WorldWideScience

Sample records for biological pathways

  1. Mining biological pathways using WikiPathways web services.

    Directory of Open Access Journals (Sweden)

    Thomas Kelder

    Full Text Available WikiPathways is a platform for creating, updating, and sharing biological pathways [1]. Pathways can be edited and downloaded using the wiki-style website. Here we present a SOAP web service that provides programmatic access to WikiPathways that is complementary to the website. We describe the functionality that this web service offers and discuss several use cases in detail. Exposing WikiPathways through a web service opens up new ways of utilizing pathway information and assisting the community curation process.

  2. Mining biological pathways using WikiPathways web services.

    Science.gov (United States)

    Kelder, Thomas; Pico, Alexander R; Hanspers, Kristina; van Iersel, Martijn P; Evelo, Chris; Conklin, Bruce R

    2009-07-30

    WikiPathways is a platform for creating, updating, and sharing biological pathways [1]. Pathways can be edited and downloaded using the wiki-style website. Here we present a SOAP web service that provides programmatic access to WikiPathways that is complementary to the website. We describe the functionality that this web service offers and discuss several use cases in detail. Exposing WikiPathways through a web service opens up new ways of utilizing pathway information and assisting the community curation process.

  3. Molecular neurodegeneration: basic biology and disease pathways.

    Science.gov (United States)

    Vassar, Robert; Zheng, Hui

    2014-09-23

    The field of neurodegeneration research has been advancing rapidly over the past few years, and has provided intriguing new insights into the normal physiological functions and pathogenic roles of a wide range of molecules associated with several devastating neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, and Down syndrome. Recent developments have also facilitated initial efforts to translate preclinical discoveries toward novel therapeutic approaches and clinical trials in humans. These recent developments are reviewed in the current Review Series on "Molecular Neurodegeneration: Basic Biology and Disease Pathways" in a number of state-of-the-art manuscripts that cover themes presented at the Third International Conference on Molecular Neurodegeneration: "Basic biology and disease pathways" held in Cannes, France, September, 2013.

  4. Using biological pathway data with paxtools.

    Directory of Open Access Journals (Sweden)

    Emek Demir

    Full Text Available A rapidly growing corpus of formal, computable pathway information can be used to answer important biological questions including finding non-trivial connections between cellular processes, identifying significantly altered portions of the cellular network in a disease state and building predictive models that can be used for precision medicine. Due to its complexity and fragmented nature, however, working with pathway data is still difficult. We present Paxtools, a Java library that contains algorithms, software components and converters for biological pathways represented in the standard BioPAX language. Paxtools allows scientists to focus on their scientific problem by removing technical barriers to access and analyse pathway information. Paxtools can run on any platform that has a Java Runtime Environment and was tested on most modern operating systems. Paxtools is open source and is available under the Lesser GNU public license (LGPL, which allows users to freely use the code in their software systems with a requirement for attribution. Source code for the current release (4.2.0 can be found in Software S1. A detailed manual for obtaining and using Paxtools can be found in Protocol S1. The latest sources and release bundles can be obtained from biopax.org/paxtools.

  5. Session on computation in biological pathways

    Energy Technology Data Exchange (ETDEWEB)

    Karp, P.D. [SRI International, Menlo Park, CA (United States); Riley, M. [Marine Biological Lab., Woods Hole, MA (United States)

    1996-12-31

    The papers in this session focus on the development of pathway databases and computational tools for pathway analysis. The discussion involves existing databases of sequenced genomes, as well as techniques for studying regulatory pathways.

  6. Computational Modeling of Biological Systems From Molecules to Pathways

    CERN Document Server

    2012-01-01

    Computational modeling is emerging as a powerful new approach for studying and manipulating biological systems. Many diverse methods have been developed to model, visualize, and rationally alter these systems at various length scales, from atomic resolution to the level of cellular pathways. Processes taking place at larger time and length scales, such as molecular evolution, have also greatly benefited from new breeds of computational approaches. Computational Modeling of Biological Systems: From Molecules to Pathways provides an overview of established computational methods for the modeling of biologically and medically relevant systems. It is suitable for researchers and professionals working in the fields of biophysics, computational biology, systems biology, and molecular medicine.

  7. Systems biology approaches and pathway tools for investigating cardiovascular disease

    NARCIS (Netherlands)

    Wheelock, C.E.; Wheelock, A.M.; Kawashima, S.; Diez, D.; Kanehisa, M.; Erk, M. van; Kleemann, R.; Haeggström, J.Z.; Goto, S.

    2009-01-01

    Systems biology aims to understand the nonlinear interactions of multiple biomolecular components that characterize a living organism. One important aspect of systems biology approaches is to identify the biological pathways or networks that connect the differing elements of a system, and examine ho

  8. Integrated pathway clusters with coherent biological themes for target prioritisation.

    Directory of Open Access Journals (Sweden)

    Yi-An Chen

    Full Text Available Prioritising candidate genes for further experimental characterisation is an essential, yet challenging task in biomedical research. One way of achieving this goal is to identify specific biological themes that are enriched within the gene set of interest to obtain insights into the biological phenomena under study. Biological pathway data have been particularly useful in identifying functional associations of genes and/or gene sets. However, biological pathway information as compiled in varied repositories often differs in scope and content, preventing a more effective and comprehensive characterisation of gene sets. Here we describe a new approach to constructing biologically coherent gene sets from pathway data in major public repositories and employing them for functional analysis of large gene sets. We first revealed significant overlaps in gene content between different pathways and then defined a clustering method based on the shared gene content and the similarity of gene overlap patterns. We established the biological relevance of the constructed pathway clusters using independent quantitative measures and we finally demonstrated the effectiveness of the constructed pathway clusters in comparative functional enrichment analysis of gene sets associated with diverse human diseases gathered from the literature. The pathway clusters and gene mappings have been integrated into the TargetMine data warehouse and are likely to provide a concise, manageable and biologically relevant means of functional analysis of gene sets and to facilitate candidate gene prioritisation.

  9. Biological Conversion of Sugars to Hydrocarbons Technology Pathway

    Energy Technology Data Exchange (ETDEWEB)

    Davis, R.; Biddy, M.; Tan, E.; Tao, L.; Jones, S.

    2013-03-01

    This technology pathway case investigates the biological conversion of biomass-derived sugars to hydrocarbon biofuels, utilizing data from recent literature references and information consistent with recent pilot-scale demonstrations at NREL. Technical barriers and key research needs have been identified that should be pursued for the pathway to become competitive with petroleum-derived gasoline-, diesel-, and jet-range hydrocarbon blendstocks.

  10. Bayesian parameter estimation for nonlinear modelling of biological pathways

    Directory of Open Access Journals (Sweden)

    Ghasemi Omid

    2011-12-01

    Full Text Available Abstract Background The availability of temporal measurements on biological experiments has significantly promoted research areas in systems biology. To gain insight into the interaction and regulation of biological systems, mathematical frameworks such as ordinary differential equations have been widely applied to model biological pathways and interpret the temporal data. Hill equations are the preferred formats to represent the reaction rate in differential equation frameworks, due to their simple structures and their capabilities for easy fitting to saturated experimental measurements. However, Hill equations are highly nonlinearly parameterized functions, and parameters in these functions cannot be measured easily. Additionally, because of its high nonlinearity, adaptive parameter estimation algorithms developed for linear parameterized differential equations cannot be applied. Therefore, parameter estimation in nonlinearly parameterized differential equation models for biological pathways is both challenging and rewarding. In this study, we propose a Bayesian parameter estimation algorithm to estimate parameters in nonlinear mathematical models for biological pathways using time series data. Results We used the Runge-Kutta method to transform differential equations to difference equations assuming a known structure of the differential equations. This transformation allowed us to generate predictions dependent on previous states and to apply a Bayesian approach, namely, the Markov chain Monte Carlo (MCMC method. We applied this approach to the biological pathways involved in the left ventricle (LV response to myocardial infarction (MI and verified our algorithm by estimating two parameters in a Hill equation embedded in the nonlinear model. We further evaluated our estimation performance with different parameter settings and signal to noise ratios. Our results demonstrated the effectiveness of the algorithm for both linearly and nonlinearly

  11. A systems biology approach reveals common metastatic pathways in osteosarcoma

    Directory of Open Access Journals (Sweden)

    Flores Ricardo J

    2012-05-01

    Full Text Available Abstract Background Osteosarcoma (OS is the most common malignant bone tumor in children and adolescents. The survival rate of patients with metastatic disease remains very dismal. Nevertheless, metastasis is a complex process and a single-level analysis is not likely to identify its key biological determinants. In this study, we used a systems biology approach to identify common metastatic pathways that are jointly supported by both mRNA and protein expression data in two distinct human metastatic OS models. Results mRNA expression microarray and N-linked glycoproteomic analyses were performed on two commonly used isogenic pairs of human metastatic OS cell lines, namely HOS/143B and SaOS-2/LM7. Pathway analysis of the differentially regulated genes and glycoproteins separately revealed pathways associated to metastasis including cell cycle regulation, immune response, and epithelial-to-mesenchymal-transition. However, no common significant pathway was found at both genomic and proteomic levels between the two metastatic models, suggesting a very different biological nature of the cell lines. To address this issue, we used a topological significance analysis based on a “shortest-path” algorithm to identify topological nodes, which uncovered additional biological information with respect to the genomic and glycoproteomic profiles but remained hidden from the direct analyses. Pathway analysis of the significant topological nodes revealed a striking concordance between the models and identified significant common pathways, including “Cytoskeleton remodeling/TGF/WNT”, “Cytoskeleton remodeling/Cytoskeleton remodeling”, and “Cell adhesion/Chemokines and adhesion”. Of these, the “Cytoskeleton remodeling/TGF/WNT” was the top ranked common pathway from the topological analysis of the genomic and proteomic profiles in the two metastatic models. The up-regulation of proteins in the “Cytoskeleton remodeling/TGF/WNT” pathway in the Sa

  12. Synthetic metabolism: engineering biology at the protein and pathway scales.

    Science.gov (United States)

    Martin, Collin H; Nielsen, David R; Solomon, Kevin V; Prather, Kristala L Jones

    2009-03-27

    Biocatalysis has become a powerful tool for the synthesis of high-value compounds, particularly so in the case of highly functionalized and/or stereoactive products. Nature has supplied thousands of enzymes and assembled them into numerous metabolic pathways. Although these native pathways can be use to produce natural bioproducts, there are many valuable and useful compounds that have no known natural biochemical route. Consequently, there is a need for both unnatural metabolic pathways and novel enzymatic activities upon which these pathways can be built. Here, we review the theoretical and experimental strategies for engineering synthetic metabolic pathways at the protein and pathway scales, and highlight the challenges that this subfield of synthetic biology currently faces.

