Finally, the fact that classical rate equations are the small noise limit of our stochastic model ensures that any validation or prediction made on the basis of the classical theory is also a validation or prediction of our model. We illustrate our framework with some simple examples of single-gene system and network motifs. PMID:27036626

  12. Measuring the evolutionary rewiring of biological networks.

    PubMed

    Shou, Chong; Bhardwaj, Nitin; Lam, Hugo Y K; Yan, Koon-Kiu; Kim, Philip M; Snyder, Michael; Gerstein, Mark B

    2011-01-01

    We have accumulated a large amount of biological network data and expect even more to come. Soon, we anticipate being able to compare many different biological networks as we commonly do for molecular sequences. It has long been believed that many of these networks change, or "rewire", at different rates. It is therefore important to develop a framework to quantify the differences between networks in a unified fashion. We developed such a formalism based on analogy to simple models of sequence evolution, and used it to conduct a systematic study of network rewiring on all the currently available biological networks. We found that, similar to sequences, biological networks show a decreased rate of change at large time divergences, because of saturation in potential substitutions. However, different types of biological networks consistently rewire at different rates. Using comparative genomics and proteomics data, we found a consistent ordering of the rewiring rates: transcription regulatory, phosphorylation regulatory, genetic interaction, miRNA regulatory, protein interaction, and metabolic pathway network, from fast to slow. This ordering was found in all comparisons we did of matched networks between organisms. To gain further intuition on network rewiring, we compared our observed rewirings with those obtained from simulation. We also investigated how readily our formalism could be mapped to other network contexts; in particular, we showed how it could be applied to analyze changes in a range of "commonplace" networks such as family trees, co-authorships and linux-kernel function dependencies. PMID:21253555

  13. Optimizing Nutrient Uptake in Biological Transport Networks

    NASA Astrophysics Data System (ADS)

    Ronellenfitsch, Henrik; Katifori, Eleni

    2013-03-01

    Many biological systems employ complex networks of vascular tubes to facilitate transport of solute nutrients, examples include the vascular system of plants (phloem), some fungi, and the slime-mold Physarum. It is believed that such networks are optimized through evolution for carrying out their designated task. We propose a set of hydrodynamic governing equations for solute transport in a complex network, and obtain the optimal network architecture for various classes of optimizing functionals. We finally discuss the topological properties and statistical mechanics of the resulting complex networks, and examine correspondence of the obtained networks to those found in actual biological systems.

  14. On Crowd-verification of Biological Networks

    PubMed Central

    Ansari, Sam; Binder, Jean; Boue, Stephanie; Di Fabio, Anselmo; Hayes, William; Hoeng, Julia; Iskandar, Anita; Kleiman, Robin; Norel, Raquel; O’Neel, Bruce; Peitsch, Manuel C.; Poussin, Carine; Pratt, Dexter; Rhrissorrakrai, Kahn; Schlage, Walter K.; Stolovitzky, Gustavo; Talikka, Marja

    2013-01-01

    Biological networks with a structured syntax are a powerful way of representing biological information generated from high density data; however, they can become unwieldy to manage as their size and complexity increase. This article presents a crowd-verification approach for the visualization and expansion of biological networks. Web-based graphical interfaces allow visualization of causal and correlative biological relationships represented using Biological Expression Language (BEL). Crowdsourcing principles enable participants to communally annotate these relationships based on literature evidences. Gamification principles are incorporated to further engage domain experts throughout biology to gather robust peer-reviewed information from which relationships can be identified and verified. The resulting network models will represent the current status of biological knowledge within the defined boundaries, here processes related to human lung disease. These models are amenable to computational analysis. For some period following conclusion of the challenge, the published models will remain available for continuous use and expansion by the scientific community. PMID:24151423

  15. On Crowd-verification of Biological Networks.

    PubMed

    Ansari, Sam; Binder, Jean; Boue, Stephanie; Di Fabio, Anselmo; Hayes, William; Hoeng, Julia; Iskandar, Anita; Kleiman, Robin; Norel, Raquel; O'Neel, Bruce; Peitsch, Manuel C; Poussin, Carine; Pratt, Dexter; Rhrissorrakrai, Kahn; Schlage, Walter K; Stolovitzky, Gustavo; Talikka, Marja

    2013-01-01

    Biological networks with a structured syntax are a powerful way of representing biological information generated from high density data; however, they can become unwieldy to manage as their size and complexity increase. This article presents a crowd-verification approach for the visualization and expansion of biological networks. Web-based graphical interfaces allow visualization of causal and correlative biological relationships represented using Biological Expression Language (BEL). Crowdsourcing principles enable participants to communally annotate these relationships based on literature evidences. Gamification principles are incorporated to further engage domain experts throughout biology to gather robust peer-reviewed information from which relationships can be identified and verified. The resulting network models will represent the current status of biological knowledge within the defined boundaries, here processes related to human lung disease. These models are amenable to computational analysis. For some period following conclusion of the challenge, the published models will remain available for continuous use and expansion by the scientific community. PMID:24151423

  16. Biological Networks for Cancer Candidate Biomarkers Discovery.

    PubMed

    Yan, Wenying; Xue, Wenjin; Chen, Jiajia; Hu, Guang

    2016-01-01

    Due to its extraordinary heterogeneity and complexity, cancer is often proposed as a model case of a systems biology disease or network disease. There is a critical need of effective biomarkers for cancer diagnosis and/or outcome prediction from system level analyses. Methods based on integrating omics data into networks have the potential to revolutionize the identification of cancer biomarkers. Deciphering the biological networks underlying cancer is undoubtedly important for understanding the molecular mechanisms of the disease and identifying effective biomarkers. In this review, the networks constructed for cancer biomarker discovery based on different omics level data are described and illustrated from recent advances in the field. PMID:27625573

  17. Biological Networks for Cancer Candidate Biomarkers Discovery

    PubMed Central

    Yan, Wenying; Xue, Wenjin; Chen, Jiajia; Hu, Guang

    2016-01-01

    Due to its extraordinary heterogeneity and complexity, cancer is often proposed as a model case of a systems biology disease or network disease. There is a critical need of effective biomarkers for cancer diagnosis and/or outcome prediction from system level analyses. Methods based on integrating omics data into networks have the potential to revolutionize the identification of cancer biomarkers. Deciphering the biological networks underlying cancer is undoubtedly important for understanding the molecular mechanisms of the disease and identifying effective biomarkers. In this review, the networks constructed for cancer biomarker discovery based on different omics level data are described and illustrated from recent advances in the field. PMID:27625573

  18. Simplified models of biological networks.

    PubMed

    Sneppen, Kim; Krishna, Sandeep; Semsey, Szabolcs

    2010-01-01

    The function of living cells is controlled by complex regulatory networks that are built of a wide diversity of interacting molecular components. The sheer size and intricacy of molecular networks of even the simplest organisms are obstacles toward understanding network functionality. This review discusses the achievements and promise of a bottom-up approach that uses well-characterized subnetworks as model systems for understanding larger networks. It highlights the interplay between the structure, logic, and function of various types of small regulatory circuits. The bottom-up approach advocates understanding regulatory networks as a collection of entangled motifs. We therefore emphasize the potential of negative and positive feedback, as well as their combinations, to generate robust homeostasis, epigenetics, and oscillations. PMID:20192769

  19. Asian Network for Biological Sciences (ANBS).

    ERIC Educational Resources Information Center

    Asian Network for Biological Sciences.

    The Asian Network for Biological Sciences (ANBS) is a group of institutions, laboratories, research centers, and scholars who are willing to cooperate in programs and activities aimed at improving teaching and research in the biological sciences. This publication: (1) outlines ANBS aims and objectives; (2) describes major activities in the past;…

  20. Network-Based Models in Molecular Biology

    NASA Astrophysics Data System (ADS)

    Beyer, Andreas

    Biological systems are characterized by a large number of diverse interactions. Interaction maps have been used to abstract those interactions at all biological scales ranging from food webs at the ecosystem level down to protein interaction networks at the molecular scale.

  1. Quantifying evolvability in small biological networks

    SciTech Connect

    Nemenman, Ilya; Mugler, Andrew; Ziv, Etay; Wiggins, Chris H

    2008-01-01

    The authors introduce a quantitative measure of the capacity of a small biological network to evolve. The measure is applied to a stochastic description of the experimental setup of Guet et al. (Science 2002, 296, pp. 1466), treating chemical inducers as functional inputs to biochemical networks and the expression of a reporter gene as the functional output. The authors take an information-theoretic approach, allowing the system to set parameters that optimise signal processing ability, thus enumerating each network's highest-fidelity functions. All networks studied are highly evolvable by the measure, meaning that change in function has little dependence on change in parameters. Moreover, each network's functions are connected by paths in the parameter space along which information is not significantly lowered, meaning a network may continuously change its functionality without completely losing it along the way. This property further underscores the evolvability of the networks.

  2. Reconstructing Causal Biological Networks through Active Learning.

    PubMed

    Cho, Hyunghoon; Berger, Bonnie; Peng, Jian

    2016-01-01

    Reverse-engineering of biological networks is a central problem in systems biology. The use of intervention data, such as gene knockouts or knockdowns, is typically used for teasing apart causal relationships among genes. Under time or resource constraints, one needs to carefully choose which intervention experiments to carry out. Previous approaches for selecting most informative interventions have largely been focused on discrete Bayesian networks. However, continuous Bayesian networks are of great practical interest, especially in the study of complex biological systems and their quantitative properties. In this work, we present an efficient, information-theoretic active learning algorithm for Gaussian Bayesian networks (GBNs), which serve as important models for gene regulatory networks. In addition to providing linear-algebraic insights unique to GBNs, leading to significant runtime improvements, we demonstrate the effectiveness of our method on data simulated with GBNs and the DREAM4 network inference challenge data sets. Our method generally leads to faster recovery of underlying network structure and faster convergence to final distribution of confidence scores over candidate graph structures using the full data, in comparison to random selection of intervention experiments. PMID:26930205

  3. Reconstructing Causal Biological Networks through Active Learning

    PubMed Central

    Cho, Hyunghoon; Berger, Bonnie; Peng, Jian

    2016-01-01

    Reverse-engineering of biological networks is a central problem in systems biology. The use of intervention data, such as gene knockouts or knockdowns, is typically used for teasing apart causal relationships among genes. Under time or resource constraints, one needs to carefully choose which intervention experiments to carry out. Previous approaches for selecting most informative interventions have largely been focused on discrete Bayesian networks. However, continuous Bayesian networks are of great practical interest, especially in the study of complex biological systems and their quantitative properties. In this work, we present an efficient, information-theoretic active learning algorithm for Gaussian Bayesian networks (GBNs), which serve as important models for gene regulatory networks. In addition to providing linear-algebraic insights unique to GBNs, leading to significant runtime improvements, we demonstrate the effectiveness of our method on data simulated with GBNs and the DREAM4 network inference challenge data sets. Our method generally leads to faster recovery of underlying network structure and faster convergence to final distribution of confidence scores over candidate graph structures using the full data, in comparison to random selection of intervention experiments. PMID:26930205

  4. Network Reverse Engineering Approach in Synthetic Biology

    NASA Astrophysics Data System (ADS)

    Zhang, Haoqian; Liu, Ao; Lu, Yuheng; Sheng, Ying; Wu, Qianzhu; Yin, Zhenzhen; Chen, Yiwei; Liu, Zairan; Pan, Heng; Ouyang, Qi

    2013-12-01

    Synthetic biology is a new branch of interdisciplinary science that has been developed in recent years. The main purpose of synthetic biology is to apply successful principles that have been developed in electronic and chemical engineering to develop basic biological functional modules, and through rational design, develop man-made biological systems that have predicted useful functions. Here, we discuss an important principle in rational design of functional biological circuits: the reverse engineering design. We will use a research project that was conducted at Peking University for the International Genetic Engineering Machine Competition (iGEM) to illustrate the principle: synthesis a cell which has a semi-log dose-response to the environment. Through this work we try to demonstrate the potential application of network engineering in synthetic biology.

  5. Biological and Environmental Research Network Requirements

    SciTech Connect

    Balaji, V.; Boden, Tom; Cowley, Dave; Dart, Eli; Dattoria, Vince; Desai, Narayan; Egan, Rob; Foster, Ian; Goldstone, Robin; Gregurick, Susan; Houghton, John; Izaurralde, Cesar; Johnston, Bill; Joseph, Renu; Kleese-van Dam, Kerstin; Lipton, Mary; Monga, Inder; Pritchard, Matt; Rotman, Lauren; Strand, Gary; Stuart, Cory; Tatusova, Tatiana; Tierney, Brian; Thomas, Brian; Williams, Dean N.; Zurawski, Jason

    2013-09-01

    The Energy Sciences Network (ESnet) is the primary provider of network connectivity for the U.S. Department of Energy (DOE) Office of Science (SC), the single largest supporter of basic research in the physical sciences in the United States. In support of SC programs, ESnet regularly updates and refreshes its understanding of the networking requirements of the instruments, facilities, scientists, and science programs that it serves. This focus has helped ESnet be a highly successful enabler of scientific discovery for over 25 years. In November 2012, ESnet and the Office of Biological and Environmental Research (BER) of the DOE SC organized a review to characterize the networking requirements of the programs funded by the BER program office. Several key findings resulted from the review. Among them: 1) The scale of data sets available to science collaborations continues to increase exponentially. This has broad impact, both on the network and on the computational and storage systems connected to the network. 2) Many science collaborations require assistance to cope with the systems and network engineering challenges inherent in managing the rapid growth in data scale. 3) Several science domains operate distributed facilities that rely on high-performance networking for success. Key examples illustrated in this report include the Earth System Grid Federation (ESGF) and the Systems Biology Knowledgebase (KBase). This report expands on these points, and addresses others as well. The report contains a findings section as well as the text of the case studies discussed at the review.

  6. Structural determinants of criticality in biological networks

    PubMed Central

    Valverde, Sergi; Ohse, Sebastian; Turalska, Malgorzata; West, Bruce J.; Garcia-Ojalvo, Jordi

    2015-01-01

    Many adaptive evolutionary systems display spatial and temporal features, such as long-range correlations, typically associated with the critical point of a phase transition in statistical physics. Empirical and theoretical studies suggest that operating near criticality enhances the functionality of biological networks, such as brain and gene networks, in terms for instance of information processing, robustness, and evolvability. While previous studies have explained criticality with specific system features, we still lack a general theory of critical behavior in biological systems. Here we look at this problem from the complex systems perspective, since in principle all critical biological circuits have in common the fact that their internal organization can be described as a complex network. An important question is how self-similar structure influences self-similar dynamics. Modularity and heterogeneity, for instance, affect the location of critical points and can be used to tune the system toward criticality. We review and discuss recent studies on the criticality of neuronal and genetic networks, and discuss the implications of network theory when assessing the evolutionary features of criticality. PMID:26005422

  7. Theoretical knock-outs on biological networks.

    PubMed

    Miranda, Pedro J; de S Pinto, Sandro E; Baptista, Murilo S; La Guardia, Giuliano G

    2016-08-21

    In this work we redefine the concept of biological importance and how to compute it, based on a model of complex networks and random walk. We call this new procedure, theoretical knock-out (KO). The proposed method generalizes the procedure presented in a recent study about Oral Tolerance. To devise this method, we make two approaches: algebraically and algorithmically. In both cases we compute a vector on an asymptotic state, called flux vector. The flux is given by a random walk on a directed graph that represents a biological phenomenon. This vector gives us the information about the relative flux of walkers on a vertex which represents a biological agent. With two vector of this kind, we can calculate the relative mean error between them by averaging over its coefficients. This quantity allows us to assess the degree of importance of each vertex of a complex network that evolves in time and has experimental background. We find out that this procedure can be applied in any sort of biological phenomena in which we can know the role and interrelationships of its agents. These results also provide experimental biologists to predict the order of importance of biological agents on a mounted complex network. PMID:27188251

  8. Discovery of Chemical Toxicity via Biological Networks and Systems Biology

    SciTech Connect

    Perkins, Edward; Habib, Tanwir; Guan, Xin; Escalon, Barbara; Falciani, Francesco; Chipman, J.K.; Antczak, Philipp; Edwards, Stephen; Taylor, Ronald C.; Vulpe, Chris; Loguinov, Alexandre; Van Aggelen, Graham; Villeneuve, Daniel L.; Garcia-Reyero, Natalia

    2010-09-30

    Both soldiers and animals are exposed to many chemicals as the result of military activities. Tools are needed to understand the hazards and risks that chemicals and new materials pose to soldiers and the environment. We have investigated the potential of global gene regulatory networks in understanding the impact of chemicals on reproduction. We characterized effects of chemicals on ovaries of the model animal system, the Fathead minnow (Pimopheles promelas) connecting chemical impacts on gene expression to circulating blood levels of the hormones testosterone and estradiol in addition to the egg yolk protein vitellogenin. We describe the application of reverse engineering complex interaction networks from high dimensional gene expression data to characterize chemicals that disrupt the hypothalamus-pituitary-gonadal endocrine axis that governs reproduction in fathead minnows. The construction of global gene regulatory networks provides deep insights into how drugs and chemicals effect key organs and biological pathways.

  9. Review of Biological Network Data and Its Applications

    PubMed Central

    Yu, Donghyeon; Kim, MinSoo; Xiao, Guanghua

    2013-01-01

    Studying biological networks, such as protein-protein interactions, is key to understanding complex biological activities. Various types of large-scale biological datasets have been collected and analyzed with high-throughput technologies, including DNA microarray, next-generation sequencing, and the two-hybrid screening system, for this purpose. In this review, we focus on network-based approaches that help in understanding biological systems and identifying biological functions. Accordingly, this paper covers two major topics in network biology: reconstruction of gene regulatory networks and network-based applications, including protein function prediction, disease gene prioritization, and network-based genome-wide association study. PMID:24465231

  10. Application of graph colouring to biological networks.

    PubMed

    Khor, S

    2010-05-01

    The author explores the application of graph colouring to biological networks, specifically protein-protein interaction (PPI) networks. First, the author finds that given similar conditions (i.e. graph size, degree distribution and clustering), fewer colours are needed to colour disassortative than assortative networks. Fewer colours create fewer independent sets which in turn imply higher concurrency potential for a network. Since PPI networks tend to be disassortative, the author suggests that in addition to functional specificity and stability proposed previously by Maslov and Sneppen (Science, 296, 2002), the disassortative nature of PPI networks may promote the ability of cells to perform multiple, crucial and functionally diverse tasks concurrently. Second, because graph colouring is closely related to the presence of cliques in a graph, the significance of node colouring information to the problem of identifying protein complexes (dense subgraphs in PPI networks), is investigated. The author finds that for PPI networks where 1-11% of nodes participate in at least one identified protein complex, such as H. sapien, DSATUR (a well-known complete graph colouring algorithm) node colouring information can improve the quality (homogeneity and separation) of initial candidate complexes. This finding may help improve existing protein complex detection methods, and/or suggest new methods. [Includes supplementary material]. PMID:20499999

  11. BIOLOGICAL NETWORK EXPLORATION WITH CYTOSCAPE 3

    PubMed Central

    Su, Gang; Morris, John H.; Demchak, Barry; Bader, Gary D.

    2014-01-01

    Cytoscape is one of the most popular open-source software tools for the visual exploration of biomedical networks composed of protein, gene and other types of interactions. It offers researchers a versatile and interactive visualization interface for exploring complex biological interconnections supported by diverse annotation and experimental data, thereby facilitating research tasks such as predicting gene function and pathway construction. Cytoscape provides core functionality to load, visualize, search, filter and save networks, and hundreds of Apps extend this functionality to address specific research needs. The latest generation of Cytoscape (version 3.0 and later) has substantial improvements in function, user interface and performance relative to previous versions. This protocol aims to jump-start new users with specific protocols for basic Cytoscape functions, such as installing Cytoscape and Cytoscape Apps, loading data, visualizing and navigating the network, visualizing network associated data (attributes) and identifying clusters. It also highlights new features that benefit experienced users. PMID:25199793

  12. Some physics problems in biological networks

    NASA Astrophysics Data System (ADS)

    Bialek, William

    2007-03-01

    Most of the interesting things that happen in living organisms require interactions among many components, and it is convenient to think of these as a ``network'' of interactions. We use this language at the level of single molecules (the network of interactions among amino acids that determine protein structure), single cells (the network of protein-DNA interactions responsible for the regulation of gene expression) and complex multicellular organisms (the networks of neurons in our brain). In this talk I'll try to look at two very different kinds of theoretical physics problems that arise in thinking about such networks. The first problems are phenomenological: Given what our experimentalists friends can measure, can we generate a global view of network function and dynamics? I'll argue that maximum entropy methods can be useful here, and show how such methods have been used in very recent work on networks of neurons, enzymes, genes and (in disguise) amino acids. In this line of reasoning there are of course interesting connections to statistical mechanics, and we'll see that natural statistical mechanics questions about the underlying models actually teach us something about how the real biological system works, in ways that will be tested through new experiments. In the second half of the talk I'll ask if there are principles from which we might actually be able to predict the structure and dynamics of biological networks. I'll focus on optimization principles, in particular the optimization of information flow in transcriptional regulation. Even setting up these arguments forces us to think critically about our understanding of the signals, specificity and noise in these systems, all current topics of research. Although we don't know if we have the right principles, trying to work out the consequences of such optimization again suggests new experiments.

  13. Random networks created by biological evolution

    NASA Astrophysics Data System (ADS)

    Slanina, František; Kotrla, Miroslav

    2000-11-01

    We investigate a model of an evolving random network, introduced by us previously [Phys. Rev. Lett. 83, 5587 (1999)]. The model is a generalization of the Bak-Sneppen model of biological evolution, with the modification that the underlying network can evolve by adding and removing sites. The behavior and the averaged properties of the network depend on the parameter p, the probability to establish a link to the newly introduced site. For p=1 the system is self-organized critical, with two distinct power-law regimes with forward-avalanche exponents τ=1.98+/-0.04 and τ'=1.65+/-0.05. The average size of the network diverges as a powerlaw when p-->1. We study various geometrical properties of the network: the probability distribution of sizes and connectivities, size and number of disconnected clusters, and the dependence of the mean distance between two sites on the cluster size. The connection with models of growing networks with a preferential attachment is discussed.

  14. Adaptation and optimization of biological transport networks.

    PubMed

    Hu, Dan; Cai, David

    2013-09-27

    It has been hypothesized that topological structures of biological transport networks are consequences of energy optimization. Motivated by experimental observation, we propose that adaptation dynamics may underlie this optimization. In contrast to the global nature of optimization, our adaptation dynamics responds only to local information and can naturally incorporate fluctuations in flow distributions. The adaptation dynamics minimizes the global energy consumption to produce optimal networks, which may possess hierarchical loop structures in the presence of strong fluctuations in flow distribution. We further show that there may exist a new phase transition as there is a critical open probability of sinks, above which there are only trees for network structures whereas below which loops begin to emerge. PMID:24116821

  15. Comparing artificial and biological dynamical neural networks

    NASA Astrophysics Data System (ADS)

    McAulay, Alastair D.

    2006-05-01

    Modern computers can be made more friendly and otherwise improved by making them behave more like humans. Perhaps we can learn how to do this from biology in which human brains evolved over a long period of time. Therefore, we first explain a commonly used biological neural network (BNN) model, the Wilson-Cowan neural oscillator, that has cross-coupled excitatory (positive) and inhibitory (negative) neurons. The two types of neurons are used for frequency modulation communication between neurons which provides immunity to electromagnetic interference. We then evolve, for the first time, an artificial neural network (ANN) to perform the same task. Two dynamical feed-forward artificial neural networks use cross-coupling feedback (like that in a flip-flop) to form an ANN nonlinear dynamic neural oscillator with the same equations as the Wilson-Cowan neural oscillator. Finally we show, through simulation, that the equations perform the basic neural threshold function, switching between stable zero output and a stable oscillation, that is a stable limit cycle. Optical implementation with an injected laser diode and future research are discussed.

  16. New scaling relation for information transfer in biological networks.

    PubMed

    Kim, Hyunju; Davies, Paul; Walker, Sara Imari

    2015-12-01

    We quantify characteristics of the informational architecture of two representative biological networks: the Boolean network model for the cell-cycle regulatory network of the fission yeast Schizosaccharomyces pombe (Davidich et al. 2008 PLoS ONE 3, e1672 (doi:10.1371/journal.pone.0001672)) and that of the budding yeast Saccharomyces cerevisiae (Li et al. 2004 Proc. Natl Acad. Sci. USA 101, 4781-4786 (doi:10.1073/pnas.0305937101)). We compare our results for these biological networks with the same analysis performed on ensembles of two different types of random networks: Erdös-Rényi and scale-free. We show that both biological networks share features in common that are not shared by either random network ensemble. In particular, the biological networks in our study process more information than the random networks on average. Both biological networks also exhibit a scaling relation in information transferred between nodes that distinguishes them from random, where the biological networks stand out as distinct even when compared with random networks that share important topological properties, such as degree distribution, with the biological network. We show that the most biologically distinct regime of this scaling relation is associated with a subset of control nodes that regulate the dynamics and function of each respective biological network. Information processing in biological networks is therefore interpreted as an emergent property of topology (causal structure) and dynamics (function). Our results demonstrate quantitatively how the informational architecture of biologically evolved networks can distinguish them from other classes of network architecture that do not share the same informational properties. PMID:26701883

  17. Noncommutative Biology: Sequential Regulation of Complex Networks

    PubMed Central

    Letsou, William; Cai, Long

    2016-01-01

    Single-cell variability in gene expression is important for generating distinct cell types, but it is unclear how cells use the same set of regulatory molecules to specifically control similarly regulated genes. While combinatorial binding of transcription factors at promoters has been proposed as a solution for cell-type specific gene expression, we found that such models resulted in substantial information bottlenecks. We sought to understand the consequences of adopting sequential logic wherein the time-ordering of factors informs the final outcome. We showed that with noncommutative control, it is possible to independently control targets that would otherwise be activated simultaneously using combinatorial logic. Consequently, sequential logic overcomes the information bottleneck inherent in complex networks. We derived scaling laws for two noncommutative models of regulation, motivated by phosphorylation/neural networks and chromosome folding, respectively, and showed that they scale super-exponentially in the number of regulators. We also showed that specificity in control is robust to the loss of a regulator. Lastly, we connected these theoretical results to real biological networks that demonstrate specificity in the context of promiscuity. These results show that achieving a desired outcome often necessitates roundabout steps. PMID:27560383

  18. Noncommutative Biology: Sequential Regulation of Complex Networks.

    PubMed

    Letsou, William; Cai, Long

    2016-08-01

    Single-cell variability in gene expression is important for generating distinct cell types, but it is unclear how cells use the same set of regulatory molecules to specifically control similarly regulated genes. While combinatorial binding of transcription factors at promoters has been proposed as a solution for cell-type specific gene expression, we found that such models resulted in substantial information bottlenecks. We sought to understand the consequences of adopting sequential logic wherein the time-ordering of factors informs the final outcome. We showed that with noncommutative control, it is possible to independently control targets that would otherwise be activated simultaneously using combinatorial logic. Consequently, sequential logic overcomes the information bottleneck inherent in complex networks. We derived scaling laws for two noncommutative models of regulation, motivated by phosphorylation/neural networks and chromosome folding, respectively, and showed that they scale super-exponentially in the number of regulators. We also showed that specificity in control is robust to the loss of a regulator. Lastly, we connected these theoretical results to real biological networks that demonstrate specificity in the context of promiscuity. These results show that achieving a desired outcome often necessitates roundabout steps. PMID:27560383

  19. Irregularity and asynchrony in biologic network signals.

    PubMed

    Pincus, S M

    2000-01-01

    ; "r" is chosen as a fixed percentage (often 20%) of the subject's SD. This version of ApEn has the property that it is decorrelated from process SD--it remains unchanged under uniform process magnification, reduction, and translation (shift by a constant). Cross-ApEn is generally applied to compare sequences from two distinct yet interwined variables in a network. Thus we can directly assess network, and not just nodal, evolution, under different settings--e.g., to directly evaluate uncoupling and/or changes in feedback and control. Hence, cross-ApEn facilitates analyses of output from myriad complicated networks, avoiding the requirement to fully model the underlying system. This is especially important, since accurate modeling of (biological) networks is often nearly impossible. Algorithmically and insofar as implementation and reproducibility properties are concerned, cross-ApEn is thematically similar to ApEn. Furthermore, cross-ApEn is shown to be complementary to the two most prominent statistical means of assessing multivariate series, correlation and power spectral methodologies. In particular, we highlight, both theoretically and by case study examples, the many physiological feedback and/or control systems and models for which cross-ApEn can detect significant changes in bivariate asynchrony, yet for which cross-correlation and cross-spectral methods fail to clearly highlight markedly changing features of the data sets under consideration. Finally, we introduce spatial ApEn, which appears to have considerable potential, both theoretically and empirically, in evaluating multidimensional lattice structures, to discern and quantify the extent of changing patterns, and for the emergence and dissolution of traveling waves, throughout multiple contexts within biology and chemistry. PMID:10909056

  20. Centrality Analysis Methods for Biological Networks and Their Application to Gene Regulatory Networks

    PubMed Central

    Koschützki, Dirk; Schreiber, Falk

    2008-01-01

    The structural analysis of biological networks includes the ranking of the vertices based on the connection structure of a network. To support this analysis we discuss centrality measures which indicate the importance of vertices, and demonstrate their applicability on a gene regulatory network. We show that common centrality measures result in different valuations of the vertices and that novel measures tailored to specific biological investigations are useful for the analysis of biological networks, in particular gene regulatory networks. PMID:19787083

  1. Topological implications of negative curvature for biological and social networks

    NASA Astrophysics Data System (ADS)

    Albert, Réka; DasGupta, Bhaskar; Mobasheri, Nasim

    2014-03-01

    Network measures that reflect the most salient properties of complex large-scale networks are in high demand in the network research community. In this paper we adapt a combinatorial measure of negative curvature (also called hyperbolicity) to parametrized finite networks, and show that a variety of biological and social networks are hyperbolic. This hyperbolicity property has strong implications on the higher-order connectivity and other topological properties of these networks. Specifically, we derive and prove bounds on the distance among shortest or approximately shortest paths in hyperbolic networks. We describe two implications of these bounds to crosstalk in biological networks, and to the existence of central, influential neighborhoods in both biological and social networks.

  2. Computer-Based Semantic Network in Molecular Biology: A Demonstration.

    ERIC Educational Resources Information Center

    Callman, Joshua L.; And Others

    This paper analyzes the hardware and software features that would be desirable in a computer-based semantic network system for representing biology knowledge. It then describes in detail a prototype network of molecular biology knowledge that has been developed using Filevision software and a Macintosh computer. The prototype contains about 100…

  3. Biology Question Generation from a Semantic Network

    NASA Astrophysics Data System (ADS)

    Zhang, Lishan

    Science instructors need questions for use in exams, homework assignments, class discussions, reviews, and other instructional activities. Textbooks never have enough questions, so instructors must find them from other sources or generate their own questions. In order to supply instructors with biology questions, a semantic network approach was developed for generating open response biology questions. The generated questions were compared to professional authorized questions. To boost students' learning experience, adaptive selection was built on the generated questions. Bayesian Knowledge Tracing was used as embedded assessment of the student's current competence so that a suitable question could be selected based on the student's previous performance. A between-subjects experiment with 42 participants was performed, where half of the participants studied with adaptive selected questions and the rest studied with mal-adaptive order of questions. Both groups significantly improved their test scores, and the participants in adaptive group registered larger learning gains than participants in the control group. To explore the possibility of generating rich instructional feedback for machine-generated questions, a question-paragraph mapping task was identified. Given a set of questions and a list of paragraphs for a textbook, the goal of the task was to map the related paragraphs to each question. An algorithm was developed whose performance was comparable to human annotators. A multiple-choice question with high quality distractors (incorrect answers) can be pedagogically valuable as well as being much easier to grade than open-response questions. Thus, an algorithm was developed to generate good distractors for multiple-choice questions. The machine-generated multiple-choice questions were compared to human-generated questions in terms of three measures: question difficulty, question discrimination and distractor usefulness. By recruiting 200 participants from

  4. Analyzing large biological datasets with association networks

    SciTech Connect

    Karpinets, T. V.; Park, B. H.; Uberbacher, E. C.

    2012-05-25

    Due to advances in high throughput biotechnologies biological information is being collected in databases at an amazing rate, requiring novel computational approaches for timely processing of the collected data into new knowledge. In this study we address this problem by developing a new approach for discovering modular structure, relationships and regularities in complex data. These goals are achieved by converting records of biological annotations of an object, like organism, gene, chemical, sequence, into networks (Anets) and rules (Arules) of the associated annotations. Anets are based on similarity of annotation profiles of objects and can be further analyzed and visualized providing a compact birds-eye view of most significant relationships in the collected data and a way of their clustering and classification. Arules are generated by Apriori considering each record of annotations as a transaction and augmenting each annotation item by its type. Arules provide a way to validate relationships discovered by Anets producing comprehensive statistics on frequently associated annotations and specific confident relationships among them. A combination of Anets and Arules represents condensed information on associations among the collected data, helping to discover new knowledge and generate hypothesis. As an example we have applied the approach to analyze bacterial metadata from the Genomes OnLine Database. The analysis allowed us to produce a map of sequenced bacterial and archaeal organisms based on their genomic, metabolic and physiological characteristics with three major clusters of metadata representing bacterial pathogens, environmental isolates, and plant symbionts. A signature profile of clustered annotations of environmental bacteria if compared with pathogens linked the aerobic respiration, the high GC content and the large genome size to diversity of metabolic activities and physiological features of the organisms.

  5. Systems Biology in the Context of Big Data and Networks

    PubMed Central

    Altaf-Ul-Amin, Md.; Afendi, Farit Mochamad; Kiboi, Samuel Kuria; Kanaya, Shigehiko

    2014-01-01

    Science is going through two rapidly changing phenomena: one is the increasing capabilities of the computers and software tools from terabytes to petabytes and beyond, and the other is the advancement in high-throughput molecular biology producing piles of data related to genomes, transcriptomes, proteomes, metabolomes, interactomes, and so on. Biology has become a data intensive science and as a consequence biology and computer science have become complementary to each other bridged by other branches of science such as statistics, mathematics, physics, and chemistry. The combination of versatile knowledge has caused the advent of big-data biology, network biology, and other new branches of biology. Network biology for instance facilitates the system-level understanding of the cell or cellular components and subprocesses. It is often also referred to as systems biology. The purpose of this field is to understand organisms or cells as a whole at various levels of functions and mechanisms. Systems biology is now facing the challenges of analyzing big molecular biological data and huge biological networks. This review gives an overview of the progress in big-data biology, and data handling and also introduces some applications of networks and multivariate analysis in systems biology. PMID:24982882

  6. BioNSi: A Discrete Biological Network Simulator Tool.

    PubMed

    Rubinstein, Amir; Bracha, Noga; Rudner, Liat; Zucker, Noga; Sloin, Hadas E; Chor, Benny

    2016-08-01

    Modeling and simulation of biological networks is an effective and widely used research methodology. The Biological Network Simulator (BioNSi) is a tool for modeling biological networks and simulating their discrete-time dynamics, implemented as a Cytoscape App. BioNSi includes a visual representation of the network that enables researchers to construct, set the parameters, and observe network behavior under various conditions. To construct a network instance in BioNSi, only partial, qualitative biological data suffices. The tool is aimed for use by experimental biologists and requires no prior computational or mathematical expertise. BioNSi is freely available at http://bionsi.wix.com/bionsi , where a complete user guide and a step-by-step manual can also be found. PMID:27354160

  7. Discovery of biological networks from diverse functional genomic data

    PubMed Central

    Myers, Chad L; Robson, Drew; Wible, Adam; Hibbs, Matthew A; Chiriac, Camelia; Theesfeld, Chandra L; Dolinski, Kara; Troyanskaya, Olga G

    2005-01-01

    We have developed a general probabilistic system for query-based discovery of pathway-specific networks through integration of diverse genome-wide data. This framework was validated by accurately recovering known networks for 31 biological processes in Saccharomyces cerevisiae and experimentally verifying predictions for the process of chromosomal segregation. Our system, bioPIXIE, a public, comprehensive system for integration, analysis, and visualization of biological network predictions for S. cerevisiae, is freely accessible over the worldwide web. PMID:16420673

  8. Causal biological network database: a comprehensive platform of causal biological network models focused on the pulmonary and vascular systems

    PubMed Central

    Boué, Stéphanie; Talikka, Marja; Westra, Jurjen Willem; Hayes, William; Di Fabio, Anselmo; Park, Jennifer; Schlage, Walter K.; Sewer, Alain; Fields, Brett; Ansari, Sam; Martin, Florian; Veljkovic, Emilija; Kenney, Renee; Peitsch, Manuel C.; Hoeng, Julia

    2015-01-01

    With the wealth of publications and data available, powerful and transparent computational approaches are required to represent measured data and scientific knowledge in a computable and searchable format. We developed a set of biological network models, scripted in the Biological Expression Language, that reflect causal signaling pathways across a wide range of biological processes, including cell fate, cell stress, cell proliferation, inflammation, tissue repair and angiogenesis in the pulmonary and cardiovascular context. This comprehensive collection of networks is now freely available to the scientific community in a centralized web-based repository, the Causal Biological Network database, which is composed of over 120 manually curated and well annotated biological network models and can be accessed at http://causalbionet.com. The website accesses a MongoDB, which stores all versions of the networks as JSON objects and allows users to search for genes, proteins, biological processes, small molecules and keywords in the network descriptions to retrieve biological networks of interest. The content of the networks can be visualized and browsed. Nodes and edges can be filtered and all supporting evidence for the edges can be browsed and is linked to the original articles in PubMed. Moreover, networks may be downloaded for further visualization and evaluation. Database URL: http://causalbionet.com PMID:25887162

  9. BioFNet: biological functional network database for analysis and synthesis of biological systems.

    PubMed

    Kurata, Hiroyuki; Maeda, Kazuhiro; Onaka, Toshikazu; Takata, Takenori

    2014-09-01

    In synthetic biology and systems biology, a bottom-up approach can be used to construct a complex, modular, hierarchical structure of biological networks. To analyze or design such networks, it is critical to understand the relationship between network structure and function, the mechanism through which biological parts or biomolecules are assembled into building blocks or functional networks. A functional network is defined as a subnetwork of biomolecules that performs a particular function. Understanding the mechanism of building functional networks would help develop a methodology for analyzing the structure of large-scale networks and design a robust biological circuit to perform a target function. We propose a biological functional network database, named BioFNet, which can cover the whole cell at the level of molecular interactions. The BioFNet takes an advantage in implementing the simulation program for the mathematical models of the functional networks, visualizing the simulated results. It presents a sound basis for rational design of biochemical networks and for understanding how functional networks are assembled to create complex high-level functions, which would reveal design principles underlying molecular architectures. PMID:23894104

  10. On the Interplay between the Evolvability and Network Robustness in an Evolutionary Biological Network: A Systems Biology Approach

    PubMed Central

    Chen, Bor-Sen; Lin, Ying-Po

    2011-01-01

    In the evolutionary process, the random transmission and mutation of genes provide biological diversities for natural selection. In order to preserve functional phenotypes between generations, gene networks need to evolve robustly under the influence of random perturbations. Therefore, the robustness of the phenotype, in the evolutionary process, exerts a selection force on gene networks to keep network functions. However, gene networks need to adjust, by variations in genetic content, to generate phenotypes for new challenges in the network’s evolution, ie, the evolvability. Hence, there should be some interplay between the evolvability and network robustness in evolutionary gene networks. In this study, the interplay between the evolvability and network robustness of a gene network and a biochemical network is discussed from a nonlinear stochastic system point of view. It was found that if the genetic robustness plus environmental robustness is less than the network robustness, the phenotype of the biological network is robust in evolution. The tradeoff between the genetic robustness and environmental robustness in evolution is discussed from the stochastic stability robustness and sensitivity of the nonlinear stochastic biological network, which may be relevant to the statistical tradeoff between bias and variance, the so-called bias/variance dilemma. Further, the tradeoff could be considered as an antagonistic pleiotropic action of a gene network and discussed from the systems biology perspective. PMID:22084563

  11. A unified biological modeling and simulation system for analyzing biological reaction networks

    NASA Astrophysics Data System (ADS)

    Yu, Seok Jong; Tung, Thai Quang; Park, Junho; Lim, Jongtae; Yoo, Jaesoo

    2013-12-01

    In order to understand the biological response in a cell, a researcher has to create a biological network and design an experiment to prove it. Although biological knowledge has been accumulated, we still don't have enough biological models to explain complex biological phenomena. If a new biological network is to be created, integrated modeling software supporting various biological models is required. In this research, we design and implement a unified biological modeling and simulation system, called ezBioNet, for analyzing biological reaction networks. ezBioNet designs kinetic and Boolean network models and simulates the biological networks using a server-side simulation system with Object Oriented Parallel Accelerator Library framework. The main advantage of ezBioNet is that a user can create a biological network by using unified modeling canvas of kinetic and Boolean models and perform massive simulations, including Ordinary Differential Equation analyses, sensitivity analyses, parameter estimates and Boolean network analysis. ezBioNet integrates useful biological databases, including the BioModels database, by connecting European Bioinformatics Institute servers through Web services Application Programming Interfaces. In addition, we employ Eclipse Rich Client Platform, which is a powerful modularity framework to allow various functional expansions. ezBioNet is intended to be an easy-to-use modeling tool and a simulation system for understanding the control mechanism by monitoring the change of each component in a biological network. The simulation result can be managed and visualized on ezBioNet, which is available free of charge at http://ezbionet.sourceforge.net or http://ezbionet.cbnu.ac.kr.

  12. Organization principles of biological networks: An explorative study.

    PubMed

    Kohestani, Havva; Giuliani, Alessandro

    2016-03-01

    The definition of general topological principles allowing for graph characterization is an important pre-requisite for investigating structure-function relationships in biological networks. Here we approached the problem by means of an explorative, data-driven strategy, building upon a size-balanced data set made of around 200 distinct biological networks from seven functional classes and simulated networks coming from three mathematical graph models. A clear link between topological structure and biological function did emerge in terms of class membership prediction (average 67% of correct predictions, p<0.0001) with a varying degree of 'peculiarity' across classes going from a very low (25%) recognition efficiency for neural and brain networks to the extremely high (80%) peculiarity of amino acid-amino acid interaction (AAI) networks. We recognized four main dimensions (principal components) as main organization principles of biological networks. These components allowed for an efficient description of network architectures and for the identification of 'not-physiological' (in this case cancer metabolic networks acting as test set) wiring patterns. We highlighted as well the need of developing new theoretical generative models for biological networks overcoming the limitations of present mathematical graph idealizations. PMID:26845173

  13. A Biologically Inspired Network Design Model

    PubMed Central

    Zhang, Xiaoge; Adamatzky, Andrew; Chan, Felix T.S.; Deng, Yong; Yang, Hai; Yang, Xin-She; Tsompanas, Michail-Antisthenis I.; Sirakoulis, Georgios Ch.; Mahadevan, Sankaran

    2015-01-01

    A network design problem is to select a subset of links in a transport network that satisfy passengers or cargo transportation demands while minimizing the overall costs of the transportation. We propose a mathematical model of the foraging behaviour of slime mould P. polycephalum to solve the network design problem and construct optimal transport networks. In our algorithm, a traffic flow between any two cities is estimated using a gravity model. The flow is imitated by the model of the slime mould. The algorithm model converges to a steady state, which represents a solution of the problem. We validate our approach on examples of major transport networks in Mexico and China. By comparing networks developed in our approach with the man-made highways, networks developed by the slime mould, and a cellular automata model inspired by slime mould, we demonstrate the flexibility and efficiency of our approach. PMID:26041508

  14. Biological solutions to transport network design.

    PubMed

    Bebber, Daniel P; Hynes, Juliet; Darrah, Peter R; Boddy, Lynne; Fricker, Mark D

    2007-09-22

    Transport networks are vital components of multicellular organisms, distributing nutrients and removing waste products. Animal and plant transport systems are branching trees whose architecture is linked to universal scaling laws in these organisms. In contrast, many fungi form reticulated mycelia via the branching and fusion of thread-like hyphae that continuously adapt to the environment. Fungal networks have evolved to explore and exploit a patchy environment, rather than ramify through a three-dimensional organism. However, there has been no explicit analysis of the network structures formed, their dynamic behaviour nor how either impact on their ecological function. Using the woodland saprotroph Phanerochaete velutina, we show that fungal networks can display both high transport capacity and robustness to damage. These properties are enhanced as the network grows, while the relative cost of building the network decreases. Thus, mycelia achieve the seemingly competing goals of efficient transport and robustness, with decreasing relative investment, by selective reinforcement and recycling of transport pathways. Fungal networks demonstrate that indeterminate, decentralized systems can yield highly adaptive networks. Understanding how these relatively simple organisms have found effective transport networks through a process of natural selection may inform the design of man-made networks. PMID:17623638

  15. Controllability and observability of Boolean networks arising from biology

    NASA Astrophysics Data System (ADS)

    Li, Rui; Yang, Meng; Chu, Tianguang

    2015-02-01

    Boolean networks are currently receiving considerable attention as a computational scheme for system level analysis and modeling of biological systems. Studying control-related problems in Boolean networks may reveal new insights into the intrinsic control in complex biological systems and enable us to develop strategies for manipulating biological systems using exogenous inputs. This paper considers controllability and observability of Boolean biological networks. We propose a new approach, which draws from the rich theory of symbolic computation, to solve the problems. Consequently, simple necessary and sufficient conditions for reachability, controllability, and observability are obtained, and algorithmic tests for controllability and observability which are based on the Gröbner basis method are presented. As practical applications, we apply the proposed approach to several different biological systems, namely, the mammalian cell-cycle network, the T-cell activation network, the large granular lymphocyte survival signaling network, and the Drosophila segment polarity network, gaining novel insights into the control and/or monitoring of the specific biological systems.

  16. Controllability and observability of Boolean networks arising from biology.

    PubMed

    Li, Rui; Yang, Meng; Chu, Tianguang

    2015-02-01

    Boolean networks are currently receiving considerable attention as a computational scheme for system level analysis and modeling of biological systems. Studying control-related problems in Boolean networks may reveal new insights into the intrinsic control in complex biological systems and enable us to develop strategies for manipulating biological systems using exogenous inputs. This paper considers controllability and observability of Boolean biological networks. We propose a new approach, which draws from the rich theory of symbolic computation, to solve the problems. Consequently, simple necessary and sufficient conditions for reachability, controllability, and observability are obtained, and algorithmic tests for controllability and observability which are based on the Gröbner basis method are presented. As practical applications, we apply the proposed approach to several different biological systems, namely, the mammalian cell-cycle network, the T-cell activation network, the large granular lymphocyte survival signaling network, and the Drosophila segment polarity network, gaining novel insights into the control and/or monitoring of the specific biological systems. PMID:25725640

  17. Modeling information flow in biological networks

    NASA Astrophysics Data System (ADS)

    Kim, Yoo-Ah; Przytycki, Jozef H.; Wuchty, Stefan; Przytycka, Teresa M.

    2011-06-01

    Large-scale molecular interaction networks are being increasingly used to provide a system level view of cellular processes. Modeling communications between nodes in such huge networks as information flows is useful for dissecting dynamical dependences between individual network components. In the information flow model, individual nodes are assumed to communicate with each other by propagating the signals through intermediate nodes in the network. In this paper, we first provide an overview of the state of the art of research in the network analysis based on information flow models. In the second part, we describe our computational method underlying our recent work on discovering dysregulated pathways in glioma. Motivated by applications to inferring information flow from genotype to phenotype in a very large human interaction network, we generalized previous approaches to compute information flows for a large number of instances and also provided a formal proof for the method.

  18. Rigidity and flexibility of biological networks.

    PubMed

    Gáspár, Merse E; Csermely, Peter

    2012-11-01

    The network approach became a widely used tool to understand the behaviour of complex systems in the last decade. We start from a short description of structural rigidity theory. A detailed account on the combinatorial rigidity analysis of protein structures, as well as local flexibility measures of proteins and their applications in explaining allostery and thermostability is given. We also briefly discuss the network aspects of cytoskeletal tensegrity. Finally, we show the importance of the balance between functional flexibility and rigidity in protein-protein interaction, metabolic, gene regulatory and neuronal networks. Our summary raises the possibility that the concepts of flexibility and rigidity can be generalized to all networks. PMID:23165349

  19. The Structure and Function of Biological Networks

    ERIC Educational Resources Information Center

    Wu, Daniel Duanqing

    2010-01-01

    Biology has been revolutionized in recent years by an explosion in the availability of data. Transforming this new wealth of data into meaningful biological insights and clinical breakthroughs requires a complete overhaul both in the questions being asked and the methodologies used to answer them. A major challenge in organizing and understanding…

  20. Identification of the connections in biologically inspired neural networks

    NASA Technical Reports Server (NTRS)

    Demuth, H.; Leung, K.; Beale, M.; Hicklin, J.

    1990-01-01

    We developed an identification method to find the strength of the connections between neurons from their behavior in small biologically-inspired artificial neural networks. That is, given the network external inputs and the temporal firing pattern of the neurons, we can calculate a solution for the strengths of the connections between neurons and the initial neuron activations if a solution exists. The method determines directly if there is a solution to a particular neural network problem. No training of the network is required. It should be noted that this is a first pass at the solution of a difficult problem. The neuron and network models chosen are related to biology but do not contain all of its complexities, some of which we hope to add to the model in future work. A variety of new results have been obtained. First, the method has been tailored to produce connection weight matrix solutions for networks with important features of biological neural (bioneural) networks. Second, a computationally efficient method of finding a robust central solution has been developed. This later method also enables us to find the most consistent solution in the presence of noisy data. Prospects of applying our method to identify bioneural network connections are exciting because such connections are almost impossible to measure in the laboratory. Knowledge of such connections would facilitate an understanding of bioneural networks and would allow the construction of the electronic counterparts of bioneural networks on very large scale integrated (VLSI) circuits.

  1. Epigenetics and Why Biological Networks are More Controllable than Expected

    NASA Astrophysics Data System (ADS)

    Motter, Adilson

    2013-03-01

    A fundamental property of networks is that perturbations to one node can affect other nodes, potentially causing the entire system to change behavior or fail. In this talk, I will show that it is possible to exploit this same principle to control network behavior. This approach takes advantage of the nonlinear dynamics inherent to real networks, and allows bringing the system to a desired target state even when this state is not directly accessible or the linear counterpart is not controllable. Applications show that this framework permits both reprogramming a network to a desired task as well as rescuing networks from the brink of failure, which I will illustrate through various biological problems. I will also briefly review the progress our group has made over the past 5 years on related control of complex networks in non-biological domains.

  2. Systematic Functional Annotation and Visualization of Biological Networks.

    PubMed

    Baryshnikova, Anastasia

    2016-06-22

    Large-scale biological networks represent relationships between genes, but our understanding of how networks are functionally organized is limited. Here, I describe spatial analysis of functional enrichment (SAFE), a systematic method for annotating biological networks and examining their functional organization. SAFE visualizes the network in 2D space and measures the continuous distribution of functional enrichment across local neighborhoods, producing a list of the associated functions and a map of their relative positioning. I applied SAFE to annotate the Saccharomyces cerevisiae genetic interaction similarity network and protein-protein interaction network with gene ontology terms. SAFE annotations of the genetic network matched manually derived annotations, while taking less than 1% of the time, and proved robust to noise and sensitive to biological signal. Integration of genetic interaction and chemical genomics data using SAFE revealed a link between vesicle-mediate transport and resistance to the anti-cancer drug bortezomib. These results demonstrate the utility of SAFE for examining biological networks and understanding their functional organization. PMID:27237738

  3. NETWORKS, BIOLOGY AND SYSTEMS ENGINEERING: A CASE STUDY IN INFLAMMATION

    PubMed Central

    Foteinou, P.T.; Yang, E.; Androulakis, I. P.

    2009-01-01

    Biological systems can be modeled as networks of interacting components across multiple scales. A central problem in computational systems biology is to identify those critical components and the rules that define their interactions and give rise to the emergent behavior of a host response. In this paper we will discuss two fundamental problems related to the construction of transcription factor networks and the identification of networks of functional modules describing disease progression. We focus on inflammation as a key physiological response of clinical and translational importance. PMID:20161495

  4. Using biological networks to improve our understanding of infectious diseases

    PubMed Central

    Mulder, Nicola J.; Akinola, Richard O.; Mazandu, Gaston K.; Rapanoel, Holifidy

    2014-01-01

    Infectious diseases are the leading cause of death, particularly in developing countries. Although many drugs are available for treating the most common infectious diseases, in many cases the mechanism of action of these drugs or even their targets in the pathogen remain unknown. In addition, the key factors or processes in pathogens that facilitate infection and disease progression are often not well understood. Since proteins do not work in isolation, understanding biological systems requires a better understanding of the interconnectivity between proteins in different pathways and processes, which includes both physical and other functional interactions. Such biological networks can be generated within organisms or between organisms sharing a common environment using experimental data and computational predictions. Though different data sources provide different levels of accuracy, confidence in interactions can be measured using interaction scores. Connections between interacting proteins in biological networks can be represented as graphs and edges, and thus studied using existing algorithms and tools from graph theory. There are many different applications of biological networks, and here we discuss three such applications, specifically applied to the infectious disease tuberculosis, with its causative agent Mycobacterium tuberculosis and host, Homo sapiens. The applications include the use of the networks for function prediction, comparison of networks for evolutionary studies, and the generation and use of host–pathogen interaction networks. PMID:25379138

  5. Biological Network Inference and Analysis using SEBINI and CABIN

    SciTech Connect

    Taylor, Ronald C.; Singhal, Mudita

    2008-01-01

    Attaining a detailed understanding of the various biological networks in an organism lies at the core of the emerging discipline of systems biology. A precise description of the relationships formed between genes, mRNA molecules, and proteins is a necessary step toward a complete description of the dynamic behavior of an organism at the cellular level; and towards intelligent, efficient and directed modification of an organism. The importance of understanding such regulatory, signaling, and interaction networks has fueled the development of numerous in silico inference algorithms, as well as new experimental techniques and a growing collection of public databases. The Software Environment for BIological Network Inference (SEBINI) has been created to provide an interactive environment for the deployment, evaluation, and improvement of algorithms used to reconstruct the structure of biological regulatory and interaction networks. SEBINI can be used to analyze high-throughput gene expression, protein expression, or protein activation data via a suite of state-of-the-art network inference algorithms. It also allows algorithm developers to compare and train network inference methods on artificial networks and simulated gene expression perturbation data. SEBINI can therefore be used by software developers wishing to evaluate, refine, or combine inference techniques, as well as by bioinformaticians analyzing experimental data. Networks inferred from the SEBINI software platform can be further analyzed using the Collective Analysis of Biological Interaction Networks (CABIN) tool, which is exploratory data analysis software that enables integration and analysis of protein-protein interaction and gene-to-gene regulatory evidence obtained from multiple sources. The collection of edges in public databases, along with the confidence held in each edge (if available), can be fed into CABIN as one “evidence network”, using the Cytoscape SIF file format. Using CABIN, one may

  6. Analysis and logical modeling of biological signaling transduction networks

    NASA Astrophysics Data System (ADS)

    Sun, Zhongyao

    The study of network theory and its application span across a multitude of seemingly disparate fields of science and technology: computer science, biology, social science, linguistics, etc. It is the intrinsic similarities embedded in the entities and the way they interact with one another in these systems that link them together. In this dissertation, I present from both the aspect of theoretical analysis and the aspect of application three projects, which primarily focus on signal transduction networks in biology. In these projects, I assembled a network model through extensively perusing literature, performed model-based simulations and validation, analyzed network topology, and proposed a novel network measure. The application of network modeling to the system of stomatal opening in plants revealed a fundamental question about the process that has been left unanswered in decades. The novel measure of the redundancy of signal transduction networks with Boolean dynamics by calculating its maximum node-independent elementary signaling mode set accurately predicts the effect of single node knockout in such signaling processes. The three projects as an organic whole advance the understanding of a real system as well as the behavior of such network models, giving me an opportunity to take a glimpse at the dazzling facets of the immense world of network science.

  7. Biological impacts and context of network theory

    SciTech Connect

    Almaas, E

    2007-01-05

    Many complex systems can be represented and analyzed as networks, and examples that have benefited from this approach span the natural sciences. For instance, we now know that systems as disparate as the World-Wide Web, the Internet, scientific collaborations, food webs, protein interactions and metabolism all have common features in their organization, the most salient of which are their scale-free connectivity distributions and their small-world behavior. The recent availability of large scale datasets that span the proteome or metabolome of an organism have made it possible to elucidate some of the organizational principles and rules that govern their function, robustness and evolution. We expect that combining the currently separate layers of information from gene regulatory-, signal transduction-, protein interaction- and metabolic networks will dramatically enhance our understanding of cellular function and dynamics.

  8. Toward modeling a dynamic biological neural network.

    PubMed

    Ross, M D; Dayhoff, J E; Mugler, D H

    1990-01-01

    Mammalian macular endorgans are linear bioaccelerometers located in the vestibular membranous labyrinth of the inner ear. In this paper, the organization of the endorgan is interpreted on physical and engineering principles. This is a necessary prerequisite to mathematical and symbolic modeling of information processing by the macular neural network. Mathematical notations that describe the functioning system were used to produce a novel, symbolic model. The model is six-tiered and is constructed to mimic the neural system. Initial simulations show that the network functions best when some of the detecting elements (type I hair cells) are excitatory and others (type II hair cells) are weakly inhibitory. The simulations also illustrate the importance of disinhibition of receptors located in the third tier in shaping nerve discharge patterns at the sixth tier in the model system. PMID:11538873

  9. Classifying pairs with trees for supervised biological network inference.

    PubMed

    Schrynemackers, Marie; Wehenkel, Louis; Babu, M Madan; Geurts, Pierre

    2015-08-01

    Networks are ubiquitous in biology, and computational approaches have been largely investigated for their inference. In particular, supervised machine learning methods can be used to complete a partially known network by integrating various measurements. Two main supervised frameworks have been proposed: the local approach, which trains a separate model for each network node, and the global approach, which trains a single model over pairs of nodes. Here, we systematically investigate, theoretically and empirically, the exploitation of tree-based ensemble methods in the context of these two approaches for biological network inference. We first formalize the problem of network inference as a classification of pairs, unifying in the process homogeneous and bipartite graphs and discussing two main sampling schemes. We then present the global and the local approaches, extending the latter for the prediction of interactions between two unseen network nodes, and discuss their specializations to tree-based ensemble methods, highlighting their interpretability and drawing links with clustering techniques. Extensive computational experiments are carried out with these methods on various biological networks that clearly highlight that these methods are competitive with existing methods. PMID:26008881

  10. Course 10: Three Lectures on Biological Networks

    NASA Astrophysics Data System (ADS)

    Magnasco, M. O.

    1 Enzymatic networks. Proofreading knots: How DNA topoisomerases disentangle DNA 1.1 Length scales and energy scales 1.2 DNA topology 1.3 Topoisomerases 1.4 Knots and supercoils 1.5 Topological equilibrium 1.6 Can topoisomerases recognize topology? 1.7 Proposal: Kinetic proofreading 1.8 How to do it twice 1.9 The care and proofreading of knots 1.10 Suppression of supercoils 1.11 Problems and outlook 1.12 Disquisition 2 Gene expression networks. Methods for analysis of DNA chip experiments 2.1 The regulation of gene expression 2.2 Gene expression arrays 2.3 Analysis of array data 2.4 Some simplifying assumptions 2.5 Probeset analysis 2.6 Discussion 3 Neural and gene expression networks: Song-induced gene expression in the canary brain 3.1 The study of songbirds 3.2 Canary song 3.3 ZENK 3.4 The blush 3.5 Histological analysis 3.6 Natural vs. artificial 3.7 The Blush II: gAP 3.8 Meditation

  11. Topology and static response of interaction networks in molecular biology.

    PubMed

    Radulescu, Ovidiu; Lagarrigue, Sandrine; Siegel, Anne; Veber, Philippe; Le Borgne, Michel

    2006-02-22

    We introduce a mathematical framework describing static response of networks occurring in molecular biology. This formalism has many similarities with the Laplace-Kirchhoff equations for electrical networks. We introduce the concept of graph boundary and we show how the response of the biological networks to external perturbations can be related to the Dirichlet or Neumann problems for the corresponding equations on the interaction graph. Solutions to these two problems are given in terms of path moduli (measuring path rigidity with respect to the propagation of interaction along the graph). Path moduli are related to loop products in the interaction graph via generalized Mason-Coates formulae. We apply our results to two specific biological examples: the lactose operon and the genetic regulation of lipogenesis. Our applications show consistency with experimental results and in the case of lipogenesis check some hypothesis on the behaviour of hepatic fatty acids on fasting. PMID:16849230

  12. Topology and static response of interaction networks in molecular biology

    PubMed Central

    Radulescu, Ovidiu; Lagarrigue, Sandrine; Siegel, Anne; Veber, Philippe; Le Borgne, Michel

    2005-01-01

    We introduce a mathematical framework describing static response of networks occurring in molecular biology. This formalism has many similarities with the Laplace–Kirchhoff equations for electrical networks. We introduce the concept of graph boundary and we show how the response of the biological networks to external perturbations can be related to the Dirichlet or Neumann problems for the corresponding equations on the interaction graph. Solutions to these two problems are given in terms of path moduli (measuring path rigidity with respect to the propagation of interaction along the graph). Path moduli are related to loop products in the interaction graph via generalized Mason–Coates formulae. We apply our results to two specific biological examples: the lactose operon and the genetic regulation of lipogenesis. Our applications show consistency with experimental results and in the case of lipogenesis check some hypothesis on the behaviour of hepatic fatty acids on fasting. PMID:16849230

  13. BiologicalNetworks 2.0 - an integrative view of genome biology data

    PubMed Central

    2010-01-01

    Background A significant problem in the study of mechanisms of an organism's development is the elucidation of interrelated factors which are making an impact on the different levels of the organism, such as genes, biological molecules, cells, and cell systems. Numerous sources of heterogeneous data which exist for these subsystems are still not integrated sufficiently enough to give researchers a straightforward opportunity to analyze them together in the same frame of study. Systematic application of data integration methods is also hampered by a multitude of such factors as the orthogonal nature of the integrated data and naming problems. Results Here we report on a new version of BiologicalNetworks, a research environment for the integral visualization and analysis of heterogeneous biological data. BiologicalNetworks can be queried for properties of thousands of different types of biological entities (genes/proteins, promoters, COGs, pathways, binding sites, and other) and their relations (interactions, co-expression, co-citations, and other). The system includes the build-pathways infrastructure for molecular interactions/relations and module discovery in high-throughput experiments. Also implemented in BiologicalNetworks are the Integrated Genome Viewer and Comparative Genomics Browser applications, which allow for the search and analysis of gene regulatory regions and their conservation in multiple species in conjunction with molecular pathways/networks, experimental data and functional annotations. Conclusions The new release of BiologicalNetworks together with its back-end database introduces extensive functionality for a more efficient integrated multi-level analysis of microarray, sequence, regulatory, and other data. BiologicalNetworks is freely available at http://www.biologicalnetworks.org. PMID:21190573

  14. Non-Hermitian localization in biological networks.

    PubMed

    Amir, Ariel; Hatano, Naomichi; Nelson, David R

    2016-04-01

    We explore the spectra and localization properties of the N-site banded one-dimensional non-Hermitian random matrices that arise naturally in sparse neural networks. Approximately equal numbers of random excitatory and inhibitory connections lead to spatially localized eigenfunctions and an intricate eigenvalue spectrum in the complex plane that controls the spontaneous activity and induced response. A finite fraction of the eigenvalues condense onto the real or imaginary axes. For large N, the spectrum has remarkable symmetries not only with respect to reflections across the real and imaginary axes but also with respect to 90^{∘} rotations, with an unusual anisotropic divergence in the localization length near the origin. When chains with periodic boundary conditions become directed, with a systematic directional bias superimposed on the randomness, a hole centered on the origin opens up in the density-of-states in the complex plane. All states are extended on the rim of this hole, while the localized eigenvalues outside the hole are unchanged. The bias-dependent shape of this hole tracks the bias-independent contours of constant localization length. We treat the large-N limit by a combination of direct numerical diagonalization and using transfer matrices, an approach that allows us to exploit an electrostatic analogy connecting the "charges" embodied in the eigenvalue distribution with the contours of constant localization length. We show that similar results are obtained for more realistic neural networks that obey "Dale's law" (each site is purely excitatory or inhibitory) and conclude with perturbation theory results that describe the limit of large directional bias, when all states are extended. Related problems arise in random ecological networks and in chains of artificial cells with randomly coupled gene expression patterns. PMID:27176315

  15. Non-Hermitian localization in biological networks

    NASA Astrophysics Data System (ADS)

    Amir, Ariel; Hatano, Naomichi; Nelson, David R.

    2016-04-01

    We explore the spectra and localization properties of the N -site banded one-dimensional non-Hermitian random matrices that arise naturally in sparse neural networks. Approximately equal numbers of random excitatory and inhibitory connections lead to spatially localized eigenfunctions and an intricate eigenvalue spectrum in the complex plane that controls the spontaneous activity and induced response. A finite fraction of the eigenvalues condense onto the real or imaginary axes. For large N , the spectrum has remarkable symmetries not only with respect to reflections across the real and imaginary axes but also with respect to 90∘ rotations, with an unusual anisotropic divergence in the localization length near the origin. When chains with periodic boundary conditions become directed, with a systematic directional bias superimposed on the randomness, a hole centered on the origin opens up in the density-of-states in the complex plane. All states are extended on the rim of this hole, while the localized eigenvalues outside the hole are unchanged. The bias-dependent shape of this hole tracks the bias-independent contours of constant localization length. We treat the large-N limit by a combination of direct numerical diagonalization and using transfer matrices, an approach that allows us to exploit an electrostatic analogy connecting the "charges" embodied in the eigenvalue distribution with the contours of constant localization length. We show that similar results are obtained for more realistic neural networks that obey "Dale's law" (each site is purely excitatory or inhibitory) and conclude with perturbation theory results that describe the limit of large directional bias, when all states are extended. Related problems arise in random ecological networks and in chains of artificial cells with randomly coupled gene expression patterns.

  16. Discriminating direct and indirect connectivities in biological networks

    PubMed Central

    Kang, Taek; Moore, Richard; Li, Yi; Sontag, Eduardo; Bleris, Leonidas

    2015-01-01

    Reverse engineering of biological pathways involves an iterative process between experiments, data processing, and theoretical analysis. Despite concurrent advances in quality and quantity of data as well as computing resources and algorithms, difficulties in deciphering direct and indirect network connections are prevalent. Here, we adopt the notions of abstraction, emulation, benchmarking, and validation in the context of discovering features specific to this family of connectivities. After subjecting benchmark synthetic circuits to perturbations, we inferred the network connections using a combination of nonparametric single-cell data resampling and modular response analysis. Intriguingly, we discovered that recovered weights of specific network edges undergo divergent shifts under differential perturbations, and that the particular behavior is markedly different between topologies. Our results point to a conceptual advance for reverse engineering beyond weight inference. Investigating topological changes under differential perturbations may address the longstanding problem of discriminating direct and indirect connectivities in biological networks. PMID:26420864

  17. Spectral algorithms for heterogeneous biological networks.

    PubMed

    McDonald, Martin; Higham, Desmond J; Vass, J Keith

    2012-11-01

    Spectral methods, which use information relating to eigenvectors, singular vectors and generalized singular vectors, help us to visualize and summarize sets of pairwise interactions. In this work, we motivate and discuss the use of spectral methods by taking a matrix computation view and applying concepts from applied linear algebra. We show that this unified approach is sufficiently flexible to allow multiple sources of network information to be combined. We illustrate the methods on microarray data arising from a large population-based study in human adipose tissue, combined with related information concerning metabolic pathways. PMID:23117863

  18. Using biological networks to integrate, visualize and analyze genomics data.

    PubMed

    Charitou, Theodosia; Bryan, Kenneth; Lynn, David J

    2016-01-01

    Network biology is a rapidly developing area of biomedical research and reflects the current view that complex phenotypes, such as disease susceptibility, are not the result of single gene mutations that act in isolation but are rather due to the perturbation of a gene's network context. Understanding the topology of these molecular interaction networks and identifying the molecules that play central roles in their structure and regulation is a key to understanding complex systems. The falling cost of next-generation sequencing is now enabling researchers to routinely catalogue the molecular components of these networks at a genome-wide scale and over a large number of different conditions. In this review, we describe how to use publicly available bioinformatics tools to integrate genome-wide 'omics' data into a network of experimentally-supported molecular interactions. In addition, we describe how to visualize and analyze these networks to identify topological features of likely functional relevance, including network hubs, bottlenecks and modules. We show that network biology provides a powerful conceptual approach to integrate and find patterns in genome-wide genomic data but we also discuss the limitations and caveats of these methods, of which researchers adopting these methods must remain aware. PMID:27036106

  19. Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders

    PubMed Central

    Parikshak, Neelroop N.; Gandal, Michael J.; Geschwind, Daniel H.