  13. Efficient algorithms for extracting biological key pathways with global constraints

    DEFF Research Database (Denmark)

    Baumbach, Jan; Friedrich, T.; Kötzing, T.

    2012-01-01

    The integrated analysis of data of different types and with various interdependencies is one of the major challenges in computational biology. Recently, we developed KeyPathwayMiner, a method that combines biological networks modeled as graphs with disease-specific genetic expression data gained...... this strategy GLONE (global node exceptions); the previous problem we call INES (individual node exceptions). Since finding GLONE-components is computationally hard, we developed an Ant Colony Optimization algorithm and implemented it with the KeyPathwayMiner Cytoscape framework as an alternative to the INES...... algorithms. KeyPathwayMiner 3.0 now offers both the INES and the GLONE algorithms. It is available as plugin from Cytoscape and online at http://keypathwayminer.mpi-inf. mpg.de. © 2012 ACM....

  14. Application of XML database technology to biological pathway datasets.

    Science.gov (United States)

    Jiang, Keyuan; Nash, Christopher

    2006-01-01

    The study of biological systems has accumulated a significant amount of biological pathway data, which is evident through the continued growth in both the number of databases and amount of data available. The development of BioPAX standard leads to the increased availability of biological pathway datasets through the use of a special XML format, but the lack of standard storage mechanism makes the querying and aggregation of BioPAX compliant data challenging. To address this shortcoming, we have developed a storage mechanism leveraging the existing XML technologies: the XML database and XQuery. The goal of our project is to provide a generic and centralized store with efficient queries for the needs of biomedical research. A SOAP-based Web service and direct HTTP request methods have also developed to facilitate public consumption of the datasets online.

  15. Constructing biological pathways by a two-step counting approach.

    Directory of Open Access Journals (Sweden)

    Hsiuying Wang

    Full Text Available Networks are widely used in biology to represent the relationships between genes and gene functions. In Boolean biological models, it is mainly assumed that there are two states to represent a gene: on-state and off-state. It is typically assumed that the relationship between two genes can be characterized by two kinds of pairwise relationships: similarity and prerequisite. Many approaches have been proposed in the literature to reconstruct biological relationships. In this article, we propose a two-step method to reconstruct the biological pathway when the binary array data have measurement error. For a pair of genes in a sample, the first step of this approach is to assign counting numbers for every relationship and select the relationship with counting number greater than a threshold. The second step is to calculate the asymptotic p-values for hypotheses of possible relationships and select relationships with a large p-value. This new method has the advantages of easy calculation for the counting numbers and simple closed forms for the p-value. The simulation study and real data example show that the two-step counting method can accurately reconstruct the biological pathway and outperform the existing methods. Compared with the other existing methods, this two-step method can provide a more accurate and efficient alternative approach for reconstructing the biological network.

  16. Biological Conversion of Sugars to Hydrocarbons Technology Pathway

    Energy Technology Data Exchange (ETDEWEB)

    Davis, Ryan; Biddy, Mary J.; Tan, Eric; Tao, Ling; Jones, Susanne B.

    2013-03-31

    In support of the Bioenergy Technologies Office, the National Renewable Energy Laboratory (NREL) and the Pacific Northwest National Laboratory (PNNL) are undertaking studies of biomass conversion technologies to identify barriers and target research toward reducing conversion costs. Process designs and preliminary economic estimates for each of these pathway cases were developed using rigorous modeling tools (Aspen Plus and Chemcad). These analyses incorporated the best information available at the time of development, including data from recent pilot and bench-scale demonstrations, collaborative industrial and academic partners, and published literature and patents. This technology pathway case investigates the biological conversion of biomass derived sugars to hydrocarbon biofuels, utilizing data from recent literature references and information consistent with recent pilot scale demonstrations at NREL. Technical barriers and key research needs have been identified that should be pursued for the pathway to become competitive with petroleum-derived gasoline, diesel and jet range hydrocarbon blendstocks.

  17. Biological therapy induces expression changes in Notch pathway in psoriasis.

    Science.gov (United States)

    Skarmoutsou, Evangelia; Trovato, Chiara; Granata, Mariagrazia; Rossi, Giulio A; Mosca, Ambra; Longo, Valentina; Gangemi, Pietro; Pettinato, Maurizio; D'Amico, Fabio; Mazzarino, Maria Clorinda

    2015-12-01

    Psoriasis is a chronic inflammatory skin disease, characterized by hyperproliferation of keratinocytes and by skin infiltration of activated T cells. To date, the pathophysiology of psoriasis has not yet been fully elucidated. The Notch pathway plays a determinant role in cell fate determination, proliferation, differentiation, immune cell development and function. Many biological agents, used in the treatment of psoriasis, include TFN-α inhibitors, such as etanercept, adalimumab, and anti IL-12/IL-23 p40 antibody, such as ustekinumab. This study aimed to determine mRNA expression levels by real-time RT-PCR, and protein expression levels, analysed by Western blot and immunohistochemistry, of some components of the Notch pathway, such as NOTCH1, NOTCH2, JAGGED1, and HES1 after biological treatments in psoriatic patients. mRNA and protein levels of NOTCH1, NOTCH2, JAGGED1 and HES1 were upregulated in skin samples from untreated psoriatic patients compared with normal controls. Biological therapy showed to downregulate differently the protein expression levels of the molecules under study. Our study suggests that Notch pathway components might be a potential therapeutic target against psoriasis.

  18. PathwayExplorer: web service for visualizing high-throughput expression data on biological pathways.

    Science.gov (United States)

    Mlecnik, Bernhard; Scheideler, Marcel; Hackl, Hubert; Hartler, Jürgen; Sanchez-Cabo, Fatima; Trajanoski, Zlatko

    2005-07-01

    While generation of high-throughput expression data is becoming routine, the fast, easy, and systematic presentation and analysis of these data in a biological context is still an obstacle. To address this need, we have developed PathwayExplorer, which maps expression profiles of genes or proteins simultaneously onto major, currently available regulatory, metabolic and cellular pathways from KEGG, BioCarta and GenMAPP. PathwayExplorer is a platform-independent web server application with an optional standalone Java application using a SOAP (simple object access protocol) interface. Mapped pathways are ranked for the easy selection of the pathway of interest, displaying all available genes of this pathway with their expression profiles in a selectable and intuitive color code. Pathway maps produced can be downloaded as PNG, JPG or as high-resolution vector graphics SVG. The web service is freely available at https://pathwayexplorer.genome.tugraz.at; the standalone client can be downloaded at http://genome.tugraz.at.

  19. Algebraic Systems Biology: A Case Study for the Wnt Pathway.

    Science.gov (United States)

    Gross, Elizabeth; Harrington, Heather A; Rosen, Zvi; Sturmfels, Bernd

    2016-01-01

    Steady-state analysis of dynamical systems for biological networks gives rise to algebraic varieties in high-dimensional spaces whose study is of interest in their own right. We demonstrate this for the shuttle model of the Wnt signaling pathway. Here, the variety is described by a polynomial system in 19 unknowns and 36 parameters. It has degree 9 over the parameter space. This case study explores multistationarity, model comparison, dynamics within regions of the state space, identifiability, and parameter estimation, from a geometric point of view. We employ current methods from computational algebraic geometry, polyhedral geometry, and combinatorics.

  20. Mnk kinase pathway: Cellular functions and biological outcomes

    Institute of Scientific and Technical Information of China (English)

    Sonali; Joshi; Leonidas; C; Platanias

    2014-01-01

    The mitogen-activated protein kinase(MAPK) interacting protein kinases 1 and 2(Mnk1 and Mnk2) play important roles in controlling signals involved in mRNA translation. In addition to the MAPKs(p38 or Erk), multiple studies suggest that the Mnk kinases can be regulated by other known kinases such as Pak2 and/or other unidentified kinases by phosphorylation of residues distinct from the sites phosphorylated by the MAPKs. Several studies have established multiple Mnk protein targets, including PSF, heterogenous nuclear ribonucleoprotein A1, Sprouty 2 and have lead to the identification of distinct biological functions and substrate specificity for the Mnk kinases. In this review we discuss the pathways regulating the Mnk kinases, their known substrates as well as the functional consequences of engagement of pathways controlled by Mnk kinases. These kinases play an important role in mRNA translation via their regulation of eukaryotic initiation factor 4E(eIF4E) and their functions have important implications in tumor biology as well as the regulation of drug resistance to anti-oncogenic therapies. Other studies have identified a role for the Mnk kinases in cap-independent mRNA translation, suggesting that the Mnk kinases can exert important functional effects independently of the phosphorylation of eIF4 E. The role of Mnk kinases in inflammation and inflammationinduced malignancies is also discussed.

  1. Inference of asynchronous Boolean network from biological pathways.

    Science.gov (United States)

    Das, Haimabati; Layek, Ritwik Kumar

    2015-01-01

    Gene regulation is a complex process with multiple levels of interactions. In order to describe this complex dynamical system with tractable parameterization, the choice of the dynamical system model is of paramount importance. The right abstraction of the modeling scheme can reduce the complexity in the inference and intervention design, both computationally and experimentally. This article proposes an asynchronous Boolean network framework to capture the transcriptional regulation as well as the protein-protein interactions in a genetic regulatory system. The inference of asynchronous Boolean network from biological pathways information and experimental evidence are explained using an algorithm. The suitability of this paradigm for the variability of several reaction rates is also discussed. This methodology and model selection open up new research challenges in understanding gene-protein interactive system in a coherent way and can be beneficial for designing effective therapeutic intervention strategy.

  2. Identifying biological pathway interrupting toxins using multi-tree ensembles

    Directory of Open Access Journals (Sweden)

    Gergo Barta

    2016-08-01

    Full Text Available The pharmaceutical industry constantly seeks new ways to improve current methods that scientists use to evaluate environmental chemicals and develop new medicines. Various automated steps are involved in the process as testing hundreds of thousands of chemicals manually would be infeasible. Our research effort and the Toxicology in the 21st Century Data Challenge focused on cost-effective automation of toxicological testing, a chemical substance screening process looking for possible toxic effects caused by interrupting biological pathways. The computational models we propose in this paper successfully combine various publicly available substance fingerprinting tools with advanced machine learning techniques. In our paper, we explore the significance and utility of assorted feature selection methods as the structural analyzers generate a plethora of features for each substance. Machine learning models were carefully selected and evaluated based on their capability to cope with the high-dimensional high-variety data with multi-tree ensemble methods coming out on top. Techniques like Random forests and Extra trees combine numerous simple tree models and proved to produce reliable predictions on toxic activity while being nearly non-parametric and insensitive to dimensionality extremes. The Tox21 Data Challenge contest offered a great platform to compare a wide range of solutions in a controlled and orderly manner. The results clearly demonstrate that the generic approach presented in this paper is comparable to advanced deep learning and domain-specific solutions. Even surpassing the competition in some nuclear receptor signaling and stress pathway assays and achieving an accuracy of up to 94 percent.

  3. Developing Molecular Interaction Database and Searching for Similar Pathways (MOLECULAR BIOLOGY AND INFORMATION-Biological Information Science)

    OpenAIRE

    Kawashima, Shuichi; Katayama, Toshiaki; Kanehisa, Minoru

    1998-01-01

    We have developed a database named BRITE, which contains knowledge of interacting molecules and/or genes concering cell cycle and early development. Here, we report an overview of the database and the method of automatic search for functionally common sub-pathways between two biological pathways in BRITE.

  4. cPath: open source software for collecting, storing, and querying biological pathways

    Directory of Open Access Journals (Sweden)

    Gross Benjamin E

    2006-11-01

    Full Text Available Abstract Background Biological pathways, including metabolic pathways, protein interaction networks, signal transduction pathways, and gene regulatory networks, are currently represented in over 220 diverse databases. These data are crucial for the study of specific biological processes, including human diseases. Standard exchange formats for pathway information, such as BioPAX, CellML, SBML and PSI-MI, enable convenient collection of this data for biological research, but mechanisms for common storage and communication are required. Results We have developed cPath, an open source database and web application for collecting, storing, and querying biological pathway data. cPath makes it easy to aggregate custom pathway data sets available in standard exchange formats from multiple databases, present pathway data to biologists via a customizable web interface, and export pathway data via a web service to third-party software, such as Cytoscape, for visualization and analysis. cPath is software only, and does not include new pathway information. Key features include: a built-in identifier mapping service for linking identical interactors and linking to external resources; built-in support for PSI-MI and BioPAX standard pathway exchange formats; a web service interface for searching and retrieving pathway data sets; and thorough documentation. The cPath software is freely available under the LGPL open source license for academic and commercial use. Conclusion cPath is a robust, scalable, modular, professional-grade software platform for collecting, storing, and querying biological pathways. It can serve as the core data handling component in information systems for pathway visualization, analysis and modeling.

  5. SLEPR: a sample-level enrichment-based pathway ranking method -- seeking biological themes through pathway-level consistency.

    Science.gov (United States)

    Yi, Ming; Stephens, Robert M

    2008-09-26

    Analysis of microarray and other high throughput data often involves identification of genes consistently up or down-regulated across samples as the first step in extraction of biological meaning. This gene-level paradigm can be limited as a result of valid sample fluctuations and biological complexities. In this report, we describe a novel method, SLEPR, which eliminates this limitation by relying on pathway-level consistencies. Our method first selects the sample-level differentiated genes from each individual sample, capturing genes missed by other analysis methods, ascertains the enrichment levels of associated pathways from each of those lists, and then ranks annotated pathways based on the consistency of enrichment levels of individual samples from both sample classes. As a proof of concept, we have used this method to analyze three public microarray datasets with a direct comparison with the GSEA method, one of the most popular pathway-level analysis methods in the field. We found that our method was able to reproduce the earlier observations with significant improvements in depth of coverage for validated or expected biological themes, but also produced additional insights that make biological sense. This new method extends existing analyses approaches and facilitates integration of different types of HTP data.

  6. Modular electron transfer circuits for synthetic biology: Insulation of an engineered biohydrogen pathway

    OpenAIRE

    Agapakis, Christina M; Silver, Pamela A

    2010-01-01

    Electron transfer is central to a wide range of essential metabolic pathways, from photosynthesis to fermentation. The evolutionary diversity and conservation of proteins that transfer electrons makes these pathways a valuable platform for engineered metabolic circuits in synthetic biology. Rational engineering of electron transfer pathways containing hydrogenases has the potential to lead to industrial scale production of hydrogen as an alternative source of clean fuel and experimental assay...

  7. 75 FR 61497 - Approval Pathway for Biosimilar and Interchangeable Biological Products; Public Hearing; Request...

    Science.gov (United States)

    2010-10-05

    ... HUMAN SERVICES Food and Drug Administration Approval Pathway for Biosimilar and Interchangeable...'' (biosimilar) to, or ``interchangeable'' with, an FDA-licensed biological product. The purpose of this public... for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed...

  8. ANIMO: a tool for modeling biological pathway dynamics

    NARCIS (Netherlands)

    Schivo, S.; Scholma, J.; Karperien, M.; Langerak, R.; Pol, van de J.; Post, J.N.

    2014-01-01

    Introduction: Computational methods are applied with increasing success to the analysis of complex biological systems. However, their adoption is sometimes made difficult by requiring prior knowledge about the foundations of such methods, which often come from a different branch of science. The soft

  9. Gene Expression Profiling of Biological Pathway Alterations by Radiation Exposure

    Directory of Open Access Journals (Sweden)

    Kuei-Fang Lee

    2014-01-01

    Full Text Available Though damage caused by radiation has been the focus of rigorous research, the mechanisms through which radiation exerts harmful effects on cells are complex and not well-understood. In particular, the influence of low dose radiation exposure on the regulation of genes and pathways remains unclear. In an attempt to investigate the molecular alterations induced by varying doses of radiation, a genome-wide expression analysis was conducted. Peripheral blood mononuclear cells were collected from five participants and each sample was subjected to 0.5 Gy, 1 Gy, 2.5 Gy, and 5 Gy of cobalt 60 radiation, followed by array-based expression profiling. Gene set enrichment analysis indicated that the immune system and cancer development pathways appeared to be the major affected targets by radiation exposure. Therefore, 1 Gy radioactive exposure seemed to be a critical threshold dosage. In fact, after 1 Gy radiation exposure, expression levels of several genes including FADD, TNFRSF10B, TNFRSF8, TNFRSF10A, TNFSF10, TNFSF8, CASP1, and CASP4 that are associated with carcinogenesis and metabolic disorders showed significant alterations. Our results suggest that exposure to low-dose radiation may elicit changes in metabolic and immune pathways, potentially increasing the risk of immune dysfunctions and metabolic disorders.

  10. Pathway Tools version 19.0 update: software for pathway/genome informatics and systems biology.

    Science.gov (United States)

    Karp, Peter D; Latendresse, Mario; Paley, Suzanne M; Krummenacker, Markus; Ong, Quang D; Billington, Richard; Kothari, Anamika; Weaver, Daniel; Lee, Thomas; Subhraveti, Pallavi; Spaulding, Aaron; Fulcher, Carol; Keseler, Ingrid M; Caspi, Ron

    2016-09-01

    Pathway Tools is a bioinformatics software environment with a broad set of capabilities. The software provides genome-informatics tools such as a genome browser, sequence alignments, a genome-variant analyzer and comparative-genomics operations. It offers metabolic-informatics tools, such as metabolic reconstruction, quantitative metabolic modeling, prediction of reaction atom mappings and metabolic route search. Pathway Tools also provides regulatory-informatics tools, such as the ability to represent and visualize a wide range of regulatory interactions. This article outlines the advances in Pathway Tools in the past 5 years. Major additions include components for metabolic modeling, metabolic route search, computation of atom mappings and estimation of compound Gibbs free energies of formation; addition of editors for signaling pathways, for genome sequences and for cellular architecture; storage of gene essentiality data and phenotype data; display of multiple alignments, and of signaling and electron-transport pathways; and development of Python and web-services application programming interfaces. Scientists around the world have created more than 9800 Pathway/Genome Databases by using Pathway Tools, many of which are curated databases for important model organisms.

  11. Recursive random forest algorithm for constructing multilayered hierarchical gene regulatory networks that govern biological pathways

    Science.gov (United States)

    Zhang, Kui; Busov, Victor; Wei, Hairong

    2017-01-01

    Background Present knowledge indicates a multilayered hierarchical gene regulatory network (ML-hGRN) often operates above a biological pathway. Although the ML-hGRN is very important for understanding how a pathway is regulated, there is almost no computational algorithm for directly constructing ML-hGRNs. Results A backward elimination random forest (BWERF) algorithm was developed for constructing the ML-hGRN operating above a biological pathway. For each pathway gene, the BWERF used a random forest model to calculate the importance values of all transcription factors (TFs) to this pathway gene recursively with a portion (e.g. 1/10) of least important TFs being excluded in each round of modeling, during which, the importance values of all TFs to the pathway gene were updated and ranked until only one TF was remained in the list. The above procedure, termed BWERF. After that, the importance values of a TF to all pathway genes were aggregated and fitted to a Gaussian mixture model to determine the TF retention for the regulatory layer immediately above the pathway layer. The acquired TFs at the secondary layer were then set to be the new bottom layer to infer the next upper layer, and this process was repeated until a ML-hGRN with the expected layers was obtained. Conclusions BWERF improved the accuracy for constructing ML-hGRNs because it used backward elimination to exclude the noise genes, and aggregated the individual importance values for determining the TFs retention. We validated the BWERF by using it for constructing ML-hGRNs operating above mouse pluripotency maintenance pathway and Arabidopsis lignocellulosic pathway. Compared to GENIE3, BWERF showed an improvement in recognizing authentic TFs regulating a pathway. Compared to the bottom-up Gaussian graphical model algorithm we developed for constructing ML-hGRNs, the BWERF can construct ML-hGRNs with significantly reduced edges that enable biologists to choose the implicit edges for experimental

  12. A guide for building biological pathways along with two case studies: hair and breast development.

    Science.gov (United States)

    Trindade, Daniel; Orsine, Lissur A; Barbosa-Silva, Adriano; Donnard, Elisa R; Ortega, J Miguel

    2015-03-01

    Genomic information is being underlined in the format of biological pathways. Building these biological pathways is an ongoing demand and benefits from methods for extracting information from biomedical literature with the aid of text-mining tools. Here we hopefully guide you in the attempt of building a customized pathway or chart representation of a system. Our manual is based on a group of software designed to look at biointeractions in a set of abstracts retrieved from PubMed. However, they aim to support the work of someone with biological background, who does not need to be an expert on the subject and will play the role of manual curator while designing the representation of the system, the pathway. We therefore illustrate with two challenging case studies: hair and breast development. They were chosen for focusing on recent acquisitions of human evolution. We produced sub-pathways for each study, representing different phases of development. Differently from most charts present in current databases, we present detailed descriptions, which will additionally guide PESCADOR users along the process. The implementation as a web interface makes PESCADOR a unique tool for guiding the user along the biointeractions, which will constitute a novel pathway.