    2015-01-01

    Genetic and genomic approaches have implicated hundreds of genetic loci in neurodevelopmental disorders and neurodegeneration, but mechanistic understanding continues to lag behind the pace of gene discovery. Understanding the role of specific genetic variants in the brain involves dissecting a functional hierarchy that encompasses molecular pathways, diverse cell types, neural circuits and, ultimately, cognition and behaviour. With a focus on transcriptomics, this Review discusses how high-throughput molecular, integrative and network approaches inform disease biology by placing human genetics in a molecular systems and neurobiological context. We provide a framework for interpreting network biology studies and leveraging big genomics data sets in neurobiology. PMID:26149713

  20. A Newtonian framework for community detection in undirected biological networks.

    PubMed

    Narayanan, Tejaswini; Subramaniam, Shankar

    2014-02-01

    Community detection is a key problem of interest in network analysis, with applications in a variety of domains such as biological networks, social network modeling, and communication pattern analysis. In this paper, we present a novel framework for community detection that is motivated by a physical system analogy. We model a network as a system of point masses, and drive the process of community detection, by leveraging the Newtonian interactions between the point masses. Our framework is designed to be generic and extensible relative to the model parameters that are most suited for the problem domain. We illustrate the applicability of our approach by applying the Newtonian Community Detection algorithm on protein-protein interaction networks of E. coli , C. elegans, and S. cerevisiae. We obtain results that are comparable in quality to those obtained from the Newman-Girvan algorithm, a widely employed divisive algorithm for community detection. We also present a detailed analysis of the structural properties of the communities produced by our proposed algorithm, together with a biological interpretation using E. coli protein network as a case study. A functional enrichment heat map is constructed with the Gene Ontology functional mapping, in addition to a pathway analysis for each community. The analysis illustrates that the proposed algorithm elicits communities that are not only meaningful from a topological standpoint, but also possess biological relevance. We believe that our algorithm has the potential to serve as a key computational tool for driving therapeutic applications involving targeted drug development for personalized care delivery. PMID:24681920

  1. Theory of interface: category theory, directed networks and evolution of biological networks.

    PubMed

    Haruna, Taichi

    2013-11-01

    Biological networks have two modes. The first mode is static: a network is a passage on which something flows. The second mode is dynamic: a network is a pattern constructed by gluing functions of entities constituting the network. In this paper, first we discuss that these two modes can be associated with the category theoretic duality (adjunction) and derive a natural network structure (a path notion) for each mode by appealing to the category theoretic universality. The path notion corresponding to the static mode is just the usual directed path. The path notion for the dynamic mode is called lateral path which is the alternating path considered on the set of arcs. Their general functionalities in a network are transport and coherence, respectively. Second, we introduce a betweenness centrality of arcs for each mode and see how the two modes are embedded in various real biological network data. We find that there is a trade-off relationship between the two centralities: if the value of one is large then the value of the other is small. This can be seen as a kind of division of labor in a network into transport on the network and coherence of the network. Finally, we propose an optimization model of networks based on a quality function involving intensities of the two modes in order to see how networks with the above trade-off relationship can emerge through evolution. We show that the trade-off relationship can be observed in the evolved networks only when the dynamic mode is dominant in the quality function by numerical simulations. We also show that the evolved networks have features qualitatively similar to real biological networks by standard complex network analysis. PMID:24012823

  2. From biological and social network metaphors to coupled bio-social wireless networks

    PubMed Central

    Barrett, Christopher L.; Eubank, Stephen; Anil Kumar, V.S.; Marathe, Madhav V.

    2010-01-01

    Biological and social analogies have been long applied to complex systems. Inspiration has been drawn from biological solutions to solve problems in engineering products and systems, ranging from Velcro to camouflage to robotics to adaptive and learning computing methods. In this paper, we present an overview of recent advances in understanding biological systems as networks and use this understanding to design and analyse wireless communication networks. We expand on two applications, namely cognitive sensing and control and wireless epidemiology. We discuss how our work in these two applications is motivated by biological metaphors. We believe that recent advances in computing and communications coupled with advances in health and social sciences raise the possibility of studying coupled bio-social communication networks. We argue that we can better utilise the advances in our understanding of one class of networks to better our understanding of the other. PMID:21643462

  3. From biological and social network metaphors to coupled bio-social wireless networks.

    PubMed

    Barrett, Christopher L; Channakeshava, Karthik; Eubank, Stephen; Anil Kumar, V S; Marathe, Madhav V

    2011-01-01

    Biological and social analogies have been long applied to complex systems. Inspiration has been drawn from biological solutions to solve problems in engineering products and systems, ranging from Velcro to camouflage to robotics to adaptive and learning computing methods. In this paper, we present an overview of recent advances in understanding biological systems as networks and use this understanding to design and analyse wireless communication networks. We expand on two applications, namely cognitive sensing and control and wireless epidemiology. We discuss how our work in these two applications is motivated by biological metaphors. We believe that recent advances in computing and communications coupled with advances in health and social sciences raise the possibility of studying coupled bio-social communication networks. We argue that we can better utilise the advances in our understanding of one class of networks to better our understanding of the other. PMID:21643462

  4. Towards the understanding of network information processing in biology

    NASA Astrophysics Data System (ADS)

    Singh, Vijay

    Living organisms perform incredibly well in detecting a signal present in the environment. This information processing is achieved near optimally and quite reliably, even though the sources of signals are highly variable and complex. The work in the last few decades has given us a fair understanding of how individual signal processing units like neurons and cell receptors process signals, but the principles of collective information processing on biological networks are far from clear. Information processing in biological networks, like the brain, metabolic circuits, cellular-signaling circuits, etc., involves complex interactions among a large number of units (neurons, receptors). The combinatorially large number of states such a system can exist in makes it impossible to study these systems from the first principles, starting from the interactions between the basic units. The principles of collective information processing on such complex networks can be identified using coarse graining approaches. This could provide insights into the organization and function of complex biological networks. Here I study models of biological networks using continuum dynamics, renormalization, maximum likelihood estimation and information theory. Such coarse graining approaches identify features that are essential for certain processes performed by underlying biological networks. We find that long-range connections in the brain allow for global scale feature detection in a signal. These also suppress the noise and remove any gaps present in the signal. Hierarchical organization with long-range connections leads to large-scale connectivity at low synapse numbers. Time delays can be utilized to separate a mixture of signals with temporal scales. Our observations indicate that the rules in multivariate signal processing are quite different from traditional single unit signal processing.

  5. Flux-concentration duality in dynamic nonequilibrium biological networks.

    PubMed

    Jamshidi, Neema; Palsson, Bernhard Ø

    2009-09-01

    The structure of dynamic states in biological networks is of fundamental importance in understanding their function. Considering the elementary reaction structure of reconstructed metabolic networks, we show how appreciation of a gradient matrix, G =dv/dx (where v is the vector of fluxes and x is the vector of concentrations), enables the formulation of dual Jacobian matrices. One is for concentrations, J(x) =S x G, and the other is for fluxes, J(v) =G x S. The fundamental properties of these two Jacobians and the underlying duality that relates them are delineated. We describe a generalized approach to decomposing reaction networks in terms of the thermodynamic and kinetic components in the context of the network structure. The thermodynamic and kinetic influences can be viewed in terms of direction-driver relationships in the network. PMID:19720010

  6. Convergence behaviour and Control in Non-Linear Biological Networks

    PubMed Central

    Karl, Stefan; Dandekar, Thomas

    2015-01-01

    Control of genetic regulatory networks is challenging to define and quantify. Previous control centrality metrics, which aim to capture the ability of individual nodes to control the system, have been found to suffer from plausibility and applicability problems. Here we present a new approach to control centrality based on network convergence behaviour, implemented as an extension of our genetic regulatory network simulation framework Jimena ( http://stefan-karl.de/jimena). We distinguish three types of network control, and show how these mathematical concepts correspond to experimentally verified node functions and signalling pathways in immunity and cell differentiation: Total control centrality quantifies the impact of node mutations and identifies potential pharmacological targets such as genes involved in oncogenesis (e.g. zinc finger protein GLI2 or bone morphogenetic proteins in chondrocytes). Dynamic control centrality describes relaying functions as observed in signalling cascades (e.g. src kinase or Jak/Stat pathways). Value control centrality measures the direct influence of the value of the node on the network (e.g. Indian hedgehog as an essential regulator of proliferation in chondrocytes). Surveying random scale-free networks and biological networks, we find that control of the network resides in few high degree driver nodes and networks can be controlled best if they are sparsely connected. PMID:26068060

  7. Composite nanowire networks for biological sensor platforms

    NASA Astrophysics Data System (ADS)

    Jabal, Jamie Marie Francisco

    The main goal of this research is to design, fabricate, and test a nanomaterial-based platform adequate for the measurement of physiological changes in living cells. The two primary objectives toward this end are (1) the synthesis and selection of a suitable nanomaterial and (2) the demonstration of cellular response to a direct stimulus. Determining a useful nanomaterial morphology and behavior within a sensor configuration presented challenges based on cellular integration and access to electrochemical characterization. The prospect for feasible optimization and eventual scale-up in technology were also significant. Constraining criteria are that the nanomaterial detector must (a) be cheap and relatively easy to fabricate controllably, (b) encourage cell attachment, (c) exhibit consistent wettability over time, and (d) facilitate electrochemical processes. The ultimate goal would be to transfer a proof-of-principle and proof-of-design for a whole-cell sensor technology that is cost effective and has a potential for hand-held packaging. Initial tasks were to determine an effective and highly-functional nanomaterial for biosensors by assessing wettability, morphology and conductivity behavior of several candidate materials: gallium nitride nanowires, silicon dioxide nanosprings and nanowires, and titania nanofibers. Electrospinning poly(vinyl pyrrolidone)-coated titania nano- and microfibers (O20 nm--2 microm) into a pseudo-random network is controllable to a uniformity of 1--2° in contact angle. The final electrode can be prepared with a precise wettability ranging from partial wetting to ultrahydrophobic (170°) on a variety of substrates: glass, indium tin oxide, silicon, and aluminum. Fiber mats exhibit excellent mechanical stability against rinsing, and support the incubation of epithelial (skin) and pancreatic cells. Impedance spectroscopy on the whole-cell sensor shows resistive changes attributed to cell growth as well as complex frequency

  8. Reduction of dynamical biochemical reactions networks in computational biology

    PubMed Central

    Radulescu, O.; Gorban, A. N.; Zinovyev, A.; Noel, V.

    2012-01-01

    Biochemical networks are used in computational biology, to model mechanistic details of systems involved in cell signaling, metabolism, and regulation of gene expression. Parametric and structural uncertainty, as well as combinatorial explosion are strong obstacles against analyzing the dynamics of large models of this type. Multiscaleness, an important property of these networks, can be used to get past some of these obstacles. Networks with many well separated time scales, can be reduced to simpler models, in a way that depends only on the orders of magnitude and not on the exact values of the kinetic parameters. The main idea used for such robust simplifications of networks is the concept of dominance among model elements, allowing hierarchical organization of these elements according to their effects on the network dynamics. This concept finds a natural formulation in tropical geometry. We revisit, in the light of these new ideas, the main approaches to model reduction of reaction networks, such as quasi-steady state (QSS) and quasi-equilibrium approximations (QE), and provide practical recipes for model reduction of linear and non-linear networks. We also discuss the application of model reduction to the problem of parameter identification, via backward pruning machine learning techniques. PMID:22833754

  9. An open system network for the biological sciences.

    PubMed Central

    Springer, G. K.; Loch, J. L.; Patrick, T. B.

    1991-01-01

    A description of an open system, distributed computing environment for the Biological Sciences is presented. This system utilizes a transparent interface in a computer network using NCS to implement an application system for molecular biologists to perform various processing activities from their local workstation. This system accepts requests for the services of a remote database server, located across the network, to perform all of the database searches needed to support the activities of the user. This database access is totally transparent to the user of the system and it appears, to the user, that all activities are being carried out on the local workstation. This system is a prototype for a much more extensive system being built to support the research efforts in the Biological Sciences at UMC. PMID:1807659

  10. High-resolution network biology: connecting sequence with function

    PubMed Central

    Ryan, Colm J.; Cimermančič, Peter; Szpiech, Zachary A.; Sali, Andrej; Hernandez, Ryan D.; Krogan, Nevan J.

    2014-01-01

    Proteins are not monolithic entities; rather, they can contain multiple domains that mediate distinct interactions, and their functionality can be regulated through post-translational modifications at multiple distinct sites. Traditionally, network biology has ignored such properties of proteins and has instead examined either the physical interactions of whole proteins or the consequences of removing entire genes. In this Review, we discuss experimental and computational methods to increase the resolution of protein– protein, genetic and drug–gene interaction studies to the domain and residue levels. Such work will be crucial for using interaction networks to connect sequence and structural information, and to understand the biological consequences of disease-associated mutations, which will hopefully lead to more effective therapeutic strategies. PMID:24197012

  11. NetDecoder: a network biology platform that decodes context-specific biological networks and gene activities.

    PubMed

    da Rocha, Edroaldo Lummertz; Ung, Choong Yong; McGehee, Cordelia D; Correia, Cristina; Li, Hu

    2016-06-01

    The sequential chain of interactions altering the binary state of a biomolecule represents the 'information flow' within a cellular network that determines phenotypic properties. Given the lack of computational tools to dissect context-dependent networks and gene activities, we developed NetDecoder, a network biology platform that models context-dependent information flows using pairwise phenotypic comparative analyses of protein-protein interactions. Using breast cancer, dyslipidemia and Alzheimer's disease as case studies, we demonstrate NetDecoder dissects subnetworks to identify key players significantly impacting cell behaviour specific to a given disease context. We further show genes residing in disease-specific subnetworks are enriched in disease-related signalling pathways and information flow profiles, which drive the resulting disease phenotypes. We also devise a novel scoring scheme to quantify key genes-network routers, which influence many genes, key targets, which are influenced by many genes, and high impact genes, which experience a significant change in regulation. We show the robustness of our results against parameter changes. Our network biology platform includes freely available source code (http://www.NetDecoder.org) for researchers to explore genome-wide context-dependent information flow profiles and key genes, given a set of genes of particular interest and transcriptome data. More importantly, NetDecoder will enable researchers to uncover context-dependent drug targets. PMID:26975659

  12. NetDecoder: a network biology platform that decodes context-specific biological networks and gene activities

    PubMed Central

    da Rocha, Edroaldo Lummertz; Ung, Choong Yong; McGehee, Cordelia D.; Correia, Cristina; Li, Hu

    2016-01-01

    The sequential chain of interactions altering the binary state of a biomolecule represents the ‘information flow’ within a cellular network that determines phenotypic properties. Given the lack of computational tools to dissect context-dependent networks and gene activities, we developed NetDecoder, a network biology platform that models context-dependent information flows using pairwise phenotypic comparative analyses of protein–protein interactions. Using breast cancer, dyslipidemia and Alzheimer's disease as case studies, we demonstrate NetDecoder dissects subnetworks to identify key players significantly impacting cell behaviour specific to a given disease context. We further show genes residing in disease-specific subnetworks are enriched in disease-related signalling pathways and information flow profiles, which drive the resulting disease phenotypes. We also devise a novel scoring scheme to quantify key genes—network routers, which influence many genes, key targets, which are influenced by many genes, and high impact genes, which experience a significant change in regulation. We show the robustness of our results against parameter changes. Our network biology platform includes freely available source code (http://www.NetDecoder.org) for researchers to explore genome-wide context-dependent information flow profiles and key genes, given a set of genes of particular interest and transcriptome data. More importantly, NetDecoder will enable researchers to uncover context-dependent drug targets. PMID:26975659

  13. A biologically inspired immunization strategy for network epidemiology.

    PubMed

    Liu, Yang; Deng, Yong; Jusup, Marko; Wang, Zhen

    2016-07-01

    Well-known immunization strategies, based on degree centrality, betweenness centrality, or closeness centrality, either neglect the structural significance of a node or require global information about the network. We propose a biologically inspired immunization strategy that circumvents both of these problems by considering the number of links of a focal node and the way the neighbors are connected among themselves. The strategy thus measures the dependence of the neighbors on the focal node, identifying the ability of this node to spread the disease. Nodes with the highest ability in the network are the first to be immunized. To test the performance of our method, we conduct numerical simulations on several computer-generated and empirical networks, using the susceptible-infected-recovered (SIR) model. The results show that the proposed strategy largely outperforms the existing well-known strategies. PMID:27113785

  14. Protozoan HSP90-heterocomplex: molecular interaction network and biological significance.

    PubMed

    Figueras, Maria J; Echeverria, Pablo C; Angel, Sergio O

    2014-05-01

    The HSP90 chaperone is a highly conserved protein from bacteria to higher eukaryotes. In eukaryotes, this chaperone participates in different large complexes, such as the HSP90 heterocomplex, which has important biological roles in cell homeostasis and differentiation. The HSP90-heterocomplex is also named the HSP90/HSP70 cycle because different co-chaperones (HIP, HSP40, HOP, p23, AHA1, immunophilins, PP5) participate in this complex by assembling sequentially, from the early to the mature complex. In this review, we analyze the conservation and relevance of HSP90 and the HSP90-heterocomplex in several protozoan parasites, with emphasis in Plasmodium spp., Toxoplasma spp., Leishmania spp. and Trypanosoma spp. In the last years, there has been an outburst of studies based on yeast two-hybrid methodology, co-immunoprecipitation-mass spectrometry and bioinformatics, which have generated a most comprehensive protein-protein interaction (PPI) network of HSP90 and its co-chaperones. This review analyzes the existing PPI networks of HSP90 and its co-chaperones of some protozoan parasites and discusses the usefulness of these powerful tools to analyze the biological role of the HSP90-heterocomplex in these parasites. The generation of a T. gondii HSP90 heterocomplex PPI network based on experimental data and a recent Plasmodium HSP90 heterocomplex PPI network are also included and discussed. As an example, the putative implication of nuclear transport and chromatin (histones and Sir2) as HSP90-heterocomplex interactors is here discussed. PMID:24694366

  15. Systems analysis of biological networks in skeletal muscle function

    PubMed Central

    Smith, Lucas R.; Meyer, Gretchen; Lieber, Richard L.

    2014-01-01

    Skeletal muscle function depends on the efficient coordination among subcellular systems. These systems are composed of proteins encoded by a subset of genes, all of which are tightly regulated. In the cases where regulation is altered because of disease or injury, dysfunction occurs. To enable objective analysis of muscle gene expression profiles, we have defined nine biological networks whose coordination is critical to muscle function. We begin by describing the expression of proteins necessary for optimal neuromuscular junction function that results in the muscle cell action potential. That action potential is transmitted to proteins involved in excitation–contraction coupling enabling Ca2+ release. Ca2+ then activates contractile proteins supporting actin and myosin cross-bridge cycling. Force generated by cross-bridges is transmitted via cytoskeletal proteins through the sarcolemma and out to critical proteins that support the muscle extracellular matrix. Muscle contraction is fueled through many proteins that regulate energy metabolism. Inflammation is a common response to injury that can result in alteration of many pathways within muscle. Muscle also has multiple pathways that regulate size through atrophy or hypertrophy. Finally, the isoforms associated with fast muscle fibers and their corresponding isoforms in slow muscle fibers are delineated. These nine networks represent important biological systems that affect skeletal muscle function. Combining high-throughput systems analysis with advanced networking software will allow researchers to use these networks to objectively study skeletal muscle systems. PMID:23188744

  16. Systems analysis of biological networks in skeletal muscle function.

    PubMed

    Smith, Lucas R; Meyer, Gretchen; Lieber, Richard L

    2013-01-01

    Skeletal muscle function depends on the efficient coordination among subcellular systems. These systems are composed of proteins encoded by a subset of genes, all of which are tightly regulated. In the cases where regulation is altered because of disease or injury, dysfunction occurs. To enable objective analysis of muscle gene expression profiles, we have defined nine biological networks whose coordination is critical to muscle function. We begin by describing the expression of proteins necessary for optimal neuromuscular junction function that results in the muscle cell action potential. That action potential is transmitted to proteins involved in excitation-contraction coupling enabling Ca(2+) release. Ca(2+) then activates contractile proteins supporting actin and myosin cross-bridge cycling. Force generated by cross-bridges is transmitted via cytoskeletal proteins through the sarcolemma and out to critical proteins that support the muscle extracellular matrix. Muscle contraction is fueled through many proteins that regulate energy metabolism. Inflammation is a common response to injury that can result in alteration of many pathways within muscle. Muscle also has multiple pathways that regulate size through atrophy or hypertrophy. Finally, the isoforms associated with fast muscle fibers and their corresponding isoforms in slow muscle fibers are delineated. These nine networks represent important biological systems that affect skeletal muscle function. Combining high-throughput systems analysis with advanced networking software will allow researchers to use these networks to objectively study skeletal muscle systems. PMID:23188744

  17. Minimum dominating set-based methods for analyzing biological networks.

    PubMed

    Nacher, Jose C; Akutsu, Tatsuya

    2016-06-01

    The fast increase of 'multi-omics' data does not only pose a computational challenge for its analysis but also requires novel algorithmic methodologies to identify complex biological patterns and decipher the ultimate roots of human disorders. To that end, the massive integration of omics data with disease phenotypes is offering a new window into the cell functionality. The minimum dominating set (MDS) approach has rapidly emerged as a promising algorithmic method to analyze complex biological networks integrated with human disorders, which can be composed of a variety of omics data, from proteomics and transcriptomics to metabolomics. Here we review the main theoretical foundations of the methodology and the key algorithms, and examine the recent applications in which biological systems are analyzed by using the MDS approach. PMID:26773457

  18. From biological neural networks to thinking machines: Transitioning biological organizational principles to computer technology

    NASA Technical Reports Server (NTRS)

    Ross, Muriel D.

    1991-01-01

    The three-dimensional organization of the vestibular macula is under study by computer assisted reconstruction and simulation methods as a model for more complex neural systems. One goal of this research is to transition knowledge of biological neural network architecture and functioning to computer technology, to contribute to the development of thinking computers. Maculas are organized as weighted neural networks for parallel distributed processing of information. The network is characterized by non-linearity of its terminal/receptive fields. Wiring appears to develop through constrained randomness. A further property is the presence of two main circuits, highly channeled and distributed modifying, that are connected through feedforward-feedback collaterals and biasing subcircuit. Computer simulations demonstrate that differences in geometry of the feedback (afferent) collaterals affects the timing and the magnitude of voltage changes delivered to the spike initiation zone. Feedforward (efferent) collaterals act as voltage followers and likely inhibit neurons of the distributed modifying circuit. These results illustrate the importance of feedforward-feedback loops, of timing, and of inhibition in refining neural network output. They also suggest that it is the distributed modifying network that is most involved in adaptation, memory, and learning. Tests of macular adaptation, through hyper- and microgravitational studies, support this hypothesis since synapses in the distributed modifying circuit, but not the channeled circuit, are altered. Transitioning knowledge of biological systems to computer technology, however, remains problematical.

  19. Biological Instability in a Chlorinated Drinking Water Distribution Network

    PubMed Central

    Nescerecka, Alina; Rubulis, Janis; Vital, Marius; Juhna, Talis; Hammes, Frederik

    2014-01-01

    The purpose of a drinking water distribution system is to deliver drinking water to the consumer, preferably with the same quality as when it left the treatment plant. In this context, the maintenance of good microbiological quality is often referred to as biological stability, and the addition of sufficient chlorine residuals is regarded as one way to achieve this. The full-scale drinking water distribution system of Riga (Latvia) was investigated with respect to biological stability in chlorinated drinking water. Flow cytometric (FCM) intact cell concentrations, intracellular adenosine tri-phosphate (ATP), heterotrophic plate counts and residual chlorine measurements were performed to evaluate the drinking water quality and stability at 49 sampling points throughout the distribution network. Cell viability methods were compared and the importance of extracellular ATP measurements was examined as well. FCM intact cell concentrations varied from 5×103 cells mL−1 to 4.66×105 cells mL−1 in the network. While this parameter did not exceed 2.1×104 cells mL−1 in the effluent from any water treatment plant, 50% of all the network samples contained more than 1.06×105 cells mL−1. This indisputably demonstrates biological instability in this particular drinking water distribution system, which was ascribed to a loss of disinfectant residuals and concomitant bacterial growth. The study highlights the potential of using cultivation-independent methods for the assessment of chlorinated water samples. In addition, it underlines the complexity of full-scale drinking water distribution systems, and the resulting challenges to establish the causes of biological instability. PMID:24796923

  20. PREFACE: Complex Networks: from Biology to Information Technology

    NASA Astrophysics Data System (ADS)

    Barrat, A.; Boccaletti, S.; Caldarelli, G.; Chessa, A.; Latora, V.; Motter, A. E.

    2008-06-01

    The field of complex networks is one of the most active areas in contemporary statistical physics. Ten years after seminal work initiated the modern study of networks, interest in the field is in fact still growing, as indicated by the ever increasing number of publications in network science. The reason for such a resounding success is most likely the simplicity and broad significance of the approach that, through graph theory, allows researchers to address a variety of different complex systems within a common framework. This special issue comprises a selection of contributions presented at the workshop 'Complex Networks: from Biology to Information Technology' held in July 2007 in Pula (Cagliari), Italy as a satellite of the general conference STATPHYS23. The contributions cover a wide range of problems that are currently among the most important questions in the area of complex networks and that are likely to stimulate future research. The issue is organised into four sections. The first two sections describe 'methods' to study the structure and the dynamics of complex networks, respectively. After this methodological part, the issue proceeds with a section on applications to biological systems. The issue closes with a section concentrating on applications to the study of social and technological networks. The first section, entitled Methods: The Structure, consists of six contributions focused on the characterisation and analysis of structural properties of complex networks: The paper Motif-based communities in complex networks by Arenas et al is a study of the occurrence of characteristic small subgraphs in complex networks. These subgraphs, known as motifs, are used to define general classes of nodes and their communities by extending the mathematical expression of the Newman-Girvan modularity. The same line of research, aimed at characterising network structure through the analysis of particular subgraphs, is explored by Bianconi and Gulbahce in Algorithm

  1. Predicting genetic interactions from Boolean models of biological networks.

    PubMed

    Calzone, Laurence; Barillot, Emmanuel; Zinovyev, Andrei

    2015-08-01

    Genetic interaction can be defined as a deviation of the phenotypic quantitative effect of a double gene mutation from the effect predicted from single mutations using a simple (e.g., multiplicative or linear additive) statistical model. Experimentally characterized genetic interaction networks in model organisms provide important insights into relationships between different biological functions. We describe a computational methodology allowing us to systematically and quantitatively characterize a Boolean mathematical model of a biological network in terms of genetic interactions between all loss of function and gain of function mutations with respect to all model phenotypes or outputs. We use the probabilistic framework defined in MaBoSS software, based on continuous time Markov chains and stochastic simulations. In addition, we suggest several computational tools for studying the distribution of double mutants in the space of model phenotype probabilities. We demonstrate this methodology on three published models for each of which we derive the genetic interaction networks and analyze their properties. We classify the obtained interactions according to their class of epistasis, dependence on the chosen initial conditions and the phenotype. The use of this methodology for validating mathematical models from experimental data and designing new experiments is discussed. PMID:25958956

  2. Competition for Catalytic Resources Alters Biological Network Dynamics

    NASA Astrophysics Data System (ADS)

    Rondelez, Yannick

    2012-01-01

    Genetic regulation networks orchestrate many complex cellular behaviors. Dynamic operations that take place within cells are thus dependent on the gene expression machinery, enabled by powerful enzymes such as polymerases, ribosomes, or nucleases. These generalist enzymes typically process many different substrates, potentially leading to competitive situations: by saturating the common enzyme, one substrate may down-regulate its competitors. However, most theoretical or experimental models simply omit these effects, focusing on the pattern of genetic regulatory interactions as the main determinant of network function. We show here that competition effects have important outcomes, which can be spotted within the global dynamics of experimental systems. Further we demonstrate that enzyme saturation creates a layer of cross couplings that may foster, but also hamper, the expected behavior of synthetic biology constructs.

  3. CellNet: Network Biology Applied to Stem Cell Engineering

    PubMed Central

    Cahan, Patrick; Li, Hu; Morris, Samantha A.; da Rocha, Edroaldo Lummertz; Daley, George Q.; Collins, James J.

    2014-01-01

    SUMMARY Somatic cell reprogramming, directed differentiation of pluripotent stem cells, and direct conversions between differentiated cell lineages represent powerful approaches to engineer cells for research and regenerative medicine. We have developed CellNet, a network biology platform that more accurately assesses the fidelity of cellular engineering than existing methodologies and generates hypotheses for improving cell derivations. Analyzing expression data from 56 published reports, we found that cells derived via directed differentiation more closely resemble their in vivo counterparts than products of direct conversion, as reflected by the establishment of target cell-type gene regulatory networks (GRNs). Furthermore, we discovered that directly converted cells fail to adequately silence expression programs of the starting population, and that the establishment of unintended GRNs is common to virtually every cellular engineering paradigm. CellNet provides a platform for quantifying how closely engineered cell populations resemble their target cell type and a rational strategy to guide enhanced cellular engineering. PMID:25126793

  4. Characterizing Loopy Biological Distribution Networks in Three Dimensions

    NASA Astrophysics Data System (ADS)

    Modes, Carl; Katifori, Eleni; Magnasco, Marcelo

    2014-03-01

    In order to develop useful predictive models for vascular or other biological distribution networks that include the effects of network architecture, development, and topology some set of tools must be chosen to characterize vasculature in a physically relevant, mathematically compact way. Few such tools are extant. To address this issue we have generalized the existing two dimensional leaf venation characterization to a fully three dimensional setting, from whence it may be brought to bear on many problems in human and mammalian vasculature, particularly where that vasculature is extremely complex, as in the organs. The new algorithm rests on the abstraction of the physical `tiling' from the two dimensional case to an effective, statistical tiling of an abstract surface that the network may be thought to sit in. Generically these abstract surfaces are richer than the flat plane and as a result there are now two families of fundamental units that may aggregate upon cutting weakest links - the plaquettes of the tiling and the longer `topological' cycles associated with the abstract surface. Upon sequential removal of these weakest links, two characterizing trees emerge that condense most of the relevant information from the full network.

  5. Algorithmic Perspectives of Network Transitive Reduction Problems and their Applications to Synthesis and Analysis of Biological Networks

    PubMed Central

    Aditya, Satabdi; DasGupta, Bhaskar; Karpinski, Marek

    2013-01-01

    In this survey paper, we will present a number of core algorithmic questions concerning several transitive reduction problems on network that have applications in network synthesis and analysis involving cellular processes. Our starting point will be the so-called minimum equivalent digraph problem, a classic computational problem in combinatorial algorithms. We will subsequently consider a few non-trivial extensions or generalizations of this problem motivated by applications in systems biology. We will then discuss the applications of these algorithmic methodologies in the context of three major biological research questions: synthesizing and simplifying signal transduction networks, analyzing disease networks, and measuring redundancy of biological networks. PMID:24833332

  6. Arena3D: visualization of biological networks in 3D

    PubMed Central

    Pavlopoulos, Georgios A; O'Donoghue, Seán I; Satagopam, Venkata P; Soldatos, Theodoros G; Pafilis, Evangelos; Schneider, Reinhard

    2008-01-01

    Background Complexity is a key problem when visualizing biological networks; as the number of entities increases, most graphical views become incomprehensible. Our goal is to enable many thousands of entities to be visualized meaningfully and with high performance. Results We present a new visualization tool, Arena3D, which introduces a new concept of staggered layers in 3D space. Related data – such as proteins, chemicals, or pathways – can be grouped onto separate layers and arranged via layout algorithms, such as Fruchterman-Reingold, distance geometry, and a novel hierarchical layout. Data on a layer can be clustered via k-means, affinity propagation, Markov clustering, neighbor joining, tree clustering, or UPGMA ('unweighted pair-group method with arithmetic mean'). A simple input format defines the name and URL for each node, and defines connections or similarity scores between pairs of nodes. The use of Arena3D is illustrated with datasets related to Huntington's disease. Conclusion Arena3D is a user friendly visualization tool that is able to visualize biological or any other network in 3D space. It is free for academic use and runs on any platform. It can be downloaded or lunched directly from . Java3D library and Java 1.5 need to be pre-installed for the software to run. PMID:19040715

  7. Network portal: a database for storage, analysis and visualization of biological networks

    PubMed Central

    Turkarslan, Serdar; Wurtmann, Elisabeth J.; Wu, Wei-Ju; Jiang, Ning; Bare, J. Christopher; Foley, Karen; Reiss, David J.; Novichkov, Pavel; Baliga, Nitin S.

    2014-01-01

    The ease of generating high-throughput data has enabled investigations into organismal complexity at the systems level through the inference of networks of interactions among the various cellular components (genes, RNAs, proteins and metabolites). The wider scientific community, however, currently has limited access to tools for network inference, visualization and analysis because these tasks often require advanced computational knowledge and expensive computing resources. We have designed the network portal (http://networks.systemsbiology.net) to serve as a modular database for the integration of user uploaded and public data, with inference algorithms and tools for the storage, visualization and analysis of biological networks. The portal is fully integrated into the Gaggle framework to seamlessly exchange data with desktop and web applications and to allow the user to create, save and modify workspaces, and it includes social networking capabilities for collaborative projects. While the current release of the database contains networks for 13 prokaryotic organisms from diverse phylogenetic clades (4678 co-regulated gene modules, 3466 regulators and 9291 cis-regulatory motifs), it will be rapidly populated with prokaryotic and eukaryotic organisms as relevant data become available in public repositories and through user input. The modular architecture, simple data formats and open API support community development of the portal. PMID:24271392

  8. Integrative Biology Identifies Shared Transcriptional Networks in CKD

    PubMed Central

    Martini, Sebastian; Nair, Viji; Keller, Benjamin J.; Eichinger, Felix; Hawkins, Jennifer J.; Randolph, Ann; Böger, Carsten A.; Gadegbeku, Crystal A.; Fox, Caroline S.; Cohen, Clemens D.

    2014-01-01

    A previous meta-analysis of genome-wide association data by the Cohorts for Heart and Aging Research in Genomic Epidemiology and CKDGen consortia identified 16 loci associated with eGFR. To define how each of these single-nucleotide polymorphisms (SNPs) could affect renal function, we integrated GFR-associated loci with regulatory pathways, producing a molecular map of CKD. In kidney biopsy specimens from 157 European subjects representing nine different CKDs, renal transcript levels for 18 genes in proximity to the SNPs significantly correlated with GFR. These 18 genes were mapped into their biologic context by testing coregulated transcripts for enriched pathways. A network of 97 pathways linked by shared genes was constructed and characterized. Of these pathways, 56 pathways were reported previously to be associated with CKD; 41 pathways without prior association with CKD were ranked on the basis of the number of candidate genes connected to the respective pathways. All pathways aggregated into a network of two main clusters comprising inflammation- and metabolism-related pathways, with the NRF2-mediated oxidative stress response pathway serving as the hub between the two clusters. In all, 78 pathways and 95% of the connections among those pathways were verified in an independent North American biopsy cohort. Disease-specific analyses showed that most pathways are shared between sets of three diseases, with closest interconnection between lupus nephritis, IgA nephritis, and diabetic nephropathy. Taken together, the network integrates candidate genes from genome-wide association studies into their functional context, revealing interactions and defining established and novel biologic mechanisms of renal impairment in renal diseases. PMID:24925724

  9. Community-Reviewed Biological Network Models for Toxicology and Drug Discovery Applications

    PubMed Central

    Namasivayam, Aishwarya Alex; Morales, Alejandro Ferreiro; Lacave, Ángela María Fajardo; Tallam, Aravind; Simovic, Borislav; Alfaro, David Garrido; Bobbili, Dheeraj Reddy; Martin, Florian; Androsova, Ganna; Shvydchenko, Irina; Park, Jennifer; Calvo, Jorge Val; Hoeng, Julia; Peitsch, Manuel C.; Racero, Manuel González Vélez; Biryukov, Maria; Talikka, Marja; Pérez, Modesto Berraquero; Rohatgi, Neha; Díaz-Díaz, Noberto; Mandarapu, Rajesh; Ruiz, Rubén Amián; Davidyan, Sergey; Narayanasamy, Shaman; Boué, Stéphanie; Guryanova, Svetlana; Arbas, Susana Martínez; Menon, Swapna; Xiang, Yang

    2016-01-01

    Biological network models offer a framework for understanding disease by describing the relationships between the mechanisms involved in the regulation of biological processes. Crowdsourcing can efficiently gather feedback from a wide audience with varying expertise. In the Network Verification Challenge, scientists verified and enhanced a set of 46 biological networks relevant to lung and chronic obstructive pulmonary disease. The networks were built using Biological Expression Language and contain detailed information for each node and edge, including supporting evidence from the literature. Network scoring of public transcriptomics data inferred perturbation of a subset of mechanisms and networks that matched the measured outcomes. These results, based on a computable network approach, can be used to identify novel mechanisms activated in disease, quantitatively compare different treatments and time points, and allow for assessment of data with low signal. These networks are periodically verified by the crowd to maintain an up-to-date suite of networks for toxicology and drug discovery applications. PMID:27429547

  10. Community-Reviewed Biological Network Models for Toxicology and Drug Discovery Applications.

    PubMed

    Namasivayam, Aishwarya Alex; Morales, Alejandro Ferreiro; Lacave, Ángela María Fajardo; Tallam, Aravind; Simovic, Borislav; Alfaro, David Garrido; Bobbili, Dheeraj Reddy; Martin, Florian; Androsova, Ganna; Shvydchenko, Irina; Park, Jennifer; Calvo, Jorge Val; Hoeng, Julia; Peitsch, Manuel C; Racero, Manuel González Vélez; Biryukov, Maria; Talikka, Marja; Pérez, Modesto Berraquero; Rohatgi, Neha; Díaz-Díaz, Noberto; Mandarapu, Rajesh; Ruiz, Rubén Amián; Davidyan, Sergey; Narayanasamy, Shaman; Boué, Stéphanie; Guryanova, Svetlana; Arbas, Susana Martínez; Menon, Swapna; Xiang, Yang

    2016-01-01

    Biological network models offer a framework for understanding disease by describing the relationships between the mechanisms involved in the regulation of biological processes. Crowdsourcing can efficiently gather feedback from a wide audience with varying expertise. In the Network Verification Challenge, scientists verified and enhanced a set of 46 biological networks relevant to lung and chronic obstructive pulmonary disease. The networks were built using Biological Expression Language and contain detailed information for each node and edge, including supporting evidence from the literature. Network scoring of public transcriptomics data inferred perturbation of a subset of mechanisms and networks that matched the measured outcomes. These results, based on a computable network approach, can be used to identify novel mechanisms activated in disease, quantitatively compare different treatments and time points, and allow for assessment of data with low signal. These networks are periodically verified by the crowd to maintain an up-to-date suite of networks for toxicology and drug discovery applications. PMID:27429547

  11. A network biology approach to denitrification in Pseudomonas aeruginosa

    DOE PAGESBeta

    Arat, Seda; Bullerjahn, George S.; Laubenbacher, Reinhard

    2015-02-23

    Pseudomonas aeruginosa is a metabolically flexible member of the Gammaproteobacteria. Under anaerobic conditions and the presence of nitrate, P. aeruginosa can perform (complete) denitrification, a respiratory process of dissimilatory nitrate reduction to nitrogen gas via nitrite (NO₂), nitric oxide (NO) and nitrous oxide (N₂O). This study focuses on understanding the influence of environmental conditions on bacterial denitrification performance, using a mathematical model of a metabolic network in P. aeruginosa. To our knowledge, this is the first mathematical model of denitrification for this bacterium. Analysis of the long-term behavior of the network under changing concentration levels of oxygen (O₂), nitrate (NO₃),more » and phosphate (PO₄) suggests that PO₄ concentration strongly affects denitrification performance. The model provides three predictions on denitrification activity of P. aeruginosa under various environmental conditions, and these predictions are either experimentally validated or supported by pertinent biological literature. One motivation for this study is to capture the effect of PO₄ on a denitrification metabolic network of P. aeruginosa in order to shed light on mechanisms for greenhouse gas N₂O accumulation during seasonal oxygen depletion in aquatic environments such as Lake Erie (Laurentian Great Lakes, USA). Simulating the microbial production of greenhouse gases in anaerobic aquatic systems such as Lake Erie allows a deeper understanding of the contributing environmental effects that will inform studies on, and remediation strategies for, other hypoxic sites worldwide.« less

  12. A Network Biology Approach to Denitrification in Pseudomonas aeruginosa

    PubMed Central

    Arat, Seda; Bullerjahn, George S.; Laubenbacher, Reinhard

    2015-01-01

    Pseudomonas aeruginosa is a metabolically flexible member of the Gammaproteobacteria. Under anaerobic conditions and the presence of nitrate, P. aeruginosa can perform (complete) denitrification, a respiratory process of dissimilatory nitrate reduction to nitrogen gas via nitrite (NO2), nitric oxide (NO) and nitrous oxide (N2O). This study focuses on understanding the influence of environmental conditions on bacterial denitrification performance, using a mathematical model of a metabolic network in P. aeruginosa. To our knowledge, this is the first mathematical model of denitrification for this bacterium. Analysis of the long-term behavior of the network under changing concentration levels of oxygen (O2), nitrate (NO3), and phosphate (PO4) suggests that PO4 concentration strongly affects denitrification performance. The model provides three predictions on denitrification activity of P. aeruginosa under various environmental conditions, and these predictions are either experimentally validated or supported by pertinent biological literature. One motivation for this study is to capture the effect of PO4 on a denitrification metabolic network of P. aeruginosa in order to shed light on mechanisms for greenhouse gas N2O accumulation during seasonal oxygen depletion in aquatic environments such as Lake Erie (Laurentian Great Lakes, USA). Simulating the microbial production of greenhouse gases in anaerobic aquatic systems such as Lake Erie allows a deeper understanding of the contributing environmental effects that will inform studies on, and remediation strategies for, other hypoxic sites worldwide. PMID:25706405

  13. A network biology approach to denitrification in Pseudomonas aeruginosa.

    PubMed

    Arat, Seda; Bullerjahn, George S; Laubenbacher, Reinhard

    2015-01-01

    Pseudomonas aeruginosa is a metabolically flexible member of the Gammaproteobacteria. Under anaerobic conditions and the presence of nitrate, P. aeruginosa can perform (complete) denitrification, a respiratory process of dissimilatory nitrate reduction to nitrogen gas via nitrite (NO2), nitric oxide (NO) and nitrous oxide (N2O). This study focuses on understanding the influence of environmental conditions on bacterial denitrification performance, using a mathematical model of a metabolic network in P. aeruginosa. To our knowledge, this is the first mathematical model of denitrification for this bacterium. Analysis of the long-term behavior of the network under changing concentration levels of oxygen (O2), nitrate (NO3), and phosphate (PO4) suggests that PO4 concentration strongly affects denitrification performance. The model provides three predictions on denitrification activity of P. aeruginosa under various environmental conditions, and these predictions are either experimentally validated or supported by pertinent biological literature. One motivation for this study is to capture the effect of PO4 on a denitrification metabolic network of P. aeruginosa in order to shed light on mechanisms for greenhouse gas N2O accumulation during seasonal oxygen depletion in aquatic environments such as Lake Erie (Laurentian Great Lakes, USA). Simulating the microbial production of greenhouse gases in anaerobic aquatic systems such as Lake Erie allows a deeper understanding of the contributing environmental effects that will inform studies on, and remediation strategies for, other hypoxic sites worldwide. PMID:25706405

  14. Alzheimer disease: modeling an Aβ-centered biological network.

    PubMed

    Campion, D; Pottier, C; Nicolas, G; Le Guennec, K; Rovelet-Lecrux, A

    2016-07-01

    In genetically complex diseases, the search for missing heritability is focusing on rare variants with large effect. Thanks to next generation sequencing technologies, genome-wide characterization of these variants is now feasible in every individual. However, a lesson from current studies is that collapsing rare variants at the gene level is often insufficient to obtain a statistically significant signal in case-control studies, and that network-based analyses are an attractive complement to classical approaches. In Alzheimer disease (AD), according to the prevalent amyloid cascade hypothesis, the pathology is driven by the amyloid beta (Aβ) peptide. In past years, based on experimental studies, several hundreds of proteins have been shown to interfere with Aβ production, clearance, aggregation or toxicity. Thanks to a manual curation of the literature, we identified 335 genes/proteins involved in this biological network and classified them according to their cellular function. The complete list of genes, or its subcomponents, will be of interest in ongoing AD genetic studies. PMID:27021818

  15. Biologically relevant neural network architectures for support vector machines.

    PubMed

    Jändel, Magnus

    2014-01-01

    Neural network architectures that implement support vector machines (SVM) are investigated for the purpose of modeling perceptual one-shot learning in biological organisms. A family of SVM algorithms including variants of maximum margin, 1-norm, 2-norm and ν-SVM is considered. SVM training rules adapted for neural computation are derived. It is found that competitive queuing memory (CQM) is ideal for storing and retrieving support vectors. Several different CQM-based neural architectures are examined for each SVM algorithm. Although most of the sixty-four scanned architectures are unconvincing for biological modeling four feasible candidates are found. The seemingly complex learning rule of a full ν-SVM implementation finds a particularly simple and natural implementation in bisymmetric architectures. Since CQM-like neural structures are thought to encode skilled action sequences and bisymmetry is ubiquitous in motor systems it is speculated that trainable pattern recognition in low-level perception has evolved as an internalized motor programme. PMID:24126252

  16. Managing biological networks by using text mining and computer-aided curation

    NASA Astrophysics Data System (ADS)

    Yu, Seok Jong; Cho, Yongseong; Lee, Min-Ho; Lim, Jongtae; Yoo, Jaesoo

    2015-11-01

    In order to understand a biological mechanism in a cell, a researcher should collect a huge number of protein interactions with experimental data from experiments and the literature. Text mining systems that extract biological interactions from papers have been used to construct biological networks for a few decades. Even though the text mining of literature is necessary to construct a biological network, few systems with a text mining tool are available for biologists who want to construct their own biological networks. We have developed a biological network construction system called BioKnowledge Viewer that can generate a biological interaction network by using a text mining tool and biological taggers. It also Boolean simulation software to provide a biological modeling system to simulate the model that is made with the text mining tool. A user can download PubMed articles and construct a biological network by using the Multi-level Knowledge Emergence Model (KMEM), MetaMap, and A Biomedical Named Entity Recognizer (ABNER) as a text mining tool. To evaluate the system, we constructed an aging-related biological network that consist 9,415 nodes (genes) by using manual curation. With network analysis, we found that several genes, including JNK, AP-1, and BCL-2, were highly related in aging biological network. We provide a semi-automatic curation environment so that users can obtain a graph database for managing text mining results that are generated in the server system and can navigate the network with BioKnowledge Viewer, which is freely available at http://bioknowledgeviewer.kisti.re.kr.

  17. Enhancement of COPD biological networks using a web-based collaboration interface.

    PubMed

    Boue, Stephanie; Fields, Brett; Hoeng, Julia; Park, Jennifer; Peitsch, Manuel C; Schlage, Walter K; Talikka, Marja; Binenbaum, Ilona; Bondarenko, Vladimir; Bulgakov, Oleg V; Cherkasova, Vera; Diaz-Diaz, Norberto; Fedorova, Larisa; Guryanova, Svetlana; Guzova, Julia; Igorevna Koroleva, Galina; Kozhemyakina, Elena; Kumar, Rahul; Lavid, Noa; Lu, Qingxian; Menon, Swapna; Ouliel, Yael; Peterson, Samantha C; Prokhorov, Alexander; Sanders, Edward; Schrier, Sarah; Schwaitzer Neta, Golan; Shvydchenko, Irina; Tallam, Aravind; Villa-Fombuena, Gema; Wu, John; Yudkevich, Ilya; Zelikman, Mariya

    2015-01-01

    The construction and application of biological network models is an approach that offers a holistic way to understand biological processes involved in disease. Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease of the airways for which therapeutic options currently are limited after diagnosis, even in its earliest stage. COPD network models are important tools to better understand the biological components and processes underlying initial disease development. With the increasing amounts of literature that are now available, crowdsourcing approaches offer new forms of collaboration for researchers to review biological findings, which can be applied to the construction and verification of complex biological networks. We report the construction of 50 biological network models relevant to lung biology and early COPD using an integrative systems biology and collaborative crowd-verification approach. By combining traditional literature curation with a data-driven approach that predicts molecular activities from transcriptomics data, we constructed an initial COPD network model set based on a previously published non-diseased lung-relevant model set. The crowd was given the opportunity to enhance and refine the networks on a website ( https://bionet.sbvimprover.com/) and to add mechanistic detail, as well as critically review existing evidence and evidence added by other users, so as to enhance the accuracy of the biological representation of the processes captured in the networks. Finally, scientists and experts in the field discussed and refined the networks during an in-person jamboree meeting. Here, we describe examples of the changes made to three of these networks: Neutrophil Signaling, Macrophage Signaling, and Th1-Th2 Signaling. We describe an innovative approach to biological network construction that combines literature and data mining and a crowdsourcing approach to generate a comprehensive set of COPD-relevant models that can be

  18. Enhancement of COPD biological networks using a web-based collaboration interface

    PubMed Central

    Boue, Stephanie; Fields, Brett; Hoeng, Julia; Park, Jennifer; Peitsch, Manuel C.; Schlage, Walter K.; Talikka, Marja; Binenbaum, Ilona; Bondarenko, Vladimir; Bulgakov, Oleg V.; Cherkasova, Vera; Diaz-Diaz, Norberto; Fedorova, Larisa; Guryanova, Svetlana; Guzova, Julia; Igorevna Koroleva, Galina; Kozhemyakina, Elena; Kumar, Rahul; Lavid, Noa; Lu, Qingxian; Menon, Swapna; Ouliel, Yael; Peterson, Samantha C.; Prokhorov, Alexander; Sanders, Edward; Schrier, Sarah; Schwaitzer Neta, Golan; Shvydchenko, Irina; Tallam, Aravind; Villa-Fombuena, Gema; Wu, John; Yudkevich, Ilya; Zelikman, Mariya

    2015-01-01

    The construction and application of biological network models is an approach that offers a holistic way to understand biological processes involved in disease. Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease of the airways for which therapeutic options currently are limited after diagnosis, even in its earliest stage. COPD network models are important tools to better understand the biological components and processes underlying initial disease development. With the increasing amounts of literature that are now available, crowdsourcing approaches offer new forms of collaboration for researchers to review biological findings, which can be applied to the construction and verification of complex biological networks. We report the construction of 50 biological network models relevant to lung biology and early COPD using an integrative systems biology and collaborative crowd-verification approach. By combining traditional literature curation with a data-driven approach that predicts molecular activities from transcriptomics data, we constructed an initial COPD network model set based on a previously published non-diseased lung-relevant model set. The crowd was given the opportunity to enhance and refine the networks on a website ( https://bionet.sbvimprover.com/) and to add mechanistic detail, as well as critically review existing evidence and evidence added by other users, so as to enhance the accuracy of the biological representation of the processes captured in the networks. Finally, scientists and experts in the field discussed and refined the networks during an in-person jamboree meeting. Here, we describe examples of the changes made to three of these networks: Neutrophil Signaling, Macrophage Signaling, and Th1-Th2 Signaling. We describe an innovative approach to biological network construction that combines literature and data mining and a crowdsourcing approach to generate a comprehensive set of COPD-relevant models that can be

  19. Complex network problems in physics, computer science and biology

    NASA Astrophysics Data System (ADS)

    Cojocaru, Radu Ionut

    There is a close relation between physics and mathematics and the exchange of ideas between these two sciences are well established. However until few years ago there was no such a close relation between physics and computer science. Even more, only recently biologists started to use methods and tools from statistical physics in order to study the behavior of complex system. In this thesis we concentrate on applying and analyzing several methods borrowed from computer science to biology and also we use methods from statistical physics in solving hard problems from computer science. In recent years physicists have been interested in studying the behavior of complex networks. Physics is an experimental science in which theoretical predictions are compared to experiments. In this definition, the term prediction plays a very important role: although the system is complex, it is still possible to get predictions for its behavior, but these predictions are of a probabilistic nature. Spin glasses, lattice gases or the Potts model are a few examples of complex systems in physics. Spin glasses and many frustrated antiferromagnets map exactly to computer science problems in the NP-hard class defined in Chapter 1. In Chapter 1 we discuss a common result from artificial intelligence (AI) which shows that there are some problems which are NP-complete, with the implication that these problems are difficult to solve. We introduce a few well known hard problems from computer science (Satisfiability, Coloring, Vertex Cover together with Maximum Independent Set and Number Partitioning) and then discuss their mapping to problems from physics. In Chapter 2 we provide a short review of combinatorial optimization algorithms and their applications to ground state problems in disordered systems. We discuss the cavity method initially developed for studying the Sherrington-Kirkpatrick model of spin glasses. We extend this model to the study of a specific case of spin glass on the Bethe

  20. The redox biology network in cancer pathophysiology and therapeutics

    PubMed Central

    Manda, Gina; Isvoranu, Gheorghita; Comanescu, Maria Victoria; Manea, Adrian; Debelec Butuner, Bilge; Korkmaz, Kemal Sami

    2015-01-01

    The review pinpoints operational concepts related to the redox biology network applied to the pathophysiology and therapeutics of solid tumors. A sophisticated network of intrinsic and extrinsic cues, integrated in the tumor niche, drives tumorigenesis and tumor progression. Critical mutations and distorted redox signaling pathways orchestrate pathologic events inside cancer cells, resulting in resistance to stress and death signals, aberrant proliferation and efficient repair mechanisms. Additionally, the complex inter-cellular crosstalk within the tumor niche, mediated by cytokines, redox-sensitive danger signals (HMGB1) and exosomes, under the pressure of multiple stresses (oxidative, inflammatory, metabolic), greatly contributes to the malignant phenotype. The tumor-associated inflammatory stress and its suppressive action on the anti-tumor immune response are highlighted. We further emphasize that ROS may act either as supporter or enemy of cancer cells, depending on the context. Oxidative stress-based therapies, such as radiotherapy and photodynamic therapy, take advantage of the cytotoxic face of ROS for killing tumor cells by a non-physiologically sudden, localized and intense oxidative burst. The type of tumor cell death elicited by these therapies is discussed. Therapy outcome depends on the differential sensitivity to oxidative stress of particular tumor cells, such as cancer stem cells, and therefore co-therapies that transiently down-regulate their intrinsic antioxidant system hold great promise. We draw attention on the consequences of the damage signals delivered by oxidative stress-injured cells to neighboring and distant cells, and emphasize the benefits of therapeutically triggered immunologic cell death in metastatic cancer. An integrative approach should be applied when designing therapeutic strategies in cancer, taking into consideration the mutational, metabolic, inflammatory and oxidative status of tumor cells, cellular heterogeneity and the

  1. Wireless address event representation system for biological sensor networks

    NASA Astrophysics Data System (ADS)

    Folowosele, Fopefolu; Tapson, Jonathan; Etienne-Cummings, Ralph

    2007-05-01

    We describe wireless networking systems for close proximity biological sensors, as would be encountered in artificial skin. The sensors communicate to a "base station" that interprets the data and decodes its origin. Using a large bundle of ultra thin metal wires from the sensors to the "base station" introduces significant technological hurdles for both the construction and maintenance of the system. Fortunately, the Address Event Representation (AER) protocol provides an elegant and biomorphic method for transmitting many impulses (i.e. neural spikes) down a single wire/channel. However, AER does not communicate any sensory information within each spike, other that the address of the origination of the spike. Therefore, each sensor must provide a number of spikes to communicate its data, typically in the form of the inter-spike intervals or spike rate. Furthermore, complex circuitry is required to arbitrate access to the channel when multiple sensors communicate simultaneously, which results in spike delay. This error is exacerbated as the number of sensors per channel increases, mandating more channels and more wires. We contend that despite the effectiveness of the wire-based AER protocol, its natural evolution will be the wireless AER protocol. A wireless AER system: (1) does not require arbitration to handle multiple simultaneous access of the channel, (2) uses cross-correlation delay to encode sensor data in every spike (eliminating the error due to arbitration delay), and (3) can be reorganized and expanded with little consequence to the network. The system uses spread spectrum communications principles, implemented with a low-power integrate-and-fire neurons. This paper discusses the design, operation and capabilities of such a system. We show that integrate-and-fire neurons can be used to both decode the origination of each spike and extract the data contained within in. We also show that there are many technical obstacles to overcome before this version

  2. Optimization-based Inference for Temporally Evolving Networks with Applications in Biology

    PubMed Central

    Chang, Young Hwan; Gray, Joe

    2012-01-01

    Abstract The problem of identifying dynamics of biological networks is of critical importance in order to understand biological systems. In this article, we propose a data-driven inference scheme to identify temporally evolving network representations of genetic networks. In the formulation of the optimization problem, we use an adjacency map as a priori information and define a cost function that both drives the connectivity of the graph to match biological data as well as generates a sparse and robust network at corresponding time intervals. Through simulation studies of simple examples, it is shown that this optimization scheme can help capture the topological change of a biological signaling pathway, and furthermore, might help to understand the structure and dynamics of biological genetic networks. PMID:23210478

  3. A Unifying Mathematical Framework for Genetic Robustness, Environmental Robustness, Network Robustness and their Trade-offs on Phenotype Robustness in Biological Networks. Part III: Synthetic Gene Networks in Synthetic Biology

    PubMed Central

    Chen, Bor-Sen; Lin, Ying-Po

    2013-01-01

    Robust stabilization and environmental disturbance attenuation are ubiquitous systematic properties that are observed in biological systems at many different levels. The underlying principles for robust stabilization and environmental disturbance attenuation are universal to both complex biological systems and sophisticated engineering systems. In many biological networks, network robustness should be large enough to confer: intrinsic robustness for tolerating intrinsic parameter fluctuations; genetic robustness for buffering genetic variations; and environmental robustness for resisting environmental disturbances. Network robustness is needed so phenotype stability of biological network can be maintained, guaranteeing phenotype robustness. Synthetic biology is foreseen to have important applications in biotechnology and medicine; it is expected to contribute significantly to a better understanding of functioning of complex biological systems. This paper presents a unifying mathematical framework for investigating the principles of both robust stabilization and environmental disturbance attenuation for synthetic gene networks in synthetic biology. Further, from the unifying mathematical framework, we found that the phenotype robustness criterion for synthetic gene networks is the following: if intrinsic robustness + genetic robustness + environmental robustness ≦ network robustness, then the phenotype robustness can be maintained in spite of intrinsic parameter fluctuations, genetic variations, and environmental disturbances. Therefore, the trade-offs between intrinsic robustness, genetic robustness, environmental robustness, and network robustness in synthetic biology can also be investigated through corresponding phenotype robustness criteria from the systematic point of view. Finally, a robust synthetic design that involves network evolution algorithms with desired behavior under intrinsic parameter fluctuations, genetic variations, and environmental

  4. A Unifying Mathematical Framework for Genetic Robustness, Environmental Robustness, Network Robustness and their Trade-offs on Phenotype Robustness in Biological Networks. Part III: Synthetic Gene Networks in Synthetic Biology.

    PubMed

    Chen, Bor-Sen; Lin, Ying-Po

    2013-01-01

    Robust stabilization and environmental disturbance attenuation are ubiquitous systematic properties that are observed in biological systems at many different levels. The underlying principles for robust stabilization and environmental disturbance attenuation are universal to both complex biological systems and sophisticated engineering systems. In many biological networks, network robustness should be large enough to confer: intrinsic robustness for tolerating intrinsic parameter fluctuations; genetic robustness for buffering genetic variations; and environmental robustness for resisting environmental disturbances. Network robustness is needed so phenotype stability of biological network can be maintained, guaranteeing phenotype robustness. Synthetic biology is foreseen to have important applications in biotechnology and medicine; it is expected to contribute significantly to a better understanding of functioning of complex biological systems. This paper presents a unifying mathematical framework for investigating the principles of both robust stabilization and environmental disturbance attenuation for synthetic gene networks in synthetic biology. Further, from the unifying mathematical framework, we found that the phenotype robustness criterion for synthetic gene networks is the following: if intrinsic robustness + genetic robustness + environmental robustness ≦ network robustness, then the phenotype robustness can be maintained in spite of intrinsic parameter fluctuations, genetic variations, and environmental disturbances. Therefore, the trade-offs between intrinsic robustness, genetic robustness, environmental robustness, and network robustness in synthetic biology can also be investigated through corresponding phenotype robustness criteria from the systematic point of view. Finally, a robust synthetic design that involves network evolution algorithms with desired behavior under intrinsic parameter fluctuations, genetic variations, and environmental

  5. Exploratory Analysis of Biological Networks through Visualization, Clustering, and Functional Annotation in Cytoscape.

    PubMed

    Baryshnikova, Anastasia

    2016-01-01

    Biological networks define how genes, proteins, and other cellular components interact with one another to carry out specific functions, providing a scaffold for understanding cellular organization. Although in-depth network analysis requires advanced mathematical and computational knowledge, a preliminary visual exploration of biological networks is accessible to anyone with basic computer skills. Visualization of biological networks is used primarily to examine network topology, identify functional modules, and predict gene functions based on gene connectivity within the network. Networks are excellent at providing a bird's-eye view of data sets and have the power of illustrating complex ideas in simple and intuitive terms. In addition, they enable exploratory analysis and generation of new hypotheses, which can then be tested using rigorous statistical and experimental tools. This protocol describes a simple procedure for visualizing a biological network using the genetic interaction similarity network for Saccharomyces cerevisiae as an example. The visualization procedure described here relies on the open-source network visualization software Cytoscape and includes detailed instructions on formatting and loading the data, clustering networks, and overlaying functional annotations. PMID:26988373

  6. A Glimpse to Background and Characteristics of Major Molecular Biological Networks

    PubMed Central

    Altaf-Ul-Amin, Md.; Katsuragi, Tetsuo; Sato, Tetsuo; Kanaya, Shigehiko

    2015-01-01

    Recently, biology has become a data intensive science because of huge data sets produced by high throughput molecular biological experiments in diverse areas including the fields of genomics, transcriptomics, proteomics, and metabolomics. These huge datasets have paved the way for system-level analysis of the processes and subprocesses of the cell. For system-level understanding, initially the elements of a system are connected based on their mutual relations and a network is formed. Among omics researchers, construction and analysis of biological networks have become highly popular. In this review, we briefly discuss both the biological background and topological properties of major types of omics networks to facilitate a comprehensive understanding and to conceptualize the foundation of network biology. PMID:26491677

  7. Gene regulatory networks and the underlying biology of developmental toxicity

    EPA Science Inventory

    Embryonic cells are specified by large-scale networks of functionally linked regulatory genes. Knowledge of the relevant gene regulatory networks is essential for understanding phenotypic heterogeneity that emerges from disruption of molecular functions, cellular processes or sig...

  8. Network integration and graph analysis in mammalian molecular systems biology

    PubMed Central

    Ma'ayan, A.

    2009-01-01

    Abstraction of intracellular biomolecular interactions into networks is useful for data integration and graph analysis. Network analysis tools facilitate predictions of novel functions for proteins, prediction of functional interactions and identification of intracellular modules. These efforts are linked with drug and phenotype data to accelerate drug-target and biomarker discovery. This review highlights the currently available varieties of mammalian biomolecular networks, and surveys methods and tools to construct, compare, integrate, visualise and analyse such networks. PMID:19045817

  9. Community Structure Reveals Biologically Functional Modules in MEF2C Transcriptional Regulatory Network

    PubMed Central

    Alcalá-Corona, Sergio A.; Velázquez-Caldelas, Tadeo E.; Espinal-Enríquez, Jesús; Hernández-Lemus, Enrique

    2016-01-01

    Gene regulatory networks are useful to understand the activity behind the complex mechanisms in transcriptional regulation. A main goal in contemporary biology is using such networks to understand the systemic regulation of gene expression. In this work, we carried out a systematic study of a transcriptional regulatory network derived from a comprehensive selection of all potential transcription factor interactions downstream from MEF2C, a human transcription factor master regulator. By analyzing the connectivity structure of such network, we were able to find different biologically functional processes and specific biochemical pathways statistically enriched in communities of genes into the network, such processes are related to cell signaling, cell cycle and metabolism. In this way we further support the hypothesis that structural properties of biological networks encode an important part of their functional behavior in eukaryotic cells. PMID:27252657

  10. Pandora, a PAthway and Network DiscOveRy Approach based on common biological evidence

    PubMed Central

    Zhang, Kelvin Xi; Ouellette, B. F. Francis

    2010-01-01

    Motivation: Many biological phenomena involve extensive interactions between many of the biological pathways present in cells. However, extraction of all the inherent biological pathways remains a major challenge in systems biology. With the advent of high-throughput functional genomic techniques, it is now possible to infer biological pathways and pathway organization in a systematic way by integrating disparate biological information. Results: Here, we propose a novel integrated approach that uses network topology to predict biological pathways. We integrated four types of biological evidence (protein–protein interaction, genetic interaction, domain–domain interaction and semantic similarity of Gene Ontology terms) to generate a functionally associated network. This network was then used to develop a new pathway finding algorithm to predict biological pathways in yeast. Our approach discovered 195 biological pathways and 31 functionally redundant pathway pairs in yeast. By comparing our identified pathways to three public pathway databases (KEGG, BioCyc and Reactome), we observed that our approach achieves a maximum positive predictive value of 12.8% and improves on other predictive approaches. This study allows us to reconstruct biological pathways and delineates cellular machinery in a systematic view. Availability: The method has been implemented in Perl and is available for downloading from http://www.oicr.on.ca/research/ouellette/pandora. It is distributed under the terms of GPL (http://opensource.org/licenses/gpl-2.0.php) Contact: francis@oicr.on.ca Supplementary information: Supplementary data are available at Bioinformatics online. PMID:20031970

  11. Robustness of the p53 network and biological hackers.

    PubMed

    Dartnell, Lewis; Simeonidis, Evangelos; Hubank, Michael; Tsoka, Sophia; Bogle, I David L; Papageorgiou, Lazaros G

    2005-06-01

    The p53 protein interaction network is crucial in regulating the metazoan cell cycle and apoptosis. Here, the robustness of the p53 network is studied by analyzing its degeneration under two modes of attack. Linear Programming is used to calculate average path lengths among proteins and the network diameter as measures of functionality. The p53 network is found to be robust to random loss of nodes, but vulnerable to a targeted attack against its hubs, as a result of its architecture. The significance of the results is considered with respect to mutational knockouts of proteins and the directed attacks mounted by tumour inducing viruses. PMID:15896791

  12. Modeling Reactivity to Biological Macromolecules with a Deep Multitask Network.

    PubMed

    Hughes, Tyler B; Dang, Na Le; Miller, Grover P; Swamidass, S Joshua

    2016-08-24

    Most small-molecule drug candidates fail before entering the market, frequently because of unexpected toxicity. Often, toxicity is detected only late in drug development, because many types of toxicities, especially idiosyncratic adverse drug reactions (IADRs), are particularly hard to predict and detect. Moreover, drug-induced liver injury (DILI) is the most frequent reason drugs are withdrawn from the market and causes 50% of acute liver failure cases in the United States. A common mechanism often underlies many types of drug toxicities, including both DILI and IADRs. Drugs are bioactivated by drug-metabolizing enzymes into reactive metabolites, which then conjugate to sites in proteins or DNA to form adducts. DNA adducts are often mutagenic and may alter the reading and copying of genes and their regulatory elements, causing gene dysregulation and even triggering cancer. Similarly, protein adducts can disrupt their normal biological functions and induce harmful immune responses. Unfortunately, reactive metabolites are not reliably detected by experiments, and it is also expensive to test drug candidates for potential to form DNA or protein adducts during the early stages of drug development. In contrast, computational methods have the potential to quickly screen for covalent binding potential, thereby flagging problematic molecules and reducing the total number of necessary experiments. Here, we train a deep convolution neural network-the XenoSite reactivity model-using literature data to accurately predict both sites and probability of reactivity for molecules with glutathione, cyanide, protein, and DNA. On the site level, cross-validated predictions had area under the curve (AUC) performances of 89.8% for DNA and 94.4% for protein. Furthermore, the model separated molecules electrophilically reactive with DNA and protein from nonreactive molecules with cross-validated AUC performances of 78.7% and 79.8%, respectively. On both the site- and molecule-level, the

  13. Why network approach can promote a new way of thinking in biology

    PubMed Central

    Giuliani, Alessandro; Filippi, Simonetta; Bertolaso, Marta

    2014-01-01

    This work deals with the particular nature of network-based approach in biology. We will comment about the shift from the consideration of the molecular layer as the definitive place where causative process start to the elucidation of the among elements (at any level of biological organization they are located) interaction network as the main goal of scientific explanation. This shift comes from the intrinsic nature of networks where the properties of a specific node are determined by its position in the entire network (top-down explanation) while the global network characteristics emerge from the nodes wiring pattern (bottom-up explanation). This promotes a “middle-out” paradigm formally identical to the time honored chemical thought holding big promises in the study of biological regulation. PMID:24782892

  14. Commentary: Biochemistry and Molecular Biology Educators Launch National Network

    ERIC Educational Resources Information Center

    Bailey, Cheryl; Bell, Ellis; Johnson, Margaret; Mattos, Carla; Sears, Duane; White, Harold B.

    2010-01-01

    The American Society of Biochemistry and Molecular Biology (ASBMB) has launched an National Science Foundation (NSF)-funded 5 year project to support biochemistry and molecular biology educators learning what and how students learn. As a part of this initiative, hundreds of life scientists will plan and develop a rich central resource for…

  15. A Unifying Mathematical Framework for Genetic Robustness, Environmental Robustness, Network Robustness and their Trade-off on Phenotype Robustness in Biological Networks Part I: Gene Regulatory Networks in Systems and Evolutionary Biology

    PubMed Central

    Chen, Bor-Sen; Lin, Ying-Po

    2013-01-01

    Robust stabilization and environmental disturbance attenuation are ubiquitous systematic properties observed in biological systems at different levels. The underlying principles for robust stabilization and environmental disturbance attenuation are universal to both complex biological systems and sophisticated engineering systems. In many biological networks, network robustness should be enough to confer intrinsic robustness in order to tolerate intrinsic parameter fluctuations, genetic robustness for buffering genetic variations, and environmental robustness for resisting environmental disturbances. With this, the phenotypic stability of biological network can be maintained, thus guaranteeing phenotype robustness. This paper presents a survey on biological systems and then develops a unifying mathematical framework for investigating the principles of both robust stabilization and environmental disturbance attenuation in systems and evolutionary biology. Further, from the unifying mathematical framework, it was discovered that the phenotype robustness criterion for biological networks at different levels relies upon intrinsic robustness + genetic robustness + environmental robustness ≦ network robustness. When this is true, the phenotype robustness can be maintained in spite of intrinsic parameter fluctuations, genetic variations, and environmental disturbances. Therefore, the trade-offs between intrinsic robustness, genetic robustness, environmental robustness, and network robustness in systems and evolutionary biology can also be investigated through their corresponding phenotype robustness criterion from the systematic point of view. PMID:23515240

  16. A Unifying Mathematical Framework for Genetic Robustness, Environmental Robustness, Network Robustness and their Trade-off on Phenotype Robustness in Biological Networks Part I: Gene Regulatory Networks in Systems and Evolutionary Biology.

    PubMed

    Chen, Bor-Sen; Lin, Ying-Po

    2013-01-01

    Robust stabilization and environmental disturbance attenuation are ubiquitous systematic properties observed in biological systems at different levels. The underlying principles for robust stabilization and environmental disturbance attenuation are universal to both complex biological systems and sophisticated engineering systems. In many biological networks, network robustness should be enough to confer intrinsic robustness in order to tolerate intrinsic parameter fluctuations, genetic robustness for buffering genetic variations, and environmental robustness for resisting environmental disturbances. With this, the phenotypic stability of biological network can be maintained, thus guaranteeing phenotype robustness. This paper presents a survey on biological systems and then develops a unifying mathematical framework for investigating the principles of both robust stabilization and environmental disturbance attenuation in systems and evolutionary biology. Further, from the unifying mathematical framework, it was discovered that the phenotype robustness criterion for biological networks at different levels relies upon intrinsic robustness + genetic robustness + environmental robustness ≦ network robustness. When this is true, the phenotype robustness can be maintained in spite of intrinsic parameter fluctuations, genetic variations, and environmental disturbances. Therefore, the trade-offs between intrinsic robustness, genetic robustness, environmental robustness, and network robustness in systems and evolutionary biology can also be investigated through their corresponding phenotype robustness criterion from the systematic point of view. PMID:23515240

  17. Inference, simulation, modeling, and analysis of complex networks, with special emphasis on complex networks in systems biology

    NASA Astrophysics Data System (ADS)

    Christensen, Claire Petra

    Across diverse fields ranging from physics to biology, sociology, and economics, the technological advances of the past decade have engendered an unprecedented explosion of data on highly complex systems with thousands, if not millions of interacting components. These systems exist at many scales of size and complexity, and it is becoming ever-more apparent that they are, in fact, universal, arising in every field of study. Moreover, they share fundamental properties---chief among these, that the individual interactions of their constituent parts may be well-understood, but the characteristic behaviour produced by the confluence of these interactions---by these complex networks---is unpredictable; in a nutshell, the whole is more than the sum of its parts. There is, perhaps, no better illustration of this concept than the discoveries being made regarding complex networks in the biological sciences. In particular, though the sequencing of the human genome in 2003 was a remarkable feat, scientists understand that the "cellular-level blueprints" for the human being are cellular-level parts lists, but they say nothing (explicitly) about cellular-level processes. The challenge of modern molecular biology is to understand these processes in terms of the networks of parts---in terms of the interactions among proteins, enzymes, genes, and metabolites---as it is these processes that ultimately differentiate animate from inanimate, giving rise to life! It is the goal of systems biology---an umbrella field encapsulating everything from molecular biology to epidemiology in social systems---to understand processes in terms of fundamental networks of core biological parts, be they proteins or people. By virtue of the fact that there are literally countless complex systems, not to mention tools and techniques used to infer, simulate, analyze, and model these systems, it is impossible to give a truly comprehensive account of the history and study of complex systems. The author

  18. Laser diagnostics of anisotropy in birefringent networks of biological tissues in different physiological conditions

    SciTech Connect

    Ushenko, Yu A; Tomka, Yu Ya; Dubolazov, A V

    2011-02-28

    We study the possibility of differentiation of optical anisotropy properties of biological tissues in different physiological conditions by means of statistical analysis of coordinate distributions of a new analytic parameter, namely, the complex degree of mutual anisotropy of extracellular matrix, formed by a network of birefringent filament-like protein crystals. (laser biology)

  19. Parenclitic networks: uncovering new functions in biological data

    NASA Astrophysics Data System (ADS)

    Zanin, Massimiliano; Alcazar, Joaquín Medina; Carbajosa, Jesus Vicente; Paez, Marcela Gomez; Papo, David; Sousa, Pedro; Menasalvas, Ernestina; Boccaletti, Stefano

    2014-05-01

    We introduce a novel method to represent time independent, scalar data sets as complex networks. We apply our method to investigate gene expression in the response to osmotic stress of Arabidopsis thaliana. In the proposed network representation, the most important genes for the plant response turn out to be the nodes with highest centrality in appropriately reconstructed networks. We also performed a target experiment, in which the predicted genes were artificially induced one by one, and the growth of the corresponding phenotypes compared to that of the wild-type. The joint application of the network reconstruction method and of the in vivo experiments allowed identifying 15 previously unknown key genes, and provided models of their mutual relationships. This novel representation extends the use of graph theory to data sets hitherto considered outside of the realm of its application, vastly simplifying the characterization of their underlying structure.

  20. A biologically inspired neural network for dynamic programming.

    PubMed

    Francelin Romero, R A; Kacpryzk, J; Gomide, F

    2001-12-01

    An artificial neural network with a two-layer feedback topology and generalized recurrent neurons, for solving nonlinear discrete dynamic optimization problems, is developed. A direct method to assign the weights of neural networks is presented. The method is based on Bellmann's Optimality Principle and on the interchange of information which occurs during the synaptic chemical processing among neurons. The neural network based algorithm is an advantageous approach for dynamic programming due to the inherent parallelism of the neural networks; further it reduces the severity of computational problems that can occur in methods like conventional methods. Some illustrative application examples are presented to show how this approach works out including the shortest path and fuzzy decision making problems. PMID:11852439

  1. Blood flow in microvascular networks: A study in nonlinear biology

    PubMed Central

    Geddes, John B.; Carr, Russell T.; Wu, Fan; Lao, Yingyi; Maher, Meaghan

    2010-01-01

    Plasma skimming and the Fahraeus–Lindqvist effect are well-known phenomena in blood rheology. By combining these peculiarities of blood flow in the microcirculation with simple topological models of microvascular networks, we have uncovered interesting nonlinear behavior regarding blood flow in networks. Nonlinearity manifests itself in the existence of multiple steady states. This is due to the nonlinear dependence of viscosity on blood cell concentration. Nonlinearity also appears in the form of spontaneous oscillations in limit cycles. These limit cycles arise from the fact that the physics of blood flow can be modeled in terms of state dependent delay equations with multiple interacting delay times. In this paper we extend our previous work on blood flow in a simple two node network and begin to explore how topological complexity influences the dynamics of network blood flow. In addition we present initial evidence that the nonlinear phenomena predicted by our model are observed experimentally. PMID:21198135

  2. Using Network Biology to Bridge Pharmacokinetics and Pharmacodynamics in Oncology

    PubMed Central

    Kirouac, D C; Onsum, M D

    2013-01-01

    If mathematical modeling is to be used effectively in cancer drug development, future models must take into account both the mechanistic details of cellular signal transduction networks and the pharmacokinetics (PK) of drugs used to inhibit their oncogenic activity. In this perspective, we present an approach to building multiscale models that capture systems-level architectural features of oncogenic signaling networks, and describe how these models can be used to design combination therapies and identify predictive biomarkers in silico. PMID:24005988

  3. Pattern Learning, Damage and Repair within Biological Neural Networks

    NASA Astrophysics Data System (ADS)

    Siu, Theodore; Fitzgerald O'Neill, Kate; Shinbrot, Troy

    2015-03-01

    Traumatic brain injury (TBI) causes damage to neural networks, potentially leading to disability or even death. Nearly one in ten of these patients die, and most of the remainder suffer from symptoms ranging from headaches and nausea to convulsions and paralysis. In vitro studies to develop treatments for TBI have limited in vivo applicability, and in vitro therapies have even proven to worsen the outcome of TBI patients. We propose that this disconnect between in vitro and in vivo outcomes may be associated with the fact that in vitro tests assess indirect measures of neuronal health, but do not investigate the actual function of neuronal networks. Therefore in this talk, we examine both in vitro and in silico neuronal networks that actually perform a function: pattern identification. We allow the networks to execute genetic, Hebbian, learning, and additionally, we examine the effects of damage and subsequent repair within our networks. We show that the length of repaired connections affects the overall pattern learning performance of the network and we propose therapies that may improve function following TBI in clinical settings.

  4. Potential unsatisfiability of cyclic constraints on stochastic biological networks biases selection towards hierarchical architectures

    PubMed Central

    Smith, Cameron; Pechuan, Ximo; Puzio, Raymond S.; Biro, Daniel; Bergman, Aviv

    2015-01-01

    Constraints placed upon the phenotypes of organisms result from their interactions with the environment. Over evolutionary time scales, these constraints feed back onto smaller molecular subnetworks comprising the organism. The evolution of biological networks is studied by considering a network of a few nodes embedded in a larger context. Taking into account this fact that any network under study is actually embedded in a larger context, we define network architecture, not on the basis of physical interactions alone, but rather as a specification of the manner in which constraints are placed upon the states of its nodes. We show that such network architectures possessing cycles in their topology, in contrast to those that do not, may be subjected to unsatisfiable constraints. This may be a significant factor leading to selection biased against those network architectures where such inconsistent constraints are more likely to arise. We proceed to quantify the likelihood of inconsistency arising as a function of network architecture finding that, in the absence of sampling bias over the space of possible constraints and for a given network size, networks with a larger number of cycles are more likely to have unsatisfiable constraints placed upon them. Our results identify a constraint that, at least in isolation, would contribute to a bias in the evolutionary process towards more hierarchical -modular versus completely connected network architectures. Together, these results highlight the context dependence of the functionality of biological networks. PMID:26040595

  5. Characterization of Adaptation by Morphology in a Planar Biological Network of Plasmodial Slime Mold

    NASA Astrophysics Data System (ADS)

    Ito, Masateru; Okamoto, Riki; Takamatsu, Atsuko

    2011-07-01

    Growth processes of a planar biological network of plasmodium of a true slime mold, Physarum polycephalum, were analyzed quantitatively. The plasmodium forms a transportation network through which protoplasm conveys nutrients, oxygen, and cellular organelles similarly to blood in a mammalian vascular network. To analyze the network structure, vertices were defined at tube bifurcation points. Then edges were defined for the tubes connecting both end vertices. Morphological analysis was attempted along with conventional topological analysis, revealing that the growth process of the plasmodial network structure depends on environmental conditions. In an attractive condition, the network is a polygonal lattice with more than six edges per vertex at the early stage and the hexagonal lattice at a later stage. Through all growing stages, the tube structure was not highly developed but an unstructured protoplasmic thin sheet was dominantly formed. The network size is small. In contrast, in the repulsive condition, the network is a mixture of polygonal lattice and tree-graph. More specifically, the polygonal lattice has more than six edges per vertex in the early stage, then a tree-graph structure is added to the lattice network at a later stage. The thick tube structure was highly developed. The network size, in the meaning of Euclidean distance but not topological one, grows considerably. Finally, the biological meaning of the environment-dependent network structure in the plasmodium is discussed.

  6. System Review about Function Role of ESCC Driver Gene KDM6A by Network Biology Approach.

    PubMed

    Ran, Jihua; Li, Hui; Li, Huiwu

    2016-01-01

    Background. KDM6A (Lysine (K)-Specific Demethylase 6A) is the driver gene related to esophageal squamous cell carcinoma (ESCC). In order to provide more biological insights into KDM6A, in this paper, we treat PPI (protein-protein interaction) network derived from KDM6A as a conceptual framework and follow it to review its biological function. Method. We constructed a PPI network with Cytoscape software and performed clustering of network with Clust&See. Then, we evaluate the pathways, which are statistically involved in the network derived from KDM6A. Lastly, gene ontology analysis of clusters of genes in the network was conducted. Result. The network includes three clusters that consist of 74 nodes connected via 453 edges. Fifty-five pathways are statistically involved in the network and most of them are functionally related to the processes of cell cycle, gene expression, and carcinogenesis. The biology themes of clusters 1, 2, and 3 are chromatin modification, regulation of gene expression by transcription factor complex, and control of cell cycle, respectively. Conclusion. The PPI network presents a panoramic view which can facilitate for us to understand the function role of KDM6A. It is a helpful way by network approach to perform system review on a certain gene. PMID:27294188

  7. System Review about Function Role of ESCC Driver Gene KDM6A by Network Biology Approach

    PubMed Central

    Ran, Jihua; Li, Hui; Li, Huiwu

    2016-01-01

    Background. KDM6A (Lysine (K)-Specific Demethylase 6A) is the driver gene related to esophageal squamous cell carcinoma (ESCC). In order to provide more biological insights into KDM6A, in this paper, we treat PPI (protein-protein interaction) network derived from KDM6A as a conceptual framework and follow it to review its biological function. Method. We constructed a PPI network with Cytoscape software and performed clustering of network with Clust&See. Then, we evaluate the pathways, which are statistically involved in the network derived from KDM6A. Lastly, gene ontology analysis of clusters of genes in the network was conducted. Result. The network includes three clusters that consist of 74 nodes connected via 453 edges. Fifty-five pathways are statistically involved in the network and most of them are functionally related to the processes of cell cycle, gene expression, and carcinogenesis. The biology themes of clusters 1, 2, and 3 are chromatin modification, regulation of gene expression by transcription factor complex, and control of cell cycle, respectively. Conclusion. The PPI network presents a panoramic view which can facilitate for us to understand the function role of KDM6A. It is a helpful way by network approach to perform system review on a certain gene. PMID:27294188

  8. Information theory in systems biology. Part I: Gene regulatory and metabolic networks.

    PubMed

    Mousavian, Zaynab; Kavousi, Kaveh; Masoudi-Nejad, Ali

    2016-03-01

    "A Mathematical Theory of Communication", was published in 1948 by Claude Shannon to establish a framework that is now known as information theory. In recent decades, information theory has gained much attention in the area of systems biology. The aim of this paper is to provide a systematic review of those contributions that have applied information theory in inferring or understanding of biological systems. Based on the type of system components and the interactions between them, we classify the biological systems into 4 main classes: gene regulatory, metabolic, protein-protein interaction and signaling networks. In the first part of this review, we attempt to introduce most of the existing studies on two types of biological networks, including gene regulatory and metabolic networks, which are founded on the concepts of information theory. PMID:26701126

  9. Computation of the effective mechanical response of biological networks accounting for large configuration changes.

    PubMed

    El Nady, K; Ganghoffer, J F

    2016-05-01

    The asymptotic homogenization technique is involved to derive the effective elastic response of biological membranes viewed as repetitive beam networks. Thereby, a systematic methodology is established, allowing the prediction of the overall mechanical properties of biological membranes in the nonlinear regime, reflecting the influence of the geometrical and mechanical micro-parameters of the network structure on the overall response of the equivalent continuum. Biomembranes networks are classified based on nodal connectivity, so that we analyze in this work 3, 4 and 6-connectivity networks, which are representative of most biological networks. The individual filaments of the network are described as undulated beams prone to entropic elasticity, with tensile moduli determined from their persistence length. The effective micropolar continuum evaluated as a continuum substitute of the biological network has a kinematics reflecting the discrete network deformation modes, involving a nodal displacement and a microrotation. The statics involves the classical Cauchy stress and internal moments encapsulated into couple stresses, which develop internal work in duality to microcurvatures reflecting local network undulations. The relative ratio of the characteristic bending length of the effective micropolar continuum to the unit cell size determines the relevant choice of the equivalent medium. In most cases, the Cauchy continuum is sufficient to model biomembranes. The peptidoglycan network may exhibit a re-entrant hexagonal configuration due to thermal or pressure fluctuations, for which micropolar effects become important. The homogenized responses are in good agreement with FE simulations performed over the whole network. The predictive nature of the employed homogenization technique allows the identification of a strain energy density of a hyperelastic model, for the purpose of performing structural calculations of the shape evolutions of biomembranes. PMID:26541071

  10. The Stochastic Evolutionary Game for a Population of Biological Networks Under Natural Selection

    PubMed Central

    Chen, Bor-Sen; Ho, Shih-Ju

    2014-01-01

    In this study, a population of evolutionary biological networks is described by a stochastic dynamic system with intrinsic random parameter fluctuations due to genetic variations and external disturbances caused by environmental changes in the evolutionary process. Since information on environmental changes is unavailable and their occurrence is unpredictable, they can be considered as a game player with the potential to destroy phenotypic stability. The biological network needs to develop an evolutionary strategy to improve phenotypic stability as much as possible, so it can be considered as another game player in the evolutionary process, ie, a stochastic Nash game of minimizing the maximum network evolution level caused by the worst environmental disturbances. Based on the nonlinear stochastic evolutionary game strategy, we find that some genetic variations can be used in natural selection to construct negative feedback loops, efficiently improving network robustness. This provides larger genetic robustness as a buffer against neutral genetic variations, as well as larger environmental robustness to resist environmental disturbances and maintain a network phenotypic traits in the evolutionary process. In this situation, the robust phenotypic traits of stochastic biological networks can be more frequently selected by natural selection in evolution. However, if the harbored neutral genetic variations are accumulated to a sufficiently large degree, and environmental disturbances are strong enough that the network robustness can no longer confer enough genetic robustness and environmental robustness, then the phenotype robustness might break down. In this case, a network phenotypic trait may be pushed from one equilibrium point to another, changing the phenotypic trait and starting a new phase of network evolution through the hidden neutral genetic variations harbored in network robustness by adaptive evolution. Further, the proposed evolutionary game is extended to

  11. Logical Reduction of Biological Networks to Their Most Determinative Components.

    PubMed

    Matache, Mihaela T; Matache, Valentin

    2016-07-01

    Boolean networks have been widely used as models for gene regulatory networks, signal transduction networks, or neural networks, among many others. One of the main difficulties in analyzing the dynamics of a Boolean network and its sensitivity to perturbations or mutations is the fact that it grows exponentially with the number of nodes. Therefore, various approaches for simplifying the computations and reducing the network to a subset of relevant nodes have been proposed in the past few years. We consider a recently introduced method for reducing a Boolean network to its most determinative nodes that yield the highest information gain. The determinative power of a node is obtained by a summation of all mutual information quantities over all nodes having the chosen node as a common input, thus representing a measure of information gain obtained by the knowledge of the node under consideration. The determinative power of nodes has been considered in the literature under the assumption that the inputs are independent in which case one can use the Bahadur orthonormal basis. In this article, we relax that assumption and use a standard orthonormal basis instead. We use techniques of Hilbert space operators and harmonic analysis to generate formulas for the sensitivity to perturbations of nodes, quantified by the notions of influence, average sensitivity, and strength. Since we work on finite-dimensional spaces, our formulas and estimates can be and are formulated in plain matrix algebra terminology. We analyze the determinative power of nodes for a Boolean model of a signal transduction network of a generic fibroblast cell. We also show the similarities and differences induced by the alternative complete orthonormal basis used. Among the similarities, we mention the fact that the knowledge of the states of the most determinative nodes reduces the entropy or uncertainty of the overall network significantly. In a special case, we obtain a stronger result than in previous

  12. BinAligner: a heuristic method to align biological networks.

    PubMed

    Yang, Jialiang; Li, Jun; Grünewald, Stefan; Wan, Xiu-Feng

    2013-01-01

    The advances in high throughput omics technologies have made it possible to characterize molecular interactions within and across various species. Alignments and comparison of molecular networks across species will help detect orthologs and conserved functional modules and provide insights on the evolutionary relationships of the compared species. However, such analyses are not trivial due to the complexity of network and high computational cost. Here we develop a mixture of global and local algorithm, BinAligner, for network alignments. Based on the hypotheses that the similarity between two vertices across networks would be context dependent and that the information from the edges and the structures of subnetworks can be more informative than vertices alone, two scoring schema, 1-neighborhood subnetwork and graphlet, were introduced to derive the scoring matrices between networks, besides the commonly used scoring scheme from vertices. Then the alignment problem is formulated as an assignment problem, which is solved by the combinatorial optimization algorithm, such as the Hungarian method. The proposed algorithm was applied and validated in aligning the protein-protein interaction network of Kaposi's sarcoma associated herpesvirus (KSHV) and that of varicella zoster virus (VZV). Interestingly, we identified several putative functional orthologous proteins with similar functions but very low sequence similarity between the two viruses. For example, KSHV open reading frame 56 (ORF56) and VZV ORF55 are helicase-primase subunits with sequence identity 14.6%, and KSHV ORF75 and VZV ORF44 are tegument proteins with sequence identity 15.3%. These functional pairs can not be identified if one restricts the alignment into orthologous protein pairs. In addition, BinAligner identified a conserved pathway between two viruses, which consists of 7 orthologous protein pairs and these proteins are connected by conserved links. This pathway might be crucial for virus packing and

  13. Revealing gene regulation and association through biological networks

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This review had first summarized traditional methods used by plant breeders for genetic improvement, such as QTL analysis and transcriptomic analysis. With accumulating data, we can draw a network that comprises all possible links between members of a community, including protein–protein interaction...

  14. Biology Inspired Approach for Communal Behavior in Sensor Networks

    NASA Technical Reports Server (NTRS)

    Jones, Kennie H.; Lodding, Kenneth N.; Olariu, Stephan; Wilson, Larry; Xin, Chunsheng

    2006-01-01

    Research in wireless sensor network technology has exploded in the last decade. Promises of complex and ubiquitous control of the physical environment by these networks open avenues for new kinds of science and business. Due to the small size and low cost of sensor devices, visionaries promise systems enabled by deployment of massive numbers of sensors working in concert. Although the reduction in size has been phenomenal it results in severe limitations on the computing, communicating, and power capabilities of these devices. Under these constraints, research efforts have concentrated on developing techniques for performing relatively simple tasks with minimal energy expense assuming some form of centralized control. Unfortunately, centralized control does not scale to massive size networks and execution of simple tasks in sparsely populated networks will not lead to the sophisticated applications predicted. These must be enabled by new techniques dependent on local and autonomous cooperation between sensors to effect global functions. As a step in that direction, in this work we detail a technique whereby a large population of sensors can attain a global goal using only local information and by making only local decisions without any form of centralized control.

  15. Biological Networks Underlying Soybean Seed Oil Composition and Content

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soybean is the most important oil crop in the United States. Production of soybean seed oil requires coordinated expression of many biological components and pathways, which is further regulated by seed development and phyto-hormones. A new research project is initiated in my laboratory to delineat...

  16. BiNA: A Visual Analytics Tool for Biological Network Data

    PubMed Central

    Gerasch, Andreas; Faber, Daniel; Küntzer, Jan; Niermann, Peter; Kohlbacher, Oliver; Lenhof, Hans-Peter; Kaufmann, Michael

    2014-01-01

    Interactive visual analysis of biological high-throughput data in the context of the underlying networks is an essential task in modern biomedicine with applications ranging from metabolic engineering to personalized medicine. The complexity and heterogeneity of data sets require flexible software architectures for data analysis. Concise and easily readable graphical representation of data and interactive navigation of large data sets are essential in this context. We present BiNA - the Biological Network Analyzer - a flexible open-source software for analyzing and visualizing biological networks. Highly configurable visualization styles for regulatory and metabolic network data offer sophisticated drawings and intuitive navigation and exploration techniques using hierarchical graph concepts. The generic projection and analysis framework provides powerful functionalities for visual analyses of high-throughput omics data in the context of networks, in particular for the differential analysis and the analysis of time series data. A direct interface to an underlying data warehouse provides fast access to a wide range of semantically integrated biological network databases. A plugin system allows simple customization and integration of new analysis algorithms or visual representations. BiNA is available under the 3-clause BSD license at http://bina.unipax.info/. PMID:24551056

  17. AN INTEGRATED NETWORK APPROACH TO IDENTIFYING BIOLOGICAL PATHWAYS AND ENVIRONMENTAL EXPOSURE INTERACTIONS IN COMPLEX DISEASES

    PubMed Central

    DARABOS, CHRISTIAN; QIU, JINGYA; MOORE, JASON H.

    2015-01-01

    Complex diseases are the result of intricate interactions between genetic, epigenetic and environmental factors. In previous studies, we used epidemiological and genetic data linking environmental exposure or genetic variants to phenotypic disease to construct Human Phenotype Networks and separately analyze the effects of both environment and genetic factors on disease interactions. To better capture the intricacies of the interactions between environmental exposure and the biological pathways in complex disorders, we integrate both aspects into a single “tripartite” network. Despite extensive research, the mechanisms by which chemical agents disrupt biological pathways are still poorly understood. In this study, we use our integrated network model to identify specific biological pathway candidates possibly disrupted by environmental agents. We conjecture that a higher number of co-occurrences between an environmental substance and biological pathway pair can be associated with a higher likelihood that the substance is involved in disrupting that pathway. We validate our model by demonstrating its ability to detect known arsenic and signal transduction pathway interactions and speculate on candidate cell-cell junction organization pathways disrupted by cadmium. The validation was supported by distinct publications of cell biology and genetic studies that associated environmental exposure to pathway disruption. The integrated network approach is a novel method for detecting the biological effects of environmental exposures. A better understanding of the molecular processes associated with specific environmental exposures will help in developing targeted molecular therapies for patients who have been exposed to the toxicity of environmental chemicals. PMID:26776169

  18. Identifying common components across biological network graphs using a bipartite data model

    PubMed Central

    2014-01-01

    The GeneWeaver bipartite data model provides an efficient means to evaluate shared molecular components from sets derived across diverse species, disease states and biological processes. In order to adapt this model for examining related molecular components and biological networks, such as pathway or gene network data, we have developed a means to leverage the bipartite data structure to extract and analyze shared edges. Using the Pathway Commons database we demonstrate the ability to rapidly identify shared connected components among a diverse set of pathways. In addition, we illustrate how results from maximal bipartite discovery can be decomposed into hierarchical relationships, allowing shared pathway components to be mapped through various parent-child relationships to help visualization and discovery of emergent kernel driven relationships. Interrogating common relationships among biological networks and conventional GeneWeaver gene lists will increase functional specificity and reliability of the shared biological components. This approach enables self-organization of biological processes through shared biological networks. PMID:25374613

  19. Ordered cyclic motifs contribute to dynamic stability in biological and engineered networks

    PubMed Central

    Ma'ayan, Avi; Cecchi, Guillermo A.; Wagner, John; Rao, A. Ravi; Iyengar, Ravi; Stolovitzky, Gustavo

    2008-01-01

    Representation and analysis of complex biological and engineered systems as directed networks is useful for understanding their global structure/function organization. Enrichment of network motifs, which are over-represented subgraphs in real networks, can be used for topological analysis. Because counting network motifs is computationally expensive, only characterization of 3- to 5-node motifs has been previously reported. In this study we used a supercomputer to analyze cyclic motifs made of 3–20 nodes for 6 biological and 3 technological networks. Using tools from statistical physics, we developed a theoretical framework for characterizing the ensemble of cyclic motifs in real networks. We have identified a generic property of real complex networks, antiferromagnetic organization, which is characterized by minimal directional coherence of edges along cyclic subgraphs, such that consecutive links tend to have opposing direction. As a consequence, we find that the lack of directional coherence in cyclic motifs leads to depletion in feedback loops, where the number of nodes affected by feedback loops appears to be at a local minimum compared with surrogate shuffled networks. This topology provides more dynamic stability in large networks. PMID:19033453

  20. A swarm intelligence framework for reconstructing gene networks: searching for biologically plausible architectures.

    PubMed

    Kentzoglanakis, Kyriakos; Poole, Matthew

    2012-01-01

    In this paper, we investigate the problem of reverse engineering the topology of gene regulatory networks from temporal gene expression data. We adopt a computational intelligence approach comprising swarm intelligence techniques, namely particle swarm optimization (PSO) and ant colony optimization (ACO). In addition, the recurrent neural network (RNN) formalism is employed for modeling the dynamical behavior of gene regulatory systems. More specifically, ACO is used for searching the discrete space of network architectures and PSO for searching the corresponding continuous space of RNN model parameters. We propose a novel solution construction process in the context of ACO for generating biologically plausible candidate architectures. The objective is to concentrate the search effort into areas of the structure space that contain architectures which are feasible in terms of their topological resemblance to real-world networks. The proposed framework is initially applied to the reconstruction of a small artificial network that has previously been studied in the context of gene network reverse engineering. Subsequently, we consider an artificial data set with added noise for reconstructing a subnetwork of the genetic interaction network of S. cerevisiae (yeast). Finally, the framework is applied to a real-world data set for reverse engineering the SOS response system of the bacterium Escherichia coli. Results demonstrate the relative advantage of utilizing problem-specific knowledge regarding biologically plausible structural properties of gene networks over conducting a problem-agnostic search in the vast space of network architectures. PMID:21576756

  1. Biological Implications of Dynamical Phases in Non-equilibrium Networks

    NASA Astrophysics Data System (ADS)

    Murugan, Arvind; Vaikuntanathan, Suriyanarayanan

    2016-03-01

    Biology achieves novel functions like error correction, ultra-sensitivity and accurate concentration measurement at the expense of free energy through Maxwell Demon-like mechanisms. The design principles and free energy trade-offs have been studied for a variety of such mechanisms. In this review, we emphasize a perspective based on dynamical phases that can explain commonalities shared by these mechanisms. Dynamical phases are defined by typical trajectories executed by non-equilibrium systems in the space of internal states. We find that coexistence of dynamical phases can have dramatic consequences for function vs free energy cost trade-offs. Dynamical phases can also provide an intuitive picture of the design principles behind such biological Maxwell Demons.

  2. Detecting modules in biological networks by edge weight clustering and entropy significance

    PubMed Central

    Lecca, Paola; Re, Angela

    2015-01-01

    Detection of the modular structure of biological networks is of interest to researchers adopting a systems perspective for the analysis of omics data. Computational systems biology has provided a rich array of methods for network clustering. To date, the majority of approaches address this task through a network node classification based on topological or external quantifiable properties of network nodes. Conversely, numerical properties of network edges are underused, even though the information content which can be associated with network edges has augmented due to steady advances in molecular biology technology over the last decade. Properly accounting for network edges in the development of clustering approaches can become crucial to improve quantitative interpretation of omics data, finally resulting in more biologically plausible models. In this study, we present a novel technique for network module detection, named WG-Cluster (Weighted Graph CLUSTERing). WG-Cluster's notable features, compared to current approaches, lie in: (1) the simultaneous exploitation of network node and edge weights to improve the biological interpretability of the connected components detected, (2) the assessment of their statistical significance, and (3) the identification of emerging topological properties in the detected connected components. WG-Cluster utilizes three major steps: (i) an unsupervised version of k-means edge-based algorithm detects sub-graphs with similar edge weights, (ii) a fast-greedy algorithm detects connected components which are then scored and selected according to the statistical significance of their scores, and (iii) an analysis of the convolution between sub-graph mean edge weight and connected component score provides a summarizing view of the connected components. WG-Cluster can be applied to directed and undirected networks of different types of interacting entities and scales up to large omics data sets. Here, we show that WG-Cluster can be

  3. Detecting modules in biological networks by edge weight clustering and entropy significance.

    PubMed

    Lecca, Paola; Re, Angela

    2015-01-01

    Detection of the modular structure of biological networks is of interest to researchers adopting a systems perspective for the analysis of omics data. Computational systems biology has provided a rich array of methods for network clustering. To date, the majority of approaches address this task through a network node classification based on topological or external quantifiable properties of network nodes. Conversely, numerical properties of network edges are underused, even though the information content which can be associated with network edges has augmented due to steady advances in molecular biology technology over the last decade. Properly accounting for network edges in the development of clustering approaches can become crucial to improve quantitative interpretation of omics data, finally resulting in more biologically plausible models. In this study, we present a novel technique for network module detection, named WG-Cluster (Weighted Graph CLUSTERing). WG-Cluster's notable features, compared to current approaches, lie in: (1) the simultaneous exploitation of network node and edge weights to improve the biological interpretability of the connected components detected, (2) the assessment of their statistical significance, and (3) the identification of emerging topological properties in the detected connected components. WG-Cluster utilizes three major steps: (i) an unsupervised version of k-means edge-based algorithm detects sub-graphs with similar edge weights, (ii) a fast-greedy algorithm detects connected components which are then scored and selected according to the statistical significance of their scores, and (iii) an analysis of the convolution between sub-graph mean edge weight and connected component score provides a summarizing view of the connected components. WG-Cluster can be applied to directed and undirected networks of different types of interacting entities and scales up to large omics data sets. Here, we show that WG-Cluster can be

  4. Quantitative assessment of biological impact using transcriptomic data and mechanistic network models

    SciTech Connect

    Thomson, Ty M.; Sewer, Alain; Martin, Florian; Belcastro, Vincenzo; Frushour, Brian P.; Gebel, Stephan; Park, Jennifer; Schlage, Walter K.; Talikka, Marja; Vasilyev, Dmitry M.; Westra, Jurjen W.; Hoeng, Julia; Peitsch, Manuel C.

    2013-11-01

    Exposure to biologically active substances such as therapeutic drugs or environmental toxicants can impact biological systems at various levels, affecting individual molecules, signaling pathways, and overall cellular processes. The ability to derive mechanistic insights from the resulting system responses requires the integration of experimental measures with a priori knowledge about the system and the interacting molecules therein. We developed a novel systems biology-based methodology that leverages mechanistic network models and transcriptomic data to quantitatively assess the biological impact of exposures to active substances. Hierarchically organized network models were first constructed to provide a coherent framework for investigating the impact of exposures at the molecular, pathway and process levels. We then validated our methodology using novel and previously published experiments. For both in vitro systems with simple exposure and in vivo systems with complex exposures, our methodology was able to recapitulate known biological responses matching expected or measured phenotypes. In addition, the quantitative results were in agreement with experimental endpoint data for many of the mechanistic effects that were assessed, providing further objective confirmation of the approach. We conclude that our methodology evaluates the biological impact of exposures in an objective, systematic, and quantifiable manner, enabling the computation of a systems-wide and pan-mechanistic biological impact measure for a given active substance or mixture. Our results suggest that various fields of human disease research, from drug development to consumer product testing and environmental impact analysis, could benefit from using this methodology. - Highlights: • The impact of biologically active substances is quantified at multiple levels. • The systems-level impact integrates the perturbations of individual networks. • The networks capture the relationships between

  5. Information theory in systems biology. Part II: protein-protein interaction and signaling networks.

    PubMed

    Mousavian, Zaynab; Díaz, José; Masoudi-Nejad, Ali

    2016-03-01

    By the development of information theory in 1948 by Claude Shannon to address the problems in the field of data storage and data communication over (noisy) communication channel, it has been successfully applied in many other research areas such as bioinformatics and systems biology. In this manuscript, we attempt to review some of the existing literatures in systems biology, which are using the information theory measures in their calculations. As we have reviewed most of the existing information-theoretic methods in gene regulatory and metabolic networks in the first part of the review, so in the second part of our study, the application of information theory in other types of biological networks including protein-protein interaction and signaling networks will be surveyed. PMID:26691180

  6. Reverse engineering biological networks :applications in immune responses to bio-toxins.

    SciTech Connect

    Martino, Anthony A.; Sinclair, Michael B.; Davidson, George S.; Haaland, David Michael; Timlin, Jerilyn Ann; Thomas, Edward Victor; Slepoy, Alexander; Zhang, Zhaoduo; May, Elebeoba Eni; Martin, Shawn Bryan; Faulon, Jean-Loup Michel

    2005-12-01

    Our aim is to determine the network of events, or the regulatory network, that defines an immune response to a bio-toxin. As a model system, we are studying T cell regulatory network triggered through tyrosine kinase receptor activation using a combination of pathway stimulation and time-series microarray experiments. Our approach is composed of five steps (1) microarray experiments and data error analysis, (2) data clustering, (3) data smoothing and discretization, (4) network reverse engineering, and (5) network dynamics analysis and fingerprint identification. The technological outcome of this study is a suite of experimental protocols and computational tools that reverse engineer regulatory networks provided gene expression data. The practical biological outcome of this work is an immune response fingerprint in terms of gene expression levels. Inferring regulatory networks from microarray data is a new field of investigation that is no more than five years old. To the best of our knowledge, this work is the first attempt that integrates experiments, error analyses, data clustering, inference, and network analysis to solve a practical problem. Our systematic approach of counting, enumeration, and sampling networks matching experimental data is new to the field of network reverse engineering. The resulting mathematical analyses and computational tools lead to new results on their own and should be useful to others who analyze and infer networks.

  7. Investigating the Combinatory Effects of Biological Networks on Gene Co-expression

    PubMed Central

    Zhang, Cheng; Lee, Sunjae; Mardinoglu, Adil; Hua, Qiang

    2016-01-01

    Co-expressed genes often share similar functions, and gene co-expression networks have been widely used in studying the functionality of gene modules. Previous analysis indicated that genes are more likely to be co-expressed if they are either regulated by the same transcription factors, forming protein complexes or sharing similar topological properties in protein-protein interaction networks. Here, we reconstructed transcriptional regulatory and protein-protein networks for Saccharomyces cerevisiae using well-established databases, and we evaluated their co-expression activities using publically available gene expression data. Based on our network-dependent analysis, we found that genes that were co-regulated in the transcription regulatory networks and shared similar neighbors in the protein-protein networks were more likely to be co-expressed. Moreover, their biological functions were closely related. PMID:27445830

  8. 3-D components of a biological neural network visualized in computer generated imagery. II - Macular neural network organization

    NASA Technical Reports Server (NTRS)

    Ross, Muriel D.; Meyer, Glenn; Lam, Tony; Cutler, Lynn; Vaziri, Parshaw

    1990-01-01

    Computer-assisted reconstructions of small parts of the macular neural network show how the nerve terminals and receptive fields are organized in 3-dimensional space. This biological neural network is anatomically organized for parallel distributed processing of information. Processing appears to be more complex than in computer-based neural network, because spatiotemporal factors figure into synaptic weighting. Serial reconstruction data show anatomical arrangements which suggest that (1) assemblies of cells analyze and distribute information with inbuilt redundancy, to improve reliability; (2) feedforward/feedback loops provide the capacity for presynaptic modulation of output during processing; (3) constrained randomness in connectivities contributes to adaptability; and (4) local variations in network complexity permit differing analyses of incoming signals to take place simultaneously. The last inference suggests that there may be segregation of information flow to central stations subserving particular functions.

  9. Slow poisoning and destruction of networks: Edge proximity and its implications for biological and infrastructure networks

    NASA Astrophysics Data System (ADS)

    Banerjee, Soumya Jyoti; Sinha, Saptarshi; Roy, Soumen

    2015-02-01

    We propose a network metric, edge proximity, Pe, which demonstrates the importance of specific edges in a network, hitherto not captured by existing network metrics. The effects of removing edges with high Pe might initially seem inconspicuous but are eventually shown to be very harmful for networks. Compared to existing strategies, the removal of edges by Pe leads to a remarkable increase in the diameter and average shortest path length in undirected real and random networks till the first disconnection and well beyond. Pe can be consistently used to rupture the network into two nearly equal parts, thus presenting a very potent strategy to greatly harm a network. Targeting by Pe causes notable efficiency loss in U.S. and European power grid networks. Pe identifies proteins with essential cellular functions in protein-protein interaction networks. It pinpoints regulatory neural connections and important portions of the neural and brain networks, respectively. Energy flow interactions identified by Pe form the backbone of long food web chains. Finally, we scrutinize the potential of Pe in edge controllability dynamics of directed networks.

  10. The multiscale backbone of the human phenotype network based on biological pathways

    PubMed Central

    2014-01-01

    Background Networks are commonly used to represent and analyze large and complex systems of interacting elements. In systems biology, human disease networks show interactions between disorders sharing common genetic background. We built pathway-based human phenotype network (PHPN) of over 800 physical attributes, diseases, and behavioral traits; based on about 2,300 genes and 1,200 biological pathways. Using GWAS phenotype-to-genes associations, and pathway data from Reactome, we connect human traits based on the common patterns of human biological pathways, detecting more pleiotropic effects, and expanding previous studies from a gene-centric approach to that of shared cell-processes. Results The resulting network has a heavily right-skewed degree distribution, placing it in the scale-free region of the network topologies spectrum. We extract the multi-scale information backbone of the PHPN based on the local densities of the network and discarding weak connection. Using a standard community detection algorithm, we construct phenotype modules of similar traits without applying expert biological knowledge. These modules can be assimilated to the disease classes. However, we are able to classify phenotypes according to shared biology, and not arbitrary disease classes. We present examples of expected clinical connections identified by PHPN as proof of principle. Conclusions We unveil a previously uncharacterized connection between phenotype modules and discuss potential mechanistic connections that are obvious only in retrospect. The PHPN shows tremendous potential to become a useful tool both in the unveiling of the diseases’ common biology, and in the elaboration of diagnosis and treatments. PMID:24460644

  11. The BIOSCI electronic newsgroup network for the biological sciences. Final report, October 1, 1992--June 30, 1996

    SciTech Connect

    Kristofferson, D.; Mack, D.

    1996-10-01

    This is the final report for a DOE funded project on BIOSCI Electronic Newsgroup Network for the biological sciences. A usable network for scientific discussion, major announcements, problem solving, etc. has been created.

  12. Construction of biological networks from unstructured information based on a semi-automated curation workflow.

    PubMed

    Szostak, Justyna; Ansari, Sam; Madan, Sumit; Fluck, Juliane; Talikka, Marja; Iskandar, Anita; De Leon, Hector; Hofmann-Apitius, Martin; Peitsch, Manuel C; Hoeng, Julia

    2015-01-01

    Capture and representation of scientific knowledge in a structured format are essential to improve the understanding of biological mechanisms involved in complex diseases. Biological knowledge and knowledge about standardized terminologies are difficult to capture from literature in a usable form. A semi-automated knowledge extraction workflow is presented that was developed to allow users to extract causal and correlative relationships from scientific literature and to transcribe them into the computable and human readable Biological Expression Language (BEL). The workflow combines state-of-the-art linguistic tools for recognition of various entities and extraction of knowledge from literature sources. Unlike most other approaches, the workflow outputs the results to a curation interface for manual curation and converts them into BEL documents that can be compiled to form biological networks. We developed a new semi-automated knowledge extraction workflow that was designed to capture and organize scientific knowledge and reduce the required curation skills and effort for this task. The workflow was used to build a network that represents the cellular and molecular mechanisms implicated in atherosclerotic plaque destabilization in an apolipoprotein-E-deficient (ApoE(-/-)) mouse model. The network was generated using knowledge extracted from the primary literature. The resultant atherosclerotic plaque destabilization network contains 304 nodes and 743 edges supported by 33 PubMed referenced articles. A comparison between the semi-automated and conventional curation processes showed similar results, but significantly reduced curation effort for the semi-automated process. Creating structured knowledge from unstructured text is an important step for the mechanistic interpretation and reusability of knowledge. Our new semi-automated knowledge extraction workflow reduced the curation skills and effort required to capture and organize scientific knowledge. The

  13. Networking Biology: The Origins of Sequence-Sharing Practices in Genomics.

    PubMed

    Stevens, Hallam

    2015-10-01

    The wide sharing of biological data, especially nucleotide sequences, is now considered to be a key feature of genomics. Historians and sociologists have attempted to account for the rise of this sharing by pointing to precedents in model organism communities and in natural history. This article supplements these approaches by examining the role that electronic networking technologies played in generating the specific forms of sharing that emerged in genomics. The links between early computer users at the Stanford Artificial Intelligence Laboratory in the 1960s, biologists using local computer networks in the 1970s, and GenBank in the 1980s, show how networking technologies carried particular practices of communication, circulation, and data distribution from computing into biology. In particular, networking practices helped to transform sequences themselves into objects that had value as a community resource. PMID:26593711

  14. Automated selection of synthetic biology parts for genetic regulatory networks.

    PubMed

    Yaman, Fusun; Bhatia, Swapnil; Adler, Aaron; Densmore, Douglas; Beal, Jacob

    2012-08-17

    Raising the level of abstraction for synthetic biology design requires solving several challenging problems, including mapping abstract designs to DNA sequences. In this paper we present the first formalism and algorithms to address this problem. The key steps of this transformation are feature matching, signal matching, and part matching. Feature matching ensures that the mapping satisfies the regulatory relationships in the abstract design. Signal matching ensures that the expression levels of functional units are compatible. Finally, part matching finds a DNA part sequence that can implement the design. Our software tool MatchMaker implements these three steps. PMID:23651287

  15. Effects of cellular homeostatic intrinsic plasticity on dynamical and computational properties of biological recurrent neural networks.

    PubMed

    Naudé, Jérémie; Cessac, Bruno; Berry, Hugues; Delord, Bruno

    2013-09-18

    Homeostatic intrinsic plasticity (HIP) is a ubiquitous cellular mechanism regulating neuronal activity, cardinal for the proper functioning of nervous systems. In invertebrates, HIP is critical for orchestrating stereotyped activity patterns. The functional impact of HIP remains more obscure in vertebrate networks, where higher order cognitive processes rely on complex neural dynamics. The hypothesis has emerged that HIP might control the complexity of activity dynamics in recurrent networks, with important computational consequences. However, conflicting results about the causal relationships between cellular HIP, network dynamics, and computational performance have arisen from machine-learning studies. Here, we assess how cellular HIP effects translate into collective dynamics and computational properties in biological recurrent networks. We develop a realistic multiscale model including a generic HIP rule regulating the neuronal threshold with actual molecular signaling pathways kinetics, Dale's principle, sparse connectivity, synaptic balance, and Hebbian synaptic plasticity (SP). Dynamic mean-field analysis and simulations unravel that HIP sets a working point at which inputs are transduced by large derivative ranges of the transfer function. This cellular mechanism ensures increased network dynamics complexity, robust balance with SP at the edge of chaos, and improved input separability. Although critically dependent upon balanced excitatory and inhibitory drives, these effects display striking robustness to changes in network architecture, learning rates, and input features. Thus, the mechanism we unveil might represent a ubiquitous cellular basis for complex dynamics in neural networks. Understanding this robustness is an important challenge to unraveling principles underlying self-organization around criticality in biological recurrent neural networks. PMID:24048833

  16. CAUSAL INFERENCE IN BIOLOGY NETWORKS WITH INTEGRATED BELIEF PROPAGATION

    PubMed Central

    CHANG, RUI; KARR, JONATHAN R; SCHADT, ERIC E

    2014-01-01

    Inferring causal relationships among molecular and higher order phenotypes is a critical step in elucidating the complexity of living systems. Here we propose a novel method for inferring causality that is no longer constrained by the conditional dependency arguments that limit the ability of statistical causal inference methods to resolve causal relationships within sets of graphical models that are Markov equivalent. Our method utilizes Bayesian belief propagation to infer the responses of perturbation events on molecular traits given a hypothesized graph structure. A distance measure between the inferred response distribution and the observed data is defined to assess the ‘fitness’ of the hypothesized causal relationships. To test our algorithm, we infer causal relationships within equivalence classes of gene networks in which the form of the functional interactions that are possible are assumed to be nonlinear, given synthetic microarray and RNA sequencing data. We also apply our method to infer causality in real metabolic network with v-structure and feedback loop. We show that our method can recapitulate the causal structure and recover the feedback loop only from steady-state data which conventional method cannot. PMID:25592596

  17. FastGGM: An Efficient Algorithm for the Inference of Gaussian Graphical Model in Biological Networks.

    PubMed

    Wang, Ting; Ren, Zhao; Ding, Ying; Fang, Zhou; Sun, Zhe; MacDonald, Matthew L; Sweet, Robert A; Wang, Jieru; Chen, Wei

    2016-02-01

    Biological networks provide additional information for the analysis of human diseases, beyond the traditional analysis that focuses on single variables. Gaussian graphical model (GGM), a probability model that characterizes the conditional dependence structure of a set of random variables by a graph, has wide applications in the analysis of biological networks, such as inferring interaction or comparing differential networks. However, existing approaches are either not statistically rigorous or are inefficient for high-dimensional data that include tens of thousands of variables for making inference. In this study, we propose an efficient algorithm to implement the estimation of GGM and obtain p-value and confidence interval for each edge in the graph, based on a recent proposal by Ren et al., 2015. Through simulation studies, we demonstrate that the algorithm is faster by several orders of magnitude than the current implemented algorithm for Ren et al. without losing any accuracy. Then, we apply our algorithm to two real data sets: transcriptomic data from a study of childhood asthma and proteomic data from a study of Alzheimer's disease. We estimate the global gene or protein interaction networks for the disease and healthy samples. The resulting networks reveal interesting interactions and the differential networks between cases and controls show functional relevance to the diseases. In conclusion, we provide a computationally fast algorithm to implement a statistically sound procedure for constructing Gaussian graphical model and making inference with high-dimensional biological data. The algorithm has been implemented in an R package named "FastGGM". PMID:26872036

  18. Reducing complexity: An iterative strategy for parameter determination in biological networks

    NASA Astrophysics Data System (ADS)

    Binder, Sebastian C.; Hernandez-Vargas, Esteban A.; Meyer-Hermann, Michael

    2015-05-01

    The dynamics of biological networks are fundamental to a variety of processes in many areas of biology and medicine. Understanding of such networks on a systemic level is facilitated by mathematical models describing these networks. However, since mathematical models of signalling networks commonly aim to describe several highly connected biological quantities and many model parameters cannot be measured directly, quantitative dynamic models often present challenges with respect to model calibration. Here, we propose an iterative fitting routine to decompose the problem of fitting a system of coupled ordinary differential equations describing a signalling network into smaller subproblems. Parameters for each differential equation are estimated separately using a Differential Evolution algorithm while all other dynamic quantities in the model are treated as input to the system. The performance of this algorithm is evaluated on artificial networks with known structure and known model parameters and compared to a conventional optimisation procedure for the same problem. Our analysis indicates that the procedure results in a significantly higher quality of fit and more efficient reconstruction of the true parameters than the conventional algorithm.

  19. Data Integration through Proximity-Based Networks Provides Biological Principles of Organization across Scales[W

    PubMed Central

    Kleessen, Sabrina; Klie, Sebastian; Nikoloski, Zoran

    2013-01-01

    Plant behaviors across levels of cellular organization, from biochemical components to tissues and organs, relate and reflect growth habitats. Quantification of the relationship between behaviors captured in various phenotypic characteristics and growth habitats can help reveal molecular mechanisms of plant adaptation. The aim of this article is to introduce the power of using statistics originally developed in the field of geographic variability analysis together with prominent network models in elucidating principles of biological organization. We provide a critical systematic review of the existing statistical and network-based approaches that can be employed to determine patterns of covariation from both uni- and multivariate phenotypic characteristics in plants. We demonstrate that parameter-independent network-based approaches result in robust insights about phenotypic covariation. These insights can be quantified and tested by applying well-established statistics combining the network structure with the phenotypic characteristics. We show that the reviewed network-based approaches are applicable from the level of genes to the study of individuals in a population of Arabidopsis thaliana. Finally, we demonstrate that the patterns of covariation can be generalized to quantifiable biological principles of organization. Therefore, these network-based approaches facilitate not only interpretation of large-scale data sets, but also prediction of biochemical and biological behaviors based on measurable characteristics. PMID:23749845

  20. Systems Biology Approaches to the Study of Biological Networks Underlying Alzheimer's Disease: Role of miRNAs.

    PubMed

    Roth, Wera; Hecker, David; Fava, Eugenio

    2016-01-01

    MicroRNAs (miRNAs) are emerging as significant regulators of mRNA complexity in the human central nervous system (CNS) thereby controlling distinct gene expression profiles in a spatio-temporal manner during development, neuronal plasticity, aging and (age-related) neurodegeneration, including Alzheimer's disease (AD). Increasing effort is expended towards dissecting and deciphering the molecular and genetic mechanisms of neurobiological and pathological functions of these brain-enriched miRNAs. Along these lines, recent data pinpoint distinct miRNAs and miRNA networks being linked to APP splicing, processing and Aβ pathology (Lukiw et al., Front Genet 3:327, 2013), and furthermore, to the regulation of tau and its cellular subnetworks (Lau et al., EMBO Mol Med 5:1613, 2013), altogether underlying the onset and propagation of Alzheimer's disease. MicroRNA profiling studies in Alzheimer's disease suffer from poor consensus which is an acknowledged concern in the field, and constitutes one of the current technical challenges. Hence, a strong demand for experimental and computational systems biology approaches arises, to incorporate and integrate distinct levels of information and scientific knowledge into a complex system of miRNA networks in the context of the transcriptome, proteome and metabolome in a given cellular environment. Here, we will discuss the state-of-the-art technologies and computational approaches on hand that may lead to a deeper understanding of the complex biological networks underlying the pathogenesis of Alzheimer's disease. PMID:26235078

  1. ezBioNet: A modeling and simulation system for analyzing biological reaction networks

    NASA Astrophysics Data System (ADS)

    Yu, Seok Jong; Tung, Thai Quang; Park, Junho; Lim, Jongtae; Yoo, Jaesoo

    2012-10-01

    To achieve robustness against living environments, a living organism is composed of complicated regulatory mechanisms ranging from gene regulations to signal transduction. If such life phenomena are to be understand, an integrated analysis tool that should have modeling and simulation functions for biological reactions, as well as new experimental methods for measuring biological phenomena, is fundamentally required. We have designed and implemented modeling and simulation software (ezBioNet) for analyzing biological reaction networks. The software can simultaneously perform an integrated modeling of various responses occurring in cells, ranging from gene expressions to signaling processes. To support massive analysis of biological networks, we have constructed a server-side simulation system (VCellSim) that can perform ordinary differential equations (ODE) analysis, sensitivity analysis, and parameter estimates. ezBioNet integrates the BioModel database by connecting the european bioinformatics institute (EBI) servers through Web services APIs and supports the handling of systems biology markup language (SBML) files. In addition, we employed eclipse RCP (rich client platform) which is a powerful modularity framework allowing various functional expansions. ezBioNet is intended to be an easy-to-use modeling tool, as well as a simulation system, to understand the control mechanism by monitoring the change of each component in a biological network. A researcher may perform the kinetic modeling and execute the simulation. The simulation result can be managed and visualized on ezBioNet, which is freely available at http://ezbionet.cbnu.ac.kr.

  2. Automatic Compilation from High-Level Biologically-Oriented Programming Language to Genetic Regulatory Networks

    PubMed Central

    Beal, Jacob; Lu, Ting; Weiss, Ron

    2011-01-01

    Background The field of synthetic biology promises to revolutionize our ability to engineer biological systems, providing important benefits for a variety of applications. Recent advances in DNA synthesis and automated DNA assembly technologies suggest that it is now possible to construct synthetic systems of significant complexity. However, while a variety of novel genetic devices and small engineered gene networks have been successfully demonstrated, the regulatory complexity of synthetic systems that have been reported recently has somewhat plateaued due to a variety of factors, including the complexity of biology itself and the lag in our ability to design and optimize sophisticated biological circuitry. Methodology/Principal Findings To address the gap between DNA synthesis and circuit design capabilities, we present a platform that enables synthetic biologists to express desired behavior using a convenient high-level biologically-oriented programming language, Proto. The high level specification is compiled, using a regulatory motif based mechanism, to a gene network, optimized, and then converted to a computational simulation for numerical verification. Through several example programs we illustrate the automated process of biological system design with our platform, and show that our compiler optimizations can yield significant reductions in the number of genes () and latency of the optimized engineered gene networks. Conclusions/Significance Our platform provides a convenient and accessible tool for the automated design of sophisticated synthetic biological systems, bridging an important gap between DNA synthesis and circuit design capabilities. Our platform is user-friendly and features biologically relevant compiler optimizations, providing an important foundation for the development of sophisticated biological systems. PMID:21850228

  3. Inference, simulation, modeling, and analysis of complex networks, with special emphasis on complex networks in systems biology

    NASA Astrophysics Data System (ADS)

    Christensen, Claire Petra

    Across diverse fields ranging from physics to biology, sociology, and economics, the technological advances of the past decade have engendered an unprecedented explosion of data on highly complex systems with thousands, if not millions of interacting components. These systems exist at many scales of size and complexity, and it is becoming ever-more apparent that they are, in fact, universal, arising in every field of study. Moreover, they share fundamental properties---chief among these, that the individual interactions of their constituent parts may be well-understood, but the characteristic behaviour produced by the confluence of these interactions---by these complex networks---is unpredictable; in a nutshell, the whole is more than the sum of its parts. There is, perhaps, no better illustration of this concept than the discoveries being made regarding complex networks in the biological sciences. In particular, though the sequencing of the human genome in 2003 was a remarkable feat, scientists understand that the "cellular-level blueprints" for the human being are cellular-level parts lists, but they say nothing (explicitly) about cellular-level processes. The challenge of modern molecular biology is to understand these processes in terms of the networks of parts---in terms of the interactions among proteins, enzymes, genes, and metabolites---as it is these processes that ultimately differentiate animate from inanimate, giving rise to life! It is the goal of systems biology---an umbrella field encapsulating everything from molecular biology to epidemiology in social systems---to understand processes in terms of fundamental networks of core biological parts, be they proteins or people. By virtue of the fact that there are literally countless complex systems, not to mention tools and techniques used to infer, simulate, analyze, and model these systems, it is impossible to give a truly comprehensive account of the history and study of complex systems. The author

  4. Laser polarization fluorescence of the networks of optically anisotropic biological crystals

    NASA Astrophysics Data System (ADS)

    Ushenko, Y. A.; Dubolazov, A. V.; Angelsky, A. P.; Sidor, M. I.; Bodnar, G. B.; Koval, G.; Zabolotna, N. I.; Smolarz, A.; Junisbekov, M. Sh.

    2013-01-01

    The present work is devoted to investigation of mechanisms of optical anisotropy of biological tissues polycrystalline networks and laser polarization fluorescence. The model of complex optical anisotropy, which takes into account both linear and circular birefringence, as well as linear and circular dichroism of fibrillar networks of histological sections of women reproductive sphere is proposed. The data of statistical, correlation and fractal processing of coordinate distributions of laser polarization fluorescence is provided. The technique of azimuthally invariant Mueller-matrix mapping of laser polarization fluorescence of protein networks in the tasks of differentiation of benign and malignant tumors of uterus wall is elaborated.

  5. Customized care 2020: how medical sequencing and network biology will enable personalized medicine

    PubMed Central

    Arnaout, Ramy; Hill, Colin

    2009-01-01

    Applications of next-generation nucleic acid sequencing technologies will lead to the development of precision diagnostics that will, in turn, be a major technology enabler of precision medicine. Terabyte-scale, multidimensional data sets derived using these technologies will be used to reverse engineer the specific disease networks that underlie individual patients’ conditions. Modeling and simulation of these networks in the presence of virtual drugs, and combinations of drugs, will identify the most efficacious therapy for precision medicine and customized care. In coming years the practice of medicine will routinely employ network biology analytics supported by high-performance supercomputing. PMID:20948615

  6. A biologically inspired neural network controller for ballistic arm movements

    PubMed Central

    Bernabucci, Ivan; Conforto, Silvia; Capozza, Marco; Accornero, Neri; Schmid, Maurizio; D'Alessio, Tommaso

    2007-01-01

    Background In humans, the implementation of multijoint tasks of the arm implies a highly complex integration of sensory information, sensorimotor transformations and motor planning. Computational models can be profitably used to better understand the mechanisms sub-serving motor control, thus providing useful perspectives and investigating different control hypotheses. To this purpose, the use of Artificial Neural Networks has been proposed to represent and interpret the movement of upper limb. In this paper, a neural network approach to the modelling of the motor control of a human arm during planar ballistic movements is presented. Methods The developed system is composed of three main computational blocks: 1) a parallel distributed learning scheme that aims at simulating the internal inverse model in the trajectory formation process; 2) a pulse generator, which is responsible for the creation of muscular synergies; and 3) a limb model based on two joints (two degrees of freedom) and six muscle-like actuators, that can accommodate for the biomechanical parameters of the arm. The learning paradigm of the neural controller is based on a pure exploration of the working space with no feedback signal. Kinematics provided by the system have been compared with those obtained in literature from experimental data of humans. Results The model reproduces kinematics of arm movements, with bell-shaped wrist velocity profiles and approximately straight trajectories, and gives rise to the generation of synergies for the execution of movements. The model allows achieving amplitude and direction errors of respectively 0.52 cm and 0.2 radians. Curvature values are similar to those encountered in experimental measures with humans. The neural controller also manages environmental modifications such as the insertion of different force fields acting on the end-effector. Conclusion The proposed system has been shown to properly simulate the development of internal models and to control

  7. Discriminating Different Classes of Biological Networks by Analyzing the Graphs Spectra Distribution

    PubMed Central

    Takahashi, Daniel Yasumasa; Sato, João Ricardo; Ferreira, Carlos Eduardo; Fujita, André

    2012-01-01

    The brain's structural and functional systems, protein-protein interaction, and gene networks are examples of biological systems that share some features of complex networks, such as highly connected nodes, modularity, and small-world topology. Recent studies indicate that some pathologies present topological network alterations relative to norms seen in the general population. Therefore, methods to discriminate the processes that generate the different classes of networks (e.g., normal and disease) might be crucial for the diagnosis, prognosis, and treatment of the disease. It is known that several topological properties of a network (graph) can be described by the distribution of the spectrum of its adjacency matrix. Moreover, large networks generated by the same random process have the same spectrum distribution, allowing us to use it as a “fingerprint”. Based on this relationship, we introduce and propose the entropy of a graph spectrum to measure the “uncertainty” of a random graph and the Kullback-Leibler and Jensen-Shannon divergences between graph spectra to compare networks. We also introduce general methods for model selection and network model parameter estimation, as well as a statistical procedure to test the nullity of divergence between two classes of complex networks. Finally, we demonstrate the usefulness of the proposed methods by applying them to (1) protein-protein interaction networks of different species and (2) on networks derived from children diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) and typically developing children. We conclude that scale-free networks best describe all the protein-protein interactions. Also, we show that our proposed measures succeeded in the identification of topological changes in the network while other commonly used measures (number of edges, clustering coefficient, average path length) failed. PMID:23284629

  8. A systems approach to the biology of mood disorders through network analysis of candidate genes.

    PubMed

    Detera-Wadleigh, S D; Akula, N

    2011-05-01

    Meta analysis of association data of mood disorders has shown evidence for the role of particular genes in genetic risk. Integration of association data from meta analysis with differential expression data in brains of mood disorder patients could heighten the level of support for specific genes. To identify molecular mechanisms that may be disrupted in disease, a systems approach that involves analysis of biological networks created by these selected genes was employed.Interaction networks of hierarchical groupings of selected genes were generated using the Michigan Molecular Interactions (MiMI) software. Large networks were deconvoluted into subclusters of core complexes by using a community clustering program, GLay. Network nodes were functionally annotated in DAVID Bioinformatics Resource to identify enriched pathways and functional clusters. MAPK and beta adrenergic receptor signaling pathways were significantly enriched in the ANK3 and CACNA1C network. The PBRM1 network bolstered the enrichment of chromatin remodeling and transcription regulation functional clusters. Lowering the stringency for inclusion of other genes in network seeds increased network complexity and expanded the recruitment of enriched pathways to include signaling by neurotransmitter and hormone receptors, neurotrophin, ErbB and the cell cycle. We present a strategy to interrogate mechanisms in the cellular system that might be perturbed in disease. Network analysis of meta analysis- generated candidate genes that exhibited differential expression in mood disorder brains identified signaling pathways and functional clusters that may be involved in genetic risk for mood disorders. PMID:21547870

  9. Temporal Expression-based Analysis of Metabolism

    PubMed Central

    Segrè, Daniel

    2012-01-01

    Metabolic flux is frequently rerouted through cellular metabolism in response to dynamic changes in the intra- and extra-cellular environment. Capturing the mechanisms underlying these metabolic transitions in quantitative and predictive models is a prominent challenge in systems biology. Progress in this regard has been made by integrating high-throughput gene expression data into genome-scale stoichiometric models of metabolism. Here, we extend previous approaches to perform a Temporal Expression-based Analysis of Metabolism (TEAM). We apply TEAM to understanding the complex metabolic dynamics of the respiratorily versatile bacterium Shewanella oneidensis grown under aerobic, lactate-limited conditions. TEAM predicts temporal metabolic flux distributions using time-series gene expression data. Increased predictive power is achieved by supplementing these data with a large reference compendium of gene expression, which allows us to take into account the unique character of the distribution of expression of each individual gene. We further propose a straightforward method for studying the sensitivity of TEAM to changes in its fundamental free threshold parameter θ, and reveal that discrete zones of distinct metabolic behavior arise as this parameter is changed. By comparing the qualitative characteristics of these zones to additional experimental data, we are able to constrain the range of θ to a small, well-defined interval. In parallel, the sensitivity analysis reveals the inherently difficult nature of dynamic metabolic flux modeling: small errors early in the simulation propagate to relatively large changes later in the simulation. We expect that handling such “history-dependent” sensitivities will be a major challenge in the future development of dynamic metabolic-modeling techniques. PMID:23209390

  10. Biological network extraction from scientific literature: state of the art and challenges.

    PubMed

    Li, Chen; Liakata, Maria; Rebholz-Schuhmann, Dietrich

    2014-09-01

    Networks of molecular interactions explain complex biological processes, and all known information on molecular events is contained in a number of public repositories including the scientific literature. Metabolic and signalling pathways are often viewed separately, even though both types are composed of interactions involving proteins and other chemical entities. It is necessary to be able to combine data from all available resources to judge the functionality, complexity and completeness of any given network overall, but especially the full integration of relevant information from the scientific literature is still an ongoing and complex task. Currently, the text-mining research community is steadily moving towards processing the full body of the scientific literature by making use of rich linguistic features such as full text parsing, to extract biological interactions. The next step will be to combine these with information from scientific databases to support hypothesis generation for the discovery of new knowledge and the extension of biological networks. The generation of comprehensive networks requires technologies such as entity grounding, coordination resolution and co-reference resolution, which are not fully solved and are required to further improve the quality of results. Here, we analyse the state of the art for the extraction of network information from the scientific literature and the evaluation of extraction methods against reference corpora, discuss challenges involved and identify directions for future research. PMID:23434632

  11. Switch-like Transitions Insulate Network Motifs to Modularize Biological Networks.

    PubMed

    Atay, Oguzhan; Doncic, Andreas; Skotheim, Jan M

    2016-08-01

    Cellular decisions are made by complex networks that are difficult to analyze. Although it is common to analyze smaller sub-networks known as network motifs, it is unclear whether this is valid, because these motifs are embedded in complex larger networks. Here, we address the general question of modularity by examining the S. cerevisiae pheromone response. We demonstrate that the feedforward motif controlling the cell-cycle inhibitor Far1 is insulated from cell-cycle dynamics by the positive feedback switch that drives reentry to the cell cycle. Before cells switch on positive feedback, the feedforward motif model predicts the behavior of the larger network. Conversely, after the switch, the feedforward motif is dismantled and has no discernable effect on the cell cycle. When insulation is broken, the feedforward motif no longer predicts network behavior. This work illustrates how, despite the interconnectivity of networks, the activity of motifs can be insulated by switches that generate well-defined cellular states. PMID:27453443

  12. Constructing simple biological networks for understanding complex high-throughput data in plants.

    PubMed

    Moyano, Tomás C; Vidal, Elena A; Contreras-López, Orlando; Gutiérrez, Rodrigo A

    2015-01-01

    Technological advances in the last decade have enabled biologists to produce increasing amounts of information for the transcriptome, proteome, interactome, and other -omics data sets in many model organisms. A major challenge is integration and biological interpretation of these massive data sets in order to generate testable hypotheses about gene regulatory networks or molecular mechanisms that govern system behaviors. Constructing gene networks requires bioinformatics skills to adequately manage, integrate, analyze and productively use the data to generate biological insights. In this chapter, we provide detailed methods for users without prior knowledge of bioinformatics to construct gene networks and derive hypotheses that can be experimentally verified. Step-by-step instructions for acquiring, integrating, analyzing, and visualizing genome-wide data are provided for two widely used open source platforms, R and Cytoscape platforms. The examples provided are based on Arabidopsis data, but the protocols presented should be readily applicable to any organism for which similar data can be obtained. PMID:25757789

  13. Systems Biology Modeling of the Radiation Sensitivity Network: A Biomarker Discovery Platform

    PubMed Central

    Eschrich, Steven; Zhang, Hongling; Zhao, Haiyan; Boulware, David; Lee, Ji-Hyun; Bloom, Gregory; Torres-Roca, Javier F.