  13. Stochastic robustness and relative stability of multiple pathways in biological networks

    CERN Document Server

    Guo, Yongyi; Qian, Min; Ge, Hao

    2015-01-01

    Multiple dynamic pathways always exist in biological networks, but their robustness against internal fluctuations and relative stability have not been well recognized and carefully analyzed yet. Here we try to address these issues through an illustrative example, namely the Siah-1/beta-catenin/p14/19 ARF loop of protein p53 dynamics. Its deterministic Boolean network model predicts that two parallel pathways with comparable magnitudes of attractive basins should exist after the protein p53 is activated when a cell becomes harmfully disturbed. Once the low but non-neglectable intrinsic fluctuations are incorporated into the model, we show that a phase transition phenomenon is emerged: in one parameter region the probability weights of the normal pathway, reported in experimental literature, are comparable with the other pathway which is seemingly abnormal with the unknown functions, whereas, in some other parameter regions, the probability weight of the abnormal pathway can even dominate and become globally at...

  14. Incorporating biological pathways via a Markov random field model in genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Min Chen

    2011-04-01

    Full Text Available Genome-wide association studies (GWAS examine a large number of markers across the genome to identify associations between genetic variants and disease. Most published studies examine only single markers, which may be less informative than considering multiple markers and multiple genes jointly because genes may interact with each other to affect disease risk. Much knowledge has been accumulated in the literature on biological pathways and interactions. It is conceivable that appropriate incorporation of such prior knowledge may improve the likelihood of making genuine discoveries. Although a number of methods have been developed recently to prioritize genes using prior biological knowledge, such as pathways, most methods treat genes in a specific pathway as an exchangeable set without considering the topological structure of a pathway. However, how genes are related with each other in a pathway may be very informative to identify association signals. To make use of the connectivity information among genes in a pathway in GWAS analysis, we propose a Markov Random Field (MRF model to incorporate pathway topology for association analysis. We show that the conditional distribution of our MRF model takes on a simple logistic regression form, and we propose an iterated conditional modes algorithm as well as a decision theoretic approach for statistical inference of each gene's association with disease. Simulation studies show that our proposed framework is more effective to identify genes associated with disease than a single gene-based method. We also illustrate the usefulness of our approach through its applications to a real data example.

  15. Revealing complex function, process and pathway interactions with high-throughput expression and biological annotation data.

    Science.gov (United States)

    Singh, Nitesh Kumar; Ernst, Mathias; Liebscher, Volkmar; Fuellen, Georg; Taher, Leila

    2016-10-20

    The biological relationships both between and within the functions, processes and pathways that operate within complex biological systems are only poorly characterized, making the interpretation of large scale gene expression datasets extremely challenging. Here, we present an approach that integrates gene expression and biological annotation data to identify and describe the interactions between biological functions, processes and pathways that govern a phenotype of interest. The product is a global, interconnected network, not of genes but of functions, processes and pathways, that represents the biological relationships within the system. We validated our approach on two high-throughput expression datasets describing organismal and organ development. Our findings are well supported by the available literature, confirming that developmental processes and apoptosis play key roles in cell differentiation. Furthermore, our results suggest that processes related to pluripotency and lineage commitment, which are known to be critical for development, interact mainly indirectly, through genes implicated in more general biological processes. Moreover, we provide evidence that supports the relevance of cell spatial organization in the developing liver for proper liver function. Our strategy can be viewed as an abstraction that is useful to interpret high-throughput data and devise further experiments.

  16. Radiotracers For Lipid Signaling Pathways In Biological Systems

    Energy Technology Data Exchange (ETDEWEB)

    Gatley, S. J. [Northeastern Univ., Boston, MA (United States)

    2016-09-26

    enzymes such as fatty acid amide hydrolase, which may regulate endocannabinoid tone in animals. Early results were presented at the 2011 ICRS meeting, and at the 2012 Society for Neurosciences. Narachidonoylethanolamine is an endocannabinoid signaling messenger in animals and is known as “anandamide”. It is one of several families of signaling molecules derived from arachidonic acid, the principal omega-6 polyunsaturated fatty acids (PUFA’s) in animal species. Other derivatives of arachidonic acid include thromboxanes and prostaglandins. Full details of the studies with the ethanolamide isotopomers were a part of the PhD dissertation of Kun Hu (nee Qian), and were submitted for publication to Nuclear Medicine and Biology in August 2016. Syntheses of [14C]docosahexanoylethanolamine isotopomers and preliminary biological investigations Docosahexaenoic acid (DHA) is the omega-3 PUFA that can be regarded in some respects as the counterpart of arachidonic acid in the omega-6 series. While arachidonic acid is proinflammatory, DHA is anti-inflammatory, and foods high in DHA (or artificially enriched in DHA) are commonly regarded as promoting health. In contrast to the large literature on the Nethanolamide of arachidonic acid (i.e. the endocannabinoid anandamide) as of now (9/25/2016) there are only six papers on the corresponding ethanolamide of DHA, and when our studies under this grant began there were none. Beneficial actions of endogenously produced DHAethanolamine (“synaptamide”) have been indicated, and to help elucidate the possible roles of synaptamide, we have synthesized this molecule for the first time labeled with C-14 in either the ethanolamine moiety or the fatty acid moiety. Studies of the disposition of endogenously administered isotopomers of DHA-ethanolamine are in progress, to complement tissue culture experiments evaluation hypothesized protective effects of this DHA derivative.

  17. Deciphering the biological effects of acupuncture treatment modulating multiple metabolism pathways.

    Science.gov (United States)

    Zhang, Aihua; Yan, Guangli; Sun, Hui; Cheng, Weiping; Meng, Xiangcai; Liu, Li; Xie, Ning; Wang, Xijun

    2016-02-16

    Acupuncture is an alternative therapy that is widely used to treat various diseases. However, detailed biological interpretation of the acupuncture stimulations is limited. We here used metabolomics and proteomics technology, thereby identifying the serum small molecular metabolites into the effect and mechanism pathways of standardized acupuncture treatments at 'Zusanli' acupoint which was the most often used acupoint in previous reports. Comprehensive overview of serum metabolic profiles during acupuncture stimulation was investigated. Thirty-four differential metabolites were identified in serum metabolome and associated with ten metabolism pathways. Importantly, we have found that high impact glycerophospholipid metabolism, fatty acid metabolism, ether lipid metabolism were acutely perturbed by acupuncture stimulation. As such, these alterations may be useful to clarify the biological mechanism of acupuncture stimulation. A series of differentially expressed proteins were identified and such effects of acupuncture stimulation were found to play a role in transport, enzymatic activity, signaling pathway or receptor interaction. Pathway analysis further revealed that most of these proteins were found to play a pivotal role in the regulation of multiple metabolism pathways. It demonstrated that the metabolomics coupled with proteomics as a powerful approach for potential applications in understanding the biological effects of acupuncture stimulation.

  18. Studying Biology to Understand Risk: Dosimetry Models and Quantitative Adverse Outcome Pathways

    Science.gov (United States)

    Confidence in the quantitative prediction of risk is increased when the prediction is based to as great an extent as possible on the relevant biological factors that constitute the pathway from exposure to adverse outcome. With the first examples now over 40 years old, physiologi...

  19. PathCards: multi-source consolidation of human biological pathways

    Science.gov (United States)

    Belinky, Frida; Nativ, Noam; Stelzer, Gil; Zimmerman, Shahar; Iny Stein, Tsippi; Safran, Marilyn; Lancet, Doron

    2015-01-01

    The study of biological pathways is key to a large number of systems analyses. However, many relevant tools consider a limited number of pathway sources, missing out on many genes and gene-to-gene connections. Simply pooling several pathways sources would result in redundancy and the lack of systematic pathway interrelations. To address this, we exercised a combination of hierarchical clustering and nearest neighbor graph representation, with judiciously selected cutoff values, thereby consolidating 3215 human pathways from 12 sources into a set of 1073 SuperPaths. Our unification algorithm finds a balance between reducing redundancy and optimizing the level of pathway-related informativeness for individual genes. We show a substantial enhancement of the SuperPaths’ capacity to infer gene-to-gene relationships when compared with individual pathway sources, separately or taken together. Further, we demonstrate that the chosen 12 sources entail nearly exhaustive gene coverage. The computed SuperPaths are presented in a new online database, PathCards, showing each SuperPath, its constituent network of pathways, and its contained genes. This provides researchers with a rich, searchable systems analysis resource.Database URL: http://pathcards.genecards.org/ PMID:25725062

  20. Escher: A Web Application for Building, Sharing, and Embedding Data-Rich Visualizations of Biological Pathways

    DEFF Research Database (Denmark)

    King, Zachary A.; Draeger, Andreas; Ebrahim, Ali;

    2015-01-01

    Escher is a web application for visualizing data on biological pathways. Three key features make Escher a uniquely effective tool for pathway visualization. First, users can rapidly design new pathway maps. Escher provides pathway suggestions based on user data and genome-scale models, so users can......IP)-in conjunction with metabolite-and reaction-oriented data types (e.g. metabolomics, fluxomics). Third, Escher harnesses the strengths of web technologies (SVG, D3, developer tools) so that visualizations can be rapidly adapted, extended, shared, and embedded. This paper provides examples of each...... of these features and explains how the development approach used for Escher can be used to guide the development of future visualization tools....

  1. The merged basins of signal transduction pathways in spatiotemporal cell biology.

    Science.gov (United States)

    Hou, Yingchun; Hou, Yang; He, Siyu; Ma, Caixia; Sun, Mengyao; He, Huimin; Gao, Ning

    2014-03-01

    Numerous evidences have indicated that a signal system is composed by signal pathways, each pathway is composed by sub-pathways, and the sub-pathway is composed by the original signal terminals initiated with a protein/gene. We infer the terminal signals merged signal transduction system as "signal basin". In this article, we discussed the composition and regulation of signal basins, and the relationship between the signal basin control and triple W of spatiotemporal cell biology. Finally, we evaluated the importance of the systemic regulation to gene expression by signal basins under triple W. We hope our discussion will be the beginning to cause the attention for this area from the scientists of life science.