    2009-01-01

    Purpose The discovery of effective biomarkers is a fundamental goal of molecular medicine. Developing a systems-biology understanding of radiosensitivity can enhance our ability of identifying radiation-specific biomarkers. Methods and Materials Radiosensitivity, as represented by the Survival Fraction at 2 Gy (SF2) was modeled in 48 human cancer cell lines. We apply a linear regression algorithm that integrates gene expression with biological variables including: ras status (mut/wt), tissue of origin (TO) and p53 status (mut/wt). Results The biomarker discovery platform is a network representation of the top 500 genes identified by linear regression. This network was reduced to a 10-hub network that includes: c-Jun, HDAC1, RELA (p65 subunit of NFKB), PKC-beta, SUMO-1, c-Abl, STAT1, AR, CDK1 and IRF1. Nine targets associated with radiosensitization drugs link to the network, demonstrating clinical relevance. Furthermore, the model identifies four significant radiosensitivity clusters of terms and genes. Ras was a dominant variable in the analysis along with TO and their interaction with gene expression but not p53. Overrepresented biological pathways differed between clusters but included: DNA repair, cell cycle, apoptosis and metabolism. The c-Jun network hub was validated using a knockdown approach in 8 human cell lines representing lung, colon and breast cancers. Conclusions We developed a novel radiation-biomarker discovery platform using a systems biology modeling approach. We propose this platform will play a central role in the integration of biology into clinical radiation oncology practice. PMID:19735874

  14. The Structure of a Gene Co-Expression Network Reveals Biological Functions Underlying eQTLs

    PubMed Central

    Villa-Vialaneix, Nathalie; Liaubet, Laurence; Laurent, Thibault; Cherel, Pierre; Gamot, Adrien; SanCristobal, Magali

    2013-01-01

    What are the commonalities between genes, whose expression level is partially controlled by eQTL, especially with regard to biological functions? Moreover, how are these genes related to a phenotype of interest? These issues are particularly difficult to address when the genome annotation is incomplete, as is the case for mammalian species. Moreover, the direct link between gene expression and a phenotype of interest may be weak, and thus difficult to handle. In this framework, the use of a co-expression network has proven useful: it is a robust approach for modeling a complex system of genetic regulations, and to infer knowledge for yet unknown genes. In this article, a case study was conducted with a mammalian species. It showed that the use of a co-expression network based on partial correlation, combined with a relevant clustering of nodes, leads to an enrichment of biological functions of around 83%. Moreover, the use of a spatial statistics approach allowed us to superimpose additional information related to a phenotype; this lead to highlighting specific genes or gene clusters that are related to the network structure and the phenotype. Three main results are worth noting: first, key genes were highlighted as a potential focus for forthcoming biological experiments; second, a set of biological functions, which support a list of genes under partial eQTL control, was set up by an overview of the global structure of the gene expression network; third, pH was found correlated with gene clusters, and then with related biological functions, as a result of a spatial analysis of the network topology. PMID:23577081

  15. The structure of a gene co-expression network reveals biological functions underlying eQTLs.

    PubMed

    Villa-Vialaneix, Nathalie; Liaubet, Laurence; Laurent, Thibault; Cherel, Pierre; Gamot, Adrien; SanCristobal, Magali

    2013-01-01

    What are the commonalities between genes, whose expression level is partially controlled by eQTL, especially with regard to biological functions? Moreover, how are these genes related to a phenotype of interest? These issues are particularly difficult to address when the genome annotation is incomplete, as is the case for mammalian species. Moreover, the direct link between gene expression and a phenotype of interest may be weak, and thus difficult to handle. In this framework, the use of a co-expression network has proven useful: it is a robust approach for modeling a complex system of genetic regulations, and to infer knowledge for yet unknown genes. In this article, a case study was conducted with a mammalian species. It showed that the use of a co-expression network based on partial correlation, combined with a relevant clustering of nodes, leads to an enrichment of biological functions of around 83%. Moreover, the use of a spatial statistics approach allowed us to superimpose additional information related to a phenotype; this lead to highlighting specific genes or gene clusters that are related to the network structure and the phenotype. Three main results are worth noting: first, key genes were highlighted as a potential focus for forthcoming biological experiments; second, a set of biological functions, which support a list of genes under partial eQTL control, was set up by an overview of the global structure of the gene expression network; third, pH was found correlated with gene clusters, and then with related biological functions, as a result of a spatial analysis of the network topology. PMID:23577081

  16. Systems Biology Modeling of the Radiation Sensitivity Network: A Biomarker Discovery Platform

    SciTech Connect

    Eschrich, Steven; Zhang Hongling; Zhao Haiyan; Boulware, David; Lee, Ji-Hyun; Bloom, Gregory; Torres-Roca, Javier F.

    2009-10-01

    Purpose: The discovery of effective biomarkers is a fundamental goal of molecular medicine. Developing a systems-biology understanding of radiosensitivity can enhance our ability of identifying radiation-specific biomarkers. Methods and Materials: Radiosensitivity, as represented by the survival fraction at 2 Gy was modeled in 48 human cancer cell lines. We applied a linear regression algorithm that integrates gene expression with biological variables, including ras status (mut/wt), tissue of origin and p53 status (mut/wt). Results: The biomarker discovery platform is a network representation of the top 500 genes identified by linear regression analysis. This network was reduced to a 10-hub network that includes c-Jun, HDAC1, RELA (p65 subunit of NFKB), PKC-beta, SUMO-1, c-Abl, STAT1, AR, CDK1, and IRF1. Nine targets associated with radiosensitization drugs are linked to the network, demonstrating clinical relevance. Furthermore, the model identified four significant radiosensitivity clusters of terms and genes. Ras was a dominant variable in the analysis, as was the tissue of origin, and their interaction with gene expression but not p53. Overrepresented biological pathways differed between clusters but included DNA repair, cell cycle, apoptosis, and metabolism. The c-Jun network hub was validated using a knockdown approach in 8 human cell lines representing lung, colon, and breast cancers. Conclusion: We have developed a novel radiation-biomarker discovery platform using a systems biology modeling approach. We believe this platform will play a central role in the integration of biology into clinical radiation oncology practice.

  17. Inference of complex biological networks: distinguishability issues and optimization-based solutions

    PubMed Central

    2011-01-01

    Background The inference of biological networks from high-throughput data has received huge attention during the last decade and can be considered an important problem class in systems biology. However, it has been recognized that reliable network inference remains an unsolved problem. Most authors have identified lack of data and deficiencies in the inference algorithms as the main reasons for this situation. Results We claim that another major difficulty for solving these inference problems is the frequent lack of uniqueness of many of these networks, especially when prior assumptions have not been taken properly into account. Our contributions aid the distinguishability analysis of chemical reaction network (CRN) models with mass action dynamics. The novel methods are based on linear programming (LP), therefore they allow the efficient analysis of CRNs containing several hundred complexes and reactions. Using these new tools and also previously published ones to obtain the network structure of biological systems from the literature, we find that, often, a unique topology cannot be determined, even if the structure of the corresponding mathematical model is assumed to be known and all dynamical variables are measurable. In other words, certain mechanisms may remain undetected (or they are falsely detected) while the inferred model is fully consistent with the measured data. It is also shown that sparsity enforcing approaches for determining 'true' reaction structures are generally not enough without additional prior information. Conclusions The inference of biological networks can be an extremely challenging problem even in the utopian case of perfect experimental information. Unfortunately, the practical situation is often more complex than that, since the measurements are typically incomplete, noisy and sometimes dynamically not rich enough, introducing further obstacles to the structure/parameter estimation process. In this paper, we show how the structural

  18. Evaluation of Gene Association Methods for Coexpression Network Construction and Biological Knowledge Discovery

    PubMed Central

    Kumari, Sapna; Nie, Jeff; Chen, Huann-Sheng; Ma, Hao; Stewart, Ron; Li, Xiang; Lu, Meng-Zhu; Taylor, William M.; Wei, Hairong

    2012-01-01

    Background Constructing coexpression networks and performing network analysis using large-scale gene expression data sets is an effective way to uncover new biological knowledge; however, the methods used for gene association in constructing these coexpression networks have not been thoroughly evaluated. Since different methods lead to structurally different coexpression networks and provide different information, selecting the optimal gene association method is critical. Methods and Results In this study, we compared eight gene association methods – Spearman rank correlation, Weighted Rank Correlation, Kendall, Hoeffding's D measure, Theil-Sen, Rank Theil-Sen, Distance Covariance, and Pearson – and focused on their true knowledge discovery rates in associating pathway genes and construction coordination networks of regulatory genes. We also examined the behaviors of different methods to microarray data with different properties, and whether the biological processes affect the efficiency of different methods. Conclusions We found that the Spearman, Hoeffding and Kendall methods are effective in identifying coexpressed pathway genes, whereas the Theil-sen, Rank Theil-Sen, Spearman, and Weighted Rank methods perform well in identifying coordinated transcription factors that control the same biological processes and traits. Surprisingly, the widely used Pearson method is generally less efficient, and so is the Distance Covariance method that can find gene pairs of multiple relationships. Some analyses we did clearly show Pearson and Distance Covariance methods have distinct behaviors as compared to all other six methods. The efficiencies of different methods vary with the data properties to some degree and are largely contingent upon the biological processes, which necessitates the pre-analysis to identify the best performing method for gene association and coexpression network construction. PMID:23226279

  19. Synthetic biology and regulatory networks: where metabolic systems biology meets control engineering

    PubMed Central

    He, Fei; Murabito, Ettore; Westerhoff, Hans V.

    2016-01-01

    Metabolic pathways can be engineered to maximize the synthesis of various products of interest. With the advent of computational systems biology, this endeavour is usually carried out through in silico theoretical studies with the aim to guide and complement further in vitro and in vivo experimental efforts. Clearly, what counts is the result in vivo, not only in terms of maximal productivity but also robustness against environmental perturbations. Engineering an organism towards an increased production flux, however, often compromises that robustness. In this contribution, we review and investigate how various analytical approaches used in metabolic engineering and synthetic biology are related to concepts developed by systems and control engineering. While trade-offs between production optimality and cellular robustness have already been studied diagnostically and statically, the dynamics also matter. Integration of the dynamic design aspects of control engineering with the more diagnostic aspects of metabolic, hierarchical control and regulation analysis is leading to the new, conceptual and operational framework required for the design of robust and productive dynamic pathways. PMID:27075000

  20. Synthetic biology and regulatory networks: where metabolic systems biology meets control engineering.

    PubMed

    He, Fei; Murabito, Ettore; Westerhoff, Hans V

    2016-04-01

    Metabolic pathways can be engineered to maximize the synthesis of various products of interest. With the advent of computational systems biology, this endeavour is usually carried out through in silico theoretical studies with the aim to guide and complement further in vitro and in vivo experimental efforts. Clearly, what counts is the result in vivo, not only in terms of maximal productivity but also robustness against environmental perturbations. Engineering an organism towards an increased production flux, however, often compromises that robustness. In this contribution, we review and investigate how various analytical approaches used in metabolic engineering and synthetic biology are related to concepts developed by systems and control engineering. While trade-offs between production optimality and cellular robustness have already been studied diagnostically and statically, the dynamics also matter. Integration of the dynamic design aspects of control engineering with the more diagnostic aspects of metabolic, hierarchical control and regulation analysis is leading to the new, conceptual and operational framework required for the design of robust and productive dynamic pathways. PMID:27075000

  1. Modeling Reactivity to Biological Macromolecules with a Deep Multitask Network

    PubMed Central

    2016-01-01

    Most small-molecule drug candidates fail before entering the market, frequently because of unexpected toxicity. Often, toxicity is detected only late in drug development, because many types of toxicities, especially idiosyncratic adverse drug reactions (IADRs), are particularly hard to predict and detect. Moreover, drug-induced liver injury (DILI) is the most frequent reason drugs are withdrawn from the market and causes 50% of acute liver failure cases in the United States. A common mechanism often underlies many types of drug toxicities, including both DILI and IADRs. Drugs are bioactivated by drug-metabolizing enzymes into reactive metabolites, which then conjugate to sites in proteins or DNA to form adducts. DNA adducts are often mutagenic and may alter the reading and copying of genes and their regulatory elements, causing gene dysregulation and even triggering cancer. Similarly, protein adducts can disrupt their normal biological functions and induce harmful immune responses. Unfortunately, reactive metabolites are not reliably detected by experiments, and it is also expensive to test drug candidates for potential to form DNA or protein adducts during the early stages of drug development. In contrast, computational methods have the potential to quickly screen for covalent binding potential, thereby flagging problematic molecules and reducing the total number of necessary experiments. Here, we train a deep convolution neural network—the XenoSite reactivity model—using literature data to accurately predict both sites and probability of reactivity for molecules with glutathione, cyanide, protein, and DNA. On the site level, cross-validated predictions had area under the curve (AUC) performances of 89.8% for DNA and 94.4% for protein. Furthermore, the model separated molecules electrophilically reactive with DNA and protein from nonreactive molecules with cross-validated AUC performances of 78.7% and 79.8%, respectively. On both the site- and molecule

  2. Vision-based force measurement using neural networks for biological cell microinjection.

    PubMed

    Karimirad, Fatemeh; Chauhan, Sunita; Shirinzadeh, Bijan

    2014-03-21

    This paper presents a vision-based force measurement method using an artificial neural network model. The proposed model is used for measuring the applied load to a spherical biological cell during micromanipulation process. The devised vision-based method is most useful when force measurement capability is required, but it is very challenging or even infeasible to use a force sensor. Artificial neural networks in conjunction with image processing techniques have been used to estimate the applied load to a cell. A bio-micromanipulation system capable of force measurement has also been established in order to collect the training data required for the proposed neural network model. The geometric characterization of zebrafish embryos membranes has been performed during the penetration of the micropipette prior to piercing. The geometric features are extracted from images using image processing techniques. These features have been used to describe the shape and quantify the deformation of the cell at different indentation depths. The neural network is trained by taking the visual data as the input and the measured corresponding force as the output. Once the neural network is trained with sufficient number of data, it can be used as a precise sensor in bio-micromanipulation setups. However, the proposed neural network model is applicable for indentation of any other spherical elastic object. The results demonstrate the capability of the proposed method. The outcomes of this study could be useful for measuring force in biological cell micromanipulation processes such as injection of the mouse oocyte/embryo. PMID:24411067

  3. Biology-Inspired Distributed Consensus in Massively-Deployed Sensor Networks

    NASA Technical Reports Server (NTRS)

    Jones, Kennie H.; Lodding, Kenneth N.; Olariu, Stephan; Wilson, Larry; Xin, Chunsheng

    2005-01-01

    Promises of ubiquitous control of the physical environment by large-scale wireless sensor networks open avenues for new applications that are expected to redefine the way we live and work. Most of recent research has concentrated on developing techniques for performing relatively simple tasks in small-scale sensor networks assuming some form of centralized control. The main contribution of this work is to propose a new way of looking at large-scale sensor networks, motivated by lessons learned from the way biological ecosystems are organized. Indeed, we believe that techniques used in small-scale sensor networks are not likely to scale to large networks; that such large-scale networks must be viewed as an ecosystem in which the sensors/effectors are organisms whose autonomous actions, based on local information, combine in a communal way to produce global results. As an example of a useful function, we demonstrate that fully distributed consensus can be attained in a scalable fashion in massively deployed sensor networks where individual motes operate based on local information, making local decisions that are aggregated across the network to achieve globally-meaningful effects.

  4. Biana: a software framework for compiling biological interactions and analyzing networks

    PubMed Central

    2010-01-01

    Background The analysis and usage of biological data is hindered by the spread of information across multiple repositories and the difficulties posed by different nomenclature systems and storage formats. In particular, there is an important need for data unification in the study and use of protein-protein interactions. Without good integration strategies, it is difficult to analyze the whole set of available data and its properties. Results We introduce BIANA (Biologic Interactions and Network Analysis), a tool for biological information integration and network management. BIANA is a Python framework designed to achieve two major goals: i) the integration of multiple sources of biological information, including biological entities and their relationships, and ii) the management of biological information as a network where entities are nodes and relationships are edges. Moreover, BIANA uses properties of proteins and genes to infer latent biomolecular relationships by transferring edges to entities sharing similar properties. BIANA is also provided as a plugin for Cytoscape, which allows users to visualize and interactively manage the data. A web interface to BIANA providing basic functionalities is also available. The software can be downloaded under GNU GPL license from http://sbi.imim.es/web/BIANA.php. Conclusions BIANA's approach to data unification solves many of the nomenclature issues common to systems dealing with biological data. BIANA can easily be extended to handle new specific data repositories and new specific data types. The unification protocol allows BIANA to be a flexible tool suitable for different user requirements: non-expert users can use a suggested unification protocol while expert users can define their own specific unification rules. PMID:20105306

  5. Networks In Real Space: Characteristics and Analysis for Biology and Mechanics

    NASA Astrophysics Data System (ADS)

    Modes, Carl; Magnasco, Marcelo; Katifori, Eleni

    Functional networks embedded in physical space play a crucial role in countless biological and physical systems, from the efficient dissemination of oxygen, blood sugars, and hormonal signals in vascular systems to the complex relaying of informational signals in the brain to the distribution of stress and strain in architecture or static sand piles. Unlike their more-studied abstract cousins, such as the hyperlinked internet, social networks, or economic and financial connections, these networks are both constrained by and intimately connected to the physicality of their real, embedding space. We report on the results of new computational and analytic approaches tailored to these physical networks with particular implications and insights for mammalian organ vasculature.

  6. Characterizing gene sets using discriminative random walks with restart on heterogeneous biological networks

    PubMed Central

    Blatti, Charles; Sinha, Saurabh

    2016-01-01

    Motivation: Analysis of co-expressed gene sets typically involves testing for enrichment of different annotations or ‘properties’ such as biological processes, pathways, transcription factor binding sites, etc., one property at a time. This common approach ignores any known relationships among the properties or the genes themselves. It is believed that known biological relationships among genes and their many properties may be exploited to more accurately reveal commonalities of a gene set. Previous work has sought to achieve this by building biological networks that combine multiple types of gene–gene or gene–property relationships, and performing network analysis to identify other genes and properties most relevant to a given gene set. Most existing network-based approaches for recognizing genes or annotations relevant to a given gene set collapse information about different properties to simplify (homogenize) the networks. Results: We present a network-based method for ranking genes or properties related to a given gene set. Such related genes or properties are identified from among the nodes of a large, heterogeneous network of biological information. Our method involves a random walk with restarts, performed on an initial network with multiple node and edge types that preserve more of the original, specific property information than current methods that operate on homogeneous networks. In this first stage of our algorithm, we find the properties that are the most relevant to the given gene set and extract a subnetwork of the original network, comprising only these relevant properties. We then re-rank genes by their similarity to the given gene set, based on a second random walk with restarts, performed on the above subnetwork. We demonstrate the effectiveness of this algorithm for ranking genes related to Drosophila embryonic development and aggressive responses in the brains of social animals. Availability and Implementation: DRaWR was implemented as

  7. MODA: an efficient algorithm for network motif discovery in biological networks.

    PubMed

    Omidi, Saeed; Schreiber, Falk; Masoudi-Nejad, Ali

    2009-10-01

    In recent years, interest has been growing in the study of complex networks. Since Erdös and Rényi (1960) proposed their random graph model about 50 years ago, many researchers have investigated and shaped this field. Many indicators have been proposed to assess the global features of networks. Recently, an active research area has developed in studying local features named motifs as the building blocks of networks. Unfortunately, network motif discovery is a computationally hard problem and finding rather large motifs (larger than 8 nodes) by means of current algorithms is impractical as it demands too much computational effort. In this paper, we present a new algorithm (MODA) that incorporates techniques such as a pattern growth approach for extracting larger motifs efficiently. We have tested our algorithm and found it able to identify larger motifs with more than 8 nodes more efficiently than most of the current state-of-the-art motif discovery algorithms. While most of the algorithms rely on induced subgraphs as motifs of the networks, MODA is able to extract both induced and non-induced subgraphs simultaneously. The MODA source code is freely available at: http://LBB.ut.ac.ir/Download/LBBsoft/MODA/ PMID:20154426

  8. Meeting report from the fourth meeting of the Computational Modeling in Biology Network (COMBINE)

    PubMed Central

    Waltemath, Dagmar; Bergmann, Frank T.; Chaouiya, Claudine; Czauderna, Tobias; Gleeson, Padraig; Goble, Carole; Golebiewski, Martin; Hucka, Michael; Juty, Nick; Krebs, Olga; Le Novère, Nicolas; Mi, Huaiyu; Moraru, Ion I.; Myers, Chris J.; Nickerson, David; Olivier, Brett G.; Rodriguez, Nicolas; Schreiber, Falk; Smith, Lucian; Zhang, Fengkai; Bonnet, Eric

    2014-01-01

    The Computational Modeling in Biology Network (COMBINE) is an initiative to coordinate the development of community standards and formats in computational systems biology and related fields. This report summarizes the topics and activities of the fourth edition of the annual COMBINE meeting, held in Paris during September 16-20 2013, and attended by a total of 96 people. This edition pioneered a first day devoted to modeling approaches in biology, which attracted a broad audience of scientists thanks to a panel of renowned speakers. During subsequent days, discussions were held on many subjects including the introduction of new features in the various COMBINE standards, new software tools that use the standards, and outreach efforts. Significant emphasis went into work on extensions of the SBML format, and also into community-building. This year’s edition once again demonstrated that the COMBINE community is thriving, and still manages to help coordinate activities between different standards in computational systems biology.

  9. Application of Kohonen Neural Networks in classification of biologically active compounds.

    PubMed

    Kirew, D B; Chretien, J R; Bernard, P; Ros, F

    1998-01-01

    Automated data classification is an indispensable tool in Drug Design. It allows to select homogeneous training sets or to distinguish compounds with required biological properties. The Kohonen Neural Networks (KNN) suggest new means for classification of biologically interesting compounds. In this paper, first, capabilities of KNN in data dimensionality reduction are presented as compared with the capabilities of Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA). The advantages of KNN become evident with increasing data dimensionality and size of the training set. Then, new methods are suggested to evaluate the quality of KNN models. Finally, a case study on chemical and biological data is presented. The database studied includes more than 2000 organophosphorous potent pesticides. The Kohonen maps were obtained which allow to distinguish compounds with different biological behavior. PMID:9517011

  10. Maria Goeppert-Mayer Award Talk: Probing the structure and dynamics of biological networks

    NASA Astrophysics Data System (ADS)

    Albert, Reka

    2011-03-01

    The relationship between the structure and dynamics of networks is one of the central topics in network science. In the context of biological regulatory networks at the molecular to cellular level, the dynamics in question is often thought of as information propagation through the network. Quantitative dynamic models help to achieve an understanding of this process, but are difficult to construct and validate because of the scarcity of known mechanistic details and kinetic parameters. Structural and qualitative analysis is emerging as a feasible and useful alternative for interpreting biological signal transduction, and at the same time probing the structure-function relation of these networks. This analysis, however, necessitates the extension of current graph theoretical frameworks to incorporate features such as the positive or negative nature of interactions and synergistic behaviors among multiple components. This talk will present a method for structural analysis in an augmented graph framework that can probe the dynamics of information transfer. The first step is to expand the network to a richer representation that incorporates negative and synergistic regulation by the addition of pseudo-nodes and new edges. Our method simulates both knockout and constitutive activation of components as node disruptions, and takes into account the possible cascading effects of a node's disruption. We introduce the concept of elementary signaling mode (ESM), as the minimal set of nodes that can perform signal transduction independently. As a first application of this method we ranked the importance of signaling components by the effects of their perturbation on the ESMs of the network. Validation on various regulatory networks shows that this method can effectively uncover the essentiality of components mediating a signal transduction process and agrees with dynamic simulation results and experimental observations. Future applications include determining the ESMs that (do

  11. PAGER: constructing PAGs and new PAG–PAG relationships for network biology

    PubMed Central

    Yue, Zongliang; Kshirsagar, Madhura M.; Nguyen, Thanh; Suphavilai, Chayaporn; Neylon, Michael T.; Zhu, Liugen; Ratliff, Timothy; Chen, Jake Y.

    2015-01-01

    In this article, we described a new database framework to perform integrative “gene-set, network, and pathway analysis” (GNPA). In this framework, we integrated heterogeneous data on pathways, annotated list, and gene-sets (PAGs) into a PAG electronic repository (PAGER). PAGs in the PAGER database are organized into P-type, A-type and G-type PAGs with a three-letter-code standard naming convention. The PAGER database currently compiles 44 313 genes from 5 species including human, 38 663 PAGs, 324 830 gene–gene relationships and two types of 3 174 323 PAG–PAG regulatory relationships—co-membership based and regulatory relationship based. To help users assess each PAG’s biological relevance, we developed a cohesion measure called Cohesion Coefficient (CoCo), which is capable of disambiguating between biologically significant PAGs and random PAGs with an area-under-curve performance of 0.98. PAGER database was set up to help users to search and retrieve PAGs from its online web interface. PAGER enable advanced users to build PAG–PAG regulatory networks that provide complementary biological insights not found in gene set analysis or individual gene network analysis. We provide a case study using cancer functional genomics data sets to demonstrate how integrative GNPA help improve network biology data coverage and therefore biological interpretability. The PAGER database can be accessible openly at http://discovery.informatics.iupui.edu/PAGER/. Contact: jakechen@iupui.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26072489

  12. FastGGM: An Efficient Algorithm for the Inference of Gaussian Graphical Model in Biological Networks

    PubMed Central

    Ding, Ying; Fang, Zhou; Sun, Zhe; MacDonald, Matthew L.; Sweet, Robert A.; Wang, Jieru; Chen, Wei

    2016-01-01

    Biological networks provide additional information for the analysis of human diseases, beyond the traditional analysis that focuses on single variables. Gaussian graphical model (GGM), a probability model that characterizes the conditional dependence structure of a set of random variables by a graph, has wide applications in the analysis of biological networks, such as inferring interaction or comparing differential networks. However, existing approaches are either not statistically rigorous or are inefficient for high-dimensional data that include tens of thousands of variables for making inference. In this study, we propose an efficient algorithm to implement the estimation of GGM and obtain p-value and confidence interval for each edge in the graph, based on a recent proposal by Ren et al., 2015. Through simulation studies, we demonstrate that the algorithm is faster by several orders of magnitude than the current implemented algorithm for Ren et al. without losing any accuracy. Then, we apply our algorithm to two real data sets: transcriptomic data from a study of childhood asthma and proteomic data from a study of Alzheimer’s disease. We estimate the global gene or protein interaction networks for the disease and healthy samples. The resulting networks reveal interesting interactions and the differential networks between cases and controls show functional relevance to the diseases. In conclusion, we provide a computationally fast algorithm to implement a statistically sound procedure for constructing Gaussian graphical model and making inference with high-dimensional biological data. The algorithm has been implemented in an R package named “FastGGM”. PMID:26872036

  13. Uncovering disease mechanisms through network biology in the era of Next Generation Sequencing

    PubMed Central

    Piñero, Janet; Berenstein, Ariel; Gonzalez-Perez, Abel; Chernomoretz, Ariel; Furlong, Laura I.

    2016-01-01

    Characterizing the behavior of disease genes in the context of biological networks has the potential to shed light on disease mechanisms, and to reveal both new candidate disease genes and therapeutic targets. Previous studies addressing the network properties of disease genes have produced contradictory results. Here we have explored the causes of these discrepancies and assessed the relationship between the network roles of disease genes and their tolerance to deleterious germline variants in human populations leveraging on: the abundance of interactome resources, a comprehensive catalog of disease genes and exome variation data. We found that the most salient network features of disease genes are driven by cancer genes and that genes related to different types of diseases play network roles whose centrality is inversely correlated to their tolerance to likely deleterious germline mutations. This proved to be a multiscale signature, including global, mesoscopic and local network centrality features. Cancer driver genes, the most sensitive to deleterious variants, occupy the most central positions, followed by dominant disease genes and then by recessive disease genes, which are tolerant to variants and isolated within their network modules. PMID:27080396

  14. Uncovering disease mechanisms through network biology in the era of Next Generation Sequencing.

    PubMed

    Piñero, Janet; Berenstein, Ariel; Gonzalez-Perez, Abel; Chernomoretz, Ariel; Furlong, Laura I

    2016-01-01

    Characterizing the behavior of disease genes in the context of biological networks has the potential to shed light on disease mechanisms, and to reveal both new candidate disease genes and therapeutic targets. Previous studies addressing the network properties of disease genes have produced contradictory results. Here we have explored the causes of these discrepancies and assessed the relationship between the network roles of disease genes and their tolerance to deleterious germline variants in human populations leveraging on: the abundance of interactome resources, a comprehensive catalog of disease genes and exome variation data. We found that the most salient network features of disease genes are driven by cancer genes and that genes related to different types of diseases play network roles whose centrality is inversely correlated to their tolerance to likely deleterious germline mutations. This proved to be a multiscale signature, including global, mesoscopic and local network centrality features. Cancer driver genes, the most sensitive to deleterious variants, occupy the most central positions, followed by dominant disease genes and then by recessive disease genes, which are tolerant to variants and isolated within their network modules. PMID:27080396

  15. The Everglades Depth Estimation Network (EDEN) for Support of Ecological and Biological Assessments

    USGS Publications Warehouse

    Telis, Pamela A.

    2006-01-01

    The Everglades Depth Estimation Network (EDEN) is an integrated network of real-time water-level monitoring, ground-elevation modeling, and water-surface modeling that provides scientists and managers with current (1999-present), online water-depth information for the entire freshwater portion of the Greater Everglades. Presented on a 400-square-meter grid spacing, EDEN offers a consistent and documented dataset that can be used by scientists and managers to (1) guide large-scale field operations, (2) integrate hydrologic and ecological responses, and (3) support biological and ecological assessments that measure ecosystem responses to the implementation of the Comprehensive Everglades Restoration Plan.

  16. PiNGO: a Cytoscape plugin to find candidate genes in biological networks

    PubMed Central

    Smoot, Michael; Ono, Keiichiro; Ideker, Trey; Maere, Steven

    2011-01-01

    Summary: PiNGO is a tool to screen biological networks for candidate genes, i.e. genes predicted to be involved in a biological process of interest. The user can narrow the search to genes with particular known functions or exclude genes belonging to particular functional classes. PiNGO provides support for a wide range of organisms and Gene Ontology classification schemes, and it can easily be customized for other organisms and functional classifications. PiNGO is implemented as a plugin for Cytoscape, a popular network visualization platform. Availability: PiNGO is distributed as an open-source Java package under the GNU General Public License (http://www.gnu.org/), and can be downloaded via the Cytoscape plugin manager. A detailed user guide and tutorial are available on the PiNGO website (http://www.psb.ugent.be/esb/PiNGO. Contact: steven.maere@psb.vib-ugent.be PMID:21278188

  17. Shadows of complexity: what biological networks reveal about epistasis and pleiotropy.

    PubMed

    Tyler, Anna L; Asselbergs, Folkert W; Williams, Scott M; Moore, Jason H

    2009-02-01

    Pleiotropy, in which one mutation causes multiple phenotypes, has traditionally been seen as a deviation from the conventional observation in which one gene affects one phenotype. Epistasis, or gene-gene interaction, has also been treated as an exception to the Mendelian one gene-one phenotype paradigm. This simplified perspective belies the pervasive complexity of biology and hinders progress toward a deeper understanding of biological systems. We assert that epistasis and pleiotropy are not isolated occurrences, but ubiquitous and inherent properties of biomolecular networks. These phenomena should not be treated as exceptions, but rather as fundamental components of genetic analyses. A systems level understanding of epistasis and pleiotropy is, therefore, critical to furthering our understanding of human genetics and its contribution to common human disease. Finally, graph theory offers an intuitive and powerful set of tools with which to study the network bases of these important genetic phenomena. PMID:19204994

  18. From systems biology to photosynthesis and whole-plant modeling: a conceptual model for integrating multi-scale networks

    SciTech Connect

    Weston, David; Hanson, Paul J; Norby, Richard J; Tuskan, Gerald A; Wullschleger, Stan D

    2012-01-01

    Network analysis is now a common statistical tool for molecular biologists. Network algorithms are readily used to model gene, protein and metabolic correlations providing insight into pathways driving biological phenomenon. One output from such an analysis is a candidate gene list that can be responsible, in part, for the biological process of interest. The question remains, however, as to whether molecular network analysis can be used to inform process models at higher levels of biological organization. In our previous work, transcriptional networks derived from three plant species were constructed, interrogated for orthology and then correlated to photosynthetic inhibition at elevated temperature. One unique aspect of that study was the link from co-expression networks to net photosynthesis. In this addendum, we propose a conceptual model where traditional network analysis can be linked to whole-plant models thereby informing predictions on key processes such as photosynthesis, nutrient uptake and assimilation, and C partitioning.

  19. ClusterViz: A Cytoscape APP for Cluster Analysis of Biological Network.

    PubMed

    Wang, Jianxin; Zhong, Jiancheng; Chen, Gang; Li, Min; Wu, Fang-xiang; Pan, Yi

    2015-01-01

    Cluster analysis of biological networks is one of the most important approaches for identifying functional modules and predicting protein functions. Furthermore, visualization of clustering results is crucial to uncover the structure of biological networks. In this paper, ClusterViz, an APP of Cytoscape 3 for cluster analysis and visualization, has been developed. In order to reduce complexity and enable extendibility for ClusterViz, we designed the architecture of ClusterViz based on the framework of Open Services Gateway Initiative. According to the architecture, the implementation of ClusterViz is partitioned into three modules including interface of ClusterViz, clustering algorithms and visualization and export. ClusterViz fascinates the comparison of the results of different algorithms to do further related analysis. Three commonly used clustering algorithms, FAG-EC, EAGLE and MCODE, are included in the current version. Due to adopting the abstract interface of algorithms in module of the clustering algorithms, more clustering algorithms can be included for the future use. To illustrate usability of ClusterViz, we provided three examples with detailed steps from the important scientific articles, which show that our tool has helped several research teams do their research work on the mechanism of the biological networks. PMID:26357321

  20. Biologically Derived Soft Conducting Hydrogels Using Heparin-Doped Polymer Networks

    PubMed Central

    2015-01-01

    The emergence of flexible and stretchable electronic components expands the range of applications of electronic devices. Flexible devices are ideally suited for electronic biointerfaces because of mechanically permissive structures that conform to curvilinear structures found in native tissue. Most electronic materials used in these applications exhibit elastic moduli on the order of 0.1–1 MPa. However, many electronically excitable tissues exhibit elasticities in the range of 1–10 kPa, several orders of magnitude smaller than existing components used in flexible devices. This work describes the use of biologically derived heparins as scaffold materials for fabricating networks with hybrid electronic/ionic conductivity and ultracompliant mechanical properties. Photo-cross-linkable heparin–methacrylate hydrogels serve as templates to control the microstructure and doping of in situ polymerized polyaniline structures. Macroscopic heparin-doped polyaniline hydrogel dual networks exhibit impedances as low as Z = 4.17 Ω at 1 kHz and storage moduli of G′ = 900 ± 100 Pa. The conductivity of heparin/polyaniline networks depends on the oxidation state and microstructure of secondary polyaniline networks. Furthermore, heparin/polyaniline networks support the attachment, proliferation, and differentiation of murine myoblasts without any surface treatments. Taken together, these results suggest that heparin/polyaniline hydrogel networks exhibit suitable physical properties as an electronically active biointerface material that can match the mechanical properties of soft tissues composed of excitable cells. PMID:24738911

  1. Cell cycle gene expression networks discovered using systems biology: Significance in carcinogenesis.

    PubMed

    Scott, Robert E; Ghule, Prachi N; Stein, Janet L; Stein, Gary S

    2015-10-01

    The early stages of carcinogenesis are linked to defects in the cell cycle. A series of cell cycle checkpoints are involved in this process. The G1/S checkpoint that serves to integrate the control of cell proliferation and differentiation is linked to carcinogenesis and the mitotic spindle checkpoint is associated with the development of chromosomal instability. This paper presents the outcome of systems biology studies designed to evaluate if networks of covariate cell cycle gene transcripts exist in proliferative mammalian tissues including mice, rats, and humans. The GeneNetwork website that contains numerous gene expression datasets from different species, sexes, and tissues represents the foundational resource for these studies (www.genenetwork.org). In addition, WebGestalt, a gene ontology tool, facilitated the identification of expression networks of genes that co-vary with key cell cycle targets, especially Cdc20 and Plk1 (www.bioinfo.vanderbilt.edu/webgestalt). Cell cycle expression networks of such covariate mRNAs exist in multiple proliferative tissues including liver, lung, pituitary, adipose, and lymphoid tissues among others but not in brain or retina that have low proliferative potential. Sixty-three covariate cell cycle gene transcripts (mRNAs) compose the average cell cycle network with P = e(-13) to e(-36) . Cell cycle expression networks show species, sex and tissue variability, and they are enriched in mRNA transcripts associated with mitosis, many of which are associated with chromosomal instability. PMID:25808367

  2. NeAT: a toolbox for the analysis of biological networks, clusters, classes and pathways

    PubMed Central

    Brohée, Sylvain; Faust, Karoline; Lima-Mendez, Gipsi; Sand, Olivier; Janky, Rekin's; Vanderstocken, Gilles; Deville, Yves; van Helden, Jacques

    2008-01-01

    The network analysis tools (NeAT) (http://rsat.ulb.ac.be/neat/) provide a user-friendly web access to a collection of modular tools for the analysis of networks (graphs) and clusters (e.g. microarray clusters, functional classes, etc.). A first set of tools supports basic operations on graphs (comparison between two graphs, neighborhood of a set of input nodes, path finding and graph randomization). Another set of programs makes the connection between networks and clusters (graph-based clustering, cliques discovery and mapping of clusters onto a network). The toolbox also includes programs for detecting significant intersections between clusters/classes (e.g. clusters of co-expression versus functional classes of genes). NeAT are designed to cope with large datasets and provide a flexible toolbox for analyzing biological networks stored in various databases (protein interactions, regulation and metabolism) or obtained from high-throughput experiments (two-hybrid, mass-spectrometry and microarrays). The web interface interconnects the programs in predefined analysis flows, enabling to address a series of questions about networks of interest. Each tool can also be used separately by entering custom data for a specific analysis. NeAT can also be used as web services (SOAP/WSDL interface), in order to design programmatic workflows and integrate them with other available resources. PMID:18524799

  3. NeAT: a toolbox for the analysis of biological networks, clusters, classes and pathways.

    PubMed

    Brohée, Sylvain; Faust, Karoline; Lima-Mendez, Gipsi; Sand, Olivier; Janky, Rekin's; Vanderstocken, Gilles; Deville, Yves; van Helden, Jacques

    2008-07-01

    The network analysis tools (NeAT) (http://rsat.ulb.ac.be/neat/) provide a user-friendly web access to a collection of modular tools for the analysis of networks (graphs) and clusters (e.g. microarray clusters, functional classes, etc.). A first set of tools supports basic operations on graphs (comparison between two graphs, neighborhood of a set of input nodes, path finding and graph randomization). Another set of programs makes the connection between networks and clusters (graph-based clustering, cliques discovery and mapping of clusters onto a network). The toolbox also includes programs for detecting significant intersections between clusters/classes (e.g. clusters of co-expression versus functional classes of genes). NeAT are designed to cope with large datasets and provide a flexible toolbox for analyzing biological networks stored in various databases (protein interactions, regulation and metabolism) or obtained from high-throughput experiments (two-hybrid, mass-spectrometry and microarrays). The web interface interconnects the programs in predefined analysis flows, enabling to address a series of questions about networks of interest. Each tool can also be used separately by entering custom data for a specific analysis. NeAT can also be used as web services (SOAP/WSDL interface), in order to design programmatic workflows and integrate them with other available resources. PMID:18524799

  4. An end-to-end workflow for engineering of biological networks from high-level specifications.

    PubMed

    Beal, Jacob; Weiss, Ron; Densmore, Douglas; Adler, Aaron; Appleton, Evan; Babb, Jonathan; Bhatia, Swapnil; Davidsohn, Noah; Haddock, Traci; Loyall, Joseph; Schantz, Richard; Vasilev, Viktor; Yaman, Fusun

    2012-08-17

    We present a workflow for the design and production of biological networks from high-level program specifications. The workflow is based on a sequence of intermediate models that incrementally translate high-level specifications into DNA samples that implement them. We identify algorithms for translating between adjacent models and implement them as a set of software tools, organized into a four-stage toolchain: Specification, Compilation, Part Assignment, and Assembly. The specification stage begins with a Boolean logic computation specified in the Proto programming language. The compilation stage uses a library of network motifs and cellular platforms, also specified in Proto, to transform the program into an optimized Abstract Genetic Regulatory Network (AGRN) that implements the programmed behavior. The part assignment stage assigns DNA parts to the AGRN, drawing the parts from a database for the target cellular platform, to create a DNA sequence implementing the AGRN. Finally, the assembly stage computes an optimized assembly plan to create the DNA sequence from available part samples, yielding a protocol for producing a sample of engineered plasmids with robotics assistance. Our workflow is the first to automate the production of biological networks from a high-level program specification. Furthermore, the workflow's modular design allows the same program to be realized on different cellular platforms simply by swapping workflow configurations. We validated our workflow by specifying a small-molecule sensor-reporter program and verifying the resulting plasmids in both HEK 293 mammalian cells and in E. coli bacterial cells. PMID:23651286

  5. Process-driven inference of biological network structure: feasibility, minimality, and multiplicity.

    PubMed

    Wang, Guanyu; Rong, Yongwu; Chen, Hao; Pearson, Carl; Du, Chenghang; Simha, Rahul; Zeng, Chen

    2012-01-01

    A common problem in molecular biology is to use experimental data, such as microarray data, to infer knowledge about the structure of interactions between important molecules in subsystems of the cell. By approximating the state of each molecule as "on" or "off", it becomes possible to simplify the problem, and exploit the tools of boolean analysis for such inference. Amongst boolean techniques, the process-driven approach has shown promise in being able to identify putative network structures, as well as stability and modularity properties. This paper examines the process-driven approach more formally, and makes four contributions about the computational complexity of the inference problem, under the "dominant inhibition" assumption of molecular interactions. The first is a proof that the feasibility problem (does there exist a network that explains the data?) can be solved in polynomial-time. Second, the minimality problem (what is the smallest network that explains the data?) is shown to be NP-hard, and therefore unlikely to result in a polynomial-time algorithm. Third, a simple polynomial-time heuristic is shown to produce near-minimal solutions, as demonstrated by simulation. Fourth, the theoretical framework explains how multiplicity (the number of network solutions to realize a given biological process), which can take exponential-time to compute, can instead be accurately estimated by a fast, polynomial-time heuristic. PMID:22815739

  6. A biological approach to assembling tissue modules through endothelial capillary network formation.

    PubMed

    Riesberg, Jeremiah J; Shen, Wei

    2015-09-01

    To create functional tissues having complex structures, bottom-up approaches to assembling small tissue modules into larger constructs have been emerging. Most of these approaches are based on chemical reactions or physical interactions at the interface between tissue modules. Here we report a biological assembly approach to integrate small tissue modules through endothelial capillary network formation. When adjacent tissue modules contain appropriate extracellular matrix materials and cell types that support robust endothelial capillary network formation, capillary tubules form and grow across the interface, resulting in assembly of the modules into a single, larger construct. It was shown that capillary networks formed in modules of dense fibrin gels seeded with human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells (MSCs); adjacent modules were firmly assembled into an integrated construct having a strain to failure of 117 ± 26%, a tensile strength of 2208 ± 83 Pa and a Young's modulus of 2548 ± 574 Pa. Under the same culture conditions, capillary networks were absent in modules of dense fibrin gels seeded with either HUVECs or MSCs alone; adjacent modules disconnected even when handled gently. This biological assembly approach eliminates the need for chemical reactions or physical interactions and their associated limitations. In addition, the integrated constructs are prevascularized, and therefore this bottom-up assembly approach may also help address the issue of vascularization, another key challenge in tissue engineering. PMID:25694020

  7. Double network bacterial cellulose hydrogel to build a biology-device interface

    NASA Astrophysics Data System (ADS)

    Shi, Zhijun; Li, Ying; Chen, Xiuli; Han, Hongwei; Yang, Guang

    2013-12-01

    Establishing a biology-device interface might enable the interaction between microelectronics and biotechnology. In this study, electroactive hydrogels have been produced using bacterial cellulose (BC) and conducting polymer (CP) deposited on the BC hydrogel surface to cover the BC fibers. The structures of these composites thus have double networks, one of which is a layer of electroactive hydrogels combined with BC and CP. The electroconductivity provides the composites with capabilities for voltage and current response, and the BC hydrogel layer provides good biocompatibility, biodegradability, bioadhesion and mass transport properties. Such a system might allow selective biological functions such as molecular recognition and specific catalysis and also for probing the detailed genetic and molecular mechanisms of life. A BC-CP composite hydrogel could then lead to a biology-device interface. Cyclic voltammetry and electrochemical impedance spectroscopy (EIS) are used here to study the composite hydrogels' electroactive property. BC-PAni and BC-PPy respond to voltage changes. This provides a mechanism to amplify electrochemical signals for analysis or detection. BC hydrogels were found to be able to support the growth, spreading and migration of human normal skin fibroblasts without causing any cytotoxic effect on the cells in the cell culture. These double network BC-CP hydrogels are biphasic Janus hydrogels which integrate electroactivity with biocompatibility, and might provide a biology-device interface to produce implantable devices for personalized and regenerative medicine.

  8. Landauer in the Age of Synthetic Biology: Energy Consumption and Information Processing in Biochemical Networks

    NASA Astrophysics Data System (ADS)

    Mehta, Pankaj; Lang, Alex H.; Schwab, David J.

    2016-03-01

    A central goal of synthetic biology is to design sophisticated synthetic cellular circuits that can perform complex computations and information processing tasks in response to specific inputs. The tremendous advances in our ability to understand and manipulate cellular information processing networks raises several fundamental physics questions: How do the molecular components of cellular circuits exploit energy consumption to improve information processing? Can one utilize ideas from thermodynamics to improve the design of synthetic cellular circuits and modules? Here, we summarize recent theoretical work addressing these questions. Energy consumption in cellular circuits serves five basic purposes: (1) increasing specificity, (2) manipulating dynamics, (3) reducing variability, (4) amplifying signal, and (5) erasing memory. We demonstrate these ideas using several simple examples and discuss the implications of these theoretical ideas for the emerging field of synthetic biology. We conclude by discussing how it may be possible to overcome these limitations using "post-translational" synthetic biology that exploits reversible protein modification.

  9. Content-rich biological network constructed by mining PubMed abstracts

    PubMed Central

    Chen, Hao; Sharp, Burt M

    2004-01-01

    Background The integration of the rapidly expanding corpus of information about the genome, transcriptome, and proteome, engendered by powerful technological advances, such as microarrays, and the availability of genomic sequence from multiple species, challenges the grasp and comprehension of the scientific community. Despite the existence of text-mining methods that identify biological relationships based on the textual co-occurrence of gene/protein terms or similarities in abstract texts, knowledge of the underlying molecular connections on a large scale, which is prerequisite to understanding novel biological processes, lags far behind the accumulation of data. While computationally efficient, the co-occurrence-based approaches fail to characterize (e.g., inhibition or stimulation, directionality) biological interactions. Programs with natural language processing (NLP) capability have been created to address these limitations, however, they are in general not readily accessible to the public. Results We present a NLP-based text-mining approach, Chilibot, which constructs content-rich relationship networks among biological concepts, genes, proteins, or drugs. Amongst its features, suggestions for new hypotheses can be generated. Lastly, we provide evidence that the connectivity of molecular networks extracted from the biological literature follows the power-law distribution, indicating scale-free topologies consistent with the results of previous experimental analyses. Conclusions Chilibot distills scientific relationships from knowledge available throughout a wide range of biological domains and presents these in a content-rich graphical format, thus integrating general biomedical knowledge with the specialized knowledge and interests of the user. Chilibot can be accessed free of charge to academic users. PMID:15473905

  10. Architecture and biological applications of artificial neural networks: a tuberculosis perspective.

    PubMed

    Darsey, Jerry A; Griffin, William O; Joginipelli, Sravanthi; Melapu, Venkata Kiran

    2015-01-01

    Advancement of science and technology has prompted researchers to develop new intelligent systems that can solve a variety of problems such as pattern recognition, prediction, and optimization. The ability of the human brain to learn in a fashion that tolerates noise and error has attracted many researchers and provided the starting point for the development of artificial neural networks: the intelligent systems. Intelligent systems can acclimatize to the environment or data and can maximize the chances of success or improve the efficiency of a search. Due to massive parallelism with large numbers of interconnected processers and their ability to learn from the data, neural networks can solve a variety of challenging computational problems. Neural networks have the ability to derive meaning from complicated and imprecise data; they are used in detecting patterns, and trends that are too complex for humans, or other computer systems. Solutions to the toughest problems will not be found through one narrow specialization; therefore we need to combine interdisciplinary approaches to discover the solutions to a variety of problems. Many researchers in different disciplines such as medicine, bioinformatics, molecular biology, and pharmacology have successfully applied artificial neural networks. This chapter helps the reader in understanding the basics of artificial neural networks, their applications, and methodology; it also outlines the network learning process and architecture. We present a brief outline of the application of neural networks to medical diagnosis, drug discovery, gene identification, and protein structure prediction. We conclude with a summary of the results from our study on tuberculosis data using neural networks, in diagnosing active tuberculosis, and predicting chronic vs. infiltrative forms of tuberculosis. PMID:25502388

  11. A vascular biology network model focused on inflammatory processes to investigate atherogenesis and plaque instability

    PubMed Central

    2014-01-01

    Background Numerous inflammation-related pathways have been shown to play important roles in atherogenesis. Rapid and efficient assessment of the relative influence of each of those pathways is a challenge in the era of “omics” data generation. The aim of the present work was to develop a network model of inflammation-related molecular pathways underlying vascular disease to assess the degree of translatability of preclinical molecular data to the human clinical setting. Methods We constructed and evaluated the Vascular Inflammatory Processes Network (V-IPN), a model representing a collection of vascular processes modulated by inflammatory stimuli that lead to the development of atherosclerosis. Results Utilizing the V-IPN as a platform for biological discovery, we have identified key vascular processes and mechanisms captured by gene expression profiling data from four independent datasets from human endothelial cells (ECs) and human and murine intact vessels. Primary ECs in culture from multiple donors revealed a richer mapping of mechanisms identified by the V-IPN compared to an immortalized EC line. Furthermore, an evaluation of gene expression datasets from aortas of old ApoE-/- mice (78 weeks) and human coronary arteries with advanced atherosclerotic lesions identified significant commonalities in the two species, as well as several mechanisms specific to human arteries that are consistent with the development of unstable atherosclerotic plaques. Conclusions We have generated a new biological network model of atherogenic processes that demonstrates the power of network analysis to advance integrative, systems biology-based knowledge of cross-species translatability, plaque development and potential mechanisms leading to plaque instability. PMID:24965703

  12. Multilevel functional genomics data integration as a tool for understanding physiology: a network biology perspective.

    PubMed

    Davidsen, Peter K; Turan, Nil; Egginton, Stuart; Falciani, Francesco

    2016-02-01

    The overall aim of physiological research is to understand how living systems function in an integrative manner. Consequently, the discipline of physiology has since its infancy attempted to link multiple levels of biological organization. Increasingly this has involved mathematical and computational approaches, typically to model a small number of components spanning several levels of biological organization. With the advent of "omics" technologies, which can characterize the molecular state of a cell or tissue (intended as the level of expression and/or activity of its molecular components), the number of molecular components we can quantify has increased exponentially. Paradoxically, the unprecedented amount of experimental data has made it more difficult to derive conceptual models underlying essential mechanisms regulating mammalian physiology. We present an overview of state-of-the-art methods currently used to identifying biological networks underlying genomewide responses. These are based on a data-driven approach that relies on advanced computational methods designed to "learn" biology from observational data. In this review, we illustrate an application of these computational methodologies using a case study integrating an in vivo model representing the transcriptional state of hypoxic skeletal muscle with a clinical study representing muscle wasting in chronic obstructive pulmonary disease patients. The broader application of these approaches to modeling multiple levels of biological data in the context of modern physiology is discussed. PMID:26542523

  13. Interfacing a Biosurveillance Portal and an International Network of Institutional Analysts to Detect Biological Threats

    PubMed Central

    Shigematsu, Mika; Chow, Catherine; McKnight, C. Jason; Linge, Jens; Doherty, Brian; Dente, Maria Grazia; Declich, Silvia; Barker, Mike; Barboza, Philippe; Vaillant, Laetitia; Donachie, Alastair; Mawudeku, Abla; Blench, Michael; Arthur, Ray

    2014-01-01

    The Early Alerting and Reporting (EAR) project, launched in 2008, is aimed at improving global early alerting and risk assessment and evaluating the feasibility and opportunity of integrating the analysis of biological, chemical, radionuclear (CBRN), and pandemic influenza threats. At a time when no international collaborations existed in the field of event-based surveillance, EAR's innovative approach involved both epidemic intelligence experts and internet-based biosurveillance system providers in the framework of an international collaboration called the Global Health Security Initiative, which involved the ministries of health of the G7 countries and Mexico, the World Health Organization, and the European Commission. The EAR project pooled data from 7 major internet-based biosurveillance systems onto a common portal that was progressively optimized for biological threat detection under the guidance of epidemic intelligence experts from public health institutions in Canada, the European Centre for Disease Prevention and Control, France, Germany, Italy, Japan, the United Kingdom, and the United States. The group became the first end users of the EAR portal, constituting a network of analysts working with a common standard operating procedure and risk assessment tools on a rotation basis to constantly screen and assess public information on the web for events that could suggest an intentional release of biological agents. Following the first 2-year pilot phase, the EAR project was tested in its capacity to monitor biological threats, proving that its working model was feasible and demonstrating the high commitment of the countries and international institutions involved. During the testing period, analysts using the EAR platform did not miss intentional events of a biological nature and did not issue false alarms. Through the findings of this initial assessment, this article provides insights into how the field of epidemic intelligence can advance through an

  14. Systems biology beyond networks: generating order from disorder through self-organization

    PubMed Central

    Saetzler, K.; Sonnenschein, C.; Soto, A.M.

    2011-01-01

    Erwin Schrödinger pointed out in his 1944 book “What is Life” that one defining attribute of biological systems seems to be their tendency to generate order from disorder defying the second law of thermodynamics. Almost parallel to his findings, the science of complex systems was founded based on observations on physical and chemical systems showing that inanimate matter can exhibit complex structures although their interacting parts follow simple rules. This is explained by a process known as self-organization and it is now widely accepted that multi-cellular biological organisms are themselves self-organizing complex systems in which the relations among their parts are dynamic, contextual and interdependent. In order to fully understand such systems, we are required to computationally and mathematically model their interactions as promulgated in systems biology. The preponderance of network models in the practice of systems biology inspired by a reductionist, bottom-up view, seems to neglect, however, the importance of bidirectional interactions across spatial scales and domains. This approach introduces a shortcoming that may hinder research on emergent phenomena such as those of tissue morphogenesis and related diseases, such as cancer. Another hindrance of current modeling attempts is that those systems operate in a parameter space that seems far removed from biological reality. This misperception calls for more tightly coupled mathematical and computational models to biological experiments by creating and designing biological model systems that are accessible to a wide range of experimental manipulations. In this way, a comprehensive understanding of fundamental processes in normal development or of aberrations, like cancer, will be generated. PMID:21569848

  15. Statistical Assessment of Crosstalk Enrichment between Gene Groups in Biological Networks

    PubMed Central

    Alexeyenko, Andrey; Sonnhammer, Erik L. L.

    2013-01-01

    Motivation Analyzing groups of functionally coupled genes or proteins in the context of global interaction networks has become an important aspect of bioinformatic investigations. Assessing the statistical significance of crosstalk enrichment between or within groups of genes can be a valuable tool for functional annotation of experimental gene sets. Results Here we present CrossTalkZ, a statistical method and software to assess the significance of crosstalk enrichment between pairs of gene or protein groups in large biological networks. We demonstrate that the standard z-score is generally an appropriate and unbiased statistic. We further evaluate the ability of four different methods to reliably recover crosstalk within known biological pathways. We conclude that the methods preserving the second-order topological network properties perform best. Finally, we show how CrossTalkZ can be used to annotate experimental gene sets using known pathway annotations and that its performance at this task is superior to gene enrichment analysis (GEA). Availability and Implementation CrossTalkZ (available at http://sonnhammer.sbc.su.se/download/software/CrossTalkZ/) is implemented in C++, easy to use, fast, accepts various input file formats, and produces a number of statistics. These include z-score, p-value, false discovery rate, and a test of normality for the null distributions. PMID:23372799

  16. Learning Biological Networks via Bootstrapping with Optimized GO-based Gene Similarity

    SciTech Connect

    Taylor, Ronald C.; Sanfilippo, Antonio P.; McDermott, Jason E.; Baddeley, Robert L.; Riensche, Roderick M.; Jensen, Russell S.; Verhagen, Marc

    2010-08-02

    Microarray gene expression data provide a unique information resource for learning biological networks using "reverse engineering" methods. However, there are a variety of cases in which we know which genes are involved in a given pathology of interest, but we do not have enough experimental evidence to support the use of fully-supervised/reverse-engineering learning methods. In this paper, we explore a novel semi-supervised approach in which biological networks are learned from a reference list of genes and a partial set of links for these genes extracted automatically from PubMed abstracts, using a knowledge-driven bootstrapping algorithm. We show how new relevant links across genes can be iteratively derived using a gene similarity measure based on the Gene Ontology that is optimized on the input network at each iteration. We describe an application of this approach to the TGFB pathway as a case study and show how the ensuing results prove the feasibility of the approach as an alternate or complementary technique to fully supervised methods.

  17. ANDSystem: an Associative Network Discovery System for automated literature mining in the field of biology

    PubMed Central

    2015-01-01

    Background Sufficient knowledge of molecular and genetic interactions, which comprise the entire basis of the functioning of living systems, is one of the necessary requirements for successfully answering almost any research question in the field of biology and medicine. To date, more than 24 million scientific papers can be found in PubMed, with many of them containing descriptions of a wide range of biological processes. The analysis of such tremendous amounts of data requires the use of automated text-mining approaches. Although a handful of tools have recently been developed to meet this need, none of them provide error-free extraction of highly detailed information. Results The ANDSystem package was developed for the reconstruction and analysis of molecular genetic networks based on an automated text-mining technique. It provides a detailed description of the various types of interactions between genes, proteins, microRNA's, metabolites, cellular components, pathways and diseases, taking into account the specificity of cell lines and organisms. Although the accuracy of ANDSystem is comparable to other well known text-mining tools, such as Pathway Studio and STRING, it outperforms them in having the ability to identify an increased number of interaction types. Conclusion The use of ANDSystem, in combination with Pathway Studio and STRING, can improve the quality of the automated reconstruction of molecular and genetic networks. ANDSystem should provide a useful tool for researchers working in a number of different fields, including biology, biotechnology, pharmacology and medicine. PMID:25881313

  18. Building the process-drug–side effect network to discover the relationship between biological Processes and side effects

    PubMed Central

    2011-01-01

    Background Side effects are unwanted responses to drug treatment and are important resources for human phenotype information. The recent development of a database on side effects, the side effect resource (SIDER), is a first step in documenting the relationship between drugs and their side effects. It is, however, insufficient to simply find the association of drugs with biological processes; that relationship is crucial because drugs that influence biological processes can have an impact on phenotype. Therefore, knowing which processes respond to drugs that influence the phenotype will enable more effective and systematic study of the effect of drugs on phenotype. To the best of our knowledge, the relationship between biological processes and side effects of drugs has not yet been systematically researched. Methods We propose 3 steps for systematically searching relationships between drugs and biological processes: enrichment scores (ES) calculations, t-score calculation, and threshold-based filtering. Subsequently, the side effect-related biological processes are found by merging the drug-biological process network and the drug-side effect network. Evaluation is conducted in 2 ways: first, by discerning the number of biological processes discovered by our method that co-occur with Gene Ontology (GO) terms in relation to effects extracted from PubMed records using a text-mining technique and second, determining whether there is improvement in performance by limiting response processes by drugs sharing the same side effect to frequent ones alone. Results The multi-level network (the process-drug-side effect network) was built by merging the drug-biological process network and the drug-side effect network. We generated a network of 74 drugs-168 side effects-2209 biological process relation resources. The preliminary results showed that the process-drug-side effect network was able to find meaningful relationships between biological processes and side effects in an

  19. Information theoretic approach to complex biological network reconstruction: application to cytokine release in RAW 264.7 macrophages

    PubMed Central

    2014-01-01

    Background High-throughput methods for biological measurements generate vast amounts of quantitative data, which necessitate the development of advanced approaches to data analysis to help understand the underlying mechanisms and networks. Reconstruction of biological networks from measured data of different components is a significant challenge in systems biology. Results We use an information theoretic approach to reconstruct phosphoprotein-cytokine networks in RAW 264.7 macrophage cells. Cytokines are secreted upon activation of a wide range of regulatory signals transduced by the phosphoprotein network. Identifying these components can help identify regulatory modules responsible for the inflammatory phenotype. The information theoretic approach is based on estimation of mutual information of interactions by using kernel density estimators. Mutual information provides a measure of statistical dependencies between interacting components. Using the topology of the network derived, we develop a data-driven parsimonious input–output model of the phosphoprotein-cytokine network. Conclusions We demonstrate the applicability of our information theoretic approach to reconstruction of biological networks. For the phosphoprotein-cytokine network, this approach not only captures most of the known signaling components involved in cytokine release but also predicts new signaling components involved in the release of cytokines. The results of this study are important for gaining a clear understanding of macrophage activation during the inflammation process. PMID:24964861

  20. Why Traditional Expository Teaching-Learning Approaches May Founder? An Experimental Examination of Neural Networks in Biology Learning

    ERIC Educational Resources Information Center

    Lee, Jun-Ki; Kwon, Yong-Ju

    2011-01-01

    Using functional magnetic resonance imaging (fMRI), this study investigates and discusses neurological explanations for, and the educational implications of, the neural network activations involved in hypothesis-generating and hypothesis-understanding for biology education. Two sets of task paradigms about biological phenomena were designed:…

  1. Networks and their applications to biological systems: From ecological dynamics to gene regulation

    NASA Astrophysics Data System (ADS)

    Sevim, Volkan

    In this dissertation, we study three biological applications of networks. The first one is a biological coevolution model, in which a species is defined by a genome in the form of a finite bitstring and the interactions between species are given by a fixed matrix with randomly distributed elements. Here we study a version of the model, in which the matrix elements are correlated to a controllable degree by means of an averaging scheme. This method allows creation of mutants resembling their ancestors (wildtype). We compare long kinetic Monte Carlo simulations of models with uncorrelated and correlated interactions. We find that while there are quantitative differences, most qualitative features, such as 1/f behavior in power spectral densities for the diversity indices and the power-law distribution of species lifetimes, are not significantly affected by the correlations in the interaction matrix. The second application is the growth of a directed network, in which the growth is constrained by the cost of adding links to the existing nodes. This is a new preferential-attachment scheme, in which a new node attaches to an existing node i with probability pi(k i, k'i ) ∝ ( k'i /ki)gamma, where ki and k'i are the number of outgoing and incoming links at i, respectively, and gamma is a constant. First, we calculate the degree distribution for the outgoing links for a simplified form of this function, pi( ki) ∝ k-1i , both analytically and by Monte Carlo simulations. The distribution decays like kmuk/Gamma(k) for large k, where mu is a constant. We relate this mechanism to simple food-web models by implementing it in the cascade model. We also study the generalized case, pi(ki, k'i ) ∝ ( k'i /ki)gamma, by simulations. The third application is the evolution of robustness to mutations and noise in gene regulatory networks. It has been shown that robustness to mutations and noise can evolve through stabilizing selection for optimal phenotypes in model gene regulatory

  2. International institute for collaborative cell biology and biochemistry--history and memoirs from an international network for biological sciences.

    PubMed

    Cameron, L C

    2013-01-01

    I was invited to write this essay on the occasion of my selection as the recipient of the 2012 Bruce Alberts Award for Excellence in Science Education from the American Society for Cell Biology (ASCB). Receiving this award is an enormous honor. When I read the email announcement for the first time, it was more than a surprise to me, it was unbelievable. I joined ASCB in 1996, when I presented a poster and received a travel award. Since then, I have attended almost every ASCB meeting. I will try to use this essay to share with readers one of the best experiences in my life. Because this is an essay, I take the liberty of mixing some of my thoughts with data in a way that it not usual in scientific writing. I hope that this sacrifice of the format will achieve the goal of conveying what I have learned over the past 20 yr, during which time a group of colleagues and friends created a nexus of knowledge and wisdom. We have worked together to build a network capable of sharing and inspiring science all over the world. PMID:24006381

  3. International Institute for Collaborative Cell Biology and Biochemistry—History and Memoirs from an International Network for Biological Sciences

    PubMed Central

    Cameron, L. C.

    2013-01-01

    I was invited to write this essay on the occasion of my selection as the recipient of the 2012 Bruce Alberts Award for Excellence in Science Education from the American Society for Cell Biology (ASCB). Receiving this award is an enormous honor. When I read the email announcement for the first time, it was more than a surprise to me, it was unbelievable. I joined ASCB in 1996, when I presented a poster and received a travel award. Since then, I have attended almost every ASCB meeting. I will try to use this essay to share with readers one of the best experiences in my life. Because this is an essay, I take the liberty of mixing some of my thoughts with data in a way that it not usual in scientific writing. I hope that this sacrifice of the format will achieve the goal of conveying what I have learned over the past 20 yr, during which time a group of colleagues and friends created a nexus of knowledge and wisdom. We have worked together to build a network capable of sharing and inspiring science all over the world. PMID:24006381

  4. Putting the Biological Species Concept to the Test: Using Mating Networks to Delimit Species

    PubMed Central

    Lagache, Lélia; Leger, Jean-Benoist; Daudin, Jean-Jacques; Petit, Rémy J.; Vacher, Corinne

    2013-01-01

    Although interfertility is the key criterion upon which Mayr’s biological species concept is based, it has never been applied directly to delimit species under natural conditions. Our study fills this gap. We used the interfertility criterion to delimit two closely related oak species in a forest stand by analyzing the network of natural mating events between individuals. The results reveal two groups of interfertile individuals connected by only few mating events. These two groups were largely congruent with those determined using other criteria (morphological similarity, genotypic similarity and individual relatedness). Our study, therefore, shows that the analysis of mating networks is an effective method to delimit species based on the interfertility criterion, provided that adequate network data can be assembled. Our study also shows that although species boundaries are highly congruent across methods of species delimitation, they are not exactly the same. Most of the differences stem from assignment of individuals to an intermediate category. The discrepancies between methods may reflect a biological reality. Indeed, the interfertility criterion is an environment-dependant criterion as species abundances typically affect rates of hybridization under natural conditions. Thus, the methods of species delimitation based on the interfertility criterion are expected to give results slightly different from those based on environment-independent criteria (such as the genotypic similarity criteria). However, whatever the criterion chosen, the challenge we face when delimiting species is to summarize continuous but non-uniform variations in biological diversity. The grade of membership model that we use in this study appears as an appropriate tool. PMID:23818990

  5. B-cell lymphoma gene regulatory networks: biological consistency among inference methods

    PubMed Central

    de Matos Simoes, Ricardo; Dehmer, Matthias; Emmert-Streib, Frank

    2013-01-01

    Despite the development of numerous gene regulatory network (GRN) inference methods in the last years, their application, usage and the biological significance of the resulting GRN remains unclear for our general understanding of large-scale gene expression data in routine practice. In our study, we conduct a structural and a functional analysis of B-cell lymphoma GRNs that were inferred using 3 mutual information-based GRN inference methods: C3Net, BC3Net and Aracne. From a comparative analysis on the global level, we find that the inferred B-cell lymphoma GRNs show major differences. However, on the edge-level and the functional-level—that are more important for our biological understanding—the B-cell lymphoma GRNs were highly similar among each other. Also, the ranks of the degree centrality values and major hub genes in the inferred networks are highly conserved as well. Interestingly, the major hub genes of all GRNs are associated with the G-protein-coupled receptor pathway, cell-cell signaling and cell cycle. This implies that hub genes of the GRNs can be highly consistently inferred with C3Net, BC3Net, and Aracne, representing prominent targets for signaling pathways. Finally, we describe the functional and structural relationship between C3Net, BC3Net and Aracne gene regulatory networks. Our study shows that these GRNs that are inferred from large-scale gene expression data are promising for the identification of novel candidate interactions and pathways that play a key role in the underlying mechanisms driving cancer hallmarks. Overall, our comparative analysis reveals that these GRNs inferred with considerably different inference methods contain large amounts of consistent, method independent, biological information. PMID:24379827

  6. Social insect colony as a biological regulatory system: modelling information flow in dominance networks

    PubMed Central

    Nandi, Anjan K.; Sumana, Annagiri; Bhattacharya, Kunal

    2014-01-01

    Social insects provide an excellent platform to investigate flow of information in regulatory systems since their successful social organization is essentially achieved by effective information transfer through complex connectivity patterns among the colony members. Network representation of such behavioural interactions offers a powerful tool for structural as well as dynamical analysis of the underlying regulatory systems. In this paper, we focus on the dominance interaction networks in the tropical social wasp Ropalidia marginata—a species where behavioural observations indicate that such interactions are principally responsible for the transfer of information between individuals about their colony needs, resulting in a regulation of their own activities. Our research reveals that the dominance networks of R. marginata are structurally similar to a class of naturally evolved information processing networks, a fact confirmed also by the predominance of a specific substructure—the ‘feed-forward loop’—a key functional component in many other information transfer networks. The dynamical analysis through Boolean modelling confirms that the networks are sufficiently stable under small fluctuations and yet capable of more efficient information transfer compared to their randomized counterparts. Our results suggest the involvement of a common structural design principle in different biological regulatory systems and a possible similarity with respect to the effect of selection on the organization levels of such systems. The findings are also consistent with the hypothesis that dominance behaviour has been shaped by natural selection to co-opt the information transfer process in such social insect species, in addition to its primal function of mediation of reproductive competition in the colony. PMID:25320069

  7. Inference of biological networks using Bi-directional Random Forest Granger causality.

    PubMed

    Furqan, Mohammad Shaheryar; Siyal, Mohammad Yakoob

    2016-01-01

    The standard ordinary least squares based Granger causality is one of the widely used methods for detecting causal interactions between time series data. However, recent developments in technology limit the utilization of some existing implementations due to the availability of high dimensional data. In this paper, we are proposing a technique called Bi-directional Random Forest Granger causality. This technique uses the random forest regularization together with the idea of reusing the time series data by reversing the time stamp to extract more causal information. We have demonstrated the effectiveness of our proposed method by applying it to simulated data and then applied it to two real biological datasets, i.e., fMRI and HeLa cell. fMRI data was used to map brain network involved in deductive reasoning while HeLa cell dataset was used to map gene network involved in cancer. PMID:27186478

  8. Partitioning Biological Networks into Highly Connected Clusters with Maximum Edge Coverage.

    PubMed

    Hüffner, Falk; Komusiewicz, Christian; Liebtrau, Adrian; Niedermeier, Rolf

    2014-01-01

    A popular clustering algorithm for biological networks which was proposed by Hartuv and Shamir identifies nonoverlapping highly connected components. We extend the approach taken by this algorithm by introducing the combinatorial optimization problem Highly Connected Deletion, which asks for removing as few edges as possible from a graph such that the resulting graph consists of highly connected components. We show that Highly Connected Deletion is NP-hard and provide a fixed-parameter algorithm and a kernelization. We propose exact and heuristic solution strategies, based on polynomial-time data reduction rules and integer linear programming with column generation. The data reduction typically identifies 75 percent of the edges that are deleted for an optimal solution; the column generation method can then optimally solve protein interaction networks with up to 6,000 vertices and 13,500 edges within five hours. Additionally, we present a new heuristic that finds more clusters than the method by Hartuv and Shamir. PMID:26356014

  9. Collaboration Networks in the Brazilian Scientific Output in Evolutionary Biology: 2000-2012.

    PubMed

    Santin, Dirce M; Vanz, Samile A S; Stumpf, Ida R C

    2016-03-01

    This article analyzes the existing collaboration networks in the Brazilian scientific output in Evolutionary Biology, considering articles published during the period from 2000 to 2012 in journals indexed by Web of Science. The methodology integrates bibliometric techniques and Social Network Analysis resources to describe the growth of Brazilian scientific output and understand the levels, dynamics and structure of collaboration between authors, institutions and countries. The results unveil an enhancement and consolidation of collaborative relationships over time and suggest the existence of key institutions and authors, whose influence on research is expressed by the variety and intensity of the relationships established in the co-authorship of articles. International collaboration, present in more than half of the publications, is highly significant and unusual in Brazilian science. The situation indicates the internationalization of scientific output and the ability of the field to take part in the science produced by the international scientific community. PMID:26871500

  10. Meeting report from the first meetings of the Computational Modeling in Biology Network (COMBINE)

    PubMed Central

    Le Novère, Nicolas; Hucka, Michael; Anwar, Nadia; Bader, Gary D; Demir, Emek; Moodie, Stuart; Sorokin, Anatoly

    2011-01-01

    The Computational Modeling in Biology Network (COMBINE), is an initiative to coordinate the development of the various community standards and formats in computational systems biology and related fields. This report summarizes the activities pursued at the first annual COMBINE meeting held in Edinburgh on October 6-9 2010 and the first HARMONY hackathon, held in New York on April 18-22 2011. The first of those meetings hosted 81 attendees. Discussions covered both official COMBINE standards-(BioPAX, SBGN and SBML), as well as emerging efforts and interoperability between different formats. The second meeting, oriented towards software developers, welcomed 59 participants and witnessed many technical discussions, development of improved standards support in community software systems and conversion between the standards. Both meetings were resounding successes and showed that the field is now mature enough to develop representation formats and related standards in a coordinated manner. PMID:22180826

  11. Physical and Biological Regulation of Neuron Regenerative Growth and Network Formation on Recombinant Dragline Silks

    PubMed Central

    Huang, Wenwen; He, Jiuyang; Jones, Justin; Lewis, Randolph V.; Kaplan, David L.

    2015-01-01

    Recombinant spider silks produced in transgenic goat milk were studied as cell culture matrices for neuronal growth. Major ampullate spidroin 1 (MaSp1) supported neuronal growth, axon extension and network connectivity, with cell morphology comparable to the gold standard poly-lysine. In addition, neurons growing on MaSp1 films had increased neural cell adhesion molecule (NCAM) expression at both mRNA and protein levels. The results indicate that MaSp1 films present useful surface charge and substrate stiffness to support the growth of primary rat cortical neurons. Moreover, a putative neuron-specific surface binding sequence GRGGL within MaSp1 may contribute to the biological regulation of neuron growth. These findings indicate that MaSp1 could regulate neuron growth through its physical and biological features. This dual regulation mode of MaSp1 could provide an alternative strategy for generating functional silk materials for neural tissue engineering. PMID:25701039

  12. Biological neural networks as model systems for designing future parallel processing computers

    NASA Technical Reports Server (NTRS)

    Ross, Muriel D.

    1991-01-01

    One of the more interesting debates of the present day centers on whether human intelligence can be simulated by computer. The author works under the premise that neurons individually are not smart at all. Rather, they are physical units which are impinged upon continuously by other matter that influences the direction of voltage shifts across the units membranes. It is only the action of a great many neurons, billions in the case of the human nervous system, that intelligent behavior emerges. What is required to understand even the simplest neural system is painstaking analysis, bit by bit, of the architecture and the physiological functioning of its various parts. The biological neural network studied, the vestibular utricular and saccular maculas of the inner ear, are among the most simple of the mammalian neural networks to understand and model. While there is still a long way to go to understand even this most simple neural network in sufficient detail for extrapolation to computers and robots, a start was made. Moreover, the insights obtained and the technologies developed help advance the understanding of the more complex neural networks that underlie human intelligence.

  13. Identifying biological pathways that underlie primordial short stature using network analysis

    PubMed Central

    Hanson, Dan; Stevens, Adam; Murray, Philip G; Black, Graeme C M; Clayton, Peter E

    2014-01-01

    Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M ‘interactome’, to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. PMID:24711643

  14. Integrated Bio-Entity Network: A System for Biological Knowledge Discovery

    PubMed Central

    Bell, Lindsey; Chowdhary, Rajesh; Liu, Jun S.; Niu, Xufeng; Zhang, Jinfeng

    2011-01-01

    A significant part of our biological knowledge is centered on relationships between biological entities (bio-entities) such as proteins, genes, small molecules, pathways, gene ontology (GO) terms and diseases. Accumulated at an increasing speed, the information on bio-entity relationships is archived in different forms at scattered places. Most of such information is buried in scientific literature as unstructured text. Organizing heterogeneous information in a structured form not only facilitates study of biological systems using integrative approaches, but also allows discovery of new knowledge in an automatic and systematic way. In this study, we performed a large scale integration of bio-entity relationship information from both databases containing manually annotated, structured information and automatic information extraction of unstructured text in scientific literature. The relationship information we integrated in this study includes protein–protein interactions, protein/gene regulations, protein–small molecule interactions, protein–GO relationships, protein–pathway relationships, and pathway–disease relationships. The relationship information is organized in a graph data structure, named integrated bio-entity network (IBN), where the vertices are the bio-entities and edges represent their relationships. Under this framework, graph theoretic algorithms can be designed to perform various knowledge discovery tasks. We designed breadth-first search with pruning (BFSP) and most probable path (MPP) algorithms to automatically generate hypotheses—the indirect relationships with high probabilities in the network. We show that IBN can be used to generate plausible hypotheses, which not only help to better understand the complex interactions in biological systems, but also provide guidance for experimental designs. PMID:21738677

  15. The role of computer networking in investigating unusual disease outbreaks and allegations of biological and toxin weapons use.

    PubMed

    Woodall, J

    1998-01-01

    Computer networking can aid in the epidemiological investigation of unusual disease outbreaks and possible uses of biological weapons. Exchange of computerized data over the Internet has many advantages in facilitating the investigation of the source of a disease outbreak. It is especially useful in the investigation of suspected or alleged releases of biological weapons. Computer networking through the Internet a fosters a truly global disease outbreak early warning system in which both government and non-government sources are contributing. Such information exchange is of great potential benefit to the Biological Weapons Convention and the attempts to develop a verification protocol. PMID:9800103

  16. miRNAs confer phenotypic robustness to gene networks by suppressing biological noise

    PubMed Central

    Siciliano, Velia; Garzilli, Immacolata; Fracassi, Chiara; Criscuolo, Stefania; Ventre, Simona; di Bernardo, Diego

    2013-01-01

    miRNAs are small non-coding RNAs able to modulate target-gene expression. It has been postulated that miRNAs confer robustness to biological processes, but a clear experimental evidence is still missing. Using a synthetic biology approach, we demonstrate that microRNAs provide phenotypic robustness to transcriptional regulatory networks by buffering fluctuations in protein levels. Here we construct a network motif in mammalian cells exhibiting a “toggle - switch” phenotype in which two alternative protein expression levels define its ON and OFF states. The motif consists of an inducible transcription factor that self-regulates its own transcription and that of a miRNA against the transcription factor itself. We confirm, using mathematical modeling and experimental approaches, that the microRNA confers robustness to the toggle-switch by enabling the cell to maintain and transmit its state. When absent, a dramatic increase in protein noise level occurs, causing the cell to randomly switch between the two states. PMID:24077216

  17. Classification of Time Series Gene Expression in Clinical Studies via Integration of Biological Network

    PubMed Central

    Qian, Liwei; Zheng, Haoran; Zhou, Hong; Qin, Ruibin; Li, Jinlong

    2013-01-01

    The increasing availability of time series expression datasets, although promising, raises a number of new computational challenges. Accordingly, the development of suitable classification methods to make reliable and sound predictions is becoming a pressing issue. We propose, here, a new method to classify time series gene expression via integration of biological networks. We evaluated our approach on 2 different datasets and showed that the use of a hidden Markov model/Gaussian mixture models hybrid explores the time-dependence of the expression data, thereby leading to better prediction results. We demonstrated that the biclustering procedure identifies function-related genes as a whole, giving rise to high accordance in prognosis prediction across independent time series datasets. In addition, we showed that integration of biological networks into our method significantly improves prediction performance. Moreover, we compared our approach with several state-of–the-art algorithms and found that our method outperformed previous approaches with regard to various criteria. Finally, our approach achieved better prediction results on early-stage data, implying the potential of our method for practical prediction. PMID:23516469

  18. Construction of polycythemia vera protein interaction network and prediction of related biological functions.

    PubMed

    Liu, L-J; Cao, X-J; Zhou, C; Sun, Y; Lv, Q-L; Feng, F-B; Zhang, Y-Y; Sun, C-G

    2016-01-01

    Here, polycythemia vera (PV)-related genes were screened by the Online Mendelian Inheritance in Man (OMIM), and literature pertaining to the identified genes was extracted and a protein-protein interaction network was constructed using various Cytoscape plugins. Various molecular complexes were detected using the Clustervize plugin and a gene ontology-enrichment analysis of the biological pathways, molecular functions, and cellular components of the selected molecular complexes were identified using the BiNGo plugin. Fifty-four PV-related genes were identified in OMIM. The protein-protein interaction network contains 5 molecular complexes with correlation integral values >4. These complexes regulated various biological processes (peptide tyrosinase acidification, cell metabolism, and macromolecular biosynthesis), molecular functions (kinase activity, receptor binding, and cytokine activity), and the cellular components were mainly concentrated in the nucleus, intracellular membrane-bounded organelles, and extracellular region. These complexes were associated with the JAK-STAT signal transduction pathway, neurotrophic factor signaling pathway, and Wnt signaling pathway, which were correlated with chronic myeloid leukemia and acute myeloid leukemia. PMID:26909922

  19. Classification of time series gene expression in clinical studies via integration of biological network.

    PubMed

    Qian, Liwei; Zheng, Haoran; Zhou, Hong; Qin, Ruibin; Li, Jinlong

    2013-01-01

    The increasing availability of time series expression datasets, although promising, raises a number of new computational challenges. Accordingly, the development of suitable classification methods to make reliable and sound predictions is becoming a pressing issue. We propose, here, a new method to classify time series gene expression via integration of biological networks. We evaluated our approach on 2 different datasets and showed that the use of a hidden Markov model/Gaussian mixture models hybrid explores the time-dependence of the expression data, thereby leading to better prediction results. We demonstrated that the biclustering procedure identifies function-related genes as a whole, giving rise to high accordance in prognosis prediction across independent time series datasets. In addition, we showed that integration of biological networks into our method significantly improves prediction performance. Moreover, we compared our approach with several state-of-the-art algorithms and found that our method outperformed previous approaches with regard to various criteria. Finally, our approach achieved better prediction results on early-stage data, implying the potential of our method for practical prediction. PMID:23516469

  20. Measuring information flow in cellular networks by the systems biology method through microarray data

    PubMed Central

    Chen, Bor-Sen; Li, Cheng-Wei

    2015-01-01

    In general, it is very difficult to measure the information flow in a cellular network directly. In this study, based on an information flow model and microarray data, we measured the information flow in cellular networks indirectly by using a systems biology method. First, we used a recursive least square parameter estimation algorithm to identify the system parameters of coupling signal transduction pathways and the cellular gene regulatory network (GRN). Then, based on the identified parameters and systems theory, we estimated the signal transductivities of the coupling signal transduction pathways from the extracellular signals to each downstream protein and the information transductivities of the GRN between transcription factors in response to environmental events. According to the proposed method, the information flow, which is characterized by signal transductivity in coupling signaling pathways and information transductivity in the GRN, can be estimated by microarray temporal data or microarray sample data. It can also be estimated by other high-throughput data such as next-generation sequencing or proteomic data. Finally, the information flows of the signal transduction pathways and the GRN in leukemia cancer cells and non-leukemia normal cells were also measured to analyze the systematic dysfunction in this cancer from microarray sample data. The results show that the signal transductivities of signal transduction pathways change substantially from normal cells to leukemia cancer cells. PMID:26082788

  1. [Regulation network and biological roles of LEAFY in Arabidopsis thaliana in floral development].

    PubMed

    Wang, Li-Lin; Liang, Hai-Man; Pang, Ji-Liang; Zhu, Mu-Yuan

    2004-01-01

    Recent research progress on regulation network and biological roles of LFY gene in Arabidopsis thaliana and its homologue genes in floral development are reviewed emphatically in the present paper. LFY gene expresses widely in both vegetative and reproductive tissues in different higher plants, therefore investigation on role of LFY gene on flowering is of general significance. LFY gene plays an important role to promote flower formation by interaction and coordination with other genes,such as TFL, EMF, AP1, AP2, CAL, FWA, FT, AP3, PI, AG, UFO, CO, LD, GA1 etc, and a critical level of LFY expression is essential. LFY gene not only controls flowering-time and floral transition,but also plays an important role in inflorescence and floral organ development. It was situated at the central site in gene network of flowering regulation,positively or negatively regulates the level or activities of flowering-related genes. Some physiological factors, such as carbon sources, phytohormones, affect directly or indirectly the expression and actions of LFY gene. This indicates that level of LFY expression can also be regulated with physiological methods. It is probable that we can explain the principal mechanism of flowering by regulation network of LFY gene. PMID:15626683

  2. Ontology-supported Research on Vaccine Efficacy, Safety, and Integrative Biological Networks

    PubMed Central

    He, Yongqun

    2016-01-01

    Summary While vaccine efficacy and safety research has dramatically progressed with the methods of in silico prediction and data mining, many challenges still exist. A formal ontology is a human- and computer-interpretable set of terms and relations that represent entities in a specific domain and how these terms relate to each other. Several community-based ontologies (including the Vaccine Ontology, Ontology of Adverse Events, and Ontology of Vaccine Adverse Events) have been developed to support vaccine and adverse event representation, classification, data integration, literature mining of host-vaccine interaction networks, and analysis of vaccine adverse events. The author further proposes minimal vaccine information standards and their ontology representations, ontology-based linked open vaccine data and meta-analysis, an integrative One Network (“OneNet”) Theory of Life, and ontology-based approaches to study and apply the OneNet theory. In the Big Data era, these proposed strategies provide a novel framework for advanced data integration and analysis of fundamental biological networks including vaccine immune mechanisms. PMID:24909153

  3. A network biology approach to denitrification in Pseudomonas aeruginosa

    SciTech Connect

    Arat, Seda; Bullerjahn, George S.; Laubenbacher, Reinhard

    2015-02-23

    Pseudomonas aeruginosa is a metabolically flexible member of the Gammaproteobacteria. Under anaerobic conditions and the presence of nitrate, P. aeruginosa can perform (complete) denitrification, a respiratory process of dissimilatory nitrate reduction to nitrogen gas via nitrite (NO₂), nitric oxide (NO) and nitrous oxide (N₂O). This study focuses on understanding the influence of environmental conditions on bacterial denitrification performance, using a mathematical model of a metabolic network in P. aeruginosa. To our knowledge, this is the first mathematical model of denitrification for this bacterium. Analysis of the long-term behavior of the network under changing concentration levels of oxygen (O₂), nitrate (NO₃), and phosphate (PO₄) suggests that PO₄ concentration strongly affects denitrification performance. The model provides three predictions on denitrification activity of P. aeruginosa under various environmental conditions, and these predictions are either experimentally validated or supported by pertinent biological literature. One motivation for this study is to capture the effect of PO₄ on a denitrification metabolic network of P. aeruginosa in order to shed light on mechanisms for greenhouse gas N₂O accumulation during seasonal oxygen depletion in aquatic environments such as Lake Erie (Laurentian Great Lakes, USA). Simulating the microbial production of greenhouse gases in anaerobic aquatic systems such as Lake Erie allows a deeper understanding of the contributing environmental effects that will inform studies on, and remediation strategies for, other hypoxic sites worldwide.

  4. Testing Foundations of Biological Scaling Theory Using Automated Measurements of Vascular Networks.

    PubMed

    Newberry, Mitchell G; Ennis, Daniel B; Savage, Van M

    2015-08-01

    Scientists have long sought to understand how vascular networks supply blood and oxygen to cells throughout the body. Recent work focuses on principles that constrain how vessel size changes through branching generations from the aorta to capillaries and uses scaling exponents to quantify these changes. Prominent scaling theories predict that combinations of these exponents explain how metabolic, growth, and other biological rates vary with body size. Nevertheless, direct measurements of individual vessel segments have been limited because existing techniques for measuring vasculature are invasive, time consuming, and technically difficult. We developed software that extracts the length, radius, and connectivity of in vivo vessels from contrast-enhanced 3D Magnetic Resonance Angiography. Using data from 20 human subjects, we calculated scaling exponents by four methods-two derived from local properties of branching junctions and two from whole-network properties. Although these methods are often used interchangeably in the literature, we do not find general agreement between these methods, particularly for vessel lengths. Measurements for length of vessels also diverge from theoretical values, but those for radius show stronger agreement. Our results demonstrate that vascular network models cannot ignore certain complexities of real vascular systems and indicate the need to discover new principles regarding vessel lengths. PMID:26317654

  5. Testing Foundations of Biological Scaling Theory Using Automated Measurements of Vascular Networks

    PubMed Central

    Newberry, Mitchell G; Ennis, Daniel B; Savage, Van M

    2015-01-01

    Scientists have long sought to understand how vascular networks supply blood and oxygen to cells throughout the body. Recent work focuses on principles that constrain how vessel size changes through branching generations from the aorta to capillaries and uses scaling exponents to quantify these changes. Prominent scaling theories predict that combinations of these exponents explain how metabolic, growth, and other biological rates vary with body size. Nevertheless, direct measurements of individual vessel segments have been limited because existing techniques for measuring vasculature are invasive, time consuming, and technically difficult. We developed software that extracts the length, radius, and connectivity of in vivo vessels from contrast-enhanced 3D Magnetic Resonance Angiography. Using data from 20 human subjects, we calculated scaling exponents by four methods—two derived from local properties of branching junctions and two from whole-network properties. Although these methods are often used interchangeably in the literature, we do not find general agreement between these methods, particularly for vessel lengths. Measurements for length of vessels also diverge from theoretical values, but those for radius show stronger agreement. Our results demonstrate that vascular network models cannot ignore certain complexities of real vascular systems and indicate the need to discover new principles regarding vessel lengths. PMID:26317654

  6. Consistent Robustness Analysis (CRA) Identifies Biologically Relevant Properties of Regulatory Network Models

    PubMed Central

    Saithong, Treenut; Painter, Kevin J.; Millar, Andrew J.

    2010-01-01

    Background A number of studies have previously demonstrated that “goodness of fit” is insufficient in reliably classifying the credibility of a biological model. Robustness and/or sensitivity analysis is commonly employed as a secondary method for evaluating the suitability of a particular model. The results of such analyses invariably depend on the particular parameter set tested, yet many parameter values for biological models are uncertain. Results Here, we propose a novel robustness analysis that aims to determine the “common robustness” of the model with multiple, biologically plausible parameter sets, rather than the local robustness for a particular parameter set. Our method is applied to two published models of the Arabidopsis circadian clock (the one-loop [1] and two-loop [2] models). The results reinforce current findings suggesting the greater reliability of the two-loop model and pinpoint the crucial role of TOC1 in the circadian network. Conclusions Consistent Robustness Analysis can indicate both the relative plausibility of different models and also the critical components and processes controlling each model. PMID:21179566

  7. Hydrologic and biologic influences on stream network nutrient concentrations: Interactions of hydrologic turnover and concentration-dependent nutrient uptake

    NASA Astrophysics Data System (ADS)

    Mallard, John; McGlynn, Brian; Covino, Tim

    2016-04-01

    Stream networks lie in a crucial landscape position between terrestrial ecosystems and downstream water bodies. As such, whether inferring terrestrial watershed processes from watershed outlet nutrient signals or predicting the effect of observed terrestrial processes on stream nutrient signals, it is requisite to understand how stream networks can modulate terrestrial nutrient inputs. To date integrated understanding and modeling of physical and biological influences on nutrient concentrations at the stream network scale have been limited. However, watershed scale groundwater ‑ surface water exchange (hydrologic turnover), concentration-variable biological uptake, and the interaction between the two can strongly modify stream water nutrient concentrations. Stream water and associated nutrients are lost to and replaced from groundwater with distinct nutrient concentrations while in-stream nutrients can also be retained by biological processes at rates that vary with concentration. We developed an empirically based network scale model to simulate the interaction between hydrologic turnover and concentration-dependent nutrient uptake across stream networks. Exchange and uptake parameters were measured using conservative and nutrient tracer addition experiments in the Bull Trout Watershed, central Idaho. We found that the interaction of hydrologic turnover and concentration-dependent uptake combined to modify and subsequently stabilize in-stream concentrations, with specific concentrations dependent on the magnitude of hydrologic turnover, groundwater concentrations, and the shape of nutrient uptake kinetic curves. We additionally found that by varying these physical and biological parameters within measured ranges we were able to generate a spectrum of stream network concentration distributions representing a continuum of shifting magnitudes of physical and biological influences on in-stream concentrations. These findings elucidate the important and variable role

  8. Hydrologic and biologic influences on stream network nutrient concentrations: Interactions of hydrologic turnover and concentration-dependent nutrient uptake

    NASA Astrophysics Data System (ADS)

    Mallard, J. M.; McGlynn, B. L.; Covino, T. P.; Bergstrom, A.

    2012-12-01

    Stream networks lie in a crucial landscape position between terrestrial ecosystems and downstream water bodies. As such, whether inferring terrestrial watershed processes from watershed outlet nutrient signals or predicting the effect of observed terrestrial processes on stream nutrient signals, it is requisite to understand how stream networks can modulate terrestrial nutrient inputs. To date integrated understanding and modeling of physical and biological influences on nutrient concentrations at the stream network scale have been limited. However, watershed scale groundwater - surface water exchange (hydrologic turnover), concentration-variable biological uptake, and the interaction between the two can strongly modify stream water nutrient concentrations. Stream water and associated nutrients are lost to and replaced from groundwater with a distinct nutrient concentrations while in-stream nutrients can also be retained by biological processes at rates that vary with concentration. We developed an empirically based network scale model to simulate the interaction between hydrologic turnover and concentration-dependent nutrient uptake across stream networks. Exchange and uptake parameters were measured using conservative and nutrient tracer addition experiments in the Bull Trout Watershed, central Idaho. We found that the interaction of hydrologic turnover and concentration-dependent uptake combined to modify and subsequently stabilize in-stream concentrations, with specific concentrations dependent on the magnitude of hydrologic turnover, groundwater concentrations, and the shape of nutrient uptake kinetic curves. We additionally found that by varying these physical and biological parameters within measured ranges we were able to generate a spectrum of stream network concentration distributions representing a continuum of shifting magnitudes of physical and biological influences on in-stream concentrations. These findings elucidate the important and variable role

  9. A Systems Biology Approach Identifies a Regulatory Network in Parotid Acinar Cell Terminal Differentiation

    PubMed Central

    Metzler, Melissa A.; Venkatesh, Srirangapatnam G.; Lakshmanan, Jaganathan; Carenbauer, Anne L.; Perez, Sara M.; Andres, Sarah A.; Appana, Savitri; Brock, Guy N.; Wittliff, James L.; Darling, Douglas S.

    2015-01-01

    Objective The transcription factor networks that drive parotid salivary gland progenitor cells to terminally differentiate, remain largely unknown and are vital to understanding the regeneration process. Methodology A systems biology approach was taken to measure mRNA and microRNA expression in vivo across acinar cell terminal differentiation in the rat parotid salivary gland. Laser capture microdissection (LCM) was used to specifically isolate acinar cell RNA at times spanning the month-long period of parotid differentiation. Results Clustering of microarray measurements suggests that expression occurs in four stages. mRNA expression patterns suggest a novel role for Pparg which is transiently increased during mid postnatal differentiation in concert with several target gene mRNAs. 79 microRNAs are significantly differentially expressed across time. Profiles of statistically significant changes of mRNA expression, combined with reciprocal correlations of microRNAs and their target mRNAs, suggest a putative network involving Klf4, a differentiation inhibiting transcription factor, which decreases as several targeting microRNAs increase late in differentiation. The network suggests a molecular switch (involving Prdm1, Sox11, Pax5, miR-200a, and miR-30a) progressively decreases repression of Xbp1 gene transcription, in concert with decreased translational repression by miR-214. The transcription factor Xbp1 mRNA is initially low, increases progressively, and may be maintained by a positive feedback loop with Atf6. Transfection studies show that Xbp1Mist1 promoter. In addition, Xbp1 and Mist1 each activate the parotid secretory protein (Psp) gene, which encodes an abundant salivary protein, and is a marker of terminal differentiation. Conclusion This study identifies novel expression patterns of Pparg, Klf4, and Sox11 during parotid acinar cell differentiation, as well as numerous differentially expressed microRNAs. Network analysis identifies a novel stemness arm, a

  10. Using Nonlinear Stochastic Evolutionary Game Strategy to Model an Evolutionary Biological Network of Organ Carcinogenesis Under a Natural Selection Scheme

    PubMed Central

    Chen, Bor-Sen; Tsai, Kun-Wei; Li, Cheng-Wei

    2015-01-01

    Molecular biologists have long recognized carcinogenesis as an evolutionary process that involves natural selection. Cancer is driven by the somatic evolution of cell lineages. In this study, the evolution of somatic cancer cell lineages during carcinogenesis was modeled as an equilibrium point (ie, phenotype of attractor) shifting, the process of a nonlinear stochastic evolutionary biological network. This process is subject to intrinsic random fluctuations because of somatic genetic and epigenetic variations, as well as extrinsic disturbances because of carcinogens and stressors. In order to maintain the normal function (ie, phenotype) of an evolutionary biological network subjected to random intrinsic fluctuations and extrinsic disturbances, a network robustness scheme that incorporates natural selection needs to be developed. This can be accomplished by selecting certain genetic and epigenetic variations to modify the network structure to attenuate intrinsic fluctuations efficiently and to resist extrinsic disturbances in order to maintain the phenotype of the evolutionary biological network at an equilibrium point (attractor). However, during carcinogenesis, the remaining (or neutral) genetic and epigenetic variations accumulate, and the extrinsic disturbances become too large to maintain the normal phenotype at the desired equilibrium point for the nonlinear evolutionary biological network. Thus, the network is shifted to a cancer phenotype at a new equilibrium point that begins a new evolutionary process. In this study, the natural selection scheme of an evolutionary biological network of carcinogenesis was derived from a robust negative feedback scheme based on the nonlinear stochastic Nash game strategy. The evolvability and phenotypic robustness criteria of the evolutionary cancer network were also estimated by solving a Hamilton–Jacobi inequality – constrained optimization problem. The simulation revealed that the phenotypic shift of the lung cancer

  11. Using Nonlinear Stochastic Evolutionary Game Strategy to Model an Evolutionary Biological Network of Organ Carcinogenesis Under a Natural Selection Scheme.

    PubMed

    Chen, Bor-Sen; Tsai, Kun-Wei; Li, Cheng-Wei

    2015-01-01

    Molecular biologists have long recognized carcinogenesis as an evolutionary process that involves natural selection. Cancer is driven by the somatic evolution of cell lineages. In this study, the evolution of somatic cancer cell lineages during carcinogenesis was modeled as an equilibrium point (ie, phenotype of attractor) shifting, the process of a nonlinear stochastic evolutionary biological network. This process is subject to intrinsic random fluctuations because of somatic genetic and epigenetic variations, as well as extrinsic disturbances because of carcinogens and stressors. In order to maintain the normal function (ie, phenotype) of an evolutionary biological network subjected to random intrinsic fluctuations and extrinsic disturbances, a network robustness scheme that incorporates natural selection needs to be developed. This can be accomplished by selecting certain genetic and epigenetic variations to modify the network structure to attenuate intrinsic fluctuations efficiently and to resist extrinsic disturbances in order to maintain the phenotype of the evolutionary biological network at an equilibrium point (attractor). However, during carcinogenesis, the remaining (or neutral) genetic and epigenetic variations accumulate, and the extrinsic disturbances become too large to maintain the normal phenotype at the desired equilibrium point for the nonlinear evolutionary biological network. Thus, the network is shifted to a cancer phenotype at a new equilibrium point that begins a new evolutionary process. In this study, the natural selection scheme of an evolutionary biological network of carcinogenesis was derived from a robust negative feedback scheme based on the nonlinear stochastic Nash game strategy. The evolvability and phenotypic robustness criteria of the evolutionary cancer network were also estimated by solving a Hamilton-Jacobi inequality - constrained optimization problem. The simulation revealed that the phenotypic shift of the lung cancer

  12. An epidemic model for biological data fusion in ad hoc sensor networks

    NASA Astrophysics Data System (ADS)

    Chang, K. C.; Kotari, Vikas

    2009-05-01

    Bio terrorism can be a very refined and a catastrophic approach of attacking a nation. This requires the development of a complete architecture dedicatedly designed for this purpose which includes but is not limited to Sensing/Detection, Tracking and Fusion, Communication, and others. In this paper we focus on one such architecture and evaluate its performance. Various sensors for this specific purpose have been studied. The accent has been on use of Distributed systems such as ad-hoc networks and on application of epidemic data fusion algorithms to better manage the bio threat data. The emphasis has been on understanding the performance characteristics of these algorithms under diversified real time scenarios which are implemented through extensive JAVA based simulations. Through comparative studies on communication and fusion the performance of channel filter algorithm for the purpose of biological sensor data fusion are validated.

  13. Object-Oriented NeuroSys: Parallel Programs for Simulating Large Networks of Biologically Accurate Neurons

    SciTech Connect

    Pacheco, P; Miller, P; Kim, J; Leese, T; Zabiyaka, Y

    2003-05-07

    Object-oriented NeuroSys (ooNeuroSys) is a collection of programs for simulating very large networks of biologically accurate neurons on distributed memory parallel computers. It includes two principle programs: ooNeuroSys, a parallel program for solving the large systems of ordinary differential equations arising from the interconnected neurons, and Neurondiz, a parallel program for visualizing the results of ooNeuroSys. Both programs are designed to be run on clusters and use the MPI library to obtain parallelism. ooNeuroSys also includes an easy-to-use Python interface. This interface allows neuroscientists to quickly develop and test complex neuron models. Both ooNeuroSys and Neurondiz have a design that allows for both high performance and relative ease of maintenance.

  14. Ligand Biological Activity Predictions Using Fingerprint-Based Artificial Neural Networks (FANN-QSAR)

    PubMed Central

    Myint, Kyaw Z.; Xie, Xiang-Qun

    2015-01-01

    This chapter focuses on the fingerprint-based artificial neural networks QSAR (FANN-QSAR) approach to predict biological activities of structurally diverse compounds. Three types of fingerprints, namely ECFP6, FP2, and MACCS, were used as inputs to train the FANN-QSAR models. The results were benchmarked against known 2D and 3D QSAR methods, and the derived models were used to predict cannabinoid (CB) ligand binding activities as a case study. In addition, the FANN-QSAR model was used as a virtual screening tool to search a large NCI compound database for lead cannabinoid compounds. We discovered several compounds with good CB2 binding affinities ranging from 6.70 nM to 3.75 μM. The studies proved that the FANN-QSAR method is a useful approach to predict bioactivities or properties of ligands and to find novel lead compounds for drug discovery research. PMID:25502380

  15. Integration, Networking, and Global Biobanking in the Age of New Biology.

    PubMed

    Karimi-Busheri, Feridoun; Rasouli-Nia, Aghdass

    2015-01-01

    Scientific revolution is changing the world forever. Many new disciplines and fields have emerged with unlimited possibilities and opportunities. Biobanking is one of many that is benefiting from revolutionary milestones in human genome, post-genomic, and computer and bioinformatics discoveries. The storage, management, and analysis of massive clinical and biological data sets cannot be achieved without a global collaboration and networking. At the same time, biobanking is facing many significant challenges that need to be addressed and solved including dealing with an ever increasing complexity of sample storage and retrieval, data management and integration, and establishing common platforms in a global context. The overall picture of the biobanking of the future, however, is promising. Many population-based biobanks have been formed, and more are under development. It is certain that amazing discoveries will emerge from this large-scale method of preserving and accessing human samples. Signs of a healthy collaboration between industry, academy, and government are encouraging. PMID:26420609

  16. Orientational tomography of optical axes directions distributions of multilayer biological tissues birefringent polycrystalline networks

    NASA Astrophysics Data System (ADS)

    Zabolotna, Natalia I.; Dovhaliuk, Rostyslav Y.

    2013-09-01

    We present a novel measurement method of optic axes orientation distribution which uses a relatively simple measurement setup. The principal difference of our method from other well-known methods lies in direct approach for measuring the orientation of optical axis of polycrystalline networks biological crystals. Our test polarimetry setup consists of HeNe laser, quarter wave plate, two linear polarizers and a CCD camera. We also propose a methodology for processing of measured optic axes orientation distribution which consists of evaluation of statistical, correlational and spectral moments. Such processing of obtained data can be used to classify particular tissue sample as "healthy" or "pathological". For our experiment we use thin layers of histological section of normal and muscular dystrophy tissue sections. It is shown that the difference between mentioned moments` values of normal and pathological samples can be quite noticeable with relative difference up to 6.26.

  17. Sieve-based relation extraction of gene regulatory networks from biological literature

    PubMed Central

    2015-01-01

    Background Relation extraction is an essential procedure in literature mining. It focuses on extracting semantic relations between parts of text, called mentions. Biomedical literature includes an enormous amount of textual descriptions of biological entities, their interactions and results of related experiments. To extract them in an explicit, computer readable format, these relations were at first extracted manually from databases. Manual curation was later replaced with automatic or semi-automatic tools with natural language processing capabilities. The current challenge is the development of information extraction procedures that can directly infer more complex relational structures, such as gene regulatory networks. Results We develop a computational approach for extraction of gene regulatory networks from textual data. Our method is designed as a sieve-based system and uses linear-chain conditional random fields and rules for relation extraction. With this method we successfully extracted the sporulation gene regulation network in the bacterium Bacillus subtilis for the information extraction challenge at the BioNLP 2013 conference. To enable extraction of distant relations using first-order models, we transform the data into skip-mention sequences. We infer multiple models, each of which is able to extract different relationship types. Following the shared task, we conducted additional analysis using different system settings that resulted in reducing the reconstruction error of bacterial sporulation network from 0.73 to 0.68, measured as the slot error rate between the predicted and the reference network. We observe that all relation extraction sieves contribute to the predictive performance of the proposed approach. Also, features constructed by considering mention words and their prefixes and suffixes are the most important features for higher accuracy of extraction. Analysis of distances between different mention types in the text shows that our choice

  18. A predicted functional gene network for the plant pathogen Phytophthora infestans as a framework for genomic biology

    PubMed Central

    2013-01-01

    Background Associations between proteins are essential to understand cell biology. While this complex interplay between proteins has been studied in model organisms, it has not yet been described for the oomycete late blight pathogen Phytophthora infestans. Results We present an integrative probabilistic functional gene network that provides associations for 37 percent of the predicted P. infestans proteome. Our method unifies available genomic, transcriptomic and comparative genomic data into a single comprehensive network using a Bayesian approach. Enrichment of proteins residing in the same or related subcellular localization validates the biological coherence of our predictions. The network serves as a framework to query existing genomic data using network-based methods, which thus far was not possible in Phytophthora. We used the network to study the set of interacting proteins that are encoded by genes co-expressed during sporulation. This identified potential novel roles for proteins in spore formation through their links to proteins known to be involved in this process such as the phosphatase Cdc14. Conclusions The functional association network represents a novel genome-wide data source for P. infestans that also acts as a framework to interrogate other system-wide data. In both capacities it will improve our understanding of the complex biology of P. infestans and related oomycete pathogens. PMID:23865555

  19. Monotonicity, frustration, and ordered response: an analysis of the energy landscape of perturbed large-scale biological networks

    PubMed Central

    2010-01-01

    Background For large-scale biological networks represented as signed graphs, the index of frustration measures how far a network is from a monotone system, i.e., how incoherently the system responds to perturbations. Results In this paper we find that the frustration is systematically lower in transcriptional networks (modeled at functional level) than in signaling and metabolic networks (modeled at stoichiometric level). A possible interpretation of this result is in terms of energetic cost of an interaction: an erroneous or contradictory transcriptional action costs much more than a signaling/metabolic error, and therefore must be avoided as much as possible. Averaging over all possible perturbations, however, we also find that unlike for transcriptional networks, in the signaling/metabolic networks the probability of finding the system in its least frustrated configuration tends to be high also in correspondence of a moderate energetic regime, meaning that, in spite of the higher frustration, these networks can achieve a globally ordered response to perturbations even for moderate values of the strength of the interactions. Furthermore, an analysis of the energy landscape shows that signaling and metabolic networks lack energetic barriers around their global optima, a property also favouring global order. Conclusion In conclusion, transcriptional and signaling/metabolic networks appear to have systematic differences in both the index of frustration and the transition to global order. These differences are interpretable in terms of the different functions of the various classes of networks. PMID:20537143

  20. A biologically plausible learning rule for the Infomax on recurrent neural networks.

    PubMed

    Hayakawa, Takashi; Kaneko, Takeshi; Aoyagi, Toshio

    2014-01-01

    A fundamental issue in neuroscience is to understand how neuronal circuits in the cerebral cortex play their functional roles through their characteristic firing activity. Several characteristics of spontaneous and sensory-evoked cortical activity have been reproduced by Infomax learning of neural networks in computational studies. There are, however, still few models of the underlying learning mechanisms that allow cortical circuits to maximize information and produce the characteristics of spontaneous and sensory-evoked cortical activity. In the present article, we derive a biologically plausible learning rule for the maximization of information retained through time in dynamics of simple recurrent neural networks. Applying the derived learning rule in a numerical simulation, we reproduce the characteristics of spontaneous and sensory-evoked cortical activity: cell-assembly-like repeats of precise firing sequences, neuronal avalanches, spontaneous replays of learned firing sequences and orientation selectivity observed in the primary visual cortex. We further discuss the similarity between the derived learning rule and the spike timing-dependent plasticity of cortical neurons. PMID:25505404

  1. Toward Building Hybrid Biological/in silico Neural Networks for Motor Neuroprosthetic Control

    PubMed Central

    Kocaturk, Mehmet; Gulcur, Halil Ozcan; Canbeyli, Resit

    2015-01-01

    In this article, we introduce the Bioinspired Neuroprosthetic Design Environment (BNDE) as a practical platform for the development of novel brain–machine interface (BMI) controllers, which are based on spiking model neurons. We built the BNDE around a hard real-time system so that it is capable of creating simulated synapses from extracellularly recorded neurons to model neurons. In order to evaluate the practicality of the BNDE for neuroprosthetic control experiments, a novel, adaptive BMI controller was developed and tested using real-time closed-loop simulations. The present controller consists of two in silico medium spiny neurons, which receive simulated synaptic inputs from recorded motor cortical neurons. In the closed-loop simulations, the recordings from the cortical neurons were imitated using an external, hardware-based neural signal synthesizer. By implementing a reward-modulated spike timing-dependent plasticity rule, the controller achieved perfect target reach accuracy for a two-target reaching task in one-dimensional space. The BNDE combines the flexibility of software-based spiking neural network (SNN) simulations with powerful online data visualization tools and is a low-cost, PC-based, and all-in-one solution for developing neurally inspired BMI controllers. We believe that the BNDE is the first implementation, which is capable of creating hybrid biological/in silico neural networks for motor neuroprosthetic control and utilizes multiple CPU cores for computationally intensive real-time SNN simulations. PMID:26321943

  2. A biologically plausible learning rule for the Infomax on recurrent neural networks

    PubMed Central

    Hayakawa, Takashi; Kaneko, Takeshi; Aoyagi, Toshio

    2014-01-01

    A fundamental issue in neuroscience is to understand how neuronal circuits in the cerebral cortex play their functional roles through their characteristic firing activity. Several characteristics of spontaneous and sensory-evoked cortical activity have been reproduced by Infomax learning of neural networks in computational studies. There are, however, still few models of the underlying learning mechanisms that allow cortical circuits to maximize information and produce the characteristics of spontaneous and sensory-evoked cortical activity. In the present article, we derive a biologically plausible learning rule for the maximization of information retained through time in dynamics of simple recurrent neural networks. Applying the derived learning rule in a numerical simulation, we reproduce the characteristics of spontaneous and sensory-evoked cortical activity: cell-assembly-like repeats of precise firing sequences, neuronal avalanches, spontaneous replays of learned firing sequences and orientation selectivity observed in the primary visual cortex. We further discuss the similarity between the derived learning rule and the spike timing-dependent plasticity of cortical neurons. PMID:25505404

  3. Toward Building Hybrid Biological/in silico Neural Networks for Motor Neuroprosthetic Control.

    PubMed

    Kocaturk, Mehmet; Gulcur, Halil Ozcan; Canbeyli, Resit

    2015-01-01

    In this article, we introduce the Bioinspired Neuroprosthetic Design Environment (BNDE) as a practical platform for the development of novel brain-machine interface (BMI) controllers, which are based on spiking model neurons. We built the BNDE around a hard real-time system so that it is capable of creating simulated synapses from extracellularly recorded neurons to model neurons. In order to evaluate the practicality of the BNDE for neuroprosthetic control experiments, a novel, adaptive BMI controller was developed and tested using real-time closed-loop simulations. The present controller consists of two in silico medium spiny neurons, which receive simulated synaptic inputs from recorded motor cortical neurons. In the closed-loop simulations, the recordings from the cortical neurons were imitated using an external, hardware-based neural signal synthesizer. By implementing a reward-modulated spike timing-dependent plasticity rule, the controller achieved perfect target reach accuracy for a two-target reaching task in one-dimensional space. The BNDE combines the flexibility of software-based spiking neural network (SNN) simulations with powerful online data visualization tools and is a low-cost, PC-based, and all-in-one solution for developing neurally inspired BMI controllers. We believe that the BNDE is the first implementation, which is capable of creating hybrid biological/in silico neural networks for motor neuroprosthetic control and utilizes multiple CPU cores for computationally intensive real-time SNN simulations. PMID:26321943

  4. Partitioning Biological Networks into Highly Connected Clusters with Maximum Edge Coverage.

    PubMed

    Hüffner, Falk; Komusiewicz, Christian; Liebtrau, Adrian; Niedermeier, Rolf

    2013-12-11

    A popular clustering algorithm for biological networks which was proposed by Hartuv and Shamir [IPL 2000] identifies nonoverlapping highly connected components. We extend the approach taken by this algorithm by introducing the combinatorial optimization problem Highly Connected Deletion, which asks for removing as few edges as possible from a graph such that the resulting graph consists of highly connected components. We show that Highly Connected Deletion is NP-hard and provide a fixed-parameter algorithm and a kernelization. We propose exact and heuristic solution strategies, based on polynomial-time data reduction rules and integer linear programming with column generation. The data reduction typically identifies 75% of the edges that are deleted for an optimal solution; the column generation method can then optimally solve protein interaction networks with up to 6,000 vertices and 13,500 edges in less than a day. Additionally, we present a new heuristic that finds more clusters than the method by Hartuv and Shamir. PMID:24344094

  5. Efficient reconstruction of biological networks via transitive reduction on general purpose graphics processors

    PubMed Central

    2012-01-01

    Background Techniques for reconstruction of biological networks which are based on perturbation experiments often predict direct interactions between nodes that do not exist. Transitive reduction removes such relations if they can be explained by an indirect path of influences. The existing algorithms for transitive reduction are sequential and might suffer from too long run times for large networks. They also exhibit the anomaly that some existing direct interactions are also removed. Results We develop efficient scalable parallel algorithms for transitive reduction on general purpose graphics processing units for both standard (unweighted) and weighted graphs. Edge weights are regarded as uncertainties of interactions. A direct interaction is removed only if there exists an indirect interaction path between the same nodes which is strictly more certain than the direct one. This is a refinement of the removal condition for the unweighted graphs and avoids to a great extent the erroneous elimination of direct edges. Conclusions Parallel implementations of these algorithms can achieve speed-ups of two orders of magnitude compared to their sequential counterparts. Our experiments show that: i) taking into account the edge weights improves the reconstruction quality compared to the unweighted case; ii) it is advantageous not to distinguish between positive and negative interactions since this lowers the complexity of the algorithms from NP-complete to polynomial without loss of quality. PMID:23110660

  6. Molecular Fingerprint-based Artificial Neural Networks QSAR for Ligand Biological Activity Predictions

    PubMed Central

    Myint, Kyaw-Zeyar; Wang, Lirong; Tong, Qin; Xie, Xiang-Qun

    2012-01-01

    In this manuscript, we have reported a novel 2D fingerprint-based artificial neural network QSAR (FANN-QSAR) method in order to effectively predict biological activities of structurally diverse chemical ligands. Three different types of fingerprints, namely ECFP6, FP2 and MACCS, were used in FANN-QSAR algorithm development, and FANN-QSAR models were compared to known 3D and 2D QSAR methods using five data sets previously reported. In addition, the derived models were used to predict GPCR cannabinoid ligand binding affinities using our manually curated cannabinoid ligand database containing 1699 structurally diverse compounds with reported cannabinoid receptor subtype CB2 activities. To demonstrate its useful applications, the established FANN-QSAR algorithm was used as a virtual screening tool to search a large NCI compound database for lead cannabinoid compounds and we have discovered several compounds with good CB2 binding affinities ranging from 6.70 nM to 3.75 μM. To the best of our knowledge, this is the first report for a fingerprint-based neural network approach validated with a successful virtual screening application in identifying lead compounds. The studies proved that the FANN-QSAR method is a useful approach to predict bioactivities or properties of ligands and to find novel lead compounds for drug discovery research. PMID:22937990

  7. In silico model-based inference: a contemporary approach for hypothesis testing in network biology

    PubMed Central

    Klinke, David J.

    2014-01-01

    Inductive inference plays a central role in the study of biological systems where one aims to increase their understanding of the system by reasoning backwards from uncertain observations to identify causal relationships among components of the system. These causal relationships are postulated from prior knowledge as a hypothesis or simply a model. Experiments are designed to test the model. Inferential statistics are used to establish a level of confidence in how well our postulated model explains the acquired data. This iterative process, commonly referred to as the scientific method, either improves our confidence in a model or suggests that we revisit our prior knowledge to develop a new model. Advances in technology impact how we use prior knowledge and data to formulate models of biological networks and how we observe cellular behavior. However, the approach for model-based inference has remained largely unchanged since Fisher, Neyman and Pearson developed the ideas in the early 1900’s that gave rise to what is now known as classical statistical hypothesis (model) testing. Here, I will summarize conventional methods for model-based inference and suggest a contemporary approach to aid in our quest to discover how cells dynamically interpret and transmit information for therapeutic aims that integrates ideas drawn from high performance computing, Bayesian statistics, and chemical kinetics. PMID:25139179

  8. Density-Profile Processes Describing Biological Signaling Networks: Almost Sure Convergence to Deterministic Trajectories

    NASA Astrophysics Data System (ADS)

    Fernández, Roberto; Fontes, Luiz R.; Neves, E. Jordão

    2009-09-01

    We introduce jump processes in ℝ k , called density-profile processes, to model biological signaling networks. Our modeling setup describes the macroscopic evolution of a finite-size spin-flip model with k types of spins with arbitrary number of internal states interacting through a non-reversible stochastic dynamics. We are mostly interested on the multi-dimensional empirical-magnetization vector in the thermodynamic limit, and prove that, within arbitrary finite time-intervals, its path converges almost surely to a deterministic trajectory determined by a first-order (non-linear) differential equation with explicit bounds on the distance between the stochastic and deterministic trajectories. As parameters of the spin-flip dynamics change, the associated dynamical system may go through bifurcations, associated to phase transitions in the statistical mechanical setting. We present a simple example of spin-flip stochastic model, associated to a synthetic biology model known as repressilator, which leads to a dynamical system with Hopf and pitchfork bifurcations. Depending on the parameter values, the magnetization random path can either converge to a unique stable fixed point, converge to one of a pair of stable fixed points, or asymptotically evolve close to a deterministic orbit in ℝ k . We also discuss a simple signaling pathway related to cancer research, called p53 module.

  9. Biological network module-based model for the analysis of differential expression in shotgun proteomics.

    PubMed

    Xu, Jia; Wang, Lily; Li, Jing

    2014-12-01

    Protein differential expression analysis plays an important role in the understanding of molecular mechanisms as well as the pathogenesis of complex diseases. With the rapid development of mass spectrometry, shotgun proteomics using spectral counts has become a prevailing method for the quantitative analysis of complex protein mixtures. Existing methods in differential proteomics expression typically carry out analysis at the single-protein level. However, it is well-known that proteins interact with each other when they function in biological processes. In this study, focusing on biological network modules, we proposed a negative binomial generalized linear model for differential expression analysis of spectral count data in shotgun proteomics. In order to show the efficacy of the model in protein expression analysis at the level of protein modules, we conducted two simulation studies using synthetic data sets generated from theoretical distribution of count data and a real data set with shuffled counts. Then, we applied our method to a colorectal cancer data set and a nonsmall cell lung cancer data set. When compared with single-protein analysis methods, the results showed that module-based statistical model which takes account of the interactions among proteins led to more effective identification of subtle but coordinated changes at the systems level. PMID:25327611

  10. SEBINI-CABIN: An Analysis Pipeline for Biological Network Inference, with a Case Study in Protein-Protein Interaction Network Reconstruction

    SciTech Connect

    Taylor, Ronald C.; Singhal, Mudita; Daly, Don S.; Domico, Kelly O.; White, Amanda M.; Auberry, Deanna L.; Auberry, Kenneth J.; Hooker, Brian S.; Hurst, G. B.; McDermott, Jason E.; McDonald, W. Hayes; Pelletier, Dale A.; Schmoyer, Denise D.; Cannon, William R.

    2007-12-01

    One of the core tasks of the emerging discipline of systems biology is the reconstruction of the various biological networks in an organism. The importance of understanding such regulatory, interaction, and signaling networks has fueled the development by bioinformatics researchers of many inference algorithms for determining their structure. The Software Environment for BIological Network Inference (SEBINI) has been created to provide an interactive environment for the deployment, testing, and improvement of algorithms used to reconstruct the structures of regulatory and interaction networks from high-throughput expression data. Networks inferred from the SEBINI software platform can be further analyzed using the Collective Analysis of Biological Interaction Networks (CABIN) tool, a software package for exploratory data analysis that allows basic integration and analysis of protein-protein interaction and gene-to-gene regulatory evidence obtained from multiple sources. Thus, the combined SEBINI–CABIN platform aids in the more accurate determination of biological networks, in less time, with less effort. In this paper, we present a case study demonstrating the use of the SEBINI and CABIN tools for protein-protein interaction network reconstruction. Incorporating the Bayesian Estimator of Protein-Protein Association Probabilities (BEPro) algorithm into the SEBINI toolkit, we have created a pipeline for structural inference and supplemental analysis of protein-protein interaction networks from sets of mass spectrometry bait-prey experiment data. To the best of our knowledge the pipeline so designed is the first to be publicly available for such use. A demonstration web site for SEBINI can be accessed from https://www.emsl.pnl.gov/NIT/NIT.html. Source code and PostgreSQL database schema are available under open source license. Contact: ronald.taylor@pnl.gov. For commercial use, some algorithms included in SEBINI require licensing from the original developers. The

  11. A biologically inspired neural network model to transformation invariant object recognition

    NASA Astrophysics Data System (ADS)

    Iftekharuddin, Khan M.; Li, Yaqin; Siddiqui, Faraz

    2007-09-01

    Transformation invariant image recognition has been an active research area due to its widespread applications in a variety of fields such as military operations, robotics, medical practices, geographic scene analysis, and many others. The primary goal for this research is detection of objects in the presence of image transformations such as changes in resolution, rotation, translation, scale and occlusion. We investigate a biologically-inspired neural network (NN) model for such transformation-invariant object recognition. In a classical training-testing setup for NN, the performance is largely dependent on the range of transformation or orientation involved in training. However, an even more serious dilemma is that there may not be enough training data available for successful learning or even no training data at all. To alleviate this problem, a biologically inspired reinforcement learning (RL) approach is proposed. In this paper, the RL approach is explored for object recognition with different types of transformations such as changes in scale, size, resolution and rotation. The RL is implemented in an adaptive critic design (ACD) framework, which approximates the neuro-dynamic programming of an action network and a critic network, respectively. Two ACD algorithms such as Heuristic Dynamic Programming (HDP) and Dual Heuristic dynamic Programming (DHP) are investigated to obtain transformation invariant object recognition. The two learning algorithms are evaluated statistically using simulated transformations in images as well as with a large-scale UMIST face database with pose variations. In the face database authentication case, the 90° out-of-plane rotation of faces from 20 different subjects in the UMIST database is used. Our simulations show promising results for both designs for transformation-invariant object recognition and authentication of faces. Comparing the two algorithms, DHP outperforms HDP in learning capability, as DHP takes fewer steps to

  12. Assessing Vermont's stream health and biological integrity using artificial neural networks and Bayesian methods

    NASA Astrophysics Data System (ADS)

    Rizzo, D. M.; Fytilis, N.; Stevens, L.

    2012-12-01

    Environmental managers are increasingly required to monitor and forecast long-term effects and vulnerability of biophysical systems to human-generated stresses. Ideally, a study involving both physical and biological assessments conducted concurrently (in space and time) could provide a better understanding of the mechanisms and complex relationships. However, costs and resources associated with monitoring the complex linkages between the physical, geomorphic and habitat conditions and the biological integrity of stream reaches are prohibitive. Researchers have used classification techniques to place individual streams and rivers into a broader spatial context (hydrologic or health condition). Such efforts require environmental managers to gather multiple forms of information - quantitative, qualitative and subjective. We research and develop a novel classification tool that combines self-organizing maps with a Naïve Bayesian classifier to direct resources to stream reaches most in need. The Vermont Agency of Natural Resources has developed and adopted protocols for physical stream geomorphic and habitat assessments throughout the state of Vermont. Separate from these assessments, the Vermont Department of Environmental Conservation monitors the biological communities and the water quality in streams. Our initial hypothesis is that the geomorphic reach assessments and water quality data may be leveraged to reduce error and uncertainty associated with predictions of biological integrity and stream health. We test our hypothesis using over 2500 Vermont stream reaches (~1371 stream miles) assessed by the two agencies. In the development of this work, we combine a Naïve Bayesian classifier with a modified Kohonen Self-Organizing Map (SOM). The SOM is an unsupervised artificial neural network that autonomously analyzes inherent dataset properties using input data only. It is typically used to cluster data into similar categories when a priori classes do not exist. The

  13. Discrete derivative: a data slicing algorithm for exploration of sharing biological networks between rheumatoid arthritis and coronary heart disease

    PubMed Central

    2011-01-01

    Background One important concept in traditional Chinese medicine (TCM) is "treating different diseases with the same therapy". In TCM practice, some patients with Rheumatoid Arthritis (RA) and some other patients with Coronary Heart Disease (CHD) can be treated with similar therapies. This suggests that there might be something commonly existed between RA and CHD, for example, biological networks or biological basis. As the amount of biomedical data in leading databases (i.e., PubMed, SinoMed, etc.) is growing at an exponential rate, it might be possible to get something interesting and meaningful through the techniques developed in data mining. Results Based on the large data sets of Western medicine literature (PubMed) and traditional Chinese medicine literature (SinoMed), by applying data slicing algorithm in text mining, we retrieved some simple and meaningful networks. The Chinese herbs used in treatment of both RA and CHD, might affect the commonly existed networks between RA and CHD. This might support the TCM concept of treating different diseases with the same therapy. Conclusions First, the data mining results might show the positive answer that there are biological basis/networks commonly existed in both RA and CHD. Second, there are basic Chinese herbs used in the treatment of both RA and CHD. Third, these commonly existed networks might be affected by the basic Chinese herbs. Forth, discrete derivative, the data slicing algorithm is feasible in mining out useful data from literature of PubMed and SinoMed. PMID:21696640

  14. Application of hierarchical dissociated neural network in closed-loop hybrid system integrating biological and mechanical intelligence.

    PubMed

    Li, Yongcheng; Sun, Rong; Zhang, Bin; Wang, Yuechao; Li, Hongyi

    2015-01-01

    Neural networks are considered the origin of intelligence in organisms. In this paper, a new design of an intelligent system merging biological intelligence with artificial intelligence was created. It was based on a neural controller bidirectionally connected to an actual mobile robot to implement a novel vehicle. Two types of experimental preparations were utilized as the neural controller including 'random' and '4Q' (cultured neurons artificially divided into four interconnected parts) neural network. Compared to the random cultures, the '4Q' cultures presented absolutely different activities, and the robot controlled by the '4Q' network presented better capabilities in search tasks. Our results showed that neural cultures could be successfully employed to control an artificial agent; the robot performed better and better with the stimulus because of the short-term plasticity. A new framework is provided to investigate the bidirectional biological-artificial interface and develop new strategies for a future intelligent system using these simplified model systems. PMID:25992579

  15. Integrated proteomic, transcriptomic, and biological network analysis of breast carcinoma reveals molecular features of tumorigenesis and clinical relapse.

    PubMed

    Imielinski, Marcin; Cha, Sangwon; Rejtar, Tomas; Richardson, Elizabeth A; Karger, Barry L; Sgroi, Dennis C

    2012-06-01

    Gene and protein expression changes observed with tumorigenesis are often interpreted independently of each other and out of context of biological networks. To address these limitations, this study examined several approaches to integrate transcriptomic and proteomic data with known protein-protein and signaling interactions in estrogen receptor positive (ER+) breast cancer tumors. An approach that built networks from differentially expressed proteins and identified among them networks enriched in differentially expressed genes yielded the greatest success. This method identified a set of genes and proteins linking pathways of cellular stress response, cancer metabolism, and tumor microenvironment. The proposed network underscores several biologically intriguing events not previously studied in the context of ER+ breast cancer, including the overexpression of p38 mitogen-activated protein kinase and the overexpression of poly(ADP-ribose) polymerase 1. A gene-based expression signature biomarker built from this network was significantly predictive of clinical relapse in multiple independent cohorts of ER+ breast cancer patients, even after correcting for standard clinicopathological variables. The results of this study demonstrate the utility and power of an integrated quantitative proteomic, transcriptomic, and network analysis approach to discover robust and clinically meaningful molecular changes in tumors. PMID:22240506

  16. NET-GE: a novel NETwork-based Gene Enrichment for detecting biological processes associated to Mendelian diseases

    PubMed Central

    2015-01-01

    Background Enrichment analysis is a widely applied procedure for shedding light on the molecular mechanisms and functions at the basis of phenotypes, for enlarging the dataset of possibly related genes/proteins and for helping interpretation and prioritization of newly determined variations. Several standard and Network-based enrichment methods are available. Both approaches rely on the annotations that characterize the genes/proteins included in the input set; network based ones also include in different ways physical and functional relationships among different genes or proteins that can be extracted from the available biological networks of interactions. Results Here we describe a novel procedure based on the extraction from the STRING interactome of sub-networks connecting proteins that share the same Gene Ontology(GO) terms for Biological Process (BP). Enrichment analysis is performed by mapping the protein set to be analyzed on the sub-networks, and then by collecting the corresponding annotations. We test the ability of our enrichment method in finding annotation terms disregarded by other enrichment methods available. We benchmarked 244 sets of proteins associated to different Mendelian diseases, according to the OMIM web resource. In 143 cases (58%), the network-based procedure extracts GO terms neglected by the standard method, and in 86 cases (35%), some of the newly enriched GO terms are not included in the set of annotations characterizing the input proteins. We present in detail six cases where our network-based enrichment provides an insight into the biological basis of the diseases, outperforming other freely available network-based methods. Conclusions Considering a set of proteins in the context of their interaction network can help in better defining their functions. Our novel method exploits the information contained in the STRING database for building the minimal connecting network containing all the proteins annotated with the same GO term

  17. Research Coordination Network: Geothermal Biology and Geochemistry in Yellowstone National Park

    NASA Astrophysics Data System (ADS)

    Inskeep, W. P.; Young, M. J.; Jay, Z.

    2006-12-01

    The number and diversity of geothermal features in Yellowstone National Park (YNP) represent a fascinating array of high temperature geochemical environments that host a corresponding number of unique and potentially novel organisms in all of the three recognized domains of life: Bacteria, Archaea and Eukarya. The geothermal features of YNP have long been the subject of scientific inquiry, especially in the fields of microbiology, geochemistry, geothermal hydrology, microbial ecology, and population biology. However, there are no organized forums for scientists working in YNP geothermal areas to present research results, exchange ideas, discuss research priorities, and enhance synergism among research groups. The primary goal of the YNP Research Coordination Network (GEOTHERM) is to develop a more unified effort among scientists and resource agencies to characterize, describe, understand and inventory the diverse biota associated with geothermal habitats in YNP. The YNP RCN commenced in January 2005 as a collaborative effort among numerous university scientists, governmental agencies and private industry. The YNP RCN hosted a workshop in February 2006 to discuss research results and to form three working groups focused on (i) web-site and digital library content, (ii) metagenomics of thermophilic microbial communities and (iii) development of geochemical methods appropriate for geomicrobiological studies. The working groups represent one strategy for enhancing communication, collaboration and most importantly, productivity among the RCN participants. If you have an interest in the geomicrobiology of geothermal systems, please feel welcome to join and or participate in the YNP RCN.

  18. The SOL Genomics Network. A Comparative Resource for Solanaceae Biology and Beyond1

    PubMed Central

    Mueller, Lukas A.; Solow, Teri H.; Taylor, Nicolas; Skwarecki, Beth; Buels, Robert; Binns, John; Lin, Chenwei; Wright, Mark H.; Ahrens, Robert; Wang, Ying; Herbst, Evan V.; Keyder, Emil R.; Menda, Naama; Zamir, Dani; Tanksley, Steven D.

    2005-01-01

    The SOL Genomics Network (SGN; http://sgn.cornell.edu) is a rapidly evolving comparative resource for the plants of the Solanaceae family, which includes important crop and model plants such as potato (Solanum tuberosum), eggplant (Solanum melongena), pepper (Capsicum annuum), and tomato (Solanum lycopersicum). The aim of SGN is to relate these species to one another using a comparative genomics approach and to tie them to the other dicots through the fully sequenced genome of Arabidopsis (Arabidopsis thaliana). SGN currently houses map and marker data for Solanaceae species, a large expressed sequence tag collection with computationally derived unigene sets, an extensive database of phenotypic information for a mutagenized tomato population, and associated tools such as real-time quantitative trait loci. Recently, the International Solanaceae Project (SOL) was formed as an umbrella organization for Solanaceae research in over 30 countries to address important questions in plant biology. The first cornerstone of the SOL project is the sequencing of the entire euchromatic portion of the tomato genome. SGN is collaborating with other bioinformatics centers in building the bioinformatics infrastructure for the tomato sequencing project and implementing the bioinformatics strategy of the larger SOL project. The overarching goal of SGN is to make information available in an intuitive comparative format, thereby facilitating a systems approach to investigations into the basis of adaptation and phenotypic diversity in the Solanaceae family, other species in the Asterid clade such as coffee (Coffea arabica), Rubiaciae, and beyond. PMID:16010005

  19. A comparative study of biological production in eastern boundary upwelling systems using an artificial neural network

    NASA Astrophysics Data System (ADS)

    Lachkar, Z.; Gruber, N.