  2. Correlation analyses of clinical and molecular findings identify candidate biological pathways in systemic juvenile idiopathic arthritis

    Directory of Open Access Journals (Sweden)

    Ling Xuefeng B

    2012-10-01

    Full Text Available Abstract Background Clinicians have long appreciated the distinct phenotype of systemic juvenile idiopathic arthritis (SJIA compared to polyarticular juvenile idiopathic arthritis (POLY. We hypothesized that gene expression profiles of peripheral blood mononuclear cells (PBMC from children with each disease would reveal distinct biological pathways when analyzed for significant associations with elevations in two markers of JIA activity, erythrocyte sedimentation rate (ESR and number of affected joints (joint count, JC. Methods PBMC RNA from SJIA and POLY patients was profiled by kinetic PCR to analyze expression of 181 genes, selected for relevance to immune response pathways. Pearson correlation and Student's t-test analyses were performed to identify transcripts significantly associated with clinical parameters (ESR and JC in SJIA or POLY samples. These transcripts were used to find related biological pathways. Results Combining Pearson and t-test analyses, we found 91 ESR-related and 92 JC-related genes in SJIA. For POLY, 20 ESR-related and 0 JC-related genes were found. Using Ingenuity Systems Pathways Analysis, we identified SJIA ESR-related and JC-related pathways. The two sets of pathways are strongly correlated. In contrast, there is a weaker correlation between SJIA and POLY ESR-related pathways. Notably, distinct biological processes were found to correlate with JC in samples from the earlier systemic plus arthritic phase (SAF of SJIA compared to samples from the later arthritis-predominant phase (AF. Within the SJIA SAF group, IL-10 expression was related to JC, whereas lack of IL-4 appeared to characterize the chronic arthritis (AF subgroup. Conclusions The strong correlation between pathways implicated in elevations of both ESR and JC in SJIA argues that the systemic and arthritic components of the disease are related mechanistically. Inflammatory pathways in SJIA are distinct from those in POLY course JIA, consistent with

  3. Using the Semantic Web for Rapid Integration of WikiPathways with Other Biological Online Data Resources.

    Science.gov (United States)

    Waagmeester, Andra; Kutmon, Martina; Riutta, Anders; Miller, Ryan; Willighagen, Egon L; Evelo, Chris T; Pico, Alexander R

    2016-06-01

    The diversity of online resources storing biological data in different formats provides a challenge for bioinformaticians to integrate and analyse their biological data. The semantic web provides a standard to facilitate knowledge integration using statements built as triples describing a relation between two objects. WikiPathways, an online collaborative pathway resource, is now available in the semantic web through a SPARQL endpoint at http://sparql.wikipathways.org. Having biological pathways in the semantic web allows rapid integration with data from other resources that contain information about elements present in pathways using SPARQL queries. In order to convert WikiPathways content into meaningful triples we developed two new vocabularies that capture the graphical representation and the pathway logic, respectively. Each gene, protein, and metabolite in a given pathway is defined with a standard set of identifiers to support linking to several other biological resources in the semantic web. WikiPathways triples were loaded into the Open PHACTS discovery platform and are available through its Web API (https://dev.openphacts.org/docs) to be used in various tools for drug development. We combined various semantic web resources with the newly converted WikiPathways content using a variety of SPARQL query types and third-party resources, such as the Open PHACTS API. The ability to use pathway information to form new links across diverse biological data highlights the utility of integrating WikiPathways in the semantic web.

  4. ArrayXPath: mapping and visualizing microarray gene-expression data with integrated biological pathway resources using Scalable Vector Graphics.

    Science.gov (United States)

    Chung, Hee-Joon; Kim, Mingoo; Park, Chan Hee; Kim, Jihoon; Kim, Ju Han

    2004-07-01

    Biological pathways can provide key information on the organization of biological systems. ArrayXPath (http://www.snubi.org/software/ArrayXPath/) is a web-based service for mapping and visualizing microarray gene-expression data for integrated biological pathway resources using Scalable Vector Graphics (SVG). By integrating major bio-databases and searching pathway resources, ArrayXPath automatically maps different types of identifiers from microarray probes and pathway elements. When one inputs gene-expression clusters, ArrayXPath produces a list of the best matching pathways for each cluster. We applied Fisher's exact test and the false discovery rate (FDR) to evaluate the statistical significance of the association between a cluster and a pathway while correcting the multiple-comparison problem. ArrayXPath produces Javascript-enabled SVGs for web-enabled interactive visualization of pathways integrated with gene-expression profiles.

  5. Escher: A Web Application for Building, Sharing, and Embedding Data-Rich Visualizations of Biological Pathways.

    Directory of Open Access Journals (Sweden)

    Zachary A King

    2015-08-01

    Full Text Available Escher is a web application for visualizing data on biological pathways. Three key features make Escher a uniquely effective tool for pathway visualization. First, users can rapidly design new pathway maps. Escher provides pathway suggestions based on user data and genome-scale models, so users can draw pathways in a semi-automated way. Second, users can visualize data related to genes or proteins on the associated reactions and pathways, using rules that define which enzymes catalyze each reaction. Thus, users can identify trends in common genomic data types (e.g. RNA-Seq, proteomics, ChIP--in conjunction with metabolite- and reaction-oriented data types (e.g. metabolomics, fluxomics. Third, Escher harnesses the strengths of web technologies (SVG, D3, developer tools so that visualizations can be rapidly adapted, extended, shared, and embedded. This paper provides examples of each of these features and explains how the development approach used for Escher can be used to guide the development of future visualization tools.

  6. Escher: A Web Application for Building, Sharing, and Embedding Data-Rich Visualizations of Biological Pathways.

    Science.gov (United States)

    King, Zachary A; Dräger, Andreas; Ebrahim, Ali; Sonnenschein, Nikolaus; Lewis, Nathan E; Palsson, Bernhard O

    2015-08-01

    Escher is a web application for visualizing data on biological pathways. Three key features make Escher a uniquely effective tool for pathway visualization. First, users can rapidly design new pathway maps. Escher provides pathway suggestions based on user data and genome-scale models, so users can draw pathways in a semi-automated way. Second, users can visualize data related to genes or proteins on the associated reactions and pathways, using rules that define which enzymes catalyze each reaction. Thus, users can identify trends in common genomic data types (e.g. RNA-Seq, proteomics, ChIP)--in conjunction with metabolite- and reaction-oriented data types (e.g. metabolomics, fluxomics). Third, Escher harnesses the strengths of web technologies (SVG, D3, developer tools) so that visualizations can be rapidly adapted, extended, shared, and embedded. This paper provides examples of each of these features and explains how the development approach used for Escher can be used to guide the development of future visualization tools.

  7. [Research advances in gene polymorphisms in biological pathways of drugs for asthma].

    Science.gov (United States)

    Guo, Dan-Dan; Zheng, Xiang-Rong

    2016-06-01

    The studies on gene polymorphisms in biological pathways of the drugs for the treatment of asthma refer to the studies in which pharmacogenetic methods, such as genome-wide association studies, candidate gene studies, genome sequencing, admixture mapping analysis, and linkage disequilibrium, are used to identify, determine, and repeatedly validate the effect of one or more single nucleotide polymorphisms on the efficacy of drugs. This can provide therapeutic strategies with optimal benefits, least side effects, and lowest costs to patients with asthma, and thus realize individualized medicine. The common drugs for asthma are β2 receptor agonists, glucocorticoids, and leukotriene modifiers. This article reviews the research achievements in polymorphisms in biological pathways of the common drugs for asthma, hoping to provide guidance for pharmacogenetic studies on asthma in future and realize individualized medicine for patients with asthma soon.

  8. Effective identification of conserved pathways in biological networks using hidden Markov models.

    Directory of Open Access Journals (Sweden)

    Xiaoning Qian

    Full Text Available BACKGROUND: The advent of various high-throughput experimental techniques for measuring molecular interactions has enabled the systematic study of biological interactions on a global scale. Since biological processes are carried out by elaborate collaborations of numerous molecules that give rise to a complex network of molecular interactions, comparative analysis of these biological networks can bring important insights into the functional organization and regulatory mechanisms of biological systems. METHODOLOGY/PRINCIPAL FINDINGS: In this paper, we present an effective framework for identifying common interaction patterns in the biological networks of different organisms based on hidden Markov models (HMMs. Given two or more networks, our method efficiently finds the top matching paths in the respective networks, where the matching paths may contain a flexible number of consecutive insertions and deletions. CONCLUSIONS/SIGNIFICANCE: Based on several protein-protein interaction (PPI networks obtained from the Database of Interacting Proteins (DIP and other public databases, we demonstrate that our method is able to detect biologically significant pathways that are conserved across different organisms. Our algorithm has a polynomial complexity that grows linearly with the size of the aligned paths. This enables the search for very long paths with more than 10 nodes within a few minutes on a desktop computer. The software program that implements this algorithm is available upon request from the authors.

  9. Seeking unique and common biological themes in multiple gene lists or datasets: pathway pattern extraction pipeline for pathway-level comparative analysis

    Directory of Open Access Journals (Sweden)

    Che Anney

    2009-06-01

    Full Text Available Abstract Background One of the challenges in the analysis of microarray data is to integrate and compare the selected (e.g., differential gene lists from multiple experiments for common or unique underlying biological themes. A common way to approach this problem is to extract common genes from these gene lists and then subject these genes to enrichment analysis to reveal the underlying biology. However, the capacity of this approach is largely restricted by the limited number of common genes shared by datasets from multiple experiments, which could be caused by the complexity of the biological system itself. Results We now introduce a new Pathway Pattern Extraction Pipeline (PPEP, which extends the existing WPS application by providing a new pathway-level comparative analysis scheme. To facilitate comparing and correlating results from different studies and sources, PPEP contains new interfaces that allow evaluation of the pathway-level enrichment patterns across multiple gene lists. As an exploratory tool, this analysis pipeline may help reveal the underlying biological themes at both the pathway and gene levels. The analysis scheme provided by PPEP begins with multiple gene lists, which may be derived from different studies in terms of the biological contexts, applied technologies, or methodologies. These lists are then subjected to pathway-level comparative analysis for extraction of pathway-level patterns. This analysis pipeline helps to explore the commonality or uniqueness of these lists at the level of pathways or biological processes from different but relevant biological systems using a combination of statistical enrichment measurements, pathway-level pattern extraction, and graphical display of the relationships of genes and their associated pathways as Gene-Term Association Networks (GTANs within the WPS platform. As a proof of concept, we have used the new method to analyze many datasets from our collaborators as well as some public

  10. Gene-based GWAS and biological pathway analysis of the resilience of executive functioning.

    Science.gov (United States)

    Mukherjee, Shubhabrata; Kim, Sungeun; Ramanan, Vijay K; Gibbons, Laura E; Nho, Kwangsik; Glymour, M Maria; Ertekin-Taner, Nilüfer; Montine, Thomas J; Saykin, Andrew J; Crane, Paul K

    2014-03-01

    Resilience in executive functioning (EF) is characterized by high EF measured by neuropsychological test performance despite structural brain damage from neurodegenerative conditions. We previously reported single nucleotide polymorphism (SNP) genome-wide association study (GWAS) results for EF resilience. Here, we report gene- and pathway-based analyses of the same resilience phenotype, using an optimal SNP-set (Sequence) Kernel Association Test (SKAT) for gene-based analyses (conservative threshold for genome-wide significance = 0.05/18,123 = 2.8 × 10(-6)) and the gene-set enrichment package GSA-SNP for biological pathway analyses (False discovery rate (FDR) resilience (p = 1.33 × 10(-7)). Genetic pathways involved with dendritic/neuron spine, presynaptic membrane, postsynaptic density, etc., were enriched with association to EF resilience. Although replication of these results is necessary, our findings indicate the potential value of gene- and pathway-based analyses in research on determinants of cognitive resilience.