    2012-01-01

    Eastern Boundary Upwelling Systems (EBUS) are highly productive ocean regions. Yet, substantial differences in net primary production (NPP) exist within and between these systems for reasons that are still not fully understood. Here, we explore the leading physical processes and environmental factors controlling NPP in EBUS through a comparative study of the California, Canary, Benguela, and Humboldt Current systems. The NPP drivers are identified with the aid of an artificial neural network analysis based on self-organizing-maps (SOM). Our results suggest that in addition to the expected NPP enhancing effect of stronger equatorward alongshore wind, three factors have an inhibiting effect: (1) strong eddy activity, (2) narrow continental shelf, and (3) deep mixed layer. The co-variability of these 4 drivers defines in the context of the SOM a continuum of 100 patterns of NPP regimes in EBUS. These are grouped into 4 distinct classes using a Hierarchical Agglomerative Clustering (HAC) method. Our objective classification of EBUS reveals important variations of NPP regimes within each of the four EBUS, particularly in the Canary and Benguela Current systems. Our results show that the Atlantic EBUS are generally more productive and more sensitive to upwelling favorable winds because of weaker factors inhibiting NPP. Perturbations of alongshore winds associated with climate change may therefore lead to contrasting biological responses in the Atlantic and the Pacific EBUS.

  20. A comparative study of biological production in eastern boundary upwelling systems using an artificial neural network

    NASA Astrophysics Data System (ADS)

    Lachkar, Z.; Gruber, N.

    2011-10-01

    Eastern Boundary Upwelling Systems (EBUS) are highly productive ocean regions. Yet, substantial differences in net primary production (NPP) exist within and between these systems for reasons that are still not fully understood. Here, we explore the leading physical processes and environmental factors controlling NPP in EBUS through a comparative study of the California, Canary, Benguela, and Humboldt Current systems. The identification of NPP drivers is done with the aid of an artificial neural network analysis based on self-organizing-maps (SOMs). We show that in addition to the expected NPP enhancing effect of stronger alongshore wind, three factors have an inhibiting effect: (1) strong eddy activity, (2) narrow continental shelf, and (3) deep mixed layer. The co-variability of these 4 drivers defines in the context of the SOM a continuum of 100 patterns of NPP regimes in EBUS. These are grouped into 4 distinct classes using a Hierarchical Agglomerative Clustering (HAC) method. Our objective classification of EBUS reveals important variations of NPP regimes within each of the four EBUS, particularly in the Canary and Benguela Current systems. Our results show that the Atlantic EBUS are generally more productive and more sensitive to upwelling favorable winds because of a weaker factors inhibiting NPP. Perturbations of alongshore winds associated with climate change may therefore lead to contrasting biological responses in the Atlantic and the Pacific EBUS.

  1. Climatic similarity and biological exchange in the worldwide airline transportation network

    PubMed Central

    Tatem, Andrew J; Hay, Simon I

    2007-01-01

    Recent increases in the rates of biological invasion and spread of infectious diseases have been linked to the continued expansion of the worldwide airline transportation network (WAN). Here, the global structure of the WAN is analysed in terms of climatic similarity to illuminate the risk of deliberate or accidental movements of climatically sensitive organisms around the world. From over 44 000 flight routes, we show, for each month of an average year, (i) those scheduled routes that link the most spatially distant but climatically similar airports, (ii) the climatically best-connected airports, and (iii) clusters of airports with similar climatic features. The way in which traffic volumes alter these findings is also examined. Climatic similarity across the WAN is skewed (most geographically close airports are climatically similar) but heavy-tailed (there are considerable numbers of geographically distant but climatically similar airports), with climate similarity highest in the June–August period, matching the annual peak in air traffic. Climatically matched, geographically distant airports form subnetworks within the WAN that change throughout the year. Further, the incorporation of passenger and freight traffic data highlight at greater risk of invasion those airports that are climatically well connected by numerous high capacity routes. PMID:17426013

  2. The biological networks in studying cell signal transduction complexity: The examples of sperm capacitation and of endocannabinoid system

    PubMed Central

    Bernabò, Nicola; Barboni, Barbara; Maccarrone, Mauro

    2014-01-01

    Cellular signal transduction is a complex phenomenon, which plays a central role in cell surviving and adaptation. The great amount of molecular data to date present in literature, together with the adoption of high throughput technologies, on the one hand, made available to scientists an enormous quantity of information, on the other hand, failed to provide a parallel increase in the understanding of biological events. In this context, a new discipline arose, the systems biology, aimed to manage the information with a computational modeling-based approach. In particular, the use of biological networks has allowed the making of huge progress in this field. Here we discuss two possible application of the use of biological networks to explore cell signaling: the study of the architecture of signaling systems that cooperate in determining the acquisition of a complex cellular function (as it is the case of the process of activation of spermatozoa) and the organization of a single specific signaling systems expressed by different cells in different tissues (i.e. the endocannabinoid system). In both the cases we have found that the networks follow a scale free and small world topology, likely due to the evolutionary advantage of robustness against random damages, fastness and specific of information processing, and easy navigability. PMID:25379139

  3. Study Under AC Stimulation on Excitement Properties of Weighted Small-World Biological Neural Networks with Side-Restrain Mechanism

    NASA Astrophysics Data System (ADS)

    Yuan, Wu-Jie; Luo, Xiao-Shu; Jiang, Pin-Qun

    2007-02-01

    In this paper, we propose a new model of weighted small-world biological neural networks based on biophysical Hodgkin-Huxley neurons with side-restrain mechanism. Then we study excitement properties of the model under alternating current (AC) stimulation. The study shows that the excitement properties in the networks are preferably consistent with the behavior properties of a brain nervous system under different AC stimuli, such as refractory period and the brain neural excitement response induced by different intensities of noise and coupling. The results of the study have reference worthiness for the brain nerve electrophysiology and epistemological science.

  4. Tissue culture on a chip: Developmental biology applications of self-organized capillary networks in microfluidic devices.

    PubMed

    Miura, Takashi; Yokokawa, Ryuji

    2016-08-01

    Organ culture systems are used to elucidate the mechanisms of pattern formation in developmental biology. Various organ culture techniques have been used, but the lack of microcirculation in such cultures impedes the long-term maintenance of larger tissues. Recent advances in microfluidic devices now enable us to utilize self-organized perfusable capillary networks in organ cultures. In this review, we will overview past approaches to organ culture and current technical advances in microfluidic devices, and discuss possible applications of microfluidics towards the study of developmental biology. PMID:27272910

  5. A survey of current software for network analysis in molecular biology

    PubMed Central

    2010-01-01

    Software for network motifs and modules is briefly reviewed, along with programs for network comparison. The three major software packages for network analysis, CYTOSCAPE, INGENUITY and PATHWAY STUDIO, and their associated databases, are compared in detail. A comparative test evaluated how these software packages perform the search for key terms and the creation of network from those terms and from experimental expression data. PMID:20650822

  6. A Network Biology Approach Identifies Molecular Cross-Talk between Normal Prostate Epithelial and Prostate Carcinoma Cells.

    PubMed

    Trevino, Victor; Cassese, Alberto; Nagy, Zsuzsanna; Zhuang, Xiaodong; Herbert, John; Antzack, Philipp; Clarke, Kim; Davies, Nicholas; Rahman, Ayesha; Campbell, Moray J; Guindani, Michele; Bicknell, Roy; Vannucci, Marina; Falciani, Francesco

    2016-04-01

    The advent of functional genomics has enabled the genome-wide characterization of the molecular state of cells and tissues, virtually at every level of biological organization. The difficulty in organizing and mining this unprecedented amount of information has stimulated the development of computational methods designed to infer the underlying structure of regulatory networks from observational data. These important developments had a profound impact in biological sciences since they triggered the development of a novel data-driven investigative approach. In cancer research, this strategy has been particularly successful. It has contributed to the identification of novel biomarkers, to a better characterization of disease heterogeneity and to a more in depth understanding of cancer pathophysiology. However, so far these approaches have not explicitly addressed the challenge of identifying networks representing the interaction of different cell types in a complex tissue. Since these interactions represent an essential part of the biology of both diseased and healthy tissues, it is of paramount importance that this challenge is addressed. Here we report the definition of a network reverse engineering strategy designed to infer directional signals linking adjacent cell types within a complex tissue. The application of this inference strategy to prostate cancer genome-wide expression profiling data validated the approach and revealed that normal epithelial cells exert an anti-tumour activity on prostate carcinoma cells. Moreover, by using a Bayesian hierarchical model integrating genetics and gene expression data and combining this with survival analysis, we show that the expression of putative cell communication genes related to focal adhesion and secretion is affected by epistatic gene copy number variation and it is predictive of patient survival. Ultimately, this study represents a generalizable approach to the challenge of deciphering cell communication networks

  7. A Network Biology Approach Identifies Molecular Cross-Talk between Normal Prostate Epithelial and Prostate Carcinoma Cells

    PubMed Central

    Trevino, Victor; Cassese, Alberto; Nagy, Zsuzsanna; Zhuang, Xiaodong; Herbert, John; Antzack, Philipp; Clarke, Kim; Davies, Nicholas; Rahman, Ayesha; Campbell, Moray J.; Bicknell, Roy; Vannucci, Marina; Falciani, Francesco

    2016-01-01

    Abstract The advent of functional genomics has enabled the genome-wide characterization of the molecular state of cells and tissues, virtually at every level of biological organization. The difficulty in organizing and mining this unprecedented amount of information has stimulated the development of computational methods designed to infer the underlying structure of regulatory networks from observational data. These important developments had a profound impact in biological sciences since they triggered the development of a novel data-driven investigative approach. In cancer research, this strategy has been particularly successful. It has contributed to the identification of novel biomarkers, to a better characterization of disease heterogeneity and to a more in depth understanding of cancer pathophysiology. However, so far these approaches have not explicitly addressed the challenge of identifying networks representing the interaction of different cell types in a complex tissue. Since these interactions represent an essential part of the biology of both diseased and healthy tissues, it is of paramount importance that this challenge is addressed. Here we report the definition of a network reverse engineering strategy designed to infer directional signals linking adjacent cell types within a complex tissue. The application of this inference strategy to prostate cancer genome-wide expression profiling data validated the approach and revealed that normal epithelial cells exert an anti-tumour activity on prostate carcinoma cells. Moreover, by using a Bayesian hierarchical model integrating genetics and gene expression data and combining this with survival analysis, we show that the expression of putative cell communication genes related to focal adhesion and secretion is affected by epistatic gene copy number variation and it is predictive of patient survival. Ultimately, this study represents a generalizable approach to the challenge of deciphering cell communication

  8. The virome: a missing component of biological interaction networks in health and disease.

    PubMed

    Handley, Scott A

    2016-01-01

    Host-associated viral populations, viromes, have been understudied relative to their contribution to human physiology. Viruses interact with host gene networks, influencing both health and disease. Analysis of host gene networks in the absence of virome analysis risks missing important network information. PMID:27037032

  9. Comparative analysis of housekeeping and tissue-selective genes in human based on network topologies and biological properties.

    PubMed

    Yang, Lei; Wang, Shiyuan; Zhou, Meng; Chen, Xiaowen; Zuo, Yongchun; Sun, Dianjun; Lv, Yingli

    2016-06-01

    Housekeeping genes are genes that are turned on most of the time in almost every tissue to maintain cellular functions. Tissue-selective genes are predominantly expressed in one or a few biologically relevant tissue types. Benefitting from the massive gene expression microarray data obtained over the past decades, the properties of housekeeping and tissue-selective genes can now be investigated on a large-scale manner. In this study, we analyzed the topological properties of housekeeping and tissue-selective genes in the protein-protein interaction (PPI) network. Furthermore, we compared the biological properties and amino acid usage between these two gene groups. The results indicated that there were significant differences in topological properties between housekeeping and tissue-selective genes in the PPI network, and housekeeping genes had higher centrality properties and may play important roles in the complex biological network environment. We also found that there were significant differences in multiple biological properties and many amino acid compositions. The functional genes enrichment and subcellular localizations analysis was also performed to investigate the characterization of housekeeping and tissue-selective genes. The results indicated that the two gene groups showed significant different enrichment in drug targets, disease genes and toxin targets, and located in different subcellular localizations. At last, the discriminations between the properties of two gene groups were measured by the F-score, and expression stage had the most discriminative index in all properties. These findings may elucidate the biological mechanisms for understanding housekeeping and tissue-selective genes and may contribute to better annotate housekeeping and tissue-selective genes in other organisms. PMID:26897376

  10. Design of a new monitoring network and first testing of new biological assessment methods according to water framework directive.

    PubMed

    Sommerhäuser, Mario; Scharner, Christoph; Schimmer, Hannes; Schindler, Anna; Plantikow, Kerstin; Vietoris, Friederike

    2007-09-01

    In most European member states, more or less completely new monitoring networks and assessment methods had to be developed as basic technical tools for the implementation of the EU Water Framework Directive (WFD). In the river basin of the Stever, the largest tributary to the river Lippe (River Rhine, Northrhine-Westphalia, Germany), a WFD-monitoring network was developed, and new German biological methods for rivers, developed for the purposes of the WFD, have been applied. Like most rivers in the German lowland areas, nearly all the river courses of the Stever system are altered by hydro-morphological degradation (straightening, bank fixation, lack of canopy etc.). In 2005 and 2006, the biological quality components of macroinvertebrates, fish and macrophytes were investigated and evaluated for the assessment of the ecological status of about 50 surface water bodies within the whole Stever system. Basic physical and chemical parameters, as well as priority substances, have been analysed in the same period. In this contribution, the design of the new monitoring network, the core principles of the German biological methods, and the most important results of the pilot monitoring will be presented. As main impacts with severe effects on the faunal and floral communities, the many migration barriers and the bad quality of the river morphology could be stated. Organic pollution is no more a severe problem in the Stever. The pilot project was successfully conducted in close collaboration with the water authorities (District Government Münster) and the water association Lippeverband. PMID:17726557

  11. Systems analysis in cell biology: from the phenomenological description towards a computer model of the intracellular signal transduction network.

    PubMed

    Kraus, M; Lais, P; Wolf, B

    1993-03-15

    In this paper we introduce a systematic approach for the modelling of complex biological systems which is especially useful for the analysis of signal transduction mechanisms in cell biology. It is shown that systems analysis in form of top-down levelled dataflow diagrams provides a powerful tool for the mathematical modelling of the system in terms of a stochastic formulation. Due to the exact formulation, the consistency of the model with the experimental results can be tested by means of a computer simulation. The method termed Structured Biological Modelling (SBM) is illustrated by modelling some aspects of the second messenger network which regulates cell proliferation. As an example for the straightforward development of a mathematical description a stochastic computer model for intracellular Ca2+ oscillations is presented. PMID:8458410

  12. Identifying influential nodes in a wound healing-related network of biological processes using mean first-passage time

    NASA Astrophysics Data System (ADS)

    Arodz, Tomasz; Bonchev, Danail

    2015-02-01

    In this study we offer an approach to network physiology, which proceeds from transcriptomic data and uses gene ontology analysis to identify the biological processes most enriched in several critical time points of wound healing process (days 0, 3 and 7). The top-ranking differentially expressed genes for each process were used to build two networks: one with all proteins regulating the transcription of selected genes, and a second one involving the proteins from the signaling pathways that activate the transcription factors. The information from these networks is used to build a network of the most enriched processes with undirected links weighted proportionally to the count of shared genes between the pair of processes, and directed links weighted by the count of relationships connecting genes from one process to genes from the other. In analyzing the network thus built we used an approach based on random walks and accounting for the temporal aspects of the spread of a signal in the network (mean-first passage time, MFPT). The MFPT scores allowed identifying the top influential, as well as the top essential biological processes, which vary with the progress in the healing process. Thus, the most essential for day 0 was found to be the Wnt-receptor signaling pathway, well known for its crucial role in wound healing, while in day 3 this was the regulation of NF-kB cascade, essential for matrix remodeling in the wound healing process. The MFPT-based scores correctly reflected the pattern of the healing process dynamics to be highly concentrated around several processes between day 0 and day 3, and becoming more diffuse at day 7.

  13. Atlas of Cancer Signalling Network: a systems biology resource for integrative analysis of cancer data with Google Maps

    PubMed Central

    Kuperstein, I; Bonnet, E; Nguyen, H-A; Cohen, D; Viara, E; Grieco, L; Fourquet, S; Calzone, L; Russo, C; Kondratova, M; Dutreix, M; Barillot, E; Zinovyev, A

    2015-01-01

    Cancerogenesis is driven by mutations leading to aberrant functioning of a complex network of molecular interactions and simultaneously affecting multiple cellular functions. Therefore, the successful application of bioinformatics and systems biology methods for analysis of high-throughput data in cancer research heavily depends on availability of global and detailed reconstructions of signalling networks amenable for computational analysis. We present here the Atlas of Cancer Signalling Network (ACSN), an interactive and comprehensive map of molecular mechanisms implicated in cancer. The resource includes tools for map navigation, visualization and analysis of molecular data in the context of signalling network maps. Constructing and updating ACSN involves careful manual curation of molecular biology literature and participation of experts in the corresponding fields. The cancer-oriented content of ACSN is completely original and covers major mechanisms involved in cancer progression, including DNA repair, cell survival, apoptosis, cell cycle, EMT and cell motility. Cell signalling mechanisms are depicted in detail, together creating a seamless ‘geographic-like' map of molecular interactions frequently deregulated in cancer. The map is browsable using NaviCell web interface using the Google Maps engine and semantic zooming principle. The associated web-blog provides a forum for commenting and curating the ACSN content. ACSN allows uploading heterogeneous omics data from users on top of the maps for visualization and performing functional analyses. We suggest several scenarios for ACSN application in cancer research, particularly for visualizing high-throughput data, starting from small interfering RNA-based screening results or mutation frequencies to innovative ways of exploring transcriptomes and phosphoproteomes. Integration and analysis of these data in the context of ACSN may help interpret their biological significance and formulate mechanistic hypotheses

  14. Atlas of Cancer Signalling Network: a systems biology resource for integrative analysis of cancer data with Google Maps.

    PubMed

    Kuperstein, I; Bonnet, E; Nguyen, H-A; Cohen, D; Viara, E; Grieco, L; Fourquet, S; Calzone, L; Russo, C; Kondratova, M; Dutreix, M; Barillot, E; Zinovyev, A

    2015-01-01

    Cancerogenesis is driven by mutations leading to aberrant functioning of a complex network of molecular interactions and simultaneously affecting multiple cellular functions. Therefore, the successful application of bioinformatics and systems biology methods for analysis of high-throughput data in cancer research heavily depends on availability of global and detailed reconstructions of signalling networks amenable for computational analysis. We present here the Atlas of Cancer Signalling Network (ACSN), an interactive and comprehensive map of molecular mechanisms implicated in cancer. The resource includes tools for map navigation, visualization and analysis of molecular data in the context of signalling network maps. Constructing and updating ACSN involves careful manual curation of molecular biology literature and participation of experts in the corresponding fields. The cancer-oriented content of ACSN is completely original and covers major mechanisms involved in cancer progression, including DNA repair, cell survival, apoptosis, cell cycle, EMT and cell motility. Cell signalling mechanisms are depicted in detail, together creating a seamless 'geographic-like' map of molecular interactions frequently deregulated in cancer. The map is browsable using NaviCell web interface using the Google Maps engine and semantic zooming principle. The associated web-blog provides a forum for commenting and curating the ACSN content. ACSN allows uploading heterogeneous omics data from users on top of the maps for visualization and performing functional analyses. We suggest several scenarios for ACSN application in cancer research, particularly for visualizing high-throughput data, starting from small interfering RNA-based screening results or mutation frequencies to innovative ways of exploring transcriptomes and phosphoproteomes. Integration and analysis of these data in the context of ACSN may help interpret their biological significance and formulate mechanistic hypotheses

  15. Large-scale photonic neural networks with biology-like processing elements: the role of electron-trapping materials

    NASA Astrophysics Data System (ADS)

    Farhat, Nabil H.; Wen, Zhimin

    1995-08-01

    Neural networks employing pulsating biology-oriented integrate-and-fire (IF) model neurons, that can exhibit synchronicity (phase-locking), bifurcation, and chaos, have features that make them potentially useful for learning and recognition of spatio-temporal patterns, generation of complex motor control, emulating higher-level cortical functions like feature binding, separation of object from background, cognition and other higher-level functions; all of which are beyond the ready reach of nonpulsating sigmoidal neuron networks. The spiking nature of biology-oriented neural networks makes their study in digital hardware impractical. Prange and Klar convincingly argued that the best way of realizing such networks is through analog CMOS technology rather than digital hardware. They showed, however, that the number of neurons one can accommodate on a VLSI chip limited to a hundred or so, even when submicron CMOS technology is used, because of the relatively large size of the neuron/dendrite cell. One way of reducing the size of neuron/dendrite cell is to reduce the structural complexity of the cell by realizing some of the processes needed in the cell's operation externally to the chip and by coupling these processes to the cell optically. Two such processes are the relaxation mechanism of the IF neuron and dendritic-tree processing. We have shown, by examining the blue light impulse response of electron trapping materials (ETMs) used under simultaneous infrared and blue light bias, that these materials offer features that can be used in realizing both the optical relaxation and synapto-dendritic response mechanisms. Experimental results demonstrating the potential of this approach in realizing dense arrays of biology-oriented neuron/dendrite cells will be presented, focusing on the concept and design of ETM-based image intensifier as new enabling technology.

  16. Connectivity matrix method for analyses of biological networks and its application to atom-level analysis of a model network of carbohydrate metabolism.

    PubMed

    Ohta, J

    2006-09-01

    An approach for analysis of biological networks is proposed. In this approach, named the connectivity matrix (CM) method, all the connectivities of interest are expressed in a matrix. Then, a variety of analyses are performed on GNU Octave or Matlab. Each node in the network is expressed as a row vector or numeral that carries information defining or characterising the node itself. Information about connectivity itself is also expressed as a row vector or numeral. Thus, connection of node n1 to node n2 through edge e is expressed as [n1, n2, e], a row vector formed by the combination of three row vectors or numerals, where n1, n2 and e indicate two different nodes and one connectivity, respectively. All the connectivities in any given network are expressed as a matrix, CM, each row of which corresponds to one connectivity. Using this CM method, intermetabolite atom-level connectivity is investigated in a model metabolic network composed of the reactions for glycolysis, oxidative decarboxylation of pyruvate, citric acid cycle, pentose phosphate pathway and gluconeogenesis. PMID:16986320

  17. Considering Unknown Unknowns: Reconstruction of Nonconfoundable Causal Relations in Biological Networks

    PubMed Central

    Moffa, Giusi; Spang, Rainer

    2013-01-01

    Abstract Our current understanding of cellular networks is rather incomplete. We over look important but so far unknown genes and mechanisms in the pathways. Moreover, we often only have a partial account of the molecular interactions and modifications of the known players. When analyzing the cell, we look through narrow windows leaving potentially important events in blind spots. Network reconstruction is naturally confined to what we have observed. Little is known on how the incompleteness of our observations confounds our interpretation of the available data. Here we ask which features of a network can be confounded by incomplete observations and which cannot. In the context of nested effects models, we show that in the presence of missing observations or hidden factors a reliable reconstruction of the full network is not feasible. Nevertheless, we can show that certain characteristics of signaling networks like the existence of cross-talk between certain branches of the network can be inferred in a nonconfoundable way. We derive a test for inferring such nonconfoundable characteristics of signaling networks. Next, we introduce a new data structure to represent partially reconstructed signaling networks. Finally, we evaluate our method both on simulated data and in the context of a study on early stem cell differentiation in mice. PMID:24195708

  18. Considering unknown unknowns: reconstruction of nonconfoundable causal relations in biological networks.

    PubMed

    Sadeh, Mohammad J; Moffa, Giusi; Spang, Rainer

    2013-11-01

    Our current understanding of cellular networks is rather incomplete. We over look important but so far unknown genes and mechanisms in the pathways. Moreover, we often only have a partial account of the molecular interactions and modifications of the known players. When analyzing the cell, we look through narrow windows leaving potentially important events in blind spots. Network reconstruction is naturally confined to what we have observed. Little is known on how the incompleteness of our observations confounds our interpretation of the available data. Here we ask which features of a network can be confounded by incomplete observations and which cannot. In the context of nested effects models, we show that in the presence of missing observations or hidden factors a reliable reconstruction of the full network is not feasible. Nevertheless, we can show that certain characteristics of signaling networks like the existence of cross-talk between certain branches of the network can be inferred in a nonconfoundable way. We derive a test for inferring such nonconfoundable characteristics of signaling networks. Next, we introduce a new data structure to represent partially reconstructed signaling networks. Finally, we evaluate our method both on simulated data and in the context of a study on early stem cell differentiation in mice. PMID:24195708

  19. Node Handprinting: A Scalable and Accurate Algorithm for Aligning Multiple Biological Networks.

    PubMed

    Radu, Alex; Charleston, Michael

    2015-07-01

    Due to recent advancements in high-throughput sequencing technologies, progressively more protein-protein interactions have been identified for a growing number of species. Subsequently, the protein-protein interaction networks for these species have been further refined. The increase in the quality and availability of these networks has in turn brought a demand for efficient methods to analyze such networks. The pairwise alignment of these networks has been moderately investigated, with numerous algorithms available, but there is very little progress in the field of multiple network alignment. Multiple alignment of networks from different organisms is ideal at finding abnormally conserved or disparate subnetworks. We present a fast and accurate algorithmic approach, Node Handprinting (NH), based on our previous work with Node Fingerprinting, which enables quick and accurate alignment of multiple networks. We also propose two new metrics for the analysis of multiple alignments, as the current metrics are not as sophisticated as their pairwise alignment counterparts. To assess the performance of NH, we use previously aligned datasets as well as protein interaction networks generated from the public database BioGRID. Our results indicate that NH compares favorably with current methodologies and is the only algorithm capable of performing the more complex alignments. PMID:25695597

  20. FPGA implementation of a biological neural network based on the Hodgkin-Huxley neuron model.

    PubMed

    Yaghini Bonabi, Safa; Asgharian, Hassan; Safari, Saeed; Nili Ahmadabadi, Majid

    2014-01-01

    A set of techniques for efficient implementation of Hodgkin-Huxley-based (H-H) model of a neural network on FPGA (Field Programmable Gate Array) is presented. The central implementation challenge is H-H model complexity that puts limits on the network size and on the execution speed. However, basics of the original model cannot be compromised when effect of synaptic specifications on the network behavior is the subject of study. To solve the problem, we used computational techniques such as CORDIC (Coordinate Rotation Digital Computer) algorithm and step-by-step integration in the implementation of arithmetic circuits. In addition, we employed different techniques such as sharing resources to preserve the details of model as well as increasing the network size in addition to keeping the network execution speed close to real time while having high precision. Implementation of a two mini-columns network with 120/30 excitatory/inhibitory neurons is provided to investigate the characteristic of our method in practice. The implementation techniques provide an opportunity to construct large FPGA-based network models to investigate the effect of different neurophysiological mechanisms, like voltage-gated channels and synaptic activities, on the behavior of a neural network in an appropriate execution time. Additional to inherent properties of FPGA, like parallelism and re-configurability, our approach makes the FPGA-based system a proper candidate for study on neural control of cognitive robots and systems as well. PMID:25484854

  1. FPGA implementation of a biological neural network based on the Hodgkin-Huxley neuron model

    PubMed Central

    Yaghini Bonabi, Safa; Asgharian, Hassan; Safari, Saeed; Nili Ahmadabadi, Majid

    2014-01-01

    A set of techniques for efficient implementation of Hodgkin-Huxley-based (H-H) model of a neural network on FPGA (Field Programmable Gate Array) is presented. The central implementation challenge is H-H model complexity that puts limits on the network size and on the execution speed. However, basics of the original model cannot be compromised when effect of synaptic specifications on the network behavior is the subject of study. To solve the problem, we used computational techniques such as CORDIC (Coordinate Rotation Digital Computer) algorithm and step-by-step integration in the implementation of arithmetic circuits. In addition, we employed different techniques such as sharing resources to preserve the details of model as well as increasing the network size in addition to keeping the network execution speed close to real time while having high precision. Implementation of a two mini-columns network with 120/30 excitatory/inhibitory neurons is provided to investigate the characteristic of our method in practice. The implementation techniques provide an opportunity to construct large FPGA-based network models to investigate the effect of different neurophysiological mechanisms, like voltage-gated channels and synaptic activities, on the behavior of a neural network in an appropriate execution time. Additional to inherent properties of FPGA, like parallelism and re-configurability, our approach makes the FPGA-based system a proper candidate for study on neural control of cognitive robots and systems as well. PMID:25484854

  2. Drivers of structural features in gene regulatory networks: From biophysical constraints to biological function.

    PubMed

    Martin, O C; Krzywicki, A; Zagorski, M

    2016-07-01

    Living cells can maintain their internal states, react to changing environments, grow, differentiate, divide, etc. All these processes are tightly controlled by what can be called a regulatory program. The logic of the underlying control can sometimes be guessed at by examining the network of influences amongst genetic components. Some associated gene regulatory networks have been studied in prokaryotes and eukaryotes, unveiling various structural features ranging from broad distributions of out-degrees to recurrent "motifs", that is small subgraphs having a specific pattern of interactions. To understand what factors may be driving such structuring, a number of groups have introduced frameworks to model the dynamics of gene regulatory networks. In that context, we review here such in silico approaches and show how selection for phenotypes, i.e., network function, can shape network structure. PMID:27365153

  3. Drivers of structural features in gene regulatory networks: From biophysical constraints to biological function

    NASA Astrophysics Data System (ADS)

    Martin, O. C.; Krzywicki, A.; Zagorski, M.

    2016-07-01

    Living cells can maintain their internal states, react to changing environments, grow, differentiate, divide, etc. All these processes are tightly controlled by what can be called a regulatory program. The logic of the underlying control can sometimes be guessed at by examining the network of influences amongst genetic components. Some associated gene regulatory networks have been studied in prokaryotes and eukaryotes, unveiling various structural features ranging from broad distributions of out-degrees to recurrent "motifs", that is small subgraphs having a specific pattern of interactions. To understand what factors may be driving such structuring, a number of groups have introduced frameworks to model the dynamics of gene regulatory networks. In that context, we review here such in silico approaches and show how selection for phenotypes, i.e., network function, can shape network structure.

  4. Application of Hierarchical Dissociated Neural Network in Closed-Loop Hybrid System Integrating Biological and Mechanical Intelligence

    PubMed Central

    Zhang, Bin; Wang, Yuechao; Li, Hongyi

    2015-01-01

    Neural networks are considered the origin of intelligence in organisms. In this paper, a new design of an intelligent system merging biological intelligence with artificial intelligence was created. It was based on a neural controller bidirectionally connected to an actual mobile robot to implement a novel vehicle. Two types of experimental preparations were utilized as the neural controller including ‘random’ and ‘4Q’ (cultured neurons artificially divided into four interconnected parts) neural network. Compared to the random cultures, the ‘4Q’ cultures presented absolutely different activities, and the robot controlled by the ‘4Q’ network presented better capabilities in search tasks. Our results showed that neural cultures could be successfully employed to control an artificial agent; the robot performed better and better with the stimulus because of the short-term plasticity. A new framework is provided to investigate the bidirectional biological-artificial interface and develop new strategies for a future intelligent system using these simplified model systems. PMID:25992579

  5. Analyzing Members' Motivations to Participate in Role-Playing and Self-Expression Based Virtual Communities

    NASA Astrophysics Data System (ADS)

    Lee, Young Eun; Saharia, Aditya

    With the rapid growth of computer mediated communication technologies in the last two decades, various types of virtual communities have emerged. Some communities provide a role playing arena, enabled by avatars, while others provide an arena for expressing and promoting detailed personal profiles to enhance their offline social networks. Due to different focus of these virtual communities, different factors motivate members to participate in these communities. In this study, we examine differences in members’ motivations to participate in role-playing versus self-expression based virtual communities. To achieve this goal, we apply the Wang and Fesenmaier (2004) framework, which explains members’ participation in terms of their functional, social, psychological, and hedonic needs. The primary contributions of this study are two folds: First, it demonstrates differences between role-playing and self-expression based communities. Second, it provides a comprehensive framework describing members’ motivation to participate in virtual communities.

  6. Exploring the topological sources of robustness against invasion in biological and technological networks

    NASA Astrophysics Data System (ADS)

    Alcalde Cuesta, Fernando; González Sequeiros, Pablo; Lozano Rojo, Álvaro

    2016-02-01

    For a network, the accomplishment of its functions despite perturbations is called robustness. Although this property has been extensively studied, in most cases, the network is modified by removing nodes. In our approach, it is no longer perturbed by site percolation, but evolves after site invasion. The process transforming resident/healthy nodes into invader/mutant/diseased nodes is described by the Moran model. We explore the sources of robustness (or its counterpart, the propensity to spread favourable innovations) of the US high-voltage power grid network, the Internet2 academic network, and the C. elegans connectome. We compare them to three modular and non-modular benchmark networks, and samples of one thousand random networks with the same degree distribution. It is found that, contrary to what happens with networks of small order, fixation probability and robustness are poorly correlated with most of standard statistics, but they depend strongly on the degree distribution. While community detection techniques are able to detect the existence of a central core in Internet2, they are not effective in detecting hierarchical structures whose topological complexity arises from the repetition of a few rules. Box counting dimension and Rent’s rule are applied to show a subtle trade-off between topological and wiring complexity.

  7. A Parallel Supercomputer Implementation of a Biological Inspired Neural Network and its use for Pattern Recognition

    NASA Astrophysics Data System (ADS)

    de Ladurantaye, Vincent; Lavoie, Jean; Bergeron, Jocelyn; Parenteau, Maxime; Lu, Huizhong; Pichevar, Ramin; Rouat, Jean

    2012-02-01

    A parallel implementation of a large spiking neural network is proposed and evaluated. The neural network implements the binding by synchrony process using the Oscillatory Dynamic Link Matcher (ODLM). Scalability, speed and performance are compared for 2 implementations: Message Passing Interface (MPI) and Compute Unified Device Architecture (CUDA) running on clusters of multicore supercomputers and NVIDIA graphical processing units respectively. A global spiking list that represents at each instant the state of the neural network is described. This list indexes each neuron that fires during the current simulation time so that the influence of their spikes are simultaneously processed on all computing units. Our implementation shows a good scalability for very large networks. A complex and large spiking neural network has been implemented in parallel with success, thus paving the road towards real-life applications based on networks of spiking neurons. MPI offers a better scalability than CUDA, while the CUDA implementation on a GeForce GTX 285 gives the best cost to performance ratio. When running the neural network on the GTX 285, the processing speed is comparable to the MPI implementation on RQCHP's Mammouth parallel with 64 notes (128 cores).

  8. Exploring the topological sources of robustness against invasion in biological and technological networks

    PubMed Central

    Alcalde Cuesta, Fernando; González Sequeiros, Pablo; Lozano Rojo, Álvaro

    2016-01-01

    For a network, the accomplishment of its functions despite perturbations is called robustness. Although this property has been extensively studied, in most cases, the network is modified by removing nodes. In our approach, it is no longer perturbed by site percolation, but evolves after site invasion. The process transforming resident/healthy nodes into invader/mutant/diseased nodes is described by the Moran model. We explore the sources of robustness (or its counterpart, the propensity to spread favourable innovations) of the US high-voltage power grid network, the Internet2 academic network, and the C. elegans connectome. We compare them to three modular and non-modular benchmark networks, and samples of one thousand random networks with the same degree distribution. It is found that, contrary to what happens with networks of small order, fixation probability and robustness are poorly correlated with most of standard statistics, but they depend strongly on the degree distribution. While community detection techniques are able to detect the existence of a central core in Internet2, they are not effective in detecting hierarchical structures whose topological complexity arises from the repetition of a few rules. Box counting dimension and Rent’s rule are applied to show a subtle trade-off between topological and wiring complexity. PMID:26861189

  9. Exploring the topological sources of robustness against invasion in biological and technological networks.

    PubMed

    Alcalde Cuesta, Fernando; González Sequeiros, Pablo; Lozano Rojo, Álvaro

    2016-01-01

    For a network, the accomplishment of its functions despite perturbations is called robustness. Although this property has been extensively studied, in most cases, the network is modified by removing nodes. In our approach, it is no longer perturbed by site percolation, but evolves after site invasion. The process transforming resident/healthy nodes into invader/mutant/diseased nodes is described by the Moran model. We explore the sources of robustness (or its counterpart, the propensity to spread favourable innovations) of the US high-voltage power grid network, the Internet2 academic network, and the C. elegans connectome. We compare them to three modular and non-modular benchmark networks, and samples of one thousand random networks with the same degree distribution. It is found that, contrary to what happens with networks of small order, fixation probability and robustness are poorly correlated with most of standard statistics, but they depend strongly on the degree distribution. While community detection techniques are able to detect the existence of a central core in Internet2, they are not effective in detecting hierarchical structures whose topological complexity arises from the repetition of a few rules. Box counting dimension and Rent's rule are applied to show a subtle trade-off between topological and wiring complexity. PMID:26861189

  10. Physarum solver: A biologically inspired method of road-network navigation

    NASA Astrophysics Data System (ADS)

    Tero, Atsushi; Kobayashi, Ryo; Nakagaki, Toshiyuki

    2006-04-01

    We have proposed a mathematical model for the adaptive dynamics of the transport network in an amoeba-like organism, the true slime mold Physarum polycephalum. The model is based on physiological observations of this species, but can also be used for path-finding in the complicated networks of mazes and road maps. In this paper, we describe the physiological basis and the formulation of the model, as well as the results of simulations of some complicated networks. The path-finding method used by Physarum is a good example of cellular computation.

  11. CeFunMO: A centrality based method for discovering functional motifs with application in biological networks.

    PubMed

    Kouhsar, Morteza; Razaghi-Moghadam, Zahra; Mousavian, Zaynab; Masoudi-Nejad, Ali

    2016-09-01

    Detecting functional motifs in biological networks is one of the challenging problems in systems biology. Given a multiset of colors as query and a list-colored graph (an undirected graph with a set of colors assigned to each of its vertices), the problem is reduced to finding connected subgraphs, which best cover the multiset of query. To solve this NP-complete problem, we propose a new color-based centrality measure for list-colored graphs. Based on this newly-defined measure of centrality, a novel polynomial time algorithm is developed to discover functional motifs in list-colored graphs, using a greedy strategy. This algorithm, called CeFunMO, has superior running time and acceptable accuracy in comparison with other well-known algorithms, such as RANGI and GraMoFoNe. PMID:27454243

  12. A systems biology approach to reconcile metabolic network models with application to Synechocystis sp. PCC 6803 for biofuel production.

    PubMed

    Mohammadi, Reza; Fallah-Mehrabadi, Jalil; Bidkhori, Gholamreza; Zahiri, Javad; Javad Niroomand, Mohammad; Masoudi-Nejad, Ali

    2016-07-19

    Production of biofuels has been one of the promising efforts in biotechnology in the past few decades. The perspective of these efforts can be reduction of increasing demands for fossil fuels and consequently reducing environmental pollution. Nonetheless, most previous approaches did not succeed in obviating many big challenges in this way. In recent years systems biology with the help of microorganisms has been trying to overcome these challenges. Unicellular cyanobacteria are widespread phototrophic microorganisms that have capabilities such as consuming solar energy and atmospheric carbon dioxide for growth and thus can be a suitable chassis for the production of valuable organic materials such as biofuels. For the ultimate use of metabolic potential of cyanobacteria, it is necessary to understand the reactions that are taking place inside the metabolic network of these microorganisms. In this study, we developed a Java tool to reconstruct an integrated metabolic network of a cyanobacterium (Synechocystis sp. PCC 6803). We merged three existing reconstructed metabolic networks of this microorganism. Then, after modeling for biofuel production, the results from flux balance analysis (FBA) disclosed an increased yield in biofuel production for ethanol, isobutanol, 3-methyl-1-butanol, 2-methyl-1-butanol, and propanol. The numbers of blocked reactions were also decreased for 2-methyl-1-butanol production. In addition, coverage of the metabolic network in terms of the number of metabolites and reactions was increased in the new obtained model. PMID:27265370

  13. Mueller-matrix mapping of biological tissues in differential diagnosis of optical anisotropy mechanisms of protein networks

    NASA Astrophysics Data System (ADS)

    Ushenko, V. A.; Sidor, M. I.; Marchuk, Yu F.; Pashkovskaya, N. V.; Andreichuk, D. R.

    2015-03-01

    We report a model of Mueller-matrix description of optical anisotropy of protein networks in biological tissues with allowance for the linear birefringence and dichroism. The model is used to construct the reconstruction algorithms of coordinate distributions of phase shifts and the linear dichroism coefficient. In the statistical analysis of such distributions, we have found the objective criteria of differentiation between benign and malignant tissues of the female reproductive system. From the standpoint of evidence-based medicine, we have determined the operating characteristics (sensitivity, specificity and accuracy) of the Mueller-matrix reconstruction method of optical anisotropy parameters and demonstrated its effectiveness in the differentiation of benign and malignant tumours.

  14. An appraisal of biological responses and network of environmental interactions in non-mining and mining impacted coastal waters.

    PubMed

    Fernandes, Christabelle E G; Malik, Ashish; Jineesh, V K; Fernandes, Sheryl O; Das, Anindita; Pandey, Sunita S; Kanolkar, Geeta; Sujith, P P; Velip, Dhillan M; Shaikh, Shagufta; Helekar, Samita; Gonsalves, Maria Judith; Nair, Shanta; LokaBharathi, P A

    2015-08-01

    The coastal waters of Goa and Ratnagiri lying on the West coast of India are influenced by terrestrial influx. However, Goa is influenced anthropogenically by iron-ore mining, while Ratnagiri is influenced by deposition of heavy minerals containing iron brought from the hinterlands. We hypothesize that there could be a shift in biological response along with changes in network of interactions between environmental and biological variables in these mining and non-mining impacted regions, lying 160 nmi apart. Biological and environmental parameters were analyzed during pre-monsoon season. Except silicates, the measured parameters were higher at Goa and related significantly, suggesting bacteria centric, detritus-driven region. At Ratnagiri, phytoplankton biomass related positively with silicate suggesting a region dominated by primary producers. This dominance perhaps got reflected as a higher tertiary yield. Thus, even though the regions are geographically proximate, the different biological response could be attributed to the differences in the web of interactions between the measured variables. PMID:25907627

  15. Novel insights into embryonic stem cell self-renewal revealed through comparative human and mouse systems biology networks.

    PubMed

    Dowell, Karen G; Simons, Allen K; Bai, Hao; Kell, Braden; Wang, Zack Z; Yun, Kyuson; Hibbs, Matthew A

    2014-05-01

    Embryonic stem cells (ESCs), characterized by their ability to both self-renew and differentiate into multiple cell lineages, are a powerful model for biomedical research and developmental biology. Human and mouse ESCs share many features, yet have distinctive aspects, including fundamental differences in the signaling pathways and cell cycle controls that support self-renewal. Here, we explore the molecular basis of human ESC self-renewal using Bayesian network machine learning to integrate cell-type-specific, high-throughput data for gene function discovery. We integrated high-throughput ESC data from 83 human studies (~1.8 million data points collected under 1,100 conditions) and 62 mouse studies (~2.4 million data points collected under 1,085 conditions) into separate human and mouse predictive networks focused on ESC self-renewal to analyze shared and distinct functional relationships among protein-coding gene orthologs. Computational evaluations show that these networks are highly accurate, literature validation confirms their biological relevance, and reverse transcriptase polymerase chain reaction (RT-PCR) validation supports our predictions. Our results reflect the importance of key regulatory genes known to be strongly associated with self-renewal and pluripotency in both species (e.g., POU5F1, SOX2, and NANOG), identify metabolic differences between species (e.g., threonine metabolism), clarify differences between human and mouse ESC developmental signaling pathways (e.g., leukemia inhibitory factor (LIF)-activated JAK/STAT in mouse; NODAL/ACTIVIN-A-activated fibroblast growth factor in human), and reveal many novel genes and pathways predicted to be functionally associated with self-renewal in each species. These interactive networks are available online at www.StemSight.org for stem cell researchers to develop new hypotheses, discover potential mechanisms involving sparsely annotated genes, and prioritize genes of interest for experimental validation

  16. DYVIPAC: an integrated analysis and visualisation framework to probe multi-dimensional biological networks

    PubMed Central

    Nguyen, Lan K.; Degasperi, Andrea; Cotter, Philip; Kholodenko, Boris N.

    2015-01-01

    Biochemical networks are dynamic and multi-dimensional systems, consisting of tens or hundreds of molecular components. Diseases such as cancer commonly arise due to changes in the dynamics of signalling and gene regulatory networks caused by genetic alternations. Elucidating the network dynamics in health and disease is crucial to better understand the disease mechanisms and derive effective therapeutic strategies. However, current approaches to analyse and visualise systems dynamics can often provide only low-dimensional projections of the network dynamics, which often does not present the multi-dimensional picture of the system behaviour. More efficient and reliable methods for multi-dimensional systems analysis and visualisation are thus required. To address this issue, we here present an integrated analysis and visualisation framework for high-dimensional network behaviour which exploits the advantages provided by parallel coordinates graphs. We demonstrate the applicability of the framework, named “Dynamics Visualisation based on Parallel Coordinates” (DYVIPAC), to a variety of signalling networks ranging in topological wirings and dynamic properties. The framework was proved useful in acquiring an integrated understanding of systems behaviour. PMID:26220783

  17. Mean field theory for biology inspired duplication-divergence network model.

    PubMed

    Cai, Shuiming; Liu, Zengrong; Lee, H C

    2015-08-01

    The duplication-divergence network model is generally thought to incorporate key ingredients underlying the growth and evolution of protein-protein interaction networks. Properties of the model have been elucidated through numerous simulation studies. However, a comprehensive theoretical study of the model is lacking. Here, we derived analytic expressions for quantities describing key characteristics of the network-the average degree, the degree distribution, the clustering coefficient, and the neighbor connectivity-in the mean-field, large-N limit of an extended version of the model, duplication-divergence complemented with heterodimerization and addition. We carried out extensive simulations and verified excellent agreement between simulation and theory except for one partial case. All four quantities obeyed power-laws even at moderate network size ( N∼10(4)), except the degree distribution, which had an additional exponential factor observed to obey power-law. It is shown that our network model can lead to the emergence of scale-free property and hierarchical modularity simultaneously, reproducing the important topological properties of real protein-protein interaction networks. PMID:26328557

  18. Hubba: hub objects analyzer--a framework of interactome hubs identification for network biology.

    PubMed

    Lin, Chung-Yen; Chin, Chia-Hao; Wu, Hsin-Hung; Chen, Shu-Hwa; Ho, Chin-Wen; Ko, Ming-Tat

    2008-07-01

    One major task in the post-genome era is to reconstruct proteomic and genomic interacting networks using high-throughput experiment data. To identify essential nodes/hubs in these interactomes is a way to decipher the critical keys inside biochemical pathways or complex networks. These essential nodes/hubs may serve as potential drug-targets for developing novel therapy of human diseases, such as cancer or infectious disease caused by emerging pathogens. Hub Objects Analyzer (Hubba) is a web-based service for exploring important nodes in an interactome network generated from specific small- or large-scale experimental methods based on graph theory. Two characteristic analysis algorithms, Maximum Neighborhood Component (MNC) and Density of Maximum Neighborhood Component (DMNC) are developed for exploring and identifying hubs/essential nodes from interactome networks. Users can submit their own interaction data in PSI format (Proteomics Standards Initiative, version 2.5 and 1.0), tab format and tab with weight values. User will get an email notification of the calculation complete in minutes or hours, depending on the size of submitted dataset. Hubba result includes a rank given by a composite index, a manifest graph of network to show the relationship amid these hubs, and links for retrieving output files. This proposed method (DMNC || MNC) can be applied to discover some unrecognized hubs from previous dataset. For example, most of the Hubba high-ranked hubs (80% in top 10 hub list, and >70% in top 40 hub list) from the yeast protein interactome data (Y2H experiment) are reported as essential proteins. Since the analysis methods of Hubba are based on topology, it can also be used on other kinds of networks to explore the essential nodes, like networks in yeast, rat, mouse and human. The website of Hubba is freely available at http://hub.iis.sinica.edu.tw/Hubba. PMID:18503085

  19. Mean field theory for biology inspired duplication-divergence network model

    NASA Astrophysics Data System (ADS)

    Cai, Shuiming; Liu, Zengrong; Lee, H. C.

    2015-08-01

    The duplication-divergence network model is generally thought to incorporate key ingredients underlying the growth and evolution of protein-protein interaction networks. Properties of the model have been elucidated through numerous simulation studies. However, a comprehensive theoretical study of the model is lacking. Here, we derived analytic expressions for quantities describing key characteristics of the network—the average degree, the degree distribution, the clustering coefficient, and the neighbor connectivity—in the mean-field, large-N limit of an extended version of the model, duplication-divergence complemented with heterodimerization and addition. We carried out extensive simulations and verified excellent agreement between simulation and theory except for one partial case. All four quantities obeyed power-laws even at moderate network size ( N ˜104 ), except the degree distribution, which had an additional exponential factor observed to obey power-law. It is shown that our network model can lead to the emergence of scale-free property and hierarchical modularity simultaneously, reproducing the important topological properties of real protein-protein interaction networks.

  20. Statistical Mechanics of Complex Networks: From the Internet to Cell Biology

    NASA Astrophysics Data System (ADS)

    Barabási, Albert-László

    2006-03-01

    Networks with complex topology describe systems as diverse as the cell, the World Wide Web or the society. In the past few years we have learned that their evolution is driven by self-organizing processes that are governed by simple but generic scaling laws, leading to the emergence of a vibrant interdisciplinary field that uses the tools of statistical physics to explain the origin and the dynamics of real networks. One of the most surprising finding is that despite their apparent differences, cells and complex man-made networks, such as the Internet or the World Wide Web, and many communication networks share the same large-scale topology, each having a scale-free structure. I will show that the scale-free topology of these complex webs have important consequences on their robustness against failures and attacks, with implications on drug design, the Internet's ability to survive attacks and failures, and our ability to understand the functional role of genes. For further information and papers, see http://www.nd.edu/˜networks

  1. Biologically inspired intelligent decision making: a commentary on the use of artificial neural networks in bioinformatics.

    PubMed

    Manning, Timmy; Sleator, Roy D; Walsh, Paul

    2014-01-01

    Artificial neural networks (ANNs) are a class of powerful machine learning models for classification and function approximation which have analogs in nature. An ANN learns to map stimuli to responses through repeated evaluation of exemplars of the mapping. This learning approach results in networks which are recognized for their noise tolerance and ability to generalize meaningful responses for novel stimuli. It is these properties of ANNs which make them appealing for applications to bioinformatics problems where interpretation of data may not always be obvious, and where the domain knowledge required for deductive techniques is incomplete or can cause a combinatorial explosion of rules. In this paper, we provide an introduction to artificial neural network theory and review some interesting recent applications to bioinformatics problems. PMID:24335433

  2. Inference of gene regulatory networks incorporating multi-source biological knowledge via a state space model with L1 regularization.

    PubMed

    Hasegawa, Takanori; Yamaguchi, Rui; Nagasaki, Masao; Miyano, Satoru; Imoto, Seiya

    2014-01-01

    Comprehensive understanding of gene regulatory networks (GRNs) is a major challenge in the field of systems biology. Currently, there are two main approaches in GRN analysis using time-course observation data, namely an ordinary differential equation (ODE)-based approach and a statistical model-based approach. The ODE-based approach can generate complex dynamics of GRNs according to biologically validated nonlinear models. However, it cannot be applied to ten or more genes to simultaneously estimate system dynamics and regulatory relationships due to the computational difficulties. The statistical model-based approach uses highly abstract models to simply describe biological systems and to infer relationships among several hundreds of genes from the data. However, the high abstraction generates false regulations that are not permitted biologically. Thus, when dealing with several tens of genes of which the relationships are partially known, a method that can infer regulatory relationships based on a model with low abstraction and that can emulate the dynamics of ODE-based models while incorporating prior knowledge is urgently required. To accomplish this, we propose a method for inference of GRNs using a state space representation of a vector auto-regressive (VAR) model with L1 regularization. This method can estimate the dynamic behavior of genes based on linear time-series modeling constructed from an ODE-based model and can infer the regulatory structure among several tens of genes maximizing prediction ability for the observational data. Furthermore, the method is capable of incorporating various types of existing biological knowledge, e.g., drug kinetics and literature-recorded pathways. The effectiveness of the proposed method is shown through a comparison of simulation studies with several previous methods. For an application example, we evaluated mRNA expression profiles over time upon corticosteroid stimulation in rats, thus incorporating corticosteroid

  3. Biological network inferences for a protection mechanism against familial Creutzfeldt-Jakob disease with E200K pathogenic mutation

    PubMed Central

    2014-01-01

    Background Human prion diseases are caused by abnormal accumulation of misfolded prion protein in the brain tissue. Inherited prion diseases, including familial Creutzfeldt-Jakob disease (fCJD), are associated with mutations of the prion protein gene (PRNP). The glutamate (E)-to-lysine (K) substitution at codon 200 (E200K) in PRNP is the most common pathogenic mutation causing fCJD, but the E200K pathogenic mutation alone is regarded insufficient to cause prion diseases; thus, additional unidentified factors are proposed to explain the penetrance of E200K-dependent fCJD. Here, exome differences and biological network analysis between fCJD patients with E200K and healthy individuals, including a non-CJD individual with E200K, were analysed to gain new insights into possible mechanisms for CJD in individuals carrying E200K. Methods Exome sequencing of the three CJD patients with E200K and 11 of the family of one patient (case1) were performed using the Illumina HiSeq 2000. The exome sequences of 24 Healthy Koreans were used as control. The bioinformatic analysis of the exome sequences was performed using the CLC Genomics Workbench v5.5. Sanger sequencing for variants validation was processed using a BigDye Terminator Cycle Sequencing Kit and an ABI 3730xl automated sequencer. Biological networks were created using Cytoscape (v2.8.3 and v3.0.2) and Pathway Studio 9.0 software. Results Nineteen sites were only observed in healthy individuals. Four proteins (NRXN2, KLKB1, KARS, and LAMA3) that harbour rarely observed single-nucleotide variants showed biological interactions that are associated with prion diseases and/or prion protein in our biological network analysis. Conclusion Through this study, we confirmed that individuals can have a CJD-free life, even if they carry a pathogenic E200K mutation. Our research provides a possible mechanism that involves a candidate protective factor; this could be exploited to prevent fCJD onset in individuals carrying E200K. PMID

  4. Identification and classification of galaxies using a biologically-inspired neutral network

    NASA Astrophysics Data System (ADS)

    Somanah, Radhakhrishna; Rughooputh, Soonil D. D. V.; Rughooputh, Harry C. S.

    2002-10-01

    Recognition/Classification of galaxies is an important issue in the large-scale study of the Universe; it is not a simple task. According to estimates computed from the Hubble Deep Field (HDF), astronomers predict that the universe may potentially contain over 100 billion galaxies. Several techniques have been reported for the classification of galaxies. Parallel developments in the field of neural networks have come to a stage that they can participate well in the recognition of objects. Recently, the Pulse-Coupled Neural Network (PCNN) has been shown to be useful for image pre-processing. In this paper, we present a novel way to identify optical galaxies by presenting the images of the galaxies to a hierarchical neural network involving two PCNNs. The image is presented to the network to generate binary barcodes (one per iteration) of the galaxies; the barcodes are unique to the input galactic image. In the current study, we exploit this property to identify optical galaxies by comparing the signatures (binary barcode) from a corresponding database.

  5. A linked spatial and temporal model of the chemical and biological status of a large, acid-sensitive river network.

    PubMed

    Evans, Chris D; Cooper, David M; Juggins, Steve; Jenkins, Alan; Norris, Dave

    2006-07-15

    Freshwater sensitivity to acidification varies according to geology, soils and land-use, and consequently it remains difficult to quantify the current extent of acidification, or its biological impacts, based on limited spot samples. The problem is particularly acute for river systems, where the transition from acid to circum-neutral conditions can occur within short distances. This paper links an established point-based long-term acidification model (MAGIC) with a landscape-based mixing model (PEARLS) to simulate spatial and temporal variations in acidification for a 256 km(2) catchment in North Wales. Empirical relationships are used to predict changes in the probability of occurrence of an indicator invertebrate species, Baetis rhodani, across the catchment as a function of changing chemical status. Results suggest that, at present, 27% of the river network has a mean acid neutralising capacity (ANC) below a biologically-relevant threshold of 20 microeq l(-1). At high flows, this proportion increases to 45%. The model suggests that only around 16% of the stream network had a mean ANC < 20 microeq l(-1) in 1850, but that this increased to 42% at the sulphur deposition peak around 1970. By 2050 recovery is predicted, but with some persistence of acid conditions in the most sensitive, peaty headwaters. Stream chemical suitability for Baetis rhodani is also expected to increase in formerly acidified areas, but for overall abundance to remain below that simulated in 1850. The approach of linking plot-scale process-based models to catchment mixing models provides a potential means of predicting the past and future spatial extent of acidification within large, heterogeneous river networks and regions. Further development of ecological response models to include other chemical predictor variables and the effects of acid episodes would allow more realistic simulation of the temporal and spatial dynamics of ecosystem recovery from acidification. PMID:16580046

  6. Genetic Networking of the Bemisia tabaci Cryptic Species Complex Reveals Pattern of Biological Invasions

    PubMed Central

    De Barro, Paul; Ahmed, Muhammad Z.

    2011-01-01

    Background A challenge within the context of cryptic species is the delimitation of individual species within the complex. Statistical parsimony network analytics offers the opportunity to explore limits in situations where there are insufficient species-specific morphological characters to separate taxa. The results also enable us to explore the spread in taxa that have invaded globally. Methodology/Principal Findings Using a 657 bp portion of mitochondrial cytochrome oxidase 1 from 352 unique haplotypes belonging to the Bemisia tabaci cryptic species complex, the analysis revealed 28 networks plus 7 unconnected individual haplotypes. Of the networks, 24 corresponded to the putative species identified using the rule set devised by Dinsdale et al. (2010). Only two species proposed in Dinsdale et al. (2010) departed substantially from the structure suggested by the analysis. The analysis of the two invasive members of the complex, Mediterranean (MED) and Middle East – Asia Minor 1 (MEAM1), showed that in both cases only a small number of haplotypes represent the majority that have spread beyond the home range; one MEAM1 and three MED haplotypes account for >80% of the GenBank records. Israel is a possible source of the globally invasive MEAM1 whereas MED has two possible sources. The first is the eastern Mediterranean which has invaded only the USA, primarily Florida and to a lesser extent California. The second are western Mediterranean haplotypes that have spread to the USA, Asia and South America. The structure for MED supports two home range distributions, a Sub-Saharan range and a Mediterranean range. The MEAM1 network supports the Middle East - Asia Minor region. Conclusion/Significance The network analyses show a high level of congruence with the species identified in a previous phylogenetic analysis. The analysis of the two globally invasive members of the complex support the view that global invasion often involve very small portions of the available

  7. Advection and Diffusion of Substances in Biological Tissues With Complex Vascular Networks

    PubMed Central

    Beard, Daniel A.; Bassingthwaighte, James B.

    2010-01-01

    For highly diffusive solutes the kinetics of blood–tissue exchange is only poorly represented by a model consisting of sets of independent parallel capillary–tissue units. We constructed a more realistic multicapillary network model conforming statistically to morphometric data. Flows through the tortuous paths in the network were calculated based on constant resistance per unit length throughout the network and the resulting advective intracapillary velocity field was used as a framework for describing the extravascular diffusion of a substance for which there is no barrier or permeability limitation. Simulated impulse responses from the system, analogous to tracer water outflow dilution curves, showed flow-limited behavior over a range of flows from about 2 to 5 ml min−1 g−1, as is observed for water in the heart in vivo. The present model serves as a reference standard against which to evaluate computationally simpler, less physically realistic models. The simulated outflow curves from the network model, like experimental water curves, were matched to outflow curves from the commonly used axially distributed models only by setting the capillary wall permeability–surface area (PS) to a value so artifactually low that it is incompatible with the experimental observations that transport is flow limited. However, simple axially distributed models with appropriately high PSs will fit water outflow dilution curves if axial diffusion coefficients are set at high enough values to account for enhanced dispersion due to the complex geometry of the capillary network. Without incorporating this enhanced dispersion, when applied to experimental curves over a range of flows, the simpler models give a false inference that there is recruitment of capillary surface area with increasing flow. Thus distributed models must account for diffusional as well as permeation processes to provide physiologically appropriate parameter estimates. PMID:10784090

  8. Modeling the collagen fibril network of biological tissues as a nonlinearly elastic material using a continuous volume fraction distribution function

    PubMed Central

    Shirazi, Reza; Vena, Pasquale; Sah, Robert L.; Klisch, Stephen M.

    2012-01-01

    Despite distinct mechanical functions, biological soft tissues have a common microstructure in which a ground matrix is reinforced by a collagen fibril network. The microstructural properties of the collagen network contribute to continuum mechanical tissue properties that are strongly anisotropic with tensile-compressive asymmetry. In this study, a novel approach based on a continuous distribution of collagen fibril volume fractions is developed to model fibril reinforced soft tissues as a nonlinearly elastic and anisotropic material. Compared with other approaches that use a normalized number of fibrils for the definition of the distribution function, this representation is based on a distribution parameter (i.e. volume fraction) that is commonly measured experimentally while also incorporating pre-stress of the collagen fibril network in a tissue natural configuration. After motivating the form of the collagen strain energy function, examples are provided for two volume fraction distribution functions. Consequently, collagen second-Piola Kirchhoff stress and elasticity tensors are derived, first in general form and then specifically for a model that may be used for immature bovine articular cartilage. It is shown that the proposed strain energy is a convex function of the deformation gradient tensor and, thus, is suitable for the formation of a polyconvex tissue strain energy function. PMID:23390357

  9. Towards a System Level Understanding of Non-Model Organisms Sampled from the Environment: A Network Biology Approach

    PubMed Central

    Williams, Tim D.; Turan, Nil; Diab, Amer M.; Wu, Huifeng; Mackenzie, Carolynn; Bartie, Katie L.; Hrydziuszko, Olga; Lyons, Brett P.; Stentiford, Grant D.; Herbert, John M.; Abraham, Joseph K.; Katsiadaki, Ioanna; Leaver, Michael J.; Taggart, John B.; George, Stephen G.; Viant, Mark R.; Chipman, Kevin J.; Falciani, Francesco

    2011-01-01

    The acquisition and analysis of datasets including multi-level omics and physiology from non-model species, sampled from field populations, is a formidable challenge, which so far has prevented the application of systems biology approaches. If successful, these could contribute enormously to improving our understanding of how populations of living organisms adapt to environmental stressors relating to, for example, pollution and climate. Here we describe the first application of a network inference approach integrating transcriptional, metabolic and phenotypic information representative of wild populations of the European flounder fish, sampled at seven estuarine locations in northern Europe with different degrees and profiles of chemical contaminants. We identified network modules, whose activity was predictive of environmental exposure and represented a link between molecular and morphometric indices. These sub-networks represented both known and candidate novel adverse outcome pathways representative of several aspects of human liver pathophysiology such as liver hyperplasia, fibrosis, and hepatocellular carcinoma. At the molecular level these pathways were linked to TNF alpha, TGF beta, PDGF, AGT and VEGF signalling. More generally, this pioneering study has important implications as it can be applied to model molecular mechanisms of compensatory adaptation to a wide range of scenarios in wild populations. PMID:21901081

  10. Biological pattern generation: the cellular and computational logic of networks in motion.

    PubMed

    Grillner, Sten

    2006-12-01

    In 1900, Ramón y Cajal advanced the neuron doctrine, defining the neuron as the fundamental signaling unit of the nervous system. Over a century later, neurobiologists address the circuit doctrine: the logic of the core units of neuronal circuitry that control animal behavior. These are circuits that can be called into action for perceptual, conceptual, and motor tasks, and we now need to understand whether there are coherent and overriding principles that govern the design and function of these modules. The discovery of central motor programs has provided crucial insight into the logic of one prototypic set of neural circuits: those that generate motor patterns. In this review, I discuss the mode of operation of these pattern generator networks and consider the neural mechanisms through which they are selected and activated. In addition, I will outline the utility of computational models in analysis of the dynamic actions of these motor networks. PMID:17145498

  11. Parametric motion control of robotic arms: A biologically based approach using neural networks

    NASA Technical Reports Server (NTRS)

    Bock, O.; D'Eleuterio, G. M. T.; Lipitkas, J.; Grodski, J. J.

    1993-01-01

    A neural network based system is presented which is able to generate point-to-point movements of robotic manipulators. The foundation of this approach is the use of prototypical control torque signals which are defined by a set of parameters. The parameter set is used for scaling and shaping of these prototypical torque signals to effect a desired outcome of the system. This approach is based on neurophysiological findings that the central nervous system stores generalized cognitive representations of movements called synergies, schemas, or motor programs. It has been proposed that these motor programs may be stored as torque-time functions in central pattern generators which can be scaled with appropriate time and magnitude parameters. The central pattern generators use these parameters to generate stereotypical torque-time profiles, which are then sent to the joint actuators. Hence, only a small number of parameters need to be determined for each point-to-point movement instead of the entire torque-time trajectory. This same principle is implemented for controlling the joint torques of robotic manipulators where a neural network is used to identify the relationship between the task requirements and the torque parameters. Movements are specified by the initial robot position in joint coordinates and the desired final end-effector position in Cartesian coordinates. This information is provided to the neural network which calculates six torque parameters for a two-link system. The prototypical torque profiles (one per joint) are then scaled by those parameters. After appropriate training of the network, our parametric control design allowed the reproduction of a trained set of movements with relatively high accuracy, and the production of previously untrained movements with comparable accuracy. We conclude that our approach was successful in discriminating between trained movements and in generalizing to untrained movements.

  12. ASD v3.0: unraveling allosteric regulation with structural mechanisms and biological networks

    PubMed Central

    Shen, Qiancheng; Wang, Guanqiao; Li, Shuai; Liu, Xinyi; Lu, Shaoyong; Chen, Zhongjie; Song, Kun; Yan, Junhao; Geng, Lv; Huang, Zhimin; Huang, Wenkang; Chen, Guoqiang; Zhang, Jian

    2016-01-01

    Allosteric regulation, the most direct and efficient way of regulating protein function, is induced by the binding of a ligand at one site that is topographically distinct from an orthosteric site. Allosteric Database (ASD, available online at http://mdl.shsmu.edu.cn/ASD) has been developed to provide comprehensive information featuring allosteric regulation. With increasing data, fundamental questions pertaining to allostery are currently receiving more attention from the mechanism of allosteric changes in an individual protein to the entire effect of the changes in the interconnected network in the cell. Thus, the following novel features were added to this updated version: (i) structural mechanisms of more than 1600 allosteric actions were elucidated by a comparison of site structures before and after the binding of an modulator; (ii) 261 allosteric networks were identified to unveil how the allosteric action in a single protein would propagate to affect downstream proteins; (iii) two of the largest human allosteromes, protein kinases and GPCRs, were thoroughly constructed; and (iv) web interface and data organization were completely redesigned for efficient access. In addition, allosteric data have largely expanded in this update. These updates are useful for facilitating the investigation of allosteric mechanisms, dynamic networks and drug discoveries. PMID:26365237

  13. ASD v3.0: unraveling allosteric regulation with structural mechanisms and biological networks.

    PubMed

    Shen, Qiancheng; Wang, Guanqiao; Li, Shuai; Liu, Xinyi; Lu, Shaoyong; Chen, Zhongjie; Song, Kun; Yan, Junhao; Geng, Lv; Huang, Zhimin; Huang, Wenkang; Chen, Guoqiang; Zhang, Jian

    2016-01-01

    Allosteric regulation, the most direct and efficient way of regulating protein function, is induced by the binding of a ligand at one site that is topographically distinct from an orthosteric site. Allosteric Database (ASD, available online at http://mdl.shsmu.edu.cn/ASD) has been developed to provide comprehensive information featuring allosteric regulation. With increasing data, fundamental questions pertaining to allostery are currently receiving more attention from the mechanism of allosteric changes in an individual protein to the entire effect of the changes in the interconnected network in the cell. Thus, the following novel features were added to this updated version: (i) structural mechanisms of more than 1600 allosteric actions were elucidated by a comparison of site structures before and after the binding of an modulator; (ii) 261 allosteric networks were identified to unveil how the allosteric action in a single protein would propagate to affect downstream proteins; (iii) two of the largest human allosteromes, protein kinases and GPCRs, were thoroughly constructed; and (iv) web interface and data organization were completely redesigned for efficient access. In addition, allosteric data have largely expanded in this update. These updates are useful for facilitating the investigation of allosteric mechanisms, dynamic networks and drug discoveries. PMID:26365237

  14. Exploiting the yeast stress-activated signaling network to inform on stress biology and disease signaling

    PubMed Central

    Ho, Yi-Hsuan

    2016-01-01

    Healthy cells utilize intricate systems to monitor their environment and mount robust responses in the event of cellular stress. Whether stress arises from external insults or defects due to mutation and disease, cells must be able to respond precisely to mount the appropriate defenses. Multi-faceted stress responses are generally coupled with arrest of growth and cell-cycle progression, which both limits the transmission of damaged materials and serves to reallocate limited cellular resources toward defense. Therefore, stress defense versus rapid growth represent competing interests in the cell. How eukaryotic cells set the balance between defense versus proliferation, and in particular knowledge of the regulatory networks that control this decision, are poorly understood. In this perspective, we expand upon our recent work inferring the stress-activated signaling network in budding yeast, which captures pathways controlling stress defense and regulators of growth and cell-cycle progression. We highlight similarities between the yeast and mammalian stress responses and explore how stress-activated signaling networks in yeast can inform on signaling defects in human cancers. PMID:25957506

  15. On the biological plausibility of grandmother cells: implications for neural network theories in psychology and neuroscience.

    PubMed

    Bowers, Jeffrey S

    2009-01-01

    A fundamental claim associated with parallel distributed processing (PDP) theories of cognition is that knowledge is coded in a distributed manner in mind and brain. This approach rejects the claim that knowledge is coded in a localist fashion, with words, objects, and simple concepts (e.g. "dog"), that is, coded with their own dedicated representations. One of the putative advantages of this approach is that the theories are biologically plausible. Indeed, advocates of the PDP approach often highlight the close parallels between distributed representations learned in connectionist models and neural coding in brain and often dismiss localist (grandmother cell) theories as biologically implausible. The author reviews a range a data that strongly challenge this claim and shows that localist models provide a better account of single-cell recording studies. The author also contrast local and alternative distributed coding schemes (sparse and coarse coding) and argues that common rejection of grandmother cell theories in neuroscience is due to a misunderstanding about how localist models behave. The author concludes that the localist representations embedded in theories of perception and cognition are consistent with neuroscience; biology only calls into question the distributed representations often learned in PDP models. PMID:19159155

  16. Regulatory networks, genes and glycerophospholipid biosynthesis pathway in schistosomiasis: a systems biology view for pharmacological intervention.

    PubMed

    Shinde, Sonali; Mol, Milsee; Singh, Shailza

    2014-10-25

    Understanding network topology through embracing the global dynamical regulation of genes in an active state space rather than traditional one-gene-one trait approach facilitates the rational drug development process. Schistosomiasis, a neglected tropical disease, has glycerophospholipids as abundant molecules present on its surface. Lack of effective clinical solutions to treat pathogens encourages us to carry out systems-level studies that could contribute to the development of an effective therapy. Development of a strategy for identifying drug targets by combined genome-scale metabolic network and essentiality analyses through in silico approaches provides tantalizing opportunity to investigate the role of protein/substrate metabolism. A genome-scale metabolic network model reconstruction represents choline-phosphate cytidyltransferase as the rate limiting enzyme and regulates the rate of phosphatidylcholine (PC) biosynthesis. The uptake of choline was regulated by choline concentration, promoting the regulation of phosphocholine synthesis. In Schistosoma, the change in developmental stage could result from the availability of choline, hampering its developmental cycle. There are no structural reports for this protein. In order to inhibit the activity of choline-phosphate cytidyltransferase (CCT), it was modeled by homology modeling using 1COZ as the template from Bacillus subtilis. The transition-state stabilization and catalytic residues were mapped as 'HXGH' and 'RTEGISTT' motif. CCT catalyzes the formation of CDP-choline from phosphocholine in which nucleotidyltransferase adds CTP to phosphocholine. The presence of phosphocholine permits the parasite to survive in an immunologically hostile environment. This feature endeavors development of an inhibitor specific for cytidyltransferase in Schistosoma. Flavonolignans were used to inhibit this activity in which hydnowightin showed the highest affinity as compared to miltefosine. PMID:25149020

  17. MicroRNA-1 properties in cancer regulatory networks and tumor biology.

    PubMed

    Weiss, Martin; Brandenburg, Lars-Ove; Burchardt, Martin; Stope, Matthias B

    2016-08-01

    Short non-coding microRNAs have been identified to orchestrate crucial mechanisms in cancer progression and treatment resistance. MicroRNAs are involved in posttranscriptional modulation of gene expression and therefore represent promising targets for anticancer therapy. As mircoRNA-1 (miR-1) exerted to be predominantly downregulated in the majority of examined tumors, miR-1 is classified to be a tumor suppressor with high potential to diminish tumor development and therapy resistance. Here we review the complex functionality of miR-1 in tumor biology. PMID:27286699

  18. The Challenge of Proteomic Data from Molecular Signals to Biological Networks and Disease

    SciTech Connect

    Webb-Robertson, Bobbie-Jo M.; Cannon, William R.; Adkins, Joshua N.; Gracio, Deborah K.

    2006-12-31

    Mass spectrometry (MS) based proteomics is a rapidly advancing field that has great promise for both understanding biological systems as well as advancing the identification and treatment of disease. Breakthroughs in science and medicine due to proteomics, however, are coupled with our ability to overcome significant challenges in the field. These challenges are multi-scalar, spanning the range from the statistics of molecules and molecular signals, to the phenomenological characterization of disease. The papers presented in this section are a representative snapshot of these challenges that span scale and scientific disciplines.

  19. Multi-objective mixed integer strategy for the optimisation of biological networks.

    PubMed

    Sendín, J O H; Exler, O; Banga, J R

    2010-05-01

    In this contribution, the authors consider multi-criteria optimisation problems arising from the field of systems biology when both continuous and integer decision variables are involved. Mathematically, they are formulated as mixed-integer non-linear programming problems. The authors present a novel solution strategy based on a global optimisation approach for dealing with this class of problems. Its usefulness and capabilities are illustrated with two metabolic engineering case studies. For these problems, the authors show how the set of optimal solutions (the so-called Pareto front) is successfully and efficiently obtained, providing further insight into the systems under consideration regarding their optimal manipulation. PMID:20500003

  20. Omics of Brucella: Species-Specific sRNA-Mediated Gene Ontology Regulatory Networks Identified by Computational Biology.

    PubMed

    Vishnu, Udayakumar S; Sankarasubramanian, Jagadesan; Gunasekaran, Paramasamy; Sridhar, Jayavel; Rajendhran, Jeyaprakash

    2016-06-01

    Brucella is an intracellular bacterium that causes the zoonotic infectious disease, brucellosis. Brucella species are currently intensively studied with a view to developing novel global health diagnostics and therapeutics. In this context, small RNAs (sRNAs) are one of the emerging topical areas; they play significant roles in regulating gene expression and cellular processes in bacteria. In the present study, we forecast sRNAs in three Brucella species that infect humans, namely Brucella melitensis, Brucella abortus, and Brucella suis, using a computational biology analysis. We combined two bioinformatic algorithms, SIPHT and sRNAscanner. In B. melitensis 16M, 21 sRNA candidates were identified, of which 14 were novel. Similarly, 14 sRNAs were identified in B. abortus, of which four were novel. In B. suis, 16 sRNAs were identified, and five of them were novel. TargetRNA2 software predicted the putative target genes that could be regulated by the identified sRNAs. The identified mRNA targets are involved in carbohydrate, amino acid, lipid, nucleotide, and coenzyme metabolism and transport, energy production and conversion, replication, recombination, repair, and transcription. Additionally, the Gene Ontology (GO) network analysis revealed the species-specific, sRNA-based regulatory networks in B. melitensis, B. abortus, and B. suis. Taken together, although sRNAs are veritable modulators of gene expression in prokaryotes, there are few reports on the significance of sRNAs in Brucella. This report begins to address this literature gap by offering a series of initial observations based on computational biology to pave the way for future experimental analysis of sRNAs and their targets to explain the complex pathogenesis of Brucella. PMID:27223678

  1. A Network Biology Approach to Decipher Stress Response in Bacteria Using Escherichia coli As a Model.

    PubMed

    Nagar, Shashwat Deepali; Aggarwal, Bhavye; Joon, Shikha; Bhatnagar, Rakesh; Bhatnagar, Sonika

    2016-05-01

    The development of drug-resistant pathogenic bacteria poses challenges to global health for their treatment and control. In this context, stress response enables bacterial populations to survive extreme perturbations in the environment but remains poorly understood. Specific modules are activated for unique stressors with few recognized global regulators. The phenomenon of cross-stress protection strongly suggests the presence of central proteins that control the diverse stress responses. In this work, Escherichia coli was used to model the bacterial stress response. A Protein-Protein Interaction Network was generated by integrating differentially expressed genes in eight stress conditions of pH, temperature, and antibiotics with relevant gene ontology terms. Topological analysis identified 24 central proteins. The well-documented role of 16 central proteins in stress indicates central control of the response, while the remaining eight proteins may have a novel role in stress response. Cluster analysis of the generated network implicated RNA binding, flagellar assembly, ABC transporters, and DNA repair as important processes during response to stress. Pathway analysis showed crosstalk of Two Component Systems with metabolic processes, oxidative phosphorylation, and ABC transporters. The results were further validated by analysis of an independent cross-stress protection dataset. This study also reports on the ways in which bacterial stress response can progress to biofilm formation. In conclusion, we suggest that drug targets or pathways disrupting bacterial stress responses can potentially be exploited to combat antibiotic tolerance and multidrug resistance in the future. PMID:27195968

  2. Identification of migratory bird flyways in North America using community detection on biological networks.

    PubMed

    Buhnerkempe, Michael G; Webb, Colleen T; Merton, Andrew A; Buhnerkempe, John E; Givens, Geof H; Miller, Ryan S; Hoeting, Jennifer A

    2016-04-01

    Migratory behavior of waterfowl populations in North America has traditionally been broadly characterized by four north-south flyways, and these flyways have been central to the management of waterfowl populations for more than 80 yr. However, previous flyway characterizations are not easily updated with current bird movement data and fail to provide assessments of the importance of specific geographical regions to the identification of flyways. Here, we developed a network model of migratory movement for four waterfowl species, Mallard (Anas platyrhnchos), Northern Pintail (A. acuta), American Green-winged Teal (A. carolinensis), and Canada Goose (Branta canadensis), in North America, using bird band and recovery data. We then identified migratory flyways using a community detection algorithm and characterized the importance of smaller geographic regions in identifying flyways using a novel metric, the consolidation factor. We identified four main flyways for Mallards, Northern Pintails, and American Green-winged Teal, with the flyway identification in Canada Geese exhibiting higher complexity. For Mallards, flyways were relatively consistent through time. However, consolidation factors revealed that for Mallards and Green-winged Teal, the presumptive Mississippi flyway was potentially a zone of high mixing between other flyways. Our results demonstrate that the network approach provides a robust method for flyway identification that is widely applicable given the relatively minimal data requirements and is easily updated with future movement data to reflect changes in flyway definitions and management goals. PMID:27411247

  3. BioMart Central Portal: an open database network for the biological community.

    PubMed

    Guberman, Jonathan M; Ai, J; Arnaiz, O; Baran, Joachim; Blake, Andrew; Baldock, Richard; Chelala, Claude; Croft, David; Cros, Anthony; Cutts, Rosalind J; Di Génova, A; Forbes, Simon; Fujisawa, T; Gadaleta, E; Goodstein, D M; Gundem, Gunes; Haggarty, Bernard; Haider, Syed; Hall, Matthew; Harris, Todd; Haw, Robin; Hu, S; Hubbard, Simon; Hsu, Jack; Iyer, Vivek; Jones, Philip; Katayama, Toshiaki; Kinsella, R; Kong, Lei; Lawson, Daniel; Liang, Yong; Lopez-Bigas, Nuria; Luo, J; Lush, Michael; Mason, Jeremy; Moreews, Francois; Ndegwa, Nelson; Oakley, Darren; Perez-Llamas, Christian; Primig, Michael; Rivkin, Elena; Rosanoff, S; Shepherd, Rebecca; Simon, Reinhard; Skarnes, B; Smedley, Damian; Sperling, Linda; Spooner, William; Stevenson, Peter; Stone, Kevin; Teague, J; Wang, Jun; Wang, Jianxin; Whitty, Brett; Wong, D T; Wong-Erasmus, Marie; Yao, L; Youens-Clark, Ken; Yung, Christina; Zhang, Junjun; Kasprzyk, Arek

    2011-01-01

    BioMart Central Portal is a first of its kind, community-driven effort to provide unified access to dozens of biological databases spanning genomics, proteomics, model organisms, cancer data, ontology information and more. Anybody can contribute an independently maintained resource to the Central Portal, allowing it to be exposed to and shared with the research community, and linking it with the other resources in the portal. Users can take advantage of the common interface to quickly utilize different sources without learning a new system for each. The system also simplifies cross-database searches that might otherwise require several complicated steps. Several integrated tools streamline common tasks, such as converting between ID formats and retrieving sequences. The combination of a wide variety of databases, an easy-to-use interface, robust programmatic access and the array of tools make Central Portal a one-stop shop for biological data querying. Here, we describe the structure of Central Portal and show example queries to demonstrate its capabilities. PMID:21930507

  4. Supramolecular assembly of biological molecules purified from bovine nerve cells: from microtubule bundles and necklaces to neurofilament networks

    NASA Astrophysics Data System (ADS)

    Needleman, Daniel J.; Jones, Jayna B.; Raviv, Uri; Ojeda-Lopez, Miguel A.; Miller, H. P.; Li, Y.; Wilson, L.; Safinya, C. R.

    2005-11-01

    With the completion of the human genome project, the biosciences community is beginning the daunting task of understanding the structures and functions of a large number of interacting biological macromolecules. Examples include the interacting molecules involved in the process of DNA condensation during the cell cycle, and in the formation of bundles and networks of filamentous actin proteins in cell attachment, motility and cytokinesis. In this proceedings paper we present examples of supramolecular assembly based on proteins derived from the vertebrate nerve cell cytoskeleton. The axonal cytoskeleton in vertebrate neurons provides a rich example of bundles and networks of neurofilaments, microtubules (MTs) and filamentous actin, where the nature of the interactions, structures, and structure-function correlations remains poorly understood. We describe synchrotron x-ray diffraction, electron microscopy, and optical imaging data, in reconstituted protein systems purified from bovine central nervous system, which reveal unexpected structures not predicted by current electrostatic theories of polyelectrolyte bundling, including three-dimensional MT bundles and two-dimensional MT necklaces.

  5. Five Years of Designing Wireless Sensor Networks in the Doñana Biological Reserve (Spain): An Applications Approach

    PubMed Central

    Larios, Diego F.; Barbancho, Julio; Sevillano, José L.; Rodríguez, Gustavo; Molina, Francisco J.; Gasull, Virginia G.; Mora-Merchan, Javier M.; León, Carlos

    2013-01-01

    Wireless Sensor Networks (WSNs) are a technology that is becoming very popular for many applications, and environmental monitoring is one of its most important application areas. This technology solves the lack of flexibility of wired sensor installations and, at the same time, reduces the deployment costs. To demonstrate the advantages of WSN technology, for the last five years we have been deploying some prototypes in the Doñana Biological Reserve, which is an important protected area in Southern Spain. These prototypes not only evaluate the technology, but also solve some of the monitoring problems that have been raised by biologists working in Doñana. This paper presents a review of the work that has been developed during these five years. Here, we demonstrate the enormous potential of using machine learning in wireless sensor networks for environmental and animal monitoring because this approach increases the amount of useful information and reduces the effort that is required by biologists in an environmental monitoring task. PMID:24025554

  6. Hybrid coordination-network-engineering for bridging cascaded channels to activate long persistent phosphorescence in the second biological window

    PubMed Central

    Qin, Xixi; Li, Yang; Zhang, Ruili; Ren, Jinjun; Gecevicius, Mindaugas; Wu, Yiling; Sharafudeen, Kaniyarakkal; Dong, Guoping; Zhou, Shifeng; Ma, Zhijun; Qiu, Jianrong

    2016-01-01

    We present a novel “Top-down” strategy to design the long phosphorescent phosphors in the second biological transparency window via energy transfer. Inherence in this approach to material design involves an ingenious engineering for hybridizing the coordination networks of hosts, tailoring the topochemical configuration of dopants, and bridging a cascaded tunnel for transferring the persistent energy from traps, to sensitizers and then to acceptors. Another significance of this endeavour is to highlight a rational scheme for functionally important hosts and dopants, Cr/Nd co-doped Zn1−xCaxGa2O4 solid solutions. Such solid-solution is employed as an optimized host to take advantage of its characteristic trap site level to establish an electron reservoir and network parameters for the precipitation of activators Nd3+ and Cr3+. The results reveal that the strategy employed here has the great potential, as well as opens new opportunities for future new-wavelength, NIR phosphorescent phosphors fabrication with many potential multifunctional bio-imaging applications. PMID:26843129

  7. Hybrid coordination-network-engineering for bridging cascaded channels to activate long persistent phosphorescence in the second biological window

    NASA Astrophysics Data System (ADS)

    Qin, Xixi; Li, Yang; Zhang, Ruili; Ren, Jinjun; Gecevicius, Mindaugas; Wu, Yiling; Sharafudeen, Kaniyarakkal; Dong, Guoping; Zhou, Shifeng; Ma, Zhijun; Qiu, Jianrong

    2016-02-01

    We present a novel “Top-down” strategy to design the long phosphorescent phosphors in the second biological transparency window via energy transfer. Inherence in this approach to material design involves an ingenious engineering for hybridizing the coordination networks of hosts, tailoring the topochemical configuration of dopants, and bridging a cascaded tunnel for transferring the persistent energy from traps, to sensitizers and then to acceptors. Another significance of this endeavour is to highlight a rational scheme for functionally important hosts and dopants, Cr/Nd co-doped Zn1-xCaxGa2O4 solid solutions. Such solid-solution is employed as an optimized host to take advantage of its characteristic trap site level to establish an electron reservoir and network parameters for the precipitation of activators Nd3+ and Cr3+. The results reveal that the strategy employed here has the great potential, as well as opens new opportunities for future new-wavelength, NIR phosphorescent phosphors fabrication with many potential multifunctional bio-imaging applications.

  8. Hybrid coordination-network-engineering for bridging cascaded channels to activate long persistent phosphorescence in the second biological window.

    PubMed

    Qin, Xixi; Li, Yang; Zhang, Ruili; Ren, Jinjun; Gecevicius, Mindaugas; Wu, Yiling; Sharafudeen, Kaniyarakkal; Dong, Guoping; Zhou, Shifeng; Ma, Zhijun; Qiu, Jianrong

    2016-01-01

    We present a novel "Top-down" strategy to design the long phosphorescent phosphors in the second biological transparency window via energy transfer. Inherence in this approach to material design involves an ingenious engineering for hybridizing the coordination networks of hosts, tailoring the topochemical configuration of dopants, and bridging a cascaded tunnel for transferring the persistent energy from traps, to sensitizers and then to acceptors. Another significance of this endeavour is to highlight a rational scheme for functionally important hosts and dopants, Cr/Nd co-doped Zn1-xCaxGa2O4 solid solutions. Such solid-solution is employed as an optimized host to take advantage of its characteristic trap site level to establish an electron reservoir and network parameters for the precipitation of activators Nd(3+) and Cr(3+). The results reveal that the strategy employed here has the great potential, as well as opens new opportunities for future new-wavelength, NIR phosphorescent phosphors fabrication with many potential multifunctional bio-imaging applications. PMID:26843129

  9. TOLKIN – Tree of Life Knowledge and Information Network: Filling a Gap for Collaborative Research in Biological Systematics

    PubMed Central

    Beaman, Reed S.; Traub, Greg H.; Dell, Christopher A.; Santiago, Nestor; Koh, Jin; Cellinese, Nico

    2012-01-01

    The development of biological informatics infrastructure capable of supporting growing data management and analysis environments is an increasing need within the systematics biology community. Although significant progress has been made in recent years on developing new algorithms and tools for analyzing and visualizing large phylogenetic data and trees, implementation of these resources is often carried out by bioinformatics experts, using one-off scripts. Therefore, a gap exists in providing data management support for a large set of non-technical users. The TOLKIN project (Tree of Life Knowledge and Information Network) addresses this need by supporting capabilities to manage, integrate, and provide public access to molecular, morphological, and biocollections data and research outcomes through a collaborative, web application. This data management framework allows aggregation and import of sequences, underlying documentation about their source, including vouchers, tissues, and DNA extraction. It combines features of LIMS and workflow environments by supporting management at the level of individual observations, sequences, and specimens, as well as assembly and versioning of data sets used in phylogenetic inference. As a web application, the system provides multi-user support that obviates current practices of sharing data sets as files or spreadsheets via email. PMID:22724002

  10. TOLKIN--Tree of Life Knowledge and Information Network: filling a gap for collaborative research in biological systematics.

    PubMed

    Beaman, Reed S; Traub, Greg H; Dell, Christopher A; Santiago, Nestor; Koh, Jin; Cellinese, Nico

    2012-01-01

    The development of biological informatics infrastructure capable of supporting growing data management and analysis environments is an increasing need within the systematics biology community. Although significant progress has been made in recent years on developing new algorithms and tools for analyzing and visualizing large phylogenetic data and trees, implementation of these resources is often carried out by bioinformatics experts, using one-off scripts. Therefore, a gap exists in providing data management support for a large set of non-technical users. The TOLKIN project (Tree of Life Knowledge and Information Network) addresses this need by supporting capabilities to manage, integrate, and provide public access to molecular, morphological, and biocollections data and research outcomes through a collaborative, web application. This data management framework allows aggregation and import of sequences, underlying documentation about their source, including vouchers, tissues, and DNA extraction. It combines features of LIMS and workflow environments by supporting management at the level of individual observations, sequences, and specimens, as well as assembly and versioning of data sets used in phylogenetic inference. As a web application, the system provides multi-user support that obviates current practices of sharing data sets as files or spreadsheets via email. PMID:22724002

  11. Investigating the Impact of Biological Impurities on the Liquid Vein Network in Polycrystalline Ice Using Magnetic Resonance Techniques

    NASA Astrophysics Data System (ADS)

    Brox, T. I.; Vogt, S. J.; Brown, J. R.; Skidmore, M. L.; Codd, S. L.; Seymour, J. D.

    2011-12-01

    Recent work has demonstrated that microorganisms can occupy the liquid filled inter-crystalline vein network in ice and maintain their metabolic activity under these conditions. Additionally, certain cold tolerant microorganisms produce extra-cellular proteins (i.e., ice-binding proteins) that have the ability to bind to the prism face of an ice crystal and inhibit ice recrystallization. One such microorganism is Chryseobacterium sp. V3519-10, a bacterium isolated from a depth of 3519 m in the Vostok Ice Core, Antarctica. While such an adaptation can impact ice crystal structure, it is not known what effect these proteins may have on the liquid vein network and to what extent these organisms may control their habitat. This study uses magnetic resonance techniques to investigate the effects of chemical and biological impurities on the liquid vein structure in ice. Magnetic resonance techniques are powerful tools for probing pore structure and transport dynamics in porous media systems, however, their ability to characterize ice as a porous media has not yet been fully explored. Three experimental conditions were evaluated in this study. Ices were prepared from 7 g/L NaCl solutions with; 1) addition of a quantified amount of extra-cellular proteins (>30kDa) extracted from Chryseobacterium sp. V3519-10 2) addition of equivalent concentrations of the protein, Bovine Serum Albumin (BSA) and 3) no protein addition. Samples were frozen and analyzed at -15°C. The liquid vein structure, as a function of salt and protein concentrations, was characterized to obtain information on liquid water content, vein surface to volume ratios and tortuosity as a measure of vein network interconnectivity. These measurements were non-destructive and made at various time intervals after freezing to monitor the evolution of microstructure due to recrystallization and assess the effects of the added proteins.

  12. Identification of network-based biomarkers of cardioembolic stroke using a systems biology approach with time series data

    PubMed Central

    2015-01-01

    Background Molecular signaling of angiogenesis begins within hours after initiation of a stroke and the following regulation of endothelial integrity mediated by growth factor receptors and vascular growth factors. Recent studies further provided insights into the coordinated patterns of post-stroke gene expressions and the relationships between neurodegenerative diseases and neural function recovery processes after a stroke. Results Differential protein-protein interaction networks (PPINs) were constructed at 3 post-stroke time points, and proteins with a significant stroke relevance value (SRV) were discovered. Genes, including UBC, CUL3, APP, NEDD8, JUP, and SIRT7, showed high associations with time after a stroke, and Ingenuity Pathway Analysis results showed that these post-stroke time series-associated genes were related to molecular and cellular functions of cell death, cell survival, the cell cycle, cellular development, cellular movement, and cell-to-cell signaling and interactions. These biomarkers may be helpful for the early detection, diagnosis, and prognosis of ischemic stroke. Conclusions This is our first attempt to use our theory of a systems biology framework on strokes. We focused on 3 key post-stroke time points. We identified the network and corresponding network biomarkers for the 3 time points, further studies are needed to experimentally confirm the findings and compare them with the causes of ischemic stroke. Our findings showed that stroke-associated biomarker genes at different time points were significantly involved in cell cycle processing, including G2-M, G1-S and meiosis, which contributes to the current understanding of the etiology of stroke. We hope this work helps scientists reveal more hidden cellular mechanisms of stroke etiology and repair processes. PMID:26679092

  13. Chemokines and Heart Disease: A Network Connecting Cardiovascular Biology to Immune and Autonomic Nervous Systems

    PubMed Central

    Dusi, Veronica; Ghidoni, Alice; Ravera, Alice; De Ferrari, Gaetano M.; Calvillo, Laura

    2016-01-01

    Among the chemokines discovered to date, nineteen are presently considered to be relevant in heart disease and are involved in all stages of cardiovascular response to injury. Chemokines are interesting as biomarkers to predict risk of cardiovascular events in apparently healthy people and as possible therapeutic targets. Moreover, they could have a role as mediators of crosstalk between immune and cardiovascular system, since they seem to act as a “working-network” in deep linkage with the autonomic nervous system. In this paper we will describe the single chemokines more involved in heart diseases; then we will present a comprehensive perspective of them as a complex network connecting the cardiovascular system to both the immune and the autonomic nervous systems. Finally, some recent evidences indicating chemokines as a possible new tool to predict cardiovascular risk will be described. PMID:27242392

  14. Towards biological plausibility of electronic noses: A spiking neural network based approach for tea odour classification.

    PubMed

    Sarkar, Sankho Turjo; Bhondekar, Amol P; Macaš, Martin; Kumar, Ritesh; Kaur, Rishemjit; Sharma, Anupma; Gulati, Ashu; Kumar, Amod

    2015-11-01

    The paper presents a novel encoding scheme for neuronal code generation for odour recognition using an electronic nose (EN). This scheme is based on channel encoding using multiple Gaussian receptive fields superimposed over the temporal EN responses. The encoded data is further applied to a spiking neural network (SNN) for pattern classification. Two forms of SNN, a back-propagation based SpikeProp and a dynamic evolving SNN are used to learn the encoded responses. The effects of information encoding on the performance of SNNs have been investigated. Statistical tests have been performed to determine the contribution of the SNN and the encoding scheme to overall odour discrimination. The approach has been implemented in odour classification of orthodox black tea (Kangra-Himachal Pradesh Region) thereby demonstrating a biomimetic approach for EN data analysis. PMID:26356597

  15. MP-GeneticSynth: inferring biological network regulations from time series.

    PubMed

    Castellini, Alberto; Paltrinieri, Daniele; Manca, Vincenzo

    2015-03-01

    MP-GeneticSynth is a Java tool for discovering the logic and regulation mechanisms responsible for observed biological dynamics in terms of finite difference recurrent equations. The software makes use of: (i) metabolic P systems as a modeling framework, (ii) an evolutionary approach to discover flux regulation functions as linear combinations of given primitive functions, (iii) a suitable reformulation of the least squares method to estimate function parameters considering simultaneously all the reactions involved in complex dynamics. The tool is available as a plugin for the virtual laboratory MetaPlab. It has graphical and interactive interfaces for data preparation, a priori knowledge integration, and flux regulator analysis. Availability and implementation: Source code, binaries, documentation (including quick start guide and videos) and case studies are freely available at http://mplab.sci.univr.it/plugins/mpgs/index.html. PMID:25344496

  16. Ligand-Target Prediction by Structural Network Biology Using nAnnoLyze

    PubMed Central

    Martínez-Jiménez, Francisco; Marti-Renom, Marc A.

    2015-01-01

    Target identification is essential for drug design, drug-drug interaction prediction, dosage adjustment and side effect anticipation. Specifically, the knowledge of structural details is essential for understanding the mode of action of a compound on a target protein. Here, we present nAnnoLyze, a method for target identification that relies on the hypothesis that structurally similar binding sites bind similar ligands. nAnnoLyze integrates structural information into a bipartite network of interactions and similarities to predict structurally detailed compound-protein interactions at proteome scale. The method was benchmarked on a dataset of 6,282 pairs of known interacting ligand-target pairs reaching a 0.96 of area under the Receiver Operating Characteristic curve (AUC) when using the drug names as an input feature for the classifier, and a 0.70 of AUC for “anonymous” compounds or compounds not present in the training set. nAnnoLyze resulted in higher accuracies than its predecessor, AnnoLyze. We applied the method to predict interactions for all the compounds in the DrugBank database with each human protein structure and provide examples of target identification for known drugs against human diseases. The accuracy and applicability of our method to any compound indicate that a comparative docking approach such as nAnnoLyze enables large-scale annotation and analysis of compound–protein interactions and thus may benefit drug development. PMID:25816344

  17. The Childhood Solid Tumor Network: A new resource for the developmental biology and oncology research communities.

    PubMed

    Stewart, Elizabeth; Federico, Sara; Karlstrom, Asa; Shelat, Anang; Sablauer, Andras; Pappo, Alberto; Dyer, Michael A

    2016-03-15

    Significant advances have been made over the past 25 years in our understanding of the most common adult solid tumors such as breast, colon, lung and prostate cancer. Much less is known about childhood solid tumors because they are rare and because they originate in developing organs during fetal development, childhood and adolescence. It can be very difficult to study the cellular origins of pediatric solid tumors in developing organs characterized by rapid proliferative expansion, growth factor signaling, developmental angiogenesis, programmed cell death, tissue reorganization and cell migration. Not only has the etiology of pediatric cancer remained elusive because of their developmental origins, but it also makes it more difficult to treat. Molecular targeted therapeutics that alter developmental pathway signaling may have devastating effects on normal organ development. Therefore, basic research focused on the mechanisms of development provides an essential foundation for pediatric solid tumor translational research. In this article, we describe new resources available for the developmental biology and oncology research communities. In a companion paper, we present the detailed characterization of an orthotopic xenograft of a pediatric solid tumor derived from sympathoadrenal lineage during development. PMID:26068307

  18. Recovery of biological motion perception and network plasticity after cerebellar tumor removal.

    PubMed

    Sokolov, Arseny A; Erb, Michael; Grodd, Wolfgang; Tatagiba, Marcos S; Frackowiak, Richard S J; Pavlova, Marina A

    2014-10-01

    Visual perception of body motion is vital for everyday activities such as social interaction, motor learning or car driving. Tumors to the left lateral cerebellum impair visual perception of body motion. However, compensatory potential after cerebellar damage and underlying neural mechanisms remain unknown. In the present study, visual sensitivity to point-light body motion was psychophysically assessed in patient SL with dysplastic gangliocytoma (Lhermitte-Duclos disease) to the left cerebellum before and after neurosurgery, and in a group of healthy matched controls. Brain activity during processing of body motion was assessed by functional magnetic resonance imaging (MRI). Alterations in underlying cerebro-cerebellar circuitry were studied by psychophysiological interaction (PPI) analysis. Visual sensitivity to body motion in patient SL before neurosurgery was substantially lower than in controls, with significant improvement after neurosurgery. Functional MRI in patient SL revealed a similar pattern of cerebellar activation during biological motion processing as in healthy participants, but located more medially, in the left cerebellar lobules III and IX. As in normalcy, PPI analysis showed cerebellar communication with a region in the superior temporal sulcus, but located more anteriorly. The findings demonstrate a potential for recovery of visual body motion processing after cerebellar damage, likely mediated by topographic shifts within the corresponding cerebro-cerebellar circuitry induced by cerebellar reorganization. The outcome is of importance for further understanding of cerebellar plasticity and neural circuits underpinning visual social cognition. PMID:25017648

  19. Workshop report on the 2nd Joint ENCCA/EuroSARC European bone sarcoma network meeting: integration of clinical trials with tumour biology

    PubMed Central

    2014-01-01

    This is the report of the 2nd Joint ENCCA/EuroSARC European Bone Sarcoma Network Meeting held in Leiden, The Netherlands, on 26-27 September 2013, bringing together preclinical and clinical investigators on bone sarcoma. The purpose of this workshop was to present the achievements of biological research and clinical trials in bone sarcomas and to stimulate crosstalk.

  20. BioCreative V track 4: a shared task for the extraction of causal network information using the Biological Expression Language.

    PubMed

    Rinaldi, Fabio; Ellendorff, Tilia Renate; Madan, Sumit; Clematide, Simon; van der Lek, Adrian; Mevissen, Theo; Fluck, Juliane

    2016-01-01

    Automatic extraction of biological network information is one of the most desired and most complex tasks in biological and medical text mining. Track 4 at BioCreative V attempts to approach this complexity using fragments of large-scale manually curated biological networks, represented in Biological Expression Language (BEL), as training and test data. BEL is an advanced knowledge representation format which has been designed to be both human readable and machine processable. The specific goal of track 4 was to evaluate text mining systems capable of automatically constructing BEL statements from given evidence text, and of retrieving evidence text for given BEL statements. Given the complexity of the task, we designed an evaluation methodology which gives credit to partially correct statements. We identified various levels of information expressed by BEL statements, such as entities, functions, relations, and introduced an evaluation framework which rewards systems capable of delivering useful BEL fragments at each of these levels. The aim of this evaluation method is to help identify the characteristics of the systems which, if combined, would be most useful for achieving the overall goal of automatically constructing causal biological networks from text. PMID:27402677

  1. BioCreative V track 4: a shared task for the extraction of causal network information using the Biological Expression Language

    PubMed Central

    Rinaldi, Fabio; Ellendorff, Tilia Renate; Madan, Sumit; Clematide, Simon; van der Lek, Adrian; Mevissen, Theo; Fluck, Juliane

    2016-01-01

    Automatic extraction of biological network information is one of the most desired and most complex tasks in biological and medical text mining. Track 4 at BioCreative V attempts to approach this complexity using fragments of large-scale manually curated biological networks, represented in Biological Expression Language (BEL), as training and test data. BEL is an advanced knowledge representation format which has been designed to be both human readable and machine processable. The specific goal of track 4 was to evaluate text mining systems capable of automatically constructing BEL statements from given evidence text, and of retrieving evidence text for given BEL statements. Given the complexity of the task, we designed an evaluation methodology which gives credit to partially correct statements. We identified various levels of information expressed by BEL statements, such as entities, functions, relations, and introduced an evaluation framework which rewards systems capable of delivering useful BEL fragments at each of these levels. The aim of this evaluation method is to help identify the characteristics of the systems which, if combined, would be most useful for achieving the overall goal of automatically constructing causal biological networks from text. PMID:27402677

  2. Systems biology study of mucopolysaccharidosis using a human metabolic reconstruction network.

    PubMed

    Salazar, Diego A; Rodríguez-López, Alexander; Herreño, Angélica; Barbosa, Hector; Herrera, Juliana; Ardila, Andrea; Barreto, George E; González, Janneth; Alméciga-Díaz, Carlos J

    2016-02-01

    Mucopolysaccharidosis (MPS) is a group of lysosomal storage diseases (LSD), characterized by the deficiency of a lysosomal enzyme responsible for the degradation of glycosaminoglycans (GAG). This deficiency leads to the lysosomal accumulation of partially degraded GAG. Nevertheless, deficiency of a single lysosomal enzyme has been associated with impairment in other cell mechanism, such as apoptosis and redox balance. Although GAG analysis represents the main biomarker for MPS diagnosis, it has several limitations that can lead to a misdiagnosis, whereby the identification of new biomarkers represents an important issue for MPS. In this study, we used a system biology approach, through the use of a genome-scale human metabolic reconstruction to understand the effect of metabolism alterations in cell homeostasis and to identify potential new biomarkers in MPS. In-silico MPS models were generated by silencing of MPS-related enzymes, and were analyzed through a flux balance and variability analysis. We found that MPS models used approximately 2286 reactions to satisfy the objective function. Impaired reactions were mainly involved in cellular respiration, mitochondrial process, amino acid and lipid metabolism, and ion exchange. Metabolic changes were similar for MPS I and II, and MPS III A to C; while the remaining MPS showed unique metabolic profiles. Eight and thirteen potential high-confidence biomarkers were identified for MPS IVB and VII, respectively, which were associated with the secondary pathologic process of LSD. In vivo evaluation of predicted intermediate confidence biomarkers (β-hexosaminidase and β-glucoronidase) for MPS IVA and VI correlated with the in-silico prediction. These results show the potential of a computational human metabolic reconstruction to understand the molecular mechanisms this group of diseases, which can be used to identify new biomarkers for MPS. PMID:26276570

  3. Comparison of Modules of Wild Type and Mutant Huntingtin and TP53 Protein Interaction Networks: Implications in Biological Processes and Functions

    PubMed Central

    Basu, Mahashweta; Bhattacharyya, Nitai P.; Mohanty, Pradeep K.

    2013-01-01

    Disease-causing mutations usually change the interacting partners of mutant proteins. In this article, we propose that the biological consequences of mutation are directly related to the alteration of corresponding protein protein interaction networks (PPIN). Mutation of Huntingtin (HTT) which causes Huntington's disease (HD) and mutations to TP53 which is associated with different cancers are studied as two example cases. We construct the PPIN of wild type and mutant proteins separately and identify the structural modules of each of the networks. The functional role of these modules are then assessed by Gene Ontology (GO) enrichment analysis for biological processes (BPs). We find that a large number of significantly enriched () GO terms in mutant PPIN were absent in the wild type PPIN indicating the gain of BPs due to mutation. Similarly some of the GO terms enriched in wild type PPIN cease to exist in the modules of mutant PPIN, representing the loss. GO terms common in modules of mutant and wild type networks indicate both loss and gain of BPs. We further assign relevant biological function(s) to each module by classifying the enriched GO terms associated with it. It turns out that most of these biological functions in HTT networks are already known to be altered in HD and those of TP53 networks are altered in cancers. We argue that gain of BPs, and the corresponding biological functions, are due to new interacting partners acquired by mutant proteins. The methodology we adopt here could be applied to genetic diseases where mutations alter the ability of the protein to interact with other proteins. PMID:23741403

  4. Networks.

    ERIC Educational Resources Information Center

    Maughan, George R.; Petitto, Karen R.; McLaughlin, Don

    2001-01-01

    Describes the connectivity features and options of modern campus communication and information system networks, including signal transmission (wire-based and wireless), signal switching, convergence of networks, and network assessment variables, to enable campus leaders to make sound future-oriented decisions. (EV)

  5. Understanding XPO1 target networks using systems biology and mathematical modeling.

    PubMed

    Muqbil, Irfana; Kauffman, Michael; Shacham, Sharon; Mohammad, Ramzi M; Azmi, Asfar S

    2014-01-01

    The nuclear transport protein Exportin 1 (XPO1), also called chromosome region maintenance 1 (CRM1), is over-expressed 2- 4 fold in cancer. XPO1 is one of seven nuclear exporter proteins, and is solely responsible for the transport of the major tumor suppressor proteins (TSPs) from the nucleus to the cytoplasm. XPO1 exports any protein that carries a leucine-rich, hydrophobic nuclear export sequence (NES). A number of inhibitors have been discovered that block XPO1 function and thereby restore TSPs to the nucleus of both malignant and normal cells. However, natural product, irreversible XPO1 antagonists such as leptomycin B (LMB) have proven toxic in both preclinical models and in the clinic. Recently, orally bioavailable, drug-like small molecule, potent and selective inhibitors of XPO1 mediated nuclear export ("SINE") have been designed and are undergoing clinical evaluations in both humans and canines with cancer. The breadth of clinical applicability and long-term viability of an XPO1 inhibition strategy requires a deeper evaluation of the consequence of global re-organization of proteins in cancer and normal cells. Unfortunately, most of the studies on XPO1 inhibitors have focused on evaluating a limited number of TSPs or other proteins. Because XPO1 carries ~220 mammalian proteins out of the nucleus, such reductionism has not permitted a global understanding of cellular behavior upon drug-induced disruption of XPO1 function. The consequence of XPO1 inhibition requires holistic investigations that consider the entire set of XPO1 targets and their respective pathways modulated without losing key details. Systems biology is one such holistic approach that can be applied to understand XPO1 regulated proteins along with the downstream players involved. This review provides comprehensive evaluations of the different computational tools that can be utilized in the better understanding of XPO1 and its target. We anticipate that such holistic approaches can allow for

  6. Biology-Driven Gene-Gene Interaction Analysis of Age-Related Cataract in the eMERGE Network.

    PubMed

    Hall, Molly A; Verma, Shefali S; Wallace, John; Lucas, Anastasia; Berg, Richard L; Connolly, John; Crawford, Dana C; Crosslin, David R; de Andrade, Mariza; Doheny, Kimberly F; Haines, Jonathan L; Harley, John B; Jarvik, Gail P; Kitchner, Terrie; Kuivaniemi, Helena; Larson, Eric B; Carrell, David S; Tromp, Gerard; Vrabec, Tamara R; Pendergrass, Sarah A; McCarty, Catherine A; Ritchie, Marylyn D

    2015-07-01

    Bioinformatics approaches to examine gene-gene models provide a means to discover interactions between multiple genes that underlie complex disease. Extensive computational demands and adjusting for multiple testing make uncovering genetic interactions a challenge. Here, we address these issues using our knowledge-driven filtering method, Biofilter, to identify putative single nucleotide polymorphism (SNP) interaction models for cataract susceptibility, thereby reducing the number of models for analysis. Models were evaluated in 3,377 European Americans (1,185 controls, 2,192 cases) from the Marshfield Clinic, a study site of the Electronic Medical Records and Genomics (eMERGE) Network, using logistic regression. All statistically significant models from the Marshfield Clinic were then evaluated in an independent dataset of 4,311 individuals (742 controls, 3,569 cases), using independent samples from additional study sites in the eMERGE Network: Mayo Clinic, Group Health/University of Washington, Vanderbilt University Medical Center, and Geisinger Health System. Eighty-three SNP-SNP models replicated in the independent dataset at likelihood ratio test P < 0.05. Among the most significant replicating models was rs12597188 (intron of CDH1)-rs11564445 (intron of CTNNB1). These genes are known to be involved in processes that include: cell-to-cell adhesion signaling, cell-cell junction organization, and cell-cell communication. Further Biofilter analysis of all replicating models revealed a number of common functions among the genes harboring the 83 replicating SNP-SNP models, which included signal transduction and PI3K-Akt signaling pathway. These findings demonstrate the utility of Biofilter as a biology-driven method, applicable for any genome-wide association study dataset. PMID:25982363

  7. Biology-Driven Gene-Gene Interaction Analysis of Age-Related Cataract in the eMERGE Network

    PubMed Central

    Hall, Molly A; Verma, Shefali S; Wallace, John; Lucas, Anastasia; Berg, Richard L; Connolly, John; Crawford, Dana C; Crosslin, David R; de Andrade, Mariza; Doheny, Kimberly F; Haines, Jonathan L; Harley, John B; Jarvik, Gail P; Kitchner, Terrie; Kuivaniemi, Helena; Larson, Eric B; Carrell, David S; Tromp, Gerard; Vrabec, Tamara R; Pendergrass, Sarah A; McCarty, Catherine A; Ritchie, Marylyn D

    2015-01-01

    Bioinformatics approaches to examine gene-gene models provide a means to discover interactions between multiple genes that underlie complex disease. Extensive computational demands and adjusting for multiple testing make uncovering genetic interactions a challenge. Here, we address these issues using our knowledge-driven filtering method, Biofilter, to identify putative single nucleotide polymorphism (SNP) interaction models for cataract susceptibility, thereby reducing the number of models for analysis. Models were evaluated in 3,377 European Americans (1,185 controls, 2,192 cases) from the Marshfield Clinic, a study site of the Electronic Medical Records and Genomics (eMERGE) Network, using logistic regression. All statistically significant models from the Marshfield Clinic were then evaluated in an independent dataset of 4,311 individuals (742 controls, 3,569 cases), using independent samples from additional study sites in the eMERGE Network: Mayo Clinic, Group Health/University of Washington, Vanderbilt University Medical Center, and Geisinger Health System. Eighty-three SNP-SNP models replicated in the independent dataset at likelihood ratio test P < 0.05. Among the most significant replicating models was rs12597188 (intron of CDH1)–rs11564445 (intron of CTNNB1). These genes are known to be involved in processes that include: cell-to-cell adhesion signaling, cell-cell junction organization, and cell-cell communication. Further Biofilter analysis of all replicating models revealed a number of common functions among the genes harboring the 83 replicating SNP-SNP models, which included signal transduction and PI3K-Akt signaling pathway. These findings demonstrate the utility of Biofilter as a biology-driven method, applicable for any genome-wide association study dataset. PMID:25982363

  8. A functional biological network centered on XRCC3: a new possible marker of chemoradiotherapy resistance in rectal cancer patients

    PubMed Central

    Agostini, Marco; Zangrando, Andrea; Pastrello, Chiara; D'Angelo, Edoardo; Romano, Gabriele; Giovannoni, Roberto; Giordan, Marco; Maretto, Isacco; Bedin, Chiara; Zanon, Carlo; Digito, Maura; Esposito, Giovanni; Mescoli, Claudia; Lavitrano, Marialuisa; Rizzolio, Flavio; Jurisica, Igor; Giordano, Antonio; Pucciarelli, Salvatore; Nitti, Donato

    2015-01-01

    Preoperative chemoradiotherapy is widely used to improve local control of disease, sphincter preservation and to improve survival in patients with locally advanced rectal cancer. Patients enrolled in the present study underwent preoperative chemoradiotherapy, followed by surgical excision. Response to chemoradiotherapy was evaluated according to Mandard's Tumor Regression Grade (TRG). TRG 3, 4 and 5 were considered as partial or no response while TRG 1 and 2 as complete response. From pretherapeutic biopsies of 84 locally advanced rectal carcinomas available for the analysis, only 42 of them showed 70% cancer cellularity at least. By determining gene expression profiles, responders and non-responders showed significantly different expression levels for 19 genes (P < 0.001). We fitted a logistic model selected with a stepwise procedure optimizing the Akaike Information Criterion (AIC) and then validated by means of leave one out cross validation (LOOCV, accuracy = 95%). Four genes were retained in the achieved model: ZNF160, XRCC3, HFM1 and ASXL2. Real time PCR confirmed that XRCC3 is overexpressed in responders group and HFM1 and ASXL2 showed a positive trend. In vitro test on colon cancer resistant/susceptible to chemoradioterapy cells, finally prove that XRCC3 deregulation is extensively involved in the chemoresistance mechanisms. Protein-protein interactions (PPI) analysis involving the predictive classifier revealed a network of 45 interacting nodes (proteins) with TRAF6 gene playing a keystone role in the network. The present study confirmed the possibility that gene expression profiling combined with integrative computational biology is useful to predict complete responses to preoperative chemoradiotherapy in patients with advanced rectal cancer. PMID:26023803

  9. Systems Biology Analysis of the Endocannabinoid System Reveals a Scale-free Network with Distinct Roles for Anandamide and 2-Arachidonoylglycerol

    PubMed Central

    Bernabò, Nicola; Barboni, Barbara

    2013-01-01

    Abstract We represented the endocannabinoid system (ECS) as a biological network, where ECS molecules are the nodes (123) and their interactions the links (189). ECS network follows a scale-free topology, which confers robustness against random damage, easy navigability, and controllability. Network topological parameters, such as clustering coefficient (i.e., how the nodes form clusters) of 0.0009, network diameter (the longest shortest path among all pairs of nodes) of 12, averaged number of neighbors (the mean number of connections per node) of 3.073, and characteristic path length (the expected distance between two connected nodes) of 4.715, suggested that molecular messages are transferred through the ECS network quickly and specifically. Interestingly, ∼75% of nodes are located on, or are active at the level of, the cell membrane. The hubs of ECS network are anandamide (AEA) and 2-arachidonoylglycerol (2-AG), which have also the highest value of betweeness centrality, and their removal causes network collapse into multiple disconnected components. Importantly, AEA is a ubiquitous player while 2-AG plays more restricted actions. Instead, the product of their degradation, arachidonic acid, and their hydrolyzing enzyme, fatty acid amide hydrolase, FAAH, have a marginal impact on ECS network, indeed their removal did not significantly affect its topology. PMID:24117401

  10. A systems biology pipeline identifies new immune and disease related molecular signatures and networks in human cells during microgravity exposure

    NASA Astrophysics Data System (ADS)

    Mukhopadhyay, Sayak; Saha, Rohini; Palanisamy, Anbarasi; Ghosh, Madhurima; Biswas, Anupriya; Roy, Saheli; Pal, Arijit; Sarkar, Kathakali; Bagh, Sangram

    2016-05-01

    Microgravity is a prominent health hazard for astronauts, yet we understand little about its effect at the molecular systems level. In this study, we have integrated a set of systems-biology tools and databases and have analysed more than 8000 molecular pathways on published global gene expression datasets of human cells in microgravity. Hundreds of new pathways have been identified with statistical confidence for each dataset and despite the difference in cell types and experiments, around 100 of the new pathways are appeared common across the datasets. They are related to reduced inflammation, autoimmunity, diabetes and asthma. We have identified downregulation of NfκB pathway via Notch1 signalling as new pathway for reduced immunity in microgravity. Induction of few cancer types including liver cancer and leukaemia and increased drug response to cancer in microgravity are also found. Increase in olfactory signal transduction is also identified. Genes, based on their expression pattern, are clustered and mathematically stable clusters are identified. The network mapping of genes within a cluster indicates the plausible functional connections in microgravity. This pipeline gives a new systems level picture of human cells under microgravity, generates testable hypothesis and may help estimating risk and developing medicine for space missions.

  11. Infrared differential-absorption Mueller matrix spectroscopy and neural network-based data fusion for biological aerosol standoff detection.

    PubMed

    Carrieri, Arthur H; Copper, Jack; Owens, David J; Roese, Erik S; Bottiger, Jerold R; Everly, Robert D; Hung, Kevin C

    2010-01-20

    An active spectrophotopolarimeter sensor and support system were developed for a military/civilian defense feasibility study concerning the identification and standoff detection of biological aerosols. Plumes of warfare agent surrogates gamma-irradiated Bacillus subtilis and chicken egg white albumen (analytes), Arizona road dust (terrestrial interferent), water mist (atmospheric interferent), and talcum powders (experiment controls) were dispersed inside windowless chambers and interrogated by multiple CO(2) laser beams spanning 9.1-12.0 microm wavelengths (lambda). Molecular vibration and vibration-rotation activities by the subject analyte are fundamentally strong within this "fingerprint" middle infrared spectral region. Distinct polarization-modulations of incident irradiance and backscatter radiance of tuned beams generate the Mueller matrix (M) of subject aerosol. Strings of all 15 normalized elements {M(ij)(lambda)/M(11)(lambda)}, which completely describe physical and geometric attributes of the aerosol particles, are input fields for training hybrid Kohonen self-organizing map feed-forward artificial neural networks (ANNs). The properly trained and validated ANN model performs pattern recognition and type-classification tasks via internal mappings. A typical ANN that mathematically clusters analyte, interferent, and control aerosols with nil overlap of species is illustrated, including sensitivity analysis of performance. PMID:20090802

  12. A systems biology pipeline identifies new immune and disease related molecular signatures and networks in human cells during microgravity exposure

    PubMed Central

    Mukhopadhyay, Sayak; Saha, Rohini; Palanisamy, Anbarasi; Ghosh, Madhurima; Biswas, Anupriya; Roy, Saheli; Pal, Arijit; Sarkar, Kathakali; Bagh, Sangram

    2016-01-01

    Microgravity is a prominent health hazard for astronauts, yet we understand little about its effect at the molecular systems level. In this study, we have integrated a set of systems-biology tools and databases and have analysed more than 8000 molecular pathways on published global gene expression datasets of human cells in microgravity. Hundreds of new pathways have been identified with statistical confidence for each dataset and despite the difference in cell types and experiments, around 100 of the new pathways are appeared common across the datasets. They are related to reduced inflammation, autoimmunity, diabetes and asthma. We have identified downregulation of NfκB pathway via Notch1 signalling as new pathway for reduced immunity in microgravity. Induction of few cancer types including liver cancer and leukaemia and increased drug response to cancer in microgravity are also found. Increase in olfactory signal transduction is also identified. Genes, based on their expression pattern, are clustered and mathematically stable clusters are identified. The network mapping of genes within a cluster indicates the plausible functional connections in microgravity. This pipeline gives a new systems level picture of human cells under microgravity, generates testable hypothesis and may help estimating risk and developing medicine for space missions. PMID:27185415

  13. Stress-sensitive neurosignalling in depression: an integrated network biology approach to candidate gene selection for genetic association analysis

    PubMed Central

    van Eekelen, J. Anke M.; Ellis, Justine A.; Pennell, Craig E.; Craig, Jeff; Saffery, Richard; Mattes, Eugen; Olsson, Craig A.

    2012-01-01

    Genetic risk for depressive disorders is poorly understood despite consistent suggestions of a high heritable component. Most genetic studies have focused on risk associated with single variants, a strategy which has so far only yielded small (often non-replicable) risks for depressive disorders. In this paper we argue that more substantial risks are likely to emerge from genetic variants acting in synergy within and across larger neurobiological systems (polygenic risk factors). We show how knowledge of major integrated neurobiological systems provides a robust basis for defining and testing theoretically defensible polygenic risk factors. We do this by describing the architecture of the overall stress response. Maladaptation via impaired stress responsiveness is central to the aetiology of depression and anxiety and provides a framework for a systems biology approach to candidate gene selection. We propose principles for identifying genes and gene networks within the neurosystems involved in the stress response and for defining polygenic risk factors based on the neurobiology of stress-related behaviour. We conclude that knowledge of the neurobiology of the stress response system is likely to play a central role in future efforts to improve genetic prediction of depression and related disorders. PMID:25478122

  14. A systems biology pipeline identifies new immune and disease related molecular signatures and networks in human cells during microgravity exposure.

    PubMed

    Mukhopadhyay, Sayak; Saha, Rohini; Palanisamy, Anbarasi; Ghosh, Madhurima; Biswas, Anupriya; Roy, Saheli; Pal, Arijit; Sarkar, Kathakali; Bagh, Sangram

    2016-01-01

    Microgravity is a prominent health hazard for astronauts, yet we understand little about its effect at the molecular systems level. In this study, we have integrated a set of systems-biology tools and databases and have analysed more than 8000 molecular pathways on published global gene expression datasets of human cells in microgravity. Hundreds of new pathways have been identified with statistical confidence for each dataset and despite the difference in cell types and experiments, around 100 of the new pathways are appeared common across the datasets. They are related to reduced inflammation, autoimmunity, diabetes and asthma. We have identified downregulation of NfκB pathway via Notch1 signalling as new pathway for reduced immunity in microgravity. Induction of few cancer types including liver cancer and leukaemia and increased drug response to cancer in microgravity are also found. Increase in olfactory signal transduction is also identified. Genes, based on their expression pattern, are clustered and mathematically stable clusters are identified. The network mapping of genes within a cluster indicates the plausible functional connections in microgravity. This pipeline gives a new systems level picture of human cells under microgravity, generates testable hypothesis and may help estimating risk and developing medicine for space missions. PMID:27185415

  15. Practical implications of gene-expression-based assays for breast oncologists

    PubMed Central

    Prat, Aleix; Ellis, Matthew J.; Perou, Charles M.

    2013-01-01

    Gene-expression profiling has had a considerable impact on our understanding of breast cancer biology, and more recently on clinical care. Two statistical approaches underlie these advancements. Supervised analyses have led to the development of gene-expression signatures designed to predict survival and/or treatment response, which has resulted in the development of new clinical assays. Unsupervised analyses have identified numerous biological signatures including signatures of cell type of origin, signaling pathways, and of cellular proliferation. Included within these biological signatures are the molecular subtypes known as the ‘intrinsic’ subtypes of breast cancer. This classification has expanded our appreciation of the heterogeneity of breast cancer and has provided a way to sub-classify the disease in a manner that might have clinical utility. In this Review, we discuss the clinical utility of gene-expression-based assays and their technical potential as clinical tools vis-a-vis the performance of breast cancer biomarkers that are the current standard of care. PMID:22143140

  16. Networking.

    ERIC Educational Resources Information Center

    Duvall, Betty

    Networking is an information giving and receiving system, a support system, and a means whereby women can get ahead in careers--either in new jobs or in current positions. Networking information can create many opportunities: women can talk about how other women handle situations and tasks, and previously established contacts can be used in…

  17. Comparative genomic analyses reveal a vast, novel network of nucleotide-centric systems in biological conflicts, immunity and signaling

    PubMed Central

    Burroughs, A. Maxwell; Zhang, Dapeng; Schäffer, Daniel E.; Iyer, Lakshminarayan M.; Aravind, L.

    2015-01-01

    Cyclic di- and linear oligo-nucleotide signals activate defenses against invasive nucleic acids in animal immunity; however, their evolutionary antecedents are poorly understood. Using comparative genomics, sequence and structure analysis, we uncovered a vast network of systems defined by conserved prokaryotic gene-neighborhoods, which encode enzymes generating such nucleotides or alternatively processing them to yield potential signaling molecules. The nucleotide-generating enzymes include several clades of the DNA-polymerase β-like superfamily (including Vibrio cholerae DncV), a minimal version of the CRISPR polymerase and DisA-like cyclic-di-AMP synthetases. Nucleotide-binding/processing domains include TIR domains and members of a superfamily prototyped by Smf/DprA proteins and base (cytokinin)-releasing LOG enzymes. They are combined in conserved gene-neighborhoods with genes for a plethora of protein superfamilies, which we predict to function as nucleotide-sensors and effectors targeting nucleic acids, proteins or membranes (pore-forming agents). These systems are sometimes combined with other biological conflict-systems such as restriction-modification and CRISPR/Cas. Interestingly, several are coupled in mutually exclusive neighborhoods with either a prokaryotic ubiquitin-system or a HORMA domain-PCH2-like AAA+ ATPase dyad. The latter are potential precursors of equivalent proteins in eukaryotic chromosome dynamics. Further, components from these nucleotide-centric systems have been utilized in several other systems including a novel diversity-generating system with a reverse transcriptase. We also found the Smf/DprA/LOG domain from these systems to be recruited as a predicted nucleotide-binding domain in eukaryotic TRPM channels. These findings point to evolutionary and mechanistic links, which bring together CRISPR/Cas, animal interferon-induced immunity, and several other systems that combine nucleic-acid-sensing and nucleotide-dependent signaling

  18. A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks

    PubMed Central

    Eissing, Thomas; Kuepfer, Lars; Becker, Corina; Block, Michael; Coboeken, Katrin; Gaub, Thomas; Goerlitz, Linus; Jaeger, Juergen; Loosen, Roland; Ludewig, Bernd; Meyer, Michaela; Niederalt, Christoph; Sevestre, Michael; Siegmund, Hans-Ulrich; Solodenko, Juri; Thelen, Kirstin; Telle, Ulrich; Weiss, Wolfgang; Wendl, Thomas; Willmann, Stefan; Lippert, Joerg

    2011-01-01

    Today, in silico studies and trial simulations already complement experimental approaches in pharmaceutical R&D and have become indispensable tools for decision making and communication with regulatory agencies. While biology is multiscale by nature, project work, and software tools usually focus on isolated aspects of drug action, such as pharmacokinetics at the organism scale or pharmacodynamic interaction on the molecular level. We present a modeling and simulation software platform consisting of PK-Sim® and MoBi® capable of building and simulating models that integrate across biological scales. A prototypical multiscale model for the progression of a pancreatic tumor and its response to pharmacotherapy is constructed and virtual patients are treated with a prodrug activated by hepatic metabolization. Tumor growth is driven by signal transduction leading to cell cycle transition and proliferation. Free tumor concentrations of the active metabolite inhibit Raf kinase in the signaling cascade and thereby cell cycle progression. In a virtual clinical study, the individual therapeutic outcome of the chemotherapeutic intervention is simulated for a large population with heterogeneous genomic background. Thereby, the platform allows efficient model building and integration of biological knowledge and prior data from all biological scales. Experimental in vitro model systems can be linked with observations in animal experiments and clinical trials. The interplay between patients, diseases, and drugs and topics with high clinical relevance such as the role of pharmacogenomics, drug–drug, or drug–metabolite interactions can be addressed using this mechanistic, insight driven multiscale modeling approach. PMID:21483730

  19. Gene-Expression-Based Predictors for Breast Cancer.

    PubMed

    Gupta, Arjun; Mutebi, Miriam; Bardia, Aditya

    2015-10-01

    An important and often complicated management decision in early stage hormone receptor (HR)-positive breast cancer relates to the use of adjuvant systemic chemotherapy. Although traditional clinicopathologic markers exist, tremendous progress has been achieved in the field of predictive biomarkers and genomics with both prognostic and predictive capabilities to identify patients who will potentially benefit from additional therapy. The use of these genomic tests in the neoadjuvant setting is also being studied and may lead to these tests providing clinical benefit even earlier in the disease course. Landmark articles published in the last few years have expanded our knowledge of breast cancer genomics to an unprecedented level, and mutational analysis via next-generation sequencing methods allows the identification of molecular targets for novel targeted therapeutic agents and clinical trials testing efficacy of targeted therapies, such as PI3K inhibitors, in addition to endocrine therapy for HR-positive breast cancer, are ongoing. We provide an in-depth review on the role of gene expression-based predictors in early stage breast cancer and an overview of future directions, including next-generation sequencing. Over the coming years, we anticipate a significant increase in utilization of genomic-based predictors for individualized selection and duration of endocrine therapy with and without genotype-driven targeted therapy, and a major decrease in the use of chemotherapy, possibly even leading to a chemotherapy-free road for early stage HR-positive breast cancer. PMID:26215189

  20. A Systems Biology-Based Investigation into the Pharmacological Mechanisms of Wu Tou Tang Acting on Rheumatoid Arthritis by Integrating Network Analysis

    PubMed Central

    Zhang, Yanqiong; Lin, Na

    2013-01-01

    Aim. To investigate pharmacological mechanisms of Wu Tou Tang acting on rheumatoid arthritis (RA) by integrating network analysis at a system level. Methods and Results. Drug similarity search tool in Therapeutic Targets Database was used to screen 153 drugs with similar structures to compositive compounds of each ingredient in Wu Tou Tang and to identify 56 known targets of these similar drugs as predicted molecules which Wu Tou Tang affects. The recall, precision, accuracy, and F1-score, which were calculated to evaluate the performance of this method, were, respectively, 0.98, 0.61, 59.67%, and 0.76. Then, the predicted effector molecules of Wu Tou Tang were significantly enriched in neuroactive ligand-receptor interaction and calcium signaling pathway. Next, the importance of these predicted effector molecules was evaluated by analyzing their network topological features, such as degree, betweenness, and k-coreness. We further elucidated the biological significance of nine major candidate effector molecules of Wu Tou Tang for RA therapy and validated their associations with compositive compounds in Wu Tou Tang by the molecular docking simulation. Conclusion. Our data suggest the potential pharmacological mechanisms of Wu Tou Tang acting on RA by combining the strategies of systems biology and network pharmacology. PMID:23690848

  1. Understanding regulatory networks requires more than computing a multitude of graph statistics. Comment on "Drivers of structural features in gene regulatory networks: From biophysical constraints to biological function" by O.C. Martin et al.

    NASA Astrophysics Data System (ADS)

    Tkačik, Gašper

    2016-07-01

    The article by O. Martin and colleagues provides a much needed systematic review of a body of work that relates the topological structure of genetic regulatory networks to evolutionary selection for function. This connection is very important. Using the current wealth of genomic data, statistical features of regulatory networks (e.g., degree distributions, motif composition, etc.) can be quantified rather easily; it is, however, often unclear how to interpret the results. On a graph theoretic level the statistical significance of the results can be evaluated by comparing observed graphs to "randomized" ones (bravely ignoring the issue of how precisely to randomize!) and comparing the frequency of appearance of a particular network structure relative to a randomized null expectation. While this is a convenient operational test for statistical significance, its biological meaning is questionable. In contrast, an in-silico genotype-to-phenotype model makes explicit the assumptions about the network function, and thus clearly defines the expected network structures that can be compared to the case of no selection for function and, ultimately, to data.

  2. GECC: Gene Expression Based Ensemble Classification of Colon Samples.

    PubMed

    Rathore, Saima; Hussain, Mutawarra; Khan, Asifullah

    2014-01-01

    Gene expression deviates from its normal composition in case a patient has cancer. This variation can be used as an effective tool to find cancer. In this study, we propose a novel gene expressions based colon classification scheme (GECC) that exploits the variations in gene expressions for classifying colon gene samples into normal and malignant classes. Novelty of GECC is in two complementary ways. First, to cater overwhelmingly larger size of gene based data sets, various feature extraction strategies, like, chi-square, F-Score, principal component analysis (PCA) and minimum redundancy and maximum relevancy (mRMR) have been employed, which select discriminative genes amongst a set of genes. Second, a majority voting based ensemble of support vector machine (SVM) has been proposed to classify the given gene based samples. Previously, individual SVM models have been used for colon classification, however, their performance is limited. In this research study, we propose an SVM-ensemble based new approach for gene based classification of colon, wherein the individual SVM models are constructed through the learning of different SVM kernels, like, linear, polynomial, radial basis function (RBF), and sigmoid. The predicted results of individual models are combined through majority voting. In this way, the combined decision space becomes more discriminative. The proposed technique has been tested on four colon, and several other binary-class gene expression data sets, and improved performance has been achieved compared to previously reported gene based colon cancer detection techniques. The computational time required for the training and testing of 208 × 5,851 data set has been 591.01 and 0.019 s, respectively. PMID:26357050

  3. Small-scale universality and large-scale diversity. Comment on "Drivers of structural features in gene regulatory networks: From biophysical constraints to biological function" by O.C. Martin, A. Krzywicki, and M. Zagorski

    NASA Astrophysics Data System (ADS)

    Ispolatov, Yaroslav

    2016-07-01

    Martin et al. undertook an arduous task of reviewing vast literature on evolution and functionality of directed biological networks and gene networks in particular. The literature is assessed addressing a question of whether a set of features particular for gene networks is repeatedly recreated among unrelated species driven by selection pressure or has evolved once and is being inherited. To argue for the former mechanism, Martin and colleagues explore the following examples: Scale-free out-degree distribution.

  4. Nodes and biological processes identified on the basis of network analysis in the brain of the senescence accelerated mice as an Alzheimer's disease animal model

    PubMed Central

    Cheng, Xiao-rui; Cui, Xiu-liang; Zheng, Yue; Zhang, Gui-rong; Li, Peng; Huang, Huang; Zhao, Yue-ying; Bo, Xiao-chen; Wang, Sheng-qi; Zhou, Wen-xia; Zhang, Yong-xiang

    2013-01-01

    Harboring the behavioral and histopathological signatures of Alzheimer's disease (AD), senescence accelerated mouse-prone 8 (SAMP8) mice are currently considered a robust model for studying AD. However, the underlying mechanisms, prioritized pathways and genes in SAMP8 mice linked to AD remain unclear. In this study, we provide a biological interpretation of the molecular underpinnings of SAMP8 mice. Our results were derived from differentially expressed genes in the hippocampus and cerebral cortex of SAMP8 mice compared to age-matched SAMR1 mice at 2, 6, and 12 months of age using cDNA microarray analysis. On the basis of PPI, MetaCore and the co-expression network, we constructed a distinct genetic sub-network in the brains of SAMP8 mice. Next, we determined that the regulation of synaptic transmission and apoptosis were disrupted in the brains of SAMP8 mice. We found abnormal gene expression of RAF1, MAPT, PTGS2, CDKN2A, CAMK2A, NTRK2, AGER, ADRBK1, MCM3AP, and STUB1, which may have initiated the dysfunction of biological processes in the brains of SAMP8 mice. Specifically, we found microRNAs, including miR-20a, miR-17, miR-34a, miR-155, miR-18a, miR-22, miR-26a, miR-101, miR-106b, and miR-125b, that might regulate the expression of nodes in the sub-network. Taken together, these results provide new insights into the biological and genetic mechanisms of SAMP8 mice and add an important dimension to our understanding of the neuro-pathogenesis in SAMP8 mice from a systems perspective. PMID:24194717

  5. Solitary wave and multi-front wave collisions for the Bogoyavlenskii-Kadomtsev-Petviashili equation in physics, biology and electrical networks

    NASA Astrophysics Data System (ADS)

    Xie, Xi-Yang; Tian, Bo; Sun, Wen-Rong; Wang, Ming; Wang, Yun-Po

    2015-11-01

    In this paper, we investigate a Bogoyavlenskii-Kadomtsev-Petviashili equation, which can be used to describe the propagation of nonlinear waves in physics, biology and electrical networks. We find that the equation is Painlevé integrable. With symbolic computation, Hirota bilinear forms, solitary waves and multi-front waves are derived. Elastic collisions between/among the two and three solitary waves are graphically discussed, where the waves maintain their shapes, amplitudes and velocities after the collision only with some phase shifts. Inelastic collisions among the multi-front waves are discussed, where the front waves coalesce into one larger front wave in their collision region.