  11. Nitrification-denitrification via nitrite pathway in biological treatment of hypersaline wastewater

    Institute of Scientific and Technical Information of China (English)

    ZHU Gui-Bing; PENG Yong-Zhen; MENG Xiang-Sheng; YU De-shuang

    2008-01-01

    Pilot-scale studies on biological treatment of hypersaline wastewater at low temperature were conduc-ted and results showed that seawater salinity had a strong negative effect on notronomonas and nitrobacter growth, but much more on the nitrobacter. The nitrification action was mainly accomplished by nitrosomonas. Bench-scale experiments using two SBRs were carried out for further investigation under different conditions of salinities, ammonia loadings and temperatures. Biological nitrogen removal via nitrite pathway from wastewater containing 30 percent seawater was achieved, but the ammonia removal efficiency was strongly related not only to the influent ammonia loading at different salinities but also to temperatures. When the ratio of seawater to wastewater was 30 percent, and the ammonia loading was below the critical value of 0. 15 kgNH4+-N/( kgMLSS and 20℃ when the influent ammonia concentration was 60-80 mg/L and pH was 7.5-8.0.

  12. Pathways to Aging: The Mitochondrion at the Intersection of Biological and Psychosocial Sciences

    Directory of Open Access Journals (Sweden)

    Martin Picard

    2011-01-01

    Full Text Available Compelling evidence suggests that both biological and psychosocial factors impact the process of aging. However, our understanding of the dynamic interplay among biological and psychosocial factors across the life course is still fragmentary. For example, it needs to be established how the interaction of individual factors (e.g., genetic and epigenetic endowment and personality, behavioral factors (e.g., physical activity, diet, and stress management, and psychosocial experiences (e.g., social support, well-being, socioeconomic status, and marriage in perinatal, childhood, and adulthood influence health across the aging continuum. This paper aims to outline potential intersection points serving as an interface between biological and psychosocial factors, with an emphasis on the mitochondrion. Mitochondria are cellular organelles which play a critical role in cellular senescence. Both chronic exposure to psychosocial stress and genetic-based mitochondrial dysfunction have strikingly similar biological consequences; both predispose individuals to adverse age-related health disorders and early mortality. Exploring the interactive nature of the factors resulting in pathways to normal healthy aging, as well as those leading to morbidity and early mortality, will continue to enhance our ability to translate research into effective practices that can be implemented throughout the life course to optimise the aging process.

  13. A retrosynthetic biology approach to metabolic pathway design for therapeutic production

    Directory of Open Access Journals (Sweden)

    Faulon Jean-Loup

    2011-08-01

    Full Text Available Abstract Background Synthetic biology is used to develop cell factories for production of chemicals by constructively importing heterologous pathways into industrial microorganisms. In this work we present a retrosynthetic approach to the production of therapeutics with the goal of developing an in situ drug delivery device in host cells. Retrosynthesis, a concept originally proposed for synthetic chemistry, iteratively applies reversed chemical transformations (reversed enzyme-catalyzed reactions in the metabolic space starting from a target product to reach precursors that are endogenous to the chassis. So far, a wider adoption of retrosynthesis into the manufacturing pipeline has been hindered by the complexity of enumerating all feasible biosynthetic pathways for a given compound. Results In our method, we efficiently address the complexity problem by coding substrates, products and reactions into molecular signatures. Metabolic maps are represented using hypergraphs and the complexity is controlled by varying the specificity of the molecular signature. Furthermore, our method enables candidate pathways to be ranked to determine which ones are best to engineer. The proposed ranking function can integrate data from different sources such as host compatibility for inserted genes, the estimation of steady-state fluxes from the genome-wide reconstruction of the organism's metabolism, or the estimation of metabolite toxicity from experimental assays. We use several machine-learning tools in order to estimate enzyme activity and reaction efficiency at each step of the identified pathways. Examples of production in bacteria and yeast for two antibiotics and for one antitumor agent, as well as for several essential metabolites are outlined. Conclusions We present here a unified framework that integrates diverse techniques involved in the design of heterologous biosynthetic pathways through a retrosynthetic approach in the reaction signature space

  14. Genome-wide association and biological pathway analysis for milk-fat composition in Danish Holstein and Danish Jersey cattle

    DEFF Research Database (Denmark)

    Buitenhuis, Bart; Janss, Luc L G; Poulsen, Nina Aagaard;

    2014-01-01

    The milk fat profile of the Danish Holstein (DH) and Danish Jersey (DJ) show clear differences. Identification of the genomic regions, genes and biological pathways underlying the milk fat biosynthesis will improve the understanding of the biology underlying bovine milk fat production and may...... provide new possibilities to change the milk fat composition by selective breeding. In this study a genome wide association scan (GWAS) in the DH and DJ was performed for a detailed milk fatty acid (FA) profile using the HD bovine SNP array and subsequently a biological pathway analysis based on the SNP...

  15. Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1--molecular pathways.

    Science.gov (United States)

    Cakir, Mehtap; Dworakowska, Dorota; Grossman, Ashley

    2010-11-01

    Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs encompass phaeochromocytomas and paragangliomas, medullary thyroid carcinoma, anterior pituitary tumour, broncho-pulmonary NETs and parathyroid tumours. Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1-5) whose ligand SST is known to inhibit endocrine and exocrine secretions and have anti-tumour effects. In the light of this knowledge, the idea of using SST analogues in the treatment of NETs has become increasingly popular and new studies have centred upon the development of new SST analogues. We attempt to review SST receptor (SSTR) biology primarily in neuroendocrine tissues, focusing on pituitary tumours. A full data search was performed through PubMed over the years 2000-2009 with keywords 'somatostatin, molecular biology, somatostatin receptors, somatostatin signalling, NET, pituitary' and all relevant publications have been included, together with selected publications prior to that date. SSTR signalling in non-neuroendocrine solid tumours is beyond the scope of this review. SST is a potent anti-proliferative and anti-secretory agent for some NETs. The successful therapeutic use of SST analogues in the treatment of these tumours depends on a thorough understanding of the diverse effects of SSTR subtypes in different tissues and cell types. Further studies will focus on critical points of SSTR biology such as homo- and heterodimerization of SSTRs and the differences between post-receptor signalling pathways of SSTR subtypes.

  16. Proteomic dissection of biological pathways/processes through profiling protein-protein interaction networks

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Cellular functions, either under the normal or pathological conditions or under different stresses, are the results of the coordinated action of multiple proteins interacting in macromolecular complexes or assemblies. The precise determination of the specific composition of protein complexes, especially using scalable and high-throughput methods, represents a systematic approach toward revealing particular cellular biological functions. In this regard, the direct profiling protein-protein interactions (PPIs) represent an efficient way to dissect functional pathways for revealing novel protein functions. In this review, we illustrate the technological evolution for the large-scale and precise identification of PPIs toward higher physiologically relevant accuracy. These techniques aim at improving the efficiency of complex pull-down, the signal specificity and accuracy in distinguishing specific PPIs, and the accuracy of identifying physiological relevant PPIs. A newly developed streamline proteomic approach for mapping the binary relationship of PPIs in a protein complex is introduced.

  17. Molecular Signaling Pathways Behind the Biological Effects of Salvia Species Diterpenes in Neuropharmacology and Cardiology.

    Science.gov (United States)

    Akaberi, M; Iranshahi, M; Mehri, S

    2016-06-01

    The genus Salvia, from the Lamiaceae family, has diverse biological properties that are primarily attributable to their diterpene contents. There is no comprehensive review on the molecular signaling pathways of these active components. In this review, we investigated the molecular targets of bioactive Salvia diterpenes responsible for the treatment of nervous and cardiovascular diseases. The effects on different pathways, including apoptosis signaling, oxidative stress phenomena, the accumulation of amyloid beta plaques, and tau phosphorylation, have all been considered to be mechanisms of the anti-Alzheimer properties of Salvia diterpenes. Additionally, effects on the benzodiazepine and kappa opioid receptors and neuroprotective effects are noted as neuropharmacological properties of Salvia diterpenes, including tanshinone IIA, salvinorin A, cryptotanshinone, and miltirone. Tanshinone IIA, as the primary diterpene of Salvia miltiorrhiza, has beneficial activities in heart diseases because of its ability to scavenge free radicals and its effects on transcription factors, such as nuclear transcription factor-kappa B (NF-κB) and the mitogen-activated protein kinases (MAPKs). Additionally, tanshinone IIA has also been proposed to have cardioprotective properties including antiarrhythmic activities and effects on myocardial infarction. With respect to the potential therapeutic effects of Salvia diterpenes, comprehensive clinical trials are warranted to evaluate these valuable molecules as lead compounds. Copyright © 2016 John Wiley & Sons, Ltd.

  18. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

    Science.gov (United States)

    Pattaro, Cristian; Teumer, Alexander; Gorski, Mathias; Chu, Audrey Y; Li, Man; Mijatovic, Vladan; Garnaas, Maija; Tin, Adrienne; Sorice, Rossella; Li, Yong; Taliun, Daniel; Olden, Matthias; Foster, Meredith; Yang, Qiong; Chen, Ming-Huei; Pers, Tune H; Johnson, Andrew D; Ko, Yi-An; Fuchsberger, Christian; Tayo, Bamidele; Nalls, Michael; Feitosa, Mary F; Isaacs, Aaron; Dehghan, Abbas; d'Adamo, Pio; Adeyemo, Adebowale; Dieffenbach, Aida Karina; Zonderman, Alan B; Nolte, Ilja M; van der Most, Peter J; Wright, Alan F; Shuldiner, Alan R; Morrison, Alanna C; Hofman, Albert; Smith, Albert V; Dreisbach, Albert W; Franke, Andre; Uitterlinden, Andre G; Metspalu, Andres; Tonjes, Anke; Lupo, Antonio; Robino, Antonietta; Johansson, Åsa; Demirkan, Ayse; Kollerits, Barbara; Freedman, Barry I; Ponte, Belen; Oostra, Ben A; Paulweber, Bernhard; Krämer, Bernhard K; Mitchell, Braxton D; Buckley, Brendan M; Peralta, Carmen A; Hayward, Caroline; Helmer, Catherine; Rotimi, Charles N; Shaffer, Christian M; Müller, Christian; Sala, Cinzia; van Duijn, Cornelia M; Saint-Pierre, Aude; Ackermann, Daniel; Shriner, Daniel; Ruggiero, Daniela; Toniolo, Daniela; Lu, Yingchang; Cusi, Daniele; Czamara, Darina; Ellinghaus, David; Siscovick, David S; Ruderfer, Douglas; Gieger, Christian; Grallert, Harald; Rochtchina, Elena; Atkinson, Elizabeth J; Holliday, Elizabeth G; Boerwinkle, Eric; Salvi, Erika; Bottinger, Erwin P; Murgia, Federico; Rivadeneira, Fernando; Ernst, Florian; Kronenberg, Florian; Hu, Frank B; Navis, Gerjan J; Curhan, Gary C; Ehret, George B; Homuth, Georg; Coassin, Stefan; Thun, Gian-Andri; Pistis, Giorgio; Gambaro, Giovanni; Malerba, Giovanni; Montgomery, Grant W; Eiriksdottir, Gudny; Jacobs, Gunnar; Li, Guo; Wichmann, H-Erich; Campbell, Harry; Schmidt, Helena; Wallaschofski, Henri; Völzke, Henry; Brenner, Hermann; Kroemer, Heyo K; Kramer, Holly; Lin, Honghuang; Leach, I Mateo; Ford, Ian; Guessous, Idris; Rudan, Igor; Prokopenko, Inga; Borecki, Ingrid; Heid, Iris M; Kolcic, Ivana; Persico, Ivana; Jukema, J Wouter; Wilson, James F; Felix, Janine F; Divers, Jasmin; Lambert, Jean-Charles; Stafford, Jeanette M; Gaspoz, Jean-Michel; Smith, Jennifer A; Faul, Jessica D; Wang, Jie Jin; Ding, Jingzhong; Hirschhorn, Joel N; Attia, John; Whitfield, John B; Chalmers, John; Viikari, Jorma; Coresh, Josef; Denny, Joshua C; Karjalainen, Juha; Fernandes, Jyotika K; Endlich, Karlhans; Butterbach, Katja; Keene, Keith L; Lohman, Kurt; Portas, Laura; Launer, Lenore J; Lyytikäinen, Leo-Pekka; Yengo, Loic; Franke, Lude; Ferrucci, Luigi; Rose, Lynda M; Kedenko, Lyudmyla; Rao, Madhumathi; Struchalin, Maksim; Kleber, Marcus E; Cavalieri, Margherita; Haun, Margot; Cornelis, Marilyn C; Ciullo, Marina; Pirastu, Mario; de Andrade, Mariza; McEvoy, Mark A; Woodward, Mark; Adam, Martin; Cocca, Massimiliano; Nauck, Matthias; Imboden, Medea; Waldenberger, Melanie; Pruijm, Menno; Metzger, Marie; Stumvoll, Michael; Evans, Michele K; Sale, Michele M; Kähönen, Mika; Boban, Mladen; Bochud, Murielle; Rheinberger, Myriam; Verweij, Niek; Bouatia-Naji, Nabila; Martin, Nicholas G; Hastie, Nick; Probst-Hensch, Nicole; Soranzo, Nicole; Devuyst, Olivier; Raitakari, Olli; Gottesman, Omri; Franco, Oscar H; Polasek, Ozren; Gasparini, Paolo; Munroe, Patricia B; Ridker, Paul M; Mitchell, Paul; Muntner, Paul; Meisinger, Christa; Smit, Johannes H; Kovacs, Peter; Wild, Philipp S; Froguel, Philippe; Rettig, Rainer; Mägi, Reedik; Biffar, Reiner; Schmidt, Reinhold; Middelberg, Rita P S; Carroll, Robert J; Penninx, Brenda W; Scott, Rodney J; Katz, Ronit; Sedaghat, Sanaz; Wild, Sarah H; Kardia, Sharon L R; Ulivi, Sheila; Hwang, Shih-Jen; Enroth, Stefan; Kloiber, Stefan; Trompet, Stella; Stengel, Benedicte; Hancock, Stephen J; Turner, Stephen T; Rosas, Sylvia E; Stracke, Sylvia; Harris, Tamara B; Zeller, Tanja; Zemunik, Tatijana; Lehtimäki, Terho; Illig, Thomas; Aspelund, Thor; Nikopensius, Tiit; Esko, Tonu; Tanaka, Toshiko; Gyllensten, Ulf; Völker, Uwe; Emilsson, Valur; Vitart, Veronique; Aalto, Ville; Gudnason, Vilmundur; Chouraki, Vincent; Chen, Wei-Min; Igl, Wilmar; März, Winfried; Koenig, Wolfgang; Lieb, Wolfgang; Loos, Ruth J F; Liu, Yongmei; Snieder, Harold; Pramstaller, Peter P; Parsa, Afshin; O'Connell, Jeffrey R; Susztak, Katalin; Hamet, Pavel; Tremblay, Johanne; de Boer, Ian H; Böger, Carsten A; Goessling, Wolfram; Chasman, Daniel I; Köttgen, Anna; Kao, W H Linda; Fox, Caroline S

    2016-01-21

    Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

  19. Molecular Biological and Biochemical Studies Reveal New Pathways Important for Cotton Fiber Development

    Institute of Scientific and Technical Information of China (English)

    Yu Xu; Hong-Bin Li; Yu-Xian Zhu

    2007-01-01

    As one of the longest single-celled seed trichomes, fibers provide an excellent model for studying fundamental biological processes such as cell differentiation, cell expansion, and cell wall biosynthesis. In this review, we summarize recent progress in cotton functional genomic studies that characterize the dynamic changes in the transcriptomes of fiber cells. Extensive expression profilings of cotton fiber transcriptomes have provided comprehensive information, as quite a number of transcription factors and enzyme-coding genes have been shown to express preferentially during the fiber elongation period. Biosynthesis of the plant hormone ethylene is found significantly upregulated during the fiber growth period as revealed by both microarray analysis and by biochemical and physiological studies. It is suggested that genetic engineering of the ethylene pathway may improve the quality and the productivity of cotton lint. Many metabolic pathways, such as biosynthesis of celiulose and matrix polysaccharides are preferentially expressed in actively growing fiber cells. Five gene families, including proline-rich proteins (PRP), arabinogalactan proteins (AGP), expansins, tubulins and lipid transfer proteins (LTP) are activated during early fiber development,indicating that they may also be needed for cell elongation. In conclusion, we identify a few areas of future research for cotton functional genomic studies.

  20. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

    Science.gov (United States)

    Pattaro, Cristian; Teumer, Alexander; Gorski, Mathias; Chu, Audrey Y.; Li, Man; Mijatovic, Vladan; Garnaas, Maija; Tin, Adrienne; Sorice, Rossella; Li, Yong; Taliun, Daniel; Olden, Matthias; Foster, Meredith; Yang, Qiong; Chen, Ming-Huei; Pers, Tune H.; Johnson, Andrew D.; Ko, Yi-An; Fuchsberger, Christian; Tayo, Bamidele; Nalls, Michael; Feitosa, Mary F.; Isaacs, Aaron; Dehghan, Abbas; d'Adamo, Pio; Adeyemo, Adebowale; Dieffenbach, Aida Karina; Zonderman, Alan B.; Nolte, Ilja M.; van der Most, Peter J.; Wright, Alan F.; Shuldiner, Alan R.; Morrison, Alanna C.; Hofman, Albert; Smith, Albert V.; Dreisbach, Albert W.; Franke, Andre; Uitterlinden, Andre G.; Metspalu, Andres; Tonjes, Anke; Lupo, Antonio; Robino, Antonietta; Johansson, Åsa; Demirkan, Ayse; Kollerits, Barbara; Freedman, Barry I.; Ponte, Belen; Oostra, Ben A.; Paulweber, Bernhard; Krämer, Bernhard K.; Mitchell, Braxton D.; Buckley, Brendan M.; Peralta, Carmen A.; Hayward, Caroline; Helmer, Catherine; Rotimi, Charles N.; Shaffer, Christian M.; Müller, Christian; Sala, Cinzia; van Duijn, Cornelia M.; Saint-Pierre, Aude; Ackermann, Daniel; Shriner, Daniel; Ruggiero, Daniela; Toniolo, Daniela; Lu, Yingchang; Cusi, Daniele; Czamara, Darina; Ellinghaus, David; Siscovick, David S.; Ruderfer, Douglas; Gieger, Christian; Grallert, Harald; Rochtchina, Elena; Atkinson, Elizabeth J.; Holliday, Elizabeth G.; Boerwinkle, Eric; Salvi, Erika; Bottinger, Erwin P.; Murgia, Federico; Rivadeneira, Fernando; Ernst, Florian; Kronenberg, Florian; Hu, Frank B.; Navis, Gerjan J.; Curhan, Gary C.; Ehret, George B.; Homuth, Georg; Coassin, Stefan; Thun, Gian-Andri; Pistis, Giorgio; Gambaro, Giovanni; Malerba, Giovanni; Montgomery, Grant W.; Eiriksdottir, Gudny; Jacobs, Gunnar; Li, Guo; Wichmann, H-Erich; Campbell, Harry; Schmidt, Helena; Wallaschofski, Henri; Völzke, Henry; Brenner, Hermann; Kroemer, Heyo K.; Kramer, Holly; Lin, Honghuang; Leach, I. Mateo; Ford, Ian; Guessous, Idris; Rudan, Igor; Prokopenko, Inga; Borecki, Ingrid; Heid, Iris M.; Kolcic, Ivana; Persico, Ivana; Jukema, J. Wouter; Wilson, James F.; Felix, Janine F.; Divers, Jasmin; Lambert, Jean-Charles; Stafford, Jeanette M.; Gaspoz, Jean-Michel; Smith, Jennifer A.; Faul, Jessica D.; Wang, Jie Jin; Ding, Jingzhong; Hirschhorn, Joel N.; Attia, John; Whitfield, John B.; Chalmers, John; Viikari, Jorma; Coresh, Josef; Denny, Joshua C.; Karjalainen, Juha; Fernandes, Jyotika K.; Endlich, Karlhans; Butterbach, Katja; Keene, Keith L.; Lohman, Kurt; Portas, Laura; Launer, Lenore J.; Lyytikäinen, Leo-Pekka; Yengo, Loic; Franke, Lude; Ferrucci, Luigi; Rose, Lynda M.; Kedenko, Lyudmyla; Rao, Madhumathi; Struchalin, Maksim; Kleber, Marcus E.; Cavalieri, Margherita; Haun, Margot; Cornelis, Marilyn C.; Ciullo, Marina; Pirastu, Mario; de Andrade, Mariza; McEvoy, Mark A.; Woodward, Mark; Adam, Martin; Cocca, Massimiliano; Nauck, Matthias; Imboden, Medea; Waldenberger, Melanie; Pruijm, Menno; Metzger, Marie; Stumvoll, Michael; Evans, Michele K.; Sale, Michele M.; Kähönen, Mika; Boban, Mladen; Bochud, Murielle; Rheinberger, Myriam; Verweij, Niek; Bouatia-Naji, Nabila; Martin, Nicholas G.; Hastie, Nick; Probst-Hensch, Nicole; Soranzo, Nicole; Devuyst, Olivier; Raitakari, Olli; Gottesman, Omri; Franco, Oscar H.; Polasek, Ozren; Gasparini, Paolo; Munroe, Patricia B.; Ridker, Paul M.; Mitchell, Paul; Muntner, Paul; Meisinger, Christa; Smit, Johannes H.; Abecasis, Goncalo R.; Adair, Linda S.; Alexander, Myriam; Altshuler, David; Amin, Najaf; Arking, Dan E.; Arora, Pankaj; Aulchenko, Yurii; Bakker, Stephan J. L.; Bandinelli, Stefania; Barroso, Ines; Beckmann, Jacques S.; Beilby, John P.; Bergman, Richard N.; Bergmann, Sven; Bis, Joshua C.; Boehnke, Michael; Bonnycastle, Lori L.; Bornstein, Stefan R.; Bots, Michiel L.; Bragg-Gresham, Jennifer L.; Brand, Stefan-Martin; Brand, Eva; Braund, Peter S.; Brown, Morris J.; Burton, Paul R.; Casas, Juan P.; Caulfield, Mark J.; Chakravarti, Aravinda; Chambers, John C.; Chandak, Giriraj R.; Chang, Yen-Pei C.; Charchar, Fadi J.; Chaturvedi, Nish; Shin Cho, Yoon; Clarke, Robert; Collins, Francis S.; Collins, Rory; Connell, John M.; Cooper, Jackie A.; Cooper, Matthew N.; Cooper, Richard S.; Corsi, Anna Maria; Dörr, Marcus; Dahgam, Santosh; Danesh, John; Smith, George Davey; Day, Ian N. M.; Deloukas, Panos; Denniff, Matthew; Dominiczak, Anna F.; Dong, Yanbin; Doumatey, Ayo; Elliott, Paul; Elosua, Roberto; Erdmann, Jeanette; Eyheramendy, Susana; Farrall, Martin; Fava, Cristiano; Forrester, Terrence; Fowkes, F. Gerald R.; Fox, Ervin R.; Frayling, Timothy M.; Galan, Pilar