  6. Exact solutions for social and biological contagion models on mixed directed and undirected, degree-correlated random networks

    NASA Astrophysics Data System (ADS)

    Payne, Joshua L.; Harris, Kameron Decker; Dodds, Peter Sheridan

    2011-07-01

    We derive analytic expressions for the possibility, probability, and expected size of global spreading events starting from a single infected seed for a broad collection of contagion processes acting on random networks with both directed and undirected edges and arbitrary degree-degree correlations. Our work extends previous theoretical developments for the undirected case, and we provide numerical support for our findings by investigating an example class of networks for which we are able to obtain closed-form expressions.

  7. Autonomous bacterial localization and gene expression based on nearby cell receptor density

    PubMed Central

    Wu, Hsuan-Chen; Tsao, Chen-Yu; Quan, David N; Cheng, Yi; Servinsky, Matthew D; Carter, Karen K; Jee, Kathleen J; Terrell, Jessica L; Zargar, Amin; Rubloff, Gary W; Payne, Gregory F; Valdes, James J; Bentley, William E

    2013-01-01

    Escherichia coli were genetically modified to enable programmed motility, sensing, and actuation based on the density of features on nearby surfaces. Then, based on calculated feature density, these cells expressed marker proteins to indicate phenotypic response. Specifically, site-specific synthesis of bacterial quorum sensing autoinducer-2 (AI-2) is used to initiate and recruit motile cells. In our model system, we rewired E. coli's AI-2 signaling pathway to direct bacteria to a squamous cancer cell line of head and neck (SCCHN), where they initiate synthesis of a reporter (drug surrogate) based on a threshold density of epidermal growth factor receptor (EGFR). This represents a new type of controller for targeted drug delivery as actuation (synthesis and delivery) depends on a receptor density marking the diseased cell. The ability to survey local surfaces and initiate gene expression based on feature density represents a new area-based switch in synthetic biology that will find use beyond the proposed cancer model here. PMID:23340842

  8. Optimizing artificial neural network models for metabolomics and systems biology: an example using HPLC retention index data

    PubMed Central

    Hall, L Mark; Hill, Dennis W; Menikarachchi, Lochana C; Chen, Ming-Hui; Hall, Lowell H; Grant, David F

    2015-01-01

    Background Artificial Neural Networks (ANN) are extensively used to model ‘omics’ data. Different modeling methodologies and combinations of adjustable parameters influence model performance and complicate model optimization. Methodology We evaluated optimization of four ANN modeling parameters (learning rate annealing, stopping criteria, data split method, network architecture) using retention index (RI) data for 390 compounds. Models were assessed by independent validation (I-Val) using newly measured RI values for 1492 compounds. Conclusion The best model demonstrated an I-Val standard error of 55 RI units and was built using a Ward’s clustering data split and a minimally nonlinear network architecture. Use of validation statistics for stopping and final model selection resulted in better independent validation performance than the use of test set statistics. PMID:25966007

  9. The Inferelator: an algorithm for learning parsimonious regulatory networks from systems-biology data sets de novo

    PubMed Central

    2006-01-01

    We present a method (the Inferelator) for deriving genome-wide transcriptional regulatory interactions, and apply the method to predict a large portion of the regulatory network of the archaeon Halobacterium NRC-1. The Inferelator uses regression and variable selection to identify transcriptional influences on genes based on the integration of genome annotation and expression data. The learned network successfully predicted Halobacterium's global expression under novel perturbations with predictive power similar to that seen over training data. Several specific regulatory predictions were experimentally tested and verified. PMID:16686963

  10. Network-based discovery through mechanistic systems biology. Implications for applications--SMEs and drug discovery: where the action is.

    PubMed

    Benson, Neil

    2015-08-01

    Phase II attrition remains the most important challenge for drug discovery. Tackling the problem requires improved understanding of the complexity of disease biology. Systems biology approaches to this problem can, in principle, deliver this. This article reviews the reports of the application of mechanistic systems models to drug discovery questions and discusses the added value. Although we are on the journey to the virtual human, the length, path and rate of learning from this remain an open question. Success will be dependent on the will to invest and make the most of the insight generated along the way. PMID:26464089

  11. Network Cosmology

    PubMed Central

    Krioukov, Dmitri; Kitsak, Maksim; Sinkovits, Robert S.; Rideout, David; Meyer, David; Boguñá, Marián

    2012-01-01

    Prediction and control of the dynamics of complex networks is a central problem in network science. Structural and dynamical similarities of different real networks suggest that some universal laws might accurately describe the dynamics of these networks, albeit the nature and common origin of such laws remain elusive. Here we show that the causal network representing the large-scale structure of spacetime in our accelerating universe is a power-law graph with strong clustering, similar to many complex networks such as the Internet, social, or biological networks. We prove that this structural similarity is a consequence of the asymptotic equivalence between the large-scale growth dynamics of complex networks and causal networks. This equivalence suggests that unexpectedly similar laws govern the dynamics of complex networks and spacetime in the universe, with implications to network science and cosmology. PMID:23162688

  12. Synthesis, physical characterization, and biological performance of sequential homointerpenetrating polymer network sponges based on poly(2-hydroxyethyl methacrylate).

    PubMed

    Lou, X; Vijayasekaran, S; Chirila, T V; Maley, M A; Hicks, C R; Constable, I J

    1999-12-01

    A limitation in the use of hydrophilic poly(2-hydroxyethyl methacrylate) (PHEMA) sponges as implantable devices is their inherently poor mechanical strength. This precludes proper surgical manipulation, especially in the eye where the size of the implant is usually small. In this study a new method was developed to produce mechanically stronger PHEMA sponges. Sequential homointerpenetrating polymer network (homo-IPN) sponges were made by using HEMA as the precursor for generating both the first network and the successive interpenetrated networks. Following the formation of network I, the sponge was squeezed to remove the interstitial water, soaked in the second monomer (also HEMA), and squeezed again to remove the excess monomer from the pores before being subjected to the second polymerization leading to the formation of network II. Two two-component IPN sponges (K2 and K4) with increasing HEMA content in the network II and a three-component IPN sponge (K3) were produced, and their properties were compared to those of a homopolymer PHEMA sponge (control). Apart from elongation, the tensile properties were all significantly enhanced in the IPN sponges; the water content was the same as in the control sponge, except for sponge K4, which was lower. Light microscopy revealed similar pore morphologies of the control and IPN sponges K2 and K3, and the majority of the pores were around 25 microm. Sponge K4 displayed smaller pores of around 10 microm. Cellular invasion into the sponges was examined in vitro (incubation with 3T3 fibroblasts) and in vivo (implantation in rabbit corneas). Although the in vitro assay detected a change in the cell behavior in the early stage of invasion, which was probably due to the formation of IPNs, such changes were not reflected in the longer term in vivo experiment. There was a proper integration of sponges K2 and K3 with the corneal stroma, but much less cellular invasion and no neovascularization in sponge K4. We concluded that IPN

  13. Classification of the micro and nanoparticles and biological agents by neural network analysis of the parameters of optical resonance of whispering gallery mode in dielectric microspheres

    NASA Astrophysics Data System (ADS)

    Saetchnikov, Vladimir A.; Tcherniavskaia, Elina A.; Schweiger, Gustav; Ostendorf, Andreas

    2011-07-01

    A novel technique for the label-free analysis of micro and nanoparticles including biomolecules using optical micro cavity resonance of whispering-gallery-type modes is being developed. Various schemes of the method using both standard and specially produced microspheres have been investigated to make further development for microbial application. It was demonstrated that optical resonance under optimal geometry could be detected under the laser power of less 1 microwatt. The sensitivity of developed schemes has been tested by monitoring the spectral shift of the whispering gallery modes. Water solutions of ethanol, ascorbic acid, blood phantoms including albumin and HCl, glucose, biotin, biomarker like C reactive protein so as bacteria and virus phantoms (gels of silica micro and nanoparticles) have been used. Structure of resonance spectra of the solutions was a specific subject of investigation. Probabilistic neural network classifier for biological agents and micro/nano particles classification has been developed. Several parameters of resonance spectra as spectral shift, broadening, diffuseness and others have been used as input parameters to develop a network classifier for micro and nanoparticles and biological agents in solution. Classification probability of approximately 98% for probes under investigation have been achieved. Developed approach have been demonstrated to be a promising technology platform for sensitive, lab-on-chip type sensor which can be used for development of diagnostic tools for different biological molecules, e.g. proteins, oligonucleotides, oligosaccharides, lipids, small molecules, viral particles, cells as well as in different experimental contexts e.g. proteomics, genomics, drug discovery, and membrane studies.

  14. Linking network topology to function. Comment on "Drivers of structural features in gene regulatory networks: From biophysical constraints to biological function" by O.C. Martin, A. Krzywicki and M. Zagorski

    NASA Astrophysics Data System (ADS)

    di Bernardo, Diego

    2016-07-01

    The review by Martin et al. deals with a long standing problem at the interface of complex systems and molecular biology, that is the relationship between the topology of a complex network and its function. In biological terms the problem translates to relating the topology of gene regulatory networks (GRNs) to specific cellular functions. GRNs control the spatial and temporal activity of the genes encoded in the cell's genome by means of specialised proteins called Transcription Factors (TFs). A TF is able to recognise and bind specifically to a sequence (TF biding site) of variable length (order of magnitude of 10) found upstream of the sequence encoding one or more genes (at least in prokaryotes) and thus activating or repressing their transcription. TFs can thus be distinguished in activator and repressor. The picture can become more complex since some classes of TFs can form hetero-dimers consisting of a protein complex whose subunits are the individual TFs. Heterodimers can have completely different binding sites and activity compared to their individual parts. In this review the authors limit their attention to prokaryotes where the complexity of GRNs is somewhat reduced. Moreover they exploit a unique feature of living systems, i.e. evolution, to understand whether function can shape network topology. Indeed, prokaryotes such as bacteria are among the oldest living systems that have become perfectly adapted to their environment over geological scales and thus have reached an evolutionary steady-state where the fitness of the population has reached a plateau. By integrating in silico analysis and comparative evolution, the authors show that indeed function does tend to shape the structure of a GRN, however this trend is not always present and depends on the properties of the network being examined. Interestingly, the trend is more apparent for sparse networks, i.e. where the density of edges is very low. Sparsity is indeed one of the most prominent features

  15. Assessing the Biological Significance of Gene Expression Signatures and Co-Expression Modules by Studying Their Network Properties

    PubMed Central

    Minguez, Pablo; Dopazo, Joaquin

    2011-01-01

    Microarray experiments have been extensively used to define signatures, which are sets of genes that can be considered markers of experimental conditions (typically diseases). Paradoxically, in spite of the apparent functional role that might be attributed to such gene sets, signatures do not seem to be reproducible across experiments. Given the close relationship between function and protein interaction, network properties can be used to study to what extent signatures are composed of genes whose resulting proteins show a considerable level of interaction (and consequently a putative common functional role). We have analysed 618 signatures and 507 modules of co-expression in cancer looking for significant values of four main protein-protein interaction (PPI) network parameters: connection degree, cluster coefficient, betweenness and number of components. A total of 3904 gene ontology (GO) modules, 146 KEGG pathways, and 263 Biocarta pathways have been used as functional modules of reference. Co-expression modules found in microarray experiments display a high level of connectivity, similar to the one shown by conventional modules based on functional definitions (GO, KEGG and Biocarta). A general observation for all the classes studied is that the networks formed by the modules improve their topological parameters when an external protein is allowed to be introduced within the paths (up to the 70% of GO modules show network parameters beyond the random expectation). This fact suggests that functional definitions are incomplete and some genes might still be missing. Conversely, signatures are clearly not capturing the altered functions in the corresponding studies. This is probably because the way in which the genes have been selected in the signatures is too conservative. These results suggest that gene selection methods which take into account relationships among genes should be superior to methods that assume independence among genes outside their functional

  16. When the human viral infectome and diseasome networks collide: towards a systems biology platform for the aetiology of human diseases

    PubMed Central

    2011-01-01

    Background Comprehensive understanding of molecular mechanisms underlying viral infection is a major challenge towards the discovery of new antiviral drugs and susceptibility factors of human diseases. New advances in the field are expected from systems-level modelling and integration of the incessant torrent of high-throughput "-omics" data. Results Here, we describe the Human Infectome protein interaction Network, a novel systems virology model of a virtual virus-infected human cell concerning 110 viruses. This in silico model was applied to comprehensively explore the molecular relationships between viruses and their associated diseases. This was done by merging virus-host and host-host physical protein-protein interactomes with the set of genes essential for viral replication and involved in human genetic diseases. This systems-level approach provides strong evidence that viral proteomes target a wide range of functional and inter-connected modules of proteins as well as highly central and bridging proteins within the human interactome. The high centrality of targeted proteins was correlated to their essentiality for viruses' lifecycle, using functional genomic RNAi data. A stealth-attack of viruses on proteins bridging cellular functions was demonstrated by simulation of cellular network perturbations, a property that could be essential in the molecular aetiology of some human diseases. Networking the Human Infectome and Diseasome unravels the connectivity of viruses to a wide range of diseases and profiled molecular basis of Hepatitis C Virus-induced diseases as well as 38 new candidate genetic predisposition factors involved in type 1 diabetes mellitus. Conclusions The Human Infectome and Diseasome Networks described here provide a unique gateway towards the comprehensive modelling and analysis of the systems level properties associated to viral infection as well as candidate genes potentially involved in the molecular aetiology of human diseases. PMID

  17. Azimuthally invariant Mueller-matrix mapping of biological tissue in differential diagnosis of mechanisms protein molecules networks an sotropy

    NASA Astrophysics Data System (ADS)

    Ushenko, V. A.; Gavrylyak, M. S.

    2013-09-01

    The optical model of polycrystalline networks of blood plasma proteins is suggested. The results of investigating the interrelation between the values of correlation (correlation area, asymmetry coefficient and autocorrelation function excess) and fractal (dispersion of logarithmic dependencies of power spectra) parameters are presented. They characterize the coordinate distributions of Mueller-matrixes elements of blood plasma smears and pathological state of the organism. The diagnostic criteria of breast cancer nascency are determined.

  18. A microRNA-1280/JAG2 network comprises a novel biological target in high-risk medulloblastoma.

    PubMed

    Wang, Fengfei; Remke, Marc; Bhat, Kruttika; Wong, Eric T; Zhou, Shuang; Ramaswamy, Vijay; Dubuc, Adrian; Fonkem, Ekokobe; Salem, Saeed; Zhang, Hongbing; Hsieh, Tze-Chen; O'Rourke, Stephen T; Wu, Lizi; Li, David W; Hawkins, Cynthia; Kohane, Isaac S; Wu, Joseph M; Wu, Min; Taylor, Michael D; Wu, Erxi

    2015-02-20

    Over-expression of PDGF receptors (PDGFRs) has been previously implicated in high-risk medulloblastoma (MB) pathogenesis. However, the exact biological functions of PDGFRα and PDGFRβ signaling in MB biology remain poorly understood. Here, we report the subgroup specific expression of PDGFRα and PDGFRβ and their associated biological pathways in MB tumors. c-MYC, a downstream target of PDGFRβ but not PDGFRα, is involved in PDGFRβ signaling associated with cell proliferation, cell death, and invasion. Concurrent inhibition of PDGFRβ and c-MYC blocks MB cell proliferation and migration synergistically. Integrated analysis of miRNA and miRNA targets regulated by both PDGFRβ and c-MYC reveals that increased expression of JAG2, a target of miR-1280, is associated with high metastatic dissemination at diagnosis and a poor outcome in MB patients. Our study may resolve the controversy on the role of PDGFRs in MB and unveils JAG2 as a key downstream effector of a PDGFRβ-driven signaling cascade and a potential therapeutic target. PMID:25576913

  19. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis

    PubMed Central

    Barnabe, Cheryl; Tomlinson, George; Marshall, Deborah; Devoe, Dan; Bombardier, Claire

    2016-01-01

    Objective To compare methotrexate based disease modifying antirheumatic drug (DMARD) treatments for rheumatoid arthritis in patients naive to or with an inadequate response to methotrexate. Design Systematic review and Bayesian random effects network meta-analysis of trials assessing methotrexate used alone or in combination with other conventional synthetic DMARDs, biologic drugs, or tofacitinib in adult patients with rheumatoid arthritis. Data sources Trials were identified from Medline, Embase, and Central databases from inception to 19 January 2016; abstracts from two major rheumatology meetings from 2009 to 2015; two trial registers; and hand searches of Cochrane reviews. Study selection criteria Randomized or quasi-randomized trials that compared methotrexate with any other DMARD or combination of DMARDs and contributed to the network of evidence between the treatments of interest. Main outcomes American College of Rheumatology (ACR) 50 response (major clinical improvement), radiographic progression, and withdrawals due to adverse events. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior. Results 158 trials were included, with between 10 and 53 trials available for each outcome. In methotrexate naive patients, several treatments were statistically superior to oral methotrexate for ACR50 response: sulfasalazine and hydroxychloroquine (“triple therapy”), several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%), compared with 41% with methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression, but the estimated mean change over one year with all

  20. Linking network topology to function. Comment on "Drivers of structural features in gene regulatory networks: From biophysical constraints to biological function" by O.C. Martin, A. Krzywicki and M. Zagorski

    NASA Astrophysics Data System (ADS)

    di Bernardo, Diego

    2016-07-01

    The review by Martin et al. deals with a long standing problem at the interface of complex systems and molecular biology, that is the relationship between the topology of a complex network and its function. In biological terms the problem translates to relating the topology of gene regulatory networks (GRNs) to specific cellular functions. GRNs control the spatial and temporal activity of the genes encoded in the cell's genome by means of specialised proteins called Transcription Factors (TFs). A TF is able to recognise and bind specifically to a sequence (TF biding site) of variable length (order of magnitude of 10) found upstream of the sequence encoding one or more genes (at least in prokaryotes) and thus activating or repressing their transcription. TFs can thus be distinguished in activator and repressor. The picture can become more complex since some classes of TFs can form hetero-dimers consisting of a protein complex whose subunits are the individual TFs. Heterodimers can have completely different binding sites and activity compared to their individual parts. In this review the authors limit their attention to prokaryotes where the complexity of GRNs is somewhat reduced. Moreover they exploit a unique feature of living systems, i.e. evolution, to understand whether function can shape network topology. Indeed, prokaryotes such as bacteria are among the oldest living systems that have become perfectly adapted to their environment over geological scales and thus have reached an evolutionary steady-state where the fitness of the population has reached a plateau. By integrating in silico analysis and comparative evolution, the authors show that indeed function does tend to shape the structure of a GRN, however this trend is not always present and depends on the properties of the network being examined. Interestingly, the trend is more apparent for sparse networks, i.e. where the density of edges is very low. Sparsity is indeed one of the most prominent features

  1. 3-D components of a biological neural network visualized in computer generated imagery. I - Macular receptive field organization

    NASA Technical Reports Server (NTRS)

    Ross, Muriel D.; Cutler, Lynn; Meyer, Glenn; Lam, Tony; Vaziri, Parshaw

    1990-01-01

    Computer-assisted, 3-dimensional reconstructions of macular receptive fields and of their linkages into a neural network have revealed new information about macular functional organization. Both type I and type II hair cells are included in the receptive fields. The fields are rounded, oblong, or elongated, but gradations between categories are common. Cell polarizations are divergent. Morphologically, each calyx of oblong and elongated fields appears to be an information processing site. Intrinsic modulation of information processing is extensive and varies with the kind of field. Each reconstructed field differs in detail from every other, suggesting that an element of randomness is introduced developmentally and contributes to endorgan adaptability.

  2. A Novel Malaria Pf/Pv Ab Rapid Diagnostic Test Using a Differential Diagnostic Marker Identified by Network Biology.

    PubMed

    Cho, Sung Jin; Lee, Jihoo; Lee, Hyun Jae; Jo, Hyun-Young; Sinniah, Mangalam; Kim, Hak-Yong; Chong, Chom-Kyu; Song, Hyun-Ok

    2016-01-01

    Rapid diagnostic tests (RDTs) can detect anti-malaria antibodies in human blood. As they can detect parasite infection at the low parasite density, they are useful in endemic areas where light infection and/or re-infection of parasites are common. Thus, malaria antibody tests can be used for screening bloods in blood banks to prevent transfusion-transmitted malaria (TTM), an emerging problem in malaria endemic areas. However, only a few malaria antibody tests are available in the microwell-based assay format and these are not suitable for field application. A novel malaria antibody (Ab)-based RDT using a differential diagnostic marker for falciparum and vivax malaria was developed as a suitable high-throughput assay that is sensitive and practical for blood screening. The marker, merozoite surface protein 1 (MSP1) was discovered by generation of a Plasmodium-specific network and the hierarchical organization of modularity in the network. Clinical evaluation revealed that the novel Malaria Pf/Pv Ab RDT shows improved sensitivity (98%) and specificity (99.7%) compared with the performance of a commercial kit, SD BioLine Malaria P.f/P.v (95.1% sensitivity and 99.1% specificity). The novel Malaria Pf/Pv Ab RDT has potential for use as a cost-effective blood-screening tool for malaria and in turn, reduces TTM risk in endemic areas. PMID:27313496

  3. Complex metabolic network of 1,3-propanediol transport mechanisms and its system identification via biological robustness.

    PubMed

    Guo, Yanjie; Feng, Enmin; Wang, Lei; Xiu, Zhilong

    2014-04-01

    The bioconversion of glycerol to 1,3-propanediol (1,3-PD) by Klebsiella pneumoniae (K. pneumoniae) can be characterized by an intricate metabolic network of interactions among biochemical fluxes, metabolic compounds, key enzymes and genetic regulation. Since there are some uncertain factors in the fermentation, especially the transport mechanisms of 1,3-PD across cell membrane, the metabolic network contains multiple possible metabolic systems. Considering the genetic regulation of dha regulon and inhibition of 3-hydroxypropionaldehyde to the growth of cells, we establish a 14-dimensional nonlinear hybrid dynamical system aiming to determine the most possible metabolic system and the corresponding optimal parameter. The existence, uniqueness and continuity of solutions are discussed. Taking the robustness index of the intracellular substances together as a performance index, a system identification model is proposed, in which 1,395 continuous variables and 90 discrete variables are involved. The identification problem is decomposed into two subproblems and a parallel particle swarm optimization procedure is constructed to solve them. Numerical results show that it is most possible that 1,3-PD passes the cell membrane by active transport coupled with passive diffusion. PMID:24002752

  4. A Novel Malaria Pf/Pv Ab Rapid Diagnostic Test Using a Differential Diagnostic Marker Identified by Network Biology

    PubMed Central

    Cho, Sung Jin; Lee, Jihoo; Lee, Hyun Jae; Jo, Hyun-Young; Sinniah, Mangalam; Kim, Hak-Yong; Chong, Chom-Kyu; Song, Hyun-Ok

    2016-01-01

    Rapid diagnostic tests (RDTs) can detect anti-malaria antibodies in human blood. As they can detect parasite infection at the low parasite density, they are useful in endemic areas where light infection and/or re-infection of parasites are common. Thus, malaria antibody tests can be used for screening bloods in blood banks to prevent transfusion-transmitted malaria (TTM), an emerging problem in malaria endemic areas. However, only a few malaria antibody tests are available in the microwell-based assay format and these are not suitable for field application. A novel malaria antibody (Ab)-based RDT using a differential diagnostic marker for falciparum and vivax malaria was developed as a suitable high-throughput assay that is sensitive and practical for blood screening. The marker, merozoite surface protein 1 (MSP1) was discovered by generation of a Plasmodium-specific network and the hierarchical organization of modularity in the network. Clinical evaluation revealed that the novel Malaria Pf/Pv Ab RDT shows improved sensitivity (98%) and specificity (99.7%) compared with the performance of a commercial kit, SD BioLine Malaria P.f/P.v (95.1% sensitivity and 99.1% specificity). The novel Malaria Pf/Pv Ab RDT has potential for use as a cost-effective blood-screening tool for malaria and in turn, reduces TTM risk in endemic areas. PMID:27313496

  5. Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer

    PubMed Central

    Tong, Xupeng; Zhang, Jin; Zhang, Yonghui; Ouyang, Liang; Liu, Bo; Huang, Jian

    2015-01-01

    The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy. PMID:25797270

  6. A Systems Biology Approach to Reveal Putative Host-Derived Biomarkers of Periodontitis by Network Topology Characterization of MMP-REDOX/NO and Apoptosis Integrated Pathways.

    PubMed

    Zeidán-Chuliá, Fares; Gürsoy, Mervi; Neves de Oliveira, Ben-Hur; Özdemir, Vural; Könönen, Eija; Gürsoy, Ulvi K

    2015-01-01

    Periodontitis, a formidable global health burden, is a common chronic disease that destroys tooth-supporting tissues. Biomarkers of the early phase of this progressive disease are of utmost importance for global health. In this context, saliva represents a non-invasive biosample. By using systems biology tools, we aimed to (1) identify an integrated interactome between matrix metalloproteinase (MMP)-REDOX/nitric oxide (NO) and apoptosis upstream pathways of periodontal inflammation, and (2) characterize the attendant topological network properties to uncover putative biomarkers to be tested in saliva from patients with periodontitis. Hence, we first generated a protein-protein network model of interactions ("BIOMARK" interactome) by using the STRING 10 database, a search tool for the retrieval of interacting genes/proteins, with "Experiments" and "Databases" as input options and a confidence score of 0.400. Second, we determined the centrality values (closeness, stress, degree or connectivity, and betweenness) for the "BIOMARK" members by using the Cytoscape software. We found Ubiquitin C (UBC), Jun proto-oncogene (JUN), and matrix metalloproteinase-14 (MMP14) as the most central hub- and non-hub-bottlenecks among the 211 genes/proteins of the whole interactome. We conclude that UBC, JUN, and MMP14 are likely an optimal candidate group of host-derived biomarkers, in combination with oral pathogenic bacteria-derived proteins, for detecting periodontitis at its early phase by using salivary samples from patients. These findings therefore have broader relevance for systems medicine in global health as well. PMID:26793622

  7. Artificial neural network modelling in biological removal of organic carbon and nitrogen for the treatment of slaughterhouse wastewater in a batch reactor.

    PubMed

    Kundu, Pradyut; Debsarkar, Anupam; Mukherjee, Somnath; Kumar, Sunil

    2014-01-01

    Wastewater containing high concentration of oxygen-demanding carbonaceous organics and nitrogenous materials (chemical oxygen demand (COD) and total Kjeldahl nitrogen (TKN)) as nutrients emanated from small- to large-scale slaughterhouse units cause depletion of dissolved oxygen in water bodies and attributes to the threat of eutrophication. Biological treatment of wastewater is a useful tool through ages for the treatment of wastewater owing to its cost-effectiveness, reliability along with its innocuous output features. This paper deals with the treatment of slaughter house wastewater by conducting a laboratory scale batch reactor with different input characterized samples, and the experimental results were explored for the formulation of feed-forward back-propagation artificial neural network (ANN) to predict the combined removal of COD and TKN. The ANN modelling was carried out using neural network tool box of MATLAB (version 7.0), with the Levenberg-Marquardt training algorithm. Various trials were examined for the training of the ANN model using the number of neurons in the hidden layer varying from 2 to 30. The mean square error function and regression analysis were also applied for performance analysis of the ANN model. All the input data were logged-in after carrying out detailed experiment in the laboratory with a view to examine the performance of the batch reactor for the treatment of slaughterhouse wastewater. The experimental results were used for testing and validating the ANN model. PMID:24701927

  8. NeuroML: A Language for Describing Data Driven Models of Neurons and Networks with a High Degree of Biological Detail

    PubMed Central

    Gleeson, Padraig; Crook, Sharon; Cannon, Robert C.; Hines, Michael L.; Billings, Guy O.; Farinella, Matteo; Morse, Thomas M.; Davison, Andrew P.; Ray, Subhasis; Bhalla, Upinder S.; Barnes, Simon R.; Dimitrova, Yoana D.; Silver, R. Angus

    2010-01-01

    Biologically detailed single neuron and network models are important for understanding how ion channels, synapses and anatomical connectivity underlie the complex electrical behavior of the brain. While neuronal simulators such as NEURON, GENESIS, MOOSE, NEST, and PSICS facilitate the development of these data-driven neuronal models, the specialized languages they employ are generally not interoperable, limiting model accessibility and preventing reuse of model components and cross-simulator validation. To overcome these problems we have used an Open Source software approach to develop NeuroML, a neuronal model description language based on XML (Extensible Markup Language). This enables these detailed models and their components to be defined in a standalone form, allowing them to be used across multiple simulators and archived in a standardized format. Here we describe the structure of NeuroML and demonstrate its scope by converting into NeuroML models of a number of different voltage- and ligand-gated conductances, models of electrical coupling, synaptic transmission and short-term plasticity, together with morphologically detailed models of individual neurons. We have also used these NeuroML-based components to develop an highly detailed cortical network model. NeuroML-based model descriptions were validated by demonstrating similar model behavior across five independently developed simulators. Although our results confirm that simulations run on different simulators converge, they reveal limits to model interoperability, by showing that for some models convergence only occurs at high levels of spatial and temporal discretisation, when the computational overhead is high. Our development of NeuroML as a common description language for biophysically detailed neuronal and network models enables interoperability across multiple simulation environments, thereby improving model transparency, accessibility and reuse in computational neuroscience. PMID:20585541

  9. Slow noise in the period of a biological oscillator underlies gradual trends and abrupt transitions in phasic relationships in hybrid neural networks.

    PubMed

    Thounaojam, Umeshkanta S; Cui, Jianxia; Norman, Sharon E; Butera, Robert J; Canavier, Carmen C

    2014-05-01

    In order to study the ability of coupled neural oscillators to synchronize in the presence of intrinsic as opposed to synaptic noise, we constructed hybrid circuits consisting of one biological and one computational model neuron with reciprocal synaptic inhibition using the dynamic clamp. Uncoupled, both neurons fired periodic trains of action potentials. Most coupled circuits exhibited qualitative changes between one-to-one phase-locking with fairly constant phasic relationships and phase slipping with a constant progression in the phasic relationships across cycles. The phase resetting curve (PRC) and intrinsic periods were measured for both neurons, and used to construct a map of the firing intervals for both the coupled and externally forced (PRC measurement) conditions. For the coupled network, a stable fixed point of the map predicted phase locking, and its absence produced phase slipping. Repetitive application of the map was used to calibrate different noise models to simultaneously fit the noise level in the measurement of the PRC and the dynamics of the hybrid circuit experiments. Only a noise model that added history-dependent variability to the intrinsic period could fit both data sets with the same parameter values, as well as capture bifurcations in the fixed points of the map that cause switching between slipping and locking. We conclude that the biological neurons in our study have slowly-fluctuating stochastic dynamics that confer history dependence on the period. Theoretical results to date on the behavior of ensembles of noisy biological oscillators may require re-evaluation to account for transitions induced by slow noise dynamics. PMID:24830924

  10. Functional Evaluation of Biological Neurotoxins in Networked Cultures of Stem Cell-derived Central Nervous System Neurons

    PubMed Central

    Hubbard, Kyle; Beske, Phillip; Lyman, Megan; McNutt, Patrick

    2015-01-01

    Therapeutic and mechanistic studies of the presynaptically targeted clostridial neurotoxins (CNTs) have been limited by the need for a scalable, cell-based model that produces functioning synapses and undergoes physiological responses to intoxication. Here we describe a simple and robust method to efficiently differentiate murine embryonic stem cells (ESCs) into defined lineages of synaptically active, networked neurons. Following an 8 day differentiation protocol, mouse embryonic stem cell-derived neurons (ESNs) rapidly express and compartmentalize neurotypic proteins, form neuronal morphologies and develop intrinsic electrical responses. By 18 days after differentiation (DIV 18), ESNs exhibit active glutamatergic and γ-aminobutyric acid (GABA)ergic synapses and emergent network behaviors characterized by an excitatory:inhibitory balance. To determine whether intoxication with CNTs functionally antagonizes synaptic neurotransmission, thereby replicating the in vivo pathophysiology that is responsible for clinical manifestations of botulism or tetanus, whole-cell patch clamp electrophysiology was used to quantify spontaneous miniature excitatory post-synaptic currents (mEPSCs) in ESNs exposed to tetanus neurotoxin (TeNT) or botulinum neurotoxin (BoNT) serotypes /A-/G. In all cases, ESNs exhibited near-complete loss of synaptic activity within 20 hr. Intoxicated neurons remained viable, as demonstrated by unchanged resting membrane potentials and intrinsic electrical responses. To further characterize the sensitivity of this approach, dose-dependent effects of intoxication on synaptic activity were measured 20 hr after addition of BoNT/A. Intoxication with 0.005 pM BoNT/A resulted in a significant decrement in mEPSCs, with a median inhibitory concentration (IC50) of 0.013 pM. Comparisons of median doses indicate that functional measurements of synaptic inhibition are faster, more specific and more sensitive than SNARE cleavage assays or the mouse lethality assay

  11. CEBPA exerts a specific and biologically important proapoptotic role in pancreatic β cells through its downstream network targets.

    PubMed

    Barbagallo, Davide; Condorelli, Angelo Giuseppe; Piro, Salvatore; Parrinello, Nunziatina; Fløyel, Tina; Ragusa, Marco; Rabuazzo, Agata Maria; Størling, Joachim; Purrello, Francesco; Di Pietro, Cinzia; Purrello, Michele

    2014-08-15

    Transcription factor CEBPA has been widely studied for its involvement in hematopoietic cell differentiation and causal role in hematological malignancies. We demonstrate here that it also performs a causal role in cytokine-induced apoptosis of pancreas β cells. Treatment of two mouse pancreatic α and β cell lines (αTC1-6 and βTC1) with proinflammatory cytokines IL-1β, IFN-γ, and TNF-α at doses that specifically induce apoptosis of βTC1 significantly increased the amount of mRNA and protein encoded by Cebpa and its proapoptotic targets, Arl6ip5 and Tnfrsf10b, in βTC1 but not in αTC1-6. Cebpa knockdown in βTC1 significantly decreased cytokine-induced apoptosis, together with the amount of Arl6ip5 and Tnfrsf10b. Analysis of the network comprising CEBPA, its targets, their first interactants, and proteins encoded by genes known to regulate cytokine-induced apoptosis in pancreatic β cells (genes from the apoptotic machinery and from MAPK and NFkB pathways) revealed that CEBPA, ARL6IP5, TNFRSF10B, TRAF2, and UBC are the top five central nodes. In silico analysis further suggests TRAF2 as trait d'union node between CEBPA and the NFkB pathway. Our results strongly suggest that Cebpa is a key regulator within the apoptotic network activated in pancreatic β cells during insulitis, and Arl6ip5, Tnfrsf10b, Traf2, and Ubc are key executioners of this program. PMID:24943845

  12. A SYSTEMS BIOLOGY APPROACH TO DEVELOPMENTAL TOXICOLOGY

    EPA Science Inventory

    Abstract
    Recent advances in developmental biology have yielded detailed models of gene regulatory networks (GRNs) involved in cell specification and other processes in embryonic differentiation. Such networks form the bedrock on which a systems biology approach to developme...

  13. Nested Neural Networks

    NASA Technical Reports Server (NTRS)

    Baram, Yoram

    1992-01-01

    Report presents analysis of nested neural networks, consisting of interconnected subnetworks. Analysis based on simplified mathematical models more appropriate for artificial electronic neural networks, partly applicable to biological neural networks. Nested structure allows for retrieval of individual subpatterns. Requires fewer wires and connection devices than fully connected networks, and allows for local reconstruction of damaged subnetworks without rewiring entire network.

  14. Arrays of microLEDs and astrocytes: biological amplifiers to optogenetically modulate neuronal networks reducing light requirement.

    PubMed

    Berlinguer-Palmini, Rolando; Narducci, Roberto; Merhan, Kamyar; Dilaghi, Arianna; Moroni, Flavio; Masi, Alessio; Scartabelli, Tania; Landucci, Elisa; Sili, Maria; Schettini, Antonio; McGovern, Brian; Maskaant, Pleun; Degenaar, Patrick; Mannaioni, Guido

    2014-01-01

    In the modern view of synaptic transmission, astrocytes are no longer confined to the role of merely supportive cells. Although they do not generate action potentials, they nonetheless exhibit electrical activity and can influence surrounding neurons through gliotransmitter release. In this work, we explored whether optogenetic activation of glial cells could act as an amplification mechanism to optical neural stimulation via gliotransmission to the neural network. We studied the modulation of gliotransmission by selective photo-activation of channelrhodopsin-2 (ChR2) and by means of a matrix of individually addressable super-bright microLEDs (μLEDs) with an excitation peak at 470 nm. We combined Ca2+ imaging techniques and concurrent patch-clamp electrophysiology to obtain subsequent glia/neural activity. First, we tested the μLEDs efficacy in stimulating ChR2-transfected astrocyte. ChR2-induced astrocytic current did not desensitize overtime, and was linearly increased and prolonged by increasing μLED irradiance in terms of intensity and surface illumination. Subsequently, ChR2 astrocytic stimulation by broad-field LED illumination with the same spectral profile, increased both glial cells and neuronal calcium transient frequency and sEPSCs suggesting that few ChR2-transfected astrocytes were able to excite surrounding not-ChR2-transfected astrocytes and neurons. Finally, by using the μLEDs array to selectively light stimulate ChR2 positive astrocytes we were able to increase the synaptic activity of single neurons surrounding it. In conclusion, ChR2-transfected astrocytes and μLEDs system were shown to be an amplifier of synaptic activity in mixed corticalneuronal and glial cells culture. PMID:25265500

  15. Arrays of MicroLEDs and Astrocytes: Biological Amplifiers to Optogenetically Modulate Neuronal Networks Reducing Light Requirement

    PubMed Central

    Berlinguer-Palmini, Rolando; Narducci, Roberto; Merhan, Kamyar; Dilaghi, Arianna; Moroni, Flavio; Masi, Alessio; Scartabelli, Tania; Landucci, Elisa; Sili, Maria; Schettini, Antonio; McGovern, Brian; Maskaant, Pleun; Degenaar, Patrick; Mannaioni, Guido

    2014-01-01

    In the modern view of synaptic transmission, astrocytes are no longer confined to the role of merely supportive cells. Although they do not generate action potentials, they nonetheless exhibit electrical activity and can influence surrounding neurons through gliotransmitter release. In this work, we explored whether optogenetic activation of glial cells could act as an amplification mechanism to optical neural stimulation via gliotransmission to the neural network. We studied the modulation of gliotransmission by selective photo-activation of channelrhodopsin-2 (ChR2) and by means of a matrix of individually addressable super-bright microLEDs (μLEDs) with an excitation peak at 470 nm. We combined Ca2+ imaging techniques and concurrent patch-clamp electrophysiology to obtain subsequent glia/neural activity. First, we tested the μLEDs efficacy in stimulating ChR2-transfected astrocyte. ChR2-induced astrocytic current did not desensitize overtime, and was linearly increased and prolonged by increasing μLED irradiance in terms of intensity and surface illumination. Subsequently, ChR2 astrocytic stimulation by broad-field LED illumination with the same spectral profile, increased both glial cells and neuronal calcium transient frequency and sEPSCs suggesting that few ChR2-transfected astrocytes were able to excite surrounding not-ChR2-transfected astrocytes and neurons. Finally, by using the μLEDs array to selectively light stimulate ChR2 positive astrocytes we were able to increase the synaptic activity of single neurons surrounding it. In conclusion, ChR2-transfected astrocytes and μLEDs system were shown to be an amplifier of synaptic activity in mixed corticalneuronal and glial cells culture. PMID:25265500

  16. Biological Networks for Predicting Chemical Hepatocarcinogenicity Using Gene Expression Data from Treated Mice and Relevance across Human and Rat Species

    PubMed Central

    Thomas, Reuben; Thomas, Russell S.; Auerbach, Scott S.; Portier, Christopher J.

    2013-01-01

    Background Several groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days) to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases. Objectives To develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra-species, dose-dependent and cross-species predictions. Methods Genome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26) chemicals (10 were positive, 2 equivocal and 14 negative for liver tumors) previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long-term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans. Results Using 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC) equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species (AUC value of 0.74 for rats and 0.91 for humans). The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions. Conclusions Pathway-based prediction models estimated from sub-chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species. PMID:23737943

  17. A Systems Biology Approach to Reveal Putative Host-Derived Biomarkers of Periodontitis by Network Topology Characterization of MMP-REDOX/NO and Apoptosis Integrated Pathways

    PubMed Central

    Zeidán-Chuliá, Fares; Gürsoy, Mervi; Neves de Oliveira, Ben-Hur; Özdemir, Vural; Könönen, Eija; Gürsoy, Ulvi K.

    2016-01-01

    Periodontitis, a formidable global health burden, is a common chronic disease that destroys tooth-supporting tissues. Biomarkers of the early phase of this progressive disease are of utmost importance for global health. In this context, saliva represents a non-invasive biosample. By using systems biology tools, we aimed to (1) identify an integrated interactome between matrix metalloproteinase (MMP)-REDOX/nitric oxide (NO) and apoptosis upstream pathways of periodontal inflammation, and (2) characterize the attendant topological network properties to uncover putative biomarkers to be tested in saliva from patients with periodontitis. Hence, we first generated a protein-protein network model of interactions (“BIOMARK” interactome) by using the STRING 10 database, a search tool for the retrieval of interacting genes/proteins, with “Experiments” and “Databases” as input options and a confidence score of 0.400. Second, we determined the centrality values (closeness, stress, degree or connectivity, and betweenness) for the “BIOMARK” members by using the Cytoscape software. We found Ubiquitin C (UBC), Jun proto-oncogene (JUN), and matrix metalloproteinase-14 (MMP14) as the most central hub- and non-hub-bottlenecks among the 211 genes/proteins of the whole interactome. We conclude that UBC, JUN, and MMP14 are likely an optimal candidate group of host-derived biomarkers, in combination with oral pathogenic bacteria-derived proteins, for detecting periodontitis at its early phase by using salivary samples from patients. These findings therefore have broader relevance for systems medicine in global health as well. PMID:26793622

  18. "Omics" of Selenium Biology: A Prospective Study of Plasma Proteome Network Before and After Selenized-Yeast Supplementation in Healthy Men.

    PubMed

    Sinha, Indu; Karagoz, Kubra; Fogle, Rachel L; Hollenbeak, Christopher S; Zea, Arnold H; Arga, Kazim Y; Stanley, Anne E; Hawkes, Wayne C; Sinha, Raghu

    2016-04-01

    Low selenium levels have been linked to a higher incidence of cancer and other diseases, including Keshan, Chagas, and Kashin-Beck, and insulin resistance. Additionally, muscle and cardiovascular disorders, immune dysfunction, cancer, neurological disorders, and endocrine function have been associated with mutations in genes encoding for selenoproteins. Selenium biology is complex, and a systems biology approach to study global metabolomics, genomics, and/or proteomics may provide important clues to examining selenium-responsive markers in circulation. In the current investigation, we applied a global proteomics approach on plasma samples collected from a previously conducted, double-blinded placebo controlled clinical study, where men were supplemented with selenized-yeast (Se-Yeast; 300 μg/day, 3.8 μmol/day) or placebo-yeast for 48 weeks. Proteomic analysis was performed by iTRAQ on 8 plasma samples from each arm at baseline and 48 weeks. A total of 161 plasma proteins were identified in both arms. Twenty-two proteins were significantly altered following Se-Yeast supplementation and thirteen proteins were significantly changed after placebo-yeast supplementation in healthy men. The differentially expressed proteins were involved in complement and coagulation pathways, immune functions, lipid metabolism, and insulin resistance. Reconstruction and analysis of protein-protein interaction network around selected proteins revealed several hub proteins. One of the interactions suggested by our analysis, PHLD-APOA4, which is involved in insulin resistance, was subsequently validated by Western blot analysis. Our systems approach illustrates a viable platform for investigating responsive proteomic profile in 'before and after' condition following Se-Yeast supplementation. The nature of proteins identified suggests that selenium may play an important role in complement and coagulation pathways, and insulin resistance. PMID:27027327

  19. Integrating Transcriptomic and Proteomic Data Using Predictive Regulatory Network Models of Host Response to Pathogens

    PubMed Central

    Chasman, Deborah; Walters, Kevin B.; Lopes, Tiago J. S.; Eisfeld, Amie J.; Kawaoka, Yoshihiro; Roy, Sushmita

    2016-01-01

    Mammalian host response to pathogenic infections is controlled by a complex regulatory network connecting regulatory proteins such as transcription factors and signaling proteins to target genes. An important challenge in infectious disease research is to understand molecular similarities and differences in mammalian host response to diverse sets of pathogens. Recently, systems biology studies have produced rich collections of omic profiles measuring host response to infectious agents such as influenza viruses at multiple levels. To gain a comprehensive understanding of the regulatory network driving host response to multiple infectious agents, we integrated host transcriptomes and proteomes using a network-based approach. Our approach combines expression-based regulatory network inference, structured-sparsity based regression, and network information flow to infer putative physical regulatory programs for expression modules. We applied our approach to identify regulatory networks, modules and subnetworks that drive host response to multiple influenza infections. The inferred regulatory network and modules are significantly enriched for known pathways of immune response and implicate apoptosis, splicing, and interferon signaling processes in the differential response of viral infections of different pathogenicities. We used the learned network to prioritize regulators and study virus and time-point specific networks. RNAi-based knockdown of predicted regulators had significant impact on viral replication and include several previously unknown regulators. Taken together, our integrated analysis identified novel module level patterns that capture strain and pathogenicity-specific patterns of expression and helped identify important regulators of host response to influenza infection. PMID:27403523

  20. Gene expression-based classifications of fibroadenomas and phyllodes tumours of the breast.

    PubMed

    Vidal, Maria; Peg, Vicente; Galván, Patricia; Tres, Alejandro; Cortés, Javier; Ramón y Cajal, Santiago; Rubio, Isabel T; Prat, Aleix

    2015-06-01

    using gene expression-based data is feasible and might provide clinically useful biological and prognostic information. PMID:25687451

  1. Linking urbanization to the Biological Condition Gradient (BCG) for stream ecosystems in the Northeastern United States using a Bayesian network approach

    USGS Publications Warehouse

    Kashuba, Roxolana; McMahon, Gerard; Cuffney, Thomas F.; Qian, Song; Reckhow, Kenneth; Gerritsen, Jeroen; Davies, Susan

    2012-01-01

    In realization of the aforementioned advantages, a Bayesian network model was constructed to characterize the effect of urban development on aquatic macroinvertebrate stream communities through three simultaneous, interacting ecological pathways affecting stream hydrology, habitat, and water quality across watersheds in the Northeastern United States. This model incorporates both empirical data and expert knowledge to calculate the probabilities of attaining desired aquatic ecosystem conditions under different urban stress levels, environmental conditions, and management options. Ecosystem conditions are characterized in terms of standardized Biological Condition Gradient (BCG) management endpoints. This approach to evaluating urban development-induced perturbations in watersheds integrates statistical and mechanistic perspectives, different information sources, and several ecological processes into a comprehensive description of the system that can be used to support decision making. The completed model can be used to infer which management actions would lead to the highest likelihood of desired BCG tier achievement. For example, if best management practices (BMP) were implemented in a highly urbanized watershed to reduce flashiness to medium levels and specific conductance to low levels, the stream would have a 70-percent chance of achieving BCG Tier 3 or better, relative to a 24-percent achievement likelihood for unmanaged high urban land cover. Results are reported probabilistically to account for modeling uncertainty that is inherent in sources such as natural variability and model simplification error.

  2. Biological switches and clocks

    PubMed Central

    Tyson, John J.; Albert, Reka; Goldbeter, Albert; Ruoff, Peter; Sible, Jill

    2008-01-01

    To introduce this special issue on biological switches and clocks, we review the historical development of mathematical models of bistability and oscillations in chemical reaction networks. In the 1960s and 1970s, these models were limited to well-studied biochemical examples, such as glycolytic oscillations and cyclic AMP signalling. After the molecular genetics revolution of the 1980s, the field of molecular cell biology was thrown wide open to mathematical modellers. We review recent advances in modelling the gene–protein interaction networks that control circadian rhythms, cell cycle progression, signal processing and the design of synthetic gene networks. PMID:18522926

  3. Video-tracking of zebrafish (Danio rerio) as a biological early warning system using two distinct artificial neural networks: Probabilistic neural network (PNN) and self-organizing map (SOM).

    PubMed

    Oliva Teles, Luis; Fernandes, Miguel; Amorim, João; Vasconcelos, Vitor

    2015-08-01

    Biological early warning systems (BEWS) are becoming very important tools in ecotoxicological studies because they can detect changes in the behavior of organisms exposed to toxic substances. In this work, a video tracking system was fully developed to detect the presence of commercial bleach (NaOCl) in water in three different concentrations (0.0005%; 0.0010% and 0.0020% (v/v)) during one hour of exposure. Zebrafish was selected as the test organism because it is widely used in many different areas and studies. Two distinct statistical models were developed, using probabilistic neural network (PNN) and correspondence analysis associated with self-organizing map (SOM-CA). The diagnosis was based only in the analysis of a few behavioral components of the fish, namely: mean angular velocity, mean linear velocity, spatial dispersion, mean value of the X coordinate and mean value of the Y coordinate. Both models showed good results in their diagnosis capabilities. However, the overall performance (accuracy) was always superior in the PNN model. The worst result was with the SOM-CA model, at the lowest concentration (0.0005% v/v), achieving only 65% of correct diagnosis. The best result was with the PNN model, at the highest concentration (0.0020% v/v), achieving 94% of correct diagnosis. PMID:26122721

  4. Gene Coexpression Network Analysis as a Source of Functional Annotation for Rice Genes

    PubMed Central

    Childs, Kevin L.; Davidson, Rebecca M.; Buell, C. Robin

    2011-01-01

    With the existence of large publicly available plant gene expression data sets, many groups have undertaken data analyses to construct gene coexpression networks and functionally annotate genes. Often, a large compendium of unrelated or condition-independent expression data is used to construct gene networks. Condition-dependent expression experiments consisting of well-defined conditions/treatments have also been used to create coexpression networks to help examine particular biological processes. Gene networks derived from either condition-dependent or condition-independent data can be difficult to interpret if a large number of genes and connections are present. However, algorithms exist to identify modules of highly connected and biologically relevant genes within coexpression networks. In this study, we have used publicly available rice (Oryza sativa) gene expression data to create gene coexpression networks using both condition-dependent and condition-independent data and have identified gene modules within these networks using the Weighted Gene Coexpression Network Analysis method. We compared the number of genes assigned to modules and the biological interpretability of gene coexpression modules to assess the utility of condition-dependent and condition-independent gene coexpression networks. For the purpose of providing functional annotation to rice genes, we found that gene modules identified by coexpression analysis of condition-dependent gene expression experiments to be more useful than gene modules identified by analysis of a condition-independent data set. We have incorporated our results into the MSU Rice Genome Annotation Project database as additional expression-based annotation for 13,537 genes, 2,980 of which lack a functional annotation description. These results provide two new types of functional annotation for our database. Genes in modules are now associated with groups of genes that constitute a collective functional annotation of those

  5. Transcription Adaptation during In Vitro Adipogenesis and Osteogenesis of Porcine Mesenchymal Stem Cells: Dynamics of Pathways, Biological Processes, Up-Stream Regulators, and Gene Networks

    PubMed Central

    Bionaz, Massimo; Monaco, Elisa; Wheeler, Matthew B.

    2015-01-01

    The importance of mesenchymal stem cells (MSC) for bone regeneration is growing. Among MSC the bone marrow-derived stem cells (BMSC) are considered the gold standard in tissue engineering and regenerative medicine; however, the adipose-derived stem cells (ASC) have very similar properties and some advantages to be considered a good alternative to BMSC. The molecular mechanisms driving adipogenesis are relatively well-known but mechanisms driving osteogenesis are poorly known, particularly in pig. In the present study we have used transcriptome analysis to unravel pathways and biological functions driving in vitro adipogenesis and osteogenesis in BMSC and ASC. The analysis was performed using the novel Dynamic Impact Approach and functional enrichment analysis. In addition, a k-mean cluster analysis in association with enrichment analysis, networks reconstruction, and transcription factors overlapping analysis were performed in order to uncover the coordination of biological functions underlining differentiations. Analysis indicated a larger and more coordinated transcriptomic adaptation during adipogenesis compared to osteogenesis, with a larger induction of metabolism, particularly lipid synthesis (mostly triglycerides), and a larger use of amino acids for synthesis of feed-forward adipogenic compounds, larger cell signaling, lower cell-to-cell interactions, particularly for the cytoskeleton organization and cell junctions, and lower cell proliferation. The coordination of adipogenesis was mostly driven by Peroxisome Proliferator-activated Receptors together with other known adipogenic transcription factors. Only a few pathways and functions were more induced during osteogenesis compared to adipogenesis and some were more inhibited during osteogenesis, such as cholesterol and protein synthesis. Up-stream transcription factor analysis indicated activation of several lipid-related transcription regulators (e.g., PPARs and CEBPα) during adipogenesis but osteogenesis

  6. Robust patterning of gene expression based on internal coordinate system of cells.

    PubMed

    Ogawa, Ken-ichiro; Miyake, Yoshihiro

    2015-06-01

    Cell-to-cell communication in multicellular organisms is established through the transmission of various kinds of chemical substances such as proteins. It is well known that gene expression triggered by a chemical substance in individuals has stable spatial patterns despite the individual differences in concentration patterns of the chemical substance. This fact reveals an important property of multicellular organisms called "robustness", which allows the organisms to generate their forms while maintaining proportion. Robustness has been conventionally accounted for by the stability of solutions of dynamical equations that represent a specific interaction network of chemical substances. However, any biological system is composed of autonomous elements. In general, an autonomous element does not merely accept information on the chemical substance from the environment; instead, it accepts the information based on its own criteria for reaction. Therefore, this phenomenon needs to be considered from the viewpoint of cells. Such a viewpoint is expected to allow the consideration of the autonomy of cells in multicellular organisms. This study aims to explain theoretically the robust patterning of gene expression from the viewpoint of cells. For this purpose, we introduced a new operator for transforming a state variable of a chemical substance from an external coordinate system to an internal coordinate system of each cell, which describes the observation of the chemical substance by cells. We then applied this operator to the simplest reaction-diffusion model of the chemical substance to investigate observation effects by cells. Our mathematical analysis of this extended model indicates that the robust patterning of gene expression against individual differences in concentration pattern of the chemical substance can be explained from the viewpoint of cells if there is a regulation field that compensates for the difference between cells seen in the observation results

  7. Designing synthetic biology.

    PubMed

    Agapakis, Christina M

    2014-03-21

    Synthetic biology is frequently defined as the application of engineering design principles to biology. Such principles are intended to streamline the practice of biological engineering, to shorten the time required to design, build, and test synthetic gene networks. This streamlining of iterative design cycles can facilitate the future construction of biological systems for a range of applications in the production of fuels, foods, materials, and medicines. The promise of these potential applications as well as the emphasis on design has prompted critical reflection on synthetic biology from design theorists and practicing designers from many fields, who can bring valuable perspectives to the discipline. While interdisciplinary connections between biologists and engineers have built synthetic biology via the science and the technology of biology, interdisciplinary collaboration with artists, designers, and social theorists can provide insight on the connections between technology and society. Such collaborations can open up new avenues and new principles for research and design, as well as shed new light on the challenging context-dependence-both biological and social-that face living technologies at many scales. This review is inspired by the session titled "Design and Synthetic Biology: Connecting People and Technology" at Synthetic Biology 6.0 and covers a range of literature on design practice in synthetic biology and beyond. Critical engagement with how design is used to shape the discipline opens up new possibilities for how we might design the future of synthetic biology. PMID:24156739

  8. The emergence of modularity in biological systems

    NASA Astrophysics Data System (ADS)

    Lorenz, Dirk M.; Jeng, Alice; Deem, Michael W.

    2011-06-01

    In this review, we discuss modularity and hierarchy in biological systems. We review examples from protein structure, genetics, and biological networks of modular partitioning of the geometry of biological space. We review theories to explain modular organization of biology, with a focus on explaining how biology may spontaneously organize to a structured form. That is, we seek to explain how biology nucleated from among the many possibilities in chemistry. The emergence of modular organization of biological structure will be described as a symmetry-breaking phase transition, with modularity as the order parameter. Experimental support for this description will be reviewed. Examples will be presented from pathogen structure, metabolic networks, gene networks, and protein-protein interaction networks. Additional examples will be presented from ecological food networks, developmental pathways, physiology, and social networks.

  9. Biological Threats

    MedlinePlus

    ... Thunderstorms & Lightning Tornadoes Tsunamis Volcanoes Wildfires Main Content Biological Threats Biological agents are organisms or toxins that ... Centers for Disease Control and Prevention . Before a Biological Threat Unlike an explosion, a biological attack may ...

  10. Computational Systems Chemical Biology

    PubMed Central

    Oprea, Tudor I.; May, Elebeoba E.; Leitão, Andrei; Tropsha, Alexander

    2013-01-01

    There is a critical need for improving the level of chemistry awareness in systems biology. The data and information related to modulation of genes and proteins by small molecules continue to accumulate at the same time as simulation tools in systems biology and whole body physiologically-based pharmacokinetics (PBPK) continue to evolve. We called this emerging area at the interface between chemical biology and systems biology systems chemical biology, SCB (Oprea et al., 2007). The overarching goal of computational SCB is to develop tools for integrated chemical-biological data acquisition, filtering and processing, by taking into account relevant information related to interactions between proteins and small molecules, possible metabolic transformations of small molecules, as well as associated information related to genes, networks, small molecules and, where applicable, mutants and variants of those proteins. There is yet an unmet need to develop an integrated in silico pharmacology / systems biology continuum that embeds drug-target-clinical outcome (DTCO) triplets, a capability that is vital to the future of chemical biology, pharmacology and systems biology. Through the development of the SCB approach, scientists will be able to start addressing, in an integrated simulation environment, questions that make the best use of our ever-growing chemical and biological data repositories at the system-wide level. This chapter reviews some of the major research concepts and describes key components that constitute the emerging area of computational systems chemical biology. PMID:20838980

  11. Boolean network model for GPR142 against Type 2 diabetes and relative dynamic change ratio analysis using systems and biological circuits approach.

    PubMed

    Kaushik, Aman Chandra; Sahi, Shakti

    2015-06-01

    Systems biology addresses challenges in the analysis of genomics data, especially for complex genes and protein interactions using Meta data approach on various signaling pathways. In this paper, we report systems biology and biological circuits approach to construct pathway and identify early gene and protein interactions for predicting GPR142 responses in Type 2 diabetes. The information regarding genes, proteins and other molecules involved in Type 2 diabetes were retrieved from literature and kinetic simulation of GPR142 was carried out in order to determine the dynamic interactions. The major objective of this work was to design a GPR142 biochemical pathway using both systems biology as well as biological circuits synthetically. The term 'synthetically' refers to building biological circuits for cell signaling pathway especially for hormonal pathway disease. The focus of the paper is on logical components and logical circuits whereby using these applications users can create complex virtual circuits. Logic gates process represents only true or false and investigates whether biological regulatory circuits are active or inactive. The basic gates used are AND, NAND, OR, XOR and NOT gates and Integrated circuit composition of many such basic gates and some derived gates. Biological circuits may have a futuristic application in biomedical sciences which may involve placing a micro chip in human cells to modulate the down or up regulation of hormonal disease. PMID:25972988

  12. Graphs in molecular biology

    PubMed Central

    Huber, Wolfgang; Carey, Vincent J; Long, Li; Falcon, Seth; Gentleman, Robert

    2007-01-01

    Graph theoretical concepts are useful for the description and analysis of interactions and relationships in biological systems. We give a brief introduction into some of the concepts and their areas of application in molecular biology. We discuss software that is available through the Bioconductor project and present a simple example application to the integration of a protein-protein interaction and a co-expression network. PMID:17903289

  13. Network morphospace.

    PubMed

    Avena-Koenigsberger, Andrea; Goñi, Joaquín; Solé, Ricard; Sporns, Olaf

    2015-02-01

    The structure of complex networks has attracted much attention in recent years. It has been noted that many real-world examples of networked systems share a set of common architectural features. This raises important questions about their origin, for example whether such network attributes reflect common design principles or constraints imposed by selectional forces that have shaped the evolution of network topology. Is it possible to place the many patterns and forms of complex networks into a common space that reveals their relations, and what are the main rules and driving forces that determine which positions in such a space are occupied by systems that have actually evolved? We suggest that these questions can be addressed by combining concepts from two currently relatively unconnected fields. One is theoretical morphology, which has conceptualized the relations between morphological traits defined by mathematical models of biological form. The second is network science, which provides numerous quantitative tools to measure and classify different patterns of local and global network architecture across disparate types of systems. Here, we explore a new theoretical concept that lies at the intersection between both fields, the 'network morphospace'. Defined by axes that represent specific network traits, each point within such a space represents a location occupied by networks that share a set of common 'morphological' characteristics related to aspects of their connectivity. Mapping a network morphospace reveals the extent to which the space is filled by existing networks, thus allowing a distinction between actual and impossible designs and highlighting the generative potential of rules and constraints that pervade the evolution of complex systems. PMID:25540237

  14. Network morphospace

    PubMed Central

    Avena-Koenigsberger, Andrea; Goñi, Joaquín; Solé, Ricard; Sporns, Olaf

    2015-01-01

    The structure of complex networks has attracted much attention in recent years. It has been noted that many real-world examples of networked systems share a set of common architectural features. This raises important questions about their origin, for example whether such network attributes reflect common design principles or constraints imposed by selectional forces that have shaped the evolution of network topology. Is it possible to place the many patterns and forms of complex networks into a common space that reveals their relations, and what are the main rules and driving forces that determine which positions in such a space are occupied by systems that have actually evolved? We suggest that these questions can be addressed by combining concepts from two currently relatively unconnected fields. One is theoretical morphology, which has conceptualized the relations between morphological traits defined by mathematical models of biological form. The second is network science, which provides numerous quantitative tools to measure and classify different patterns of local and global network architecture across disparate types of systems. Here, we explore a new theoretical concept that lies at the intersection between both fields, the ‘network morphospace’. Defined by axes that represent specific network traits, each point within such a space represents a location occupied by networks that share a set of common ‘morphological’ characteristics related to aspects of their connectivity. Mapping a network morphospace reveals the extent to which the space is filled by existing networks, thus allowing a distinction between actual and impossible designs and highlighting the generative potential of rules and constraints that pervade the evolution of complex systems. PMID:25540237

  15. Theoretical and Computational Studies of Condensed-Phase Phenomena: The Origin of Biological Homochirality, and the Liquid-Liquid Phase Transition in Network-Forming Fluids

    NASA Astrophysics Data System (ADS)

    Ricci, Francesco

    This dissertation describes theoretical and computational studies of the origin of biological homochirality, and the existence of a liquid-liquid phase transition in pure-component network-forming fluids. A common theme throughout these studies is the use of sophisticated computer simulation and statistical mechanics techniques to study complex condensed-phase phenomena. In the first part of this dissertation, we use an elementary lattice model with molecular degrees of freedom, and satisfying microscopic reversibility, to investigate the effect of reaction reversibility on the evolution of stochastic symmetry breaking via autocatalysis and mutual inhibition in a closed system. We identify conditions under which the system's evolution towards racemic equilibrium becomes extremely slow, allowing for long-time persistence of a symmetry-broken state. We also identify a "monomer purification" mechanism, due to which a nearly homochiral state can persist for long times, even in the presence of significant reverse reaction rates. Order of magnitude estimates show that with reasonable physical parameters a symmetry broken state could persist over geologically-relevant time scales. In the second part of this dissertation, we study a chiral-symmetry breaking mechanism known as Viedma ripening. We develop a Monte Carlo model to gain further insights into the mechanisms capable of reproducing key experimental signatures associated with this phenomenon. We also provide a comprehensive investigation of how the model parameters impact the system's overall behavior. It is shown that size-dependent crystal solubility alone is insufficient to reproduce most experimental signatures, and that some form of a solid-phase chiral feedback mechanism (e.g., agglomeration) must be invoked in our model. In the third part of this dissertation, we perform rigorous free energy calculations to investigate the possibility of a liquid-liquid phase transition (LLPT) in the Stillinger-Weber (SW

  16. Networks’ Characteristics Matter for Systems Biology

    PubMed Central

    Rider, Andrew K.; Milenković, Tijana; Siwo, Geoffrey H.; Pinapati, Richard S.; Emrich, Scott J.; Ferdig, Michael T.; Chawla, Nitesh V.

    2015-01-01

    A fundamental goal of systems biology is to create models that describe relationships between biological components. Networks are an increasingly popular approach to this problem. However, a scientist interested in modeling biological (e.g., gene expression) data as a network is quickly confounded by the fundamental problem: how to construct the network? It is fairly easy to construct a network, but is it the network for the problem being considered? This is an important problem with three fundamental issues: How to weight edges in the network in order to capture actual biological interactions? What is the effect of the type of biological experiment used to collect the data from which the network is constructed? How to prune the weighted edges (or what cut-off to apply)? Differences in the construction of networks could lead to different biological interpretations. Indeed, we find that there are statistically significant dissimilarities in the functional content and topology between gene co-expression networks constructed using different edge weighting methods, data types, and edge cut-offs. We show that different types of known interactions, such as those found through Affinity Capture-Luminescence or Synthetic Lethality experiments, appear in significantly varying amounts in networks constructed in different ways. Hence, we demonstrate that different biological questions may be answered by the different networks. Consequently, we posit that the approach taken to build a network can be matched to biological questions to get targeted answers. More study is required to understand the implications of different network inference approaches and to draw reliable conclusions from networks used in the field of systems biology. PMID:26500772

  17. Concurrency and network disassortativity.

    PubMed

    Khor, Susan

    2010-01-01

    The relationship between a network's degree-degree correlation and a loose version of graph coloring is studied on networks with broad degree distributions. We find that, given similar conditions on the number of nodes, number of links, and clustering levels, fewer colors are needed to color disassortative than assortative networks. Since fewer colors create fewer independent sets, our finding implies that disassortative networks may have higher concurrency potential than assortative networks. This in turn suggests another reason for the disassortative mixing pattern observed in biological networks such as those of protein-protein interaction and gene regulation. In addition to the functional specificity and stability suggested by Maslov and Sneppen, a disassortative network topology may also enhance the ability of cells to perform crucial tasks concurrently. Hence, increased concurrency may also be a driving force in the evolution of biological networks. PMID:20586579

  18. A Systems Biology Approach to the Coordination of Defensive and Offensive Molecular Mechanisms in the Innate and Adaptive Host-Pathogen Interaction Networks.

    PubMed

    Wu, Chia-Chou; Chen, Bor-Sen

    2016-01-01

    Infected zebrafish coordinates defensive and offensive molecular mechanisms in response to Candida albicans infections, and invasive C. albicans coordinates corresponding molecular mechanisms to interact with the host. However, knowledge of the ensuing infection-activated signaling networks in both host and pathogen and their interspecific crosstalk during the innate and adaptive phases of the infection processes remains incomplete. In the present study, dynamic network modeling, protein interaction databases, and dual transcriptome data from zebrafish and C. albicans during infection were used to infer infection-activated host-pathogen dynamic interaction networks. The consideration of host-pathogen dynamic interaction systems as innate and adaptive loops and subsequent comparisons of inferred innate and adaptive networks indicated previously unrecognized crosstalk between known pathways and suggested roles of immunological memory in the coordination of host defensive and offensive molecular mechanisms to achieve specific and powerful defense against pathogens. Moreover, pathogens enhance intraspecific crosstalk and abrogate host apoptosis to accommodate enhanced host defense mechanisms during the adaptive phase. Accordingly, links between physiological phenomena and changes in the coordination of defensive and offensive molecular mechanisms highlight the importance of host-pathogen molecular interaction networks, and consequent inferences of the host-pathogen relationship could be translated into biomedical applications. PMID:26881892

  19. A Systems Biolog