    2016-01-01

    Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. PMID:26831199

  1. Systems biology and brain activity in neuronal pathways by smart device and advanced signal processing

    Science.gov (United States)

    Castellani, Gastone; Intrator, Nathan; Remondini, Daniel

    2014-01-01

    Contemporary biomedicine is producing large amount of data, especially within the fields of “omic” sciences. Nevertheless, other fields, such as neuroscience, are producing similar amount of data by using non-invasive techniques such as imaging, functional magnetic resonance and electroencephalography. Nowadays a big challenge and a new research horizon for Systems Biology is to develop methods to integrate and model this data in an unifying framework capable to disentangle this amazing complexity. In this paper we show how methods from genomic data analysis can be applied to brain data. In particular the concept of pathways, networks and multiplex are discussed. These methods can lead to a clear distinction of various regimes of brain activity. Moreover, this method could be the basis for a Systems Biology analysis of brain data and for the integration of these data in a multivariate and multidimensional framework. The feasibility of this integration is strongly dependent from the feature extraction method used. In our case we used an “alphabet” derived from a multi-resolution analysis that is capable to capture the most relevant information from these complex signals. PMID:25206359

  2. Systems Biology and brain activity in neuronal pathways by smart device and advanced signal processing.

    Directory of Open Access Journals (Sweden)

    Gastone eCastellani

    2014-08-01

    Full Text Available Contemporary biomedicine is producing large amount of data, especially within the fields of omic sciences. Nevertheless, other fields, such as neuroscience, are producing similar amount of data by using non invasive techniques such as imaging, Functional Magnetic Resonance and Electroencephalography. Nowadays a big challenge and a new research horizon for Systems Biology is to develop methods to integrate and model this data in an unifying framework capable to disentangle this amazing complexity. In this paper we show how methods from genomic data analysis can be applied to brain data. In particular the concept of pathways, networks and multiplex are discussed. These methods can lead to a clear distinction of various regimes of brain activity. Moreover, this method could be the basis for a Systems Biology analysis of brain data and for the integration of these data in a multivariate and multidimensional framework. The feasibility of this integration is strongly dependent from the feature extraction method used. In our case we used an alphabet derived from a multi-resolution analysis that is capable to capture the most relevant information from these complex signals.

  3. A Systems Biology Analysis Unfolds the Molecular Pathways and Networks of Two Proteobacteria in Spaceflight and Simulated Microgravity Conditions

    Science.gov (United States)

    Roy, Raktim; Phani Shilpa, P.; Bagh, Sangram

    2016-09-01

    Bacteria are important organisms for space missions due to their increased pathogenesis in microgravity that poses risks to the health of astronauts and for projected synthetic biology applications at the space station. We understand little about the effect, at the molecular systems level, of microgravity on bacteria, despite their significant incidence. In this study, we proposed a systems biology pipeline and performed an analysis on published gene expression data sets from multiple seminal studies on Pseudomonas aeruginosa and Salmonella enterica serovar Typhimurium under spaceflight and simulated microgravity conditions. By applying gene set enrichment analysis on the global gene expression data, we directly identified a large number of new, statistically significant cellular and metabolic pathways involved in response to microgravity. Alteration of metabolic pathways in microgravity has rarely been reported before, whereas in this analysis metabolic pathways are prevalent. Several of those pathways were found to be common across studies and species, indicating a common cellular response in microgravity. We clustered genes based on their expression patterns using consensus non-negative matrix factorization. The genes from different mathematically stable clusters showed protein-protein association networks with distinct biological functions, suggesting the plausible functional or regulatory network motifs in response to microgravity. The newly identified pathways and networks showed connection with increased survival of pathogens within macrophages, virulence, and antibiotic resistance in microgravity. Our work establishes a systems biology pipeline and provides an integrated insight into the effect of microgravity at the molecular systems level.

  4. Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1 – molecular pathways

    Science.gov (United States)

    Cakir, Mehtap; Dworakowska, Dorota; Grossman, Ashley

    2010-01-01

    Abstract Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs encompass phaeochromocytomas and paragangliomas, medullary thyroid carcinoma, anterior pituitary tumour, broncho-pulmonary NETs and parathyroid tumours. Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1–5) whose ligand SST is known to inhibit endocrine and exocrine secretions and have anti-tumour effects. In the light of this knowledge, the idea of using SST analogues in the treatment of NETs has become increasingly popular and new studies have centred upon the development of new SST analogues. We attempt to review SST receptor (SSTR) biology primarily in neuroendocrine tissues, focusing on pituitary tumours. A full data search was performed through PubMed over the years 2000–2009 with keywords ‘somatostatin, molecular biology, somatostatin receptors, somatostatin signalling, NET, pituitary’ and all relevant publications have been included, together with selected publications prior to that date. SSTR signalling in non-neuroendocrine solid tumours is beyond the scope of this review. SST is a potent anti-proliferative and anti-secretory agent for some NETs. The successful therapeutic use of SST analogues in the treatment of these tumours depends on a thorough understanding of the diverse effects of SSTR subtypes in different tissues and cell types. Further studies will focus on critical points of SSTR biology such as homo- and heterodimerization of SSTRs and the differences between post-receptor signalling pathways of SSTR subtypes. PMID:20629989

  5. The plumbing of the global biological pump: Efficiency control through leaks, pathways, and time scales

    Science.gov (United States)

    Pasquier, Benoît; Holzer, Mark

    2016-08-01

    We systematically quantify the pathways and time scales that set the efficiency, Ebio, of the global biological pump by applying Green-function-based diagnostics to a data-assimilated phosphorus cycle embedded in a jointly assimilated ocean circulation. We consider "bio pipes" that consist of phosphorus paths that connect specified regions of last biological utilization with regions where regenerated phosphate first reemerges into the euphotic zone. The bio pipes that contribute most to Ebio connect the Eastern Equatorial Pacific (EEqP) and Equatorial Atlantic to the Southern Ocean ((21 ± 3)% of Ebio), as well as the Southern Ocean to itself ((15 ± 3)% of Ebio). The bio pipes with the largest phosphorus flow rates connect the EEqP to itself and the subantarctic Southern Ocean to itself. The global mean sequestration time of the biological pump is 130 ± 70 years, while the sequestration time of the bio pipe from anywhere to the Antarctic region of the Southern Ocean is 430 ± 30 years. The distribution of phosphorus flowing within a given bio pipe is quantified by its transit-time partitioned path density. For the largest bio pipes, ˜1/7 of their phosphorus is carried by thermocline paths with transit times less than ˜300-400 years, while ˜4/7 of their phosphorus is carried by abyssal paths with transit times exceeding ˜700 years. The path density reveals that Antarctic Intermediate Water carries about a third of the regenerated phosphate last utilized in the EEqP that is destined for the Southern Ocean euphotic zone. The Southern Ocean is where (62 ± 2)% of the regenerated inventory and (69 ± 1)% of the preformed inventory first reemerge into the euphotic zone.

  6. RANTES/CCL5 mediated-biological effects depend on the syndecan-4/PKCα signaling pathway

    Directory of Open Access Journals (Sweden)

    Loïc Maillard

    2014-09-01

    Full Text Available The perpetuation of angiogenesis is involved in certain chronic inflammatory diseases. The accelerated neovascularisation may result from an inflammatory status with a response of both endothelial cells and monocytes to inflammatory mediators such as chemokines. We have previously described in vitro and in vivo the pro-angiogenic effects of the chemokine Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES/CCL5. The effects of RANTES/CCL5 may be related to its binding to G protein-coupled receptors and to proteoglycans such as syndecan-1 and -4. The aim of this study was to evaluate the functionality of syndecan-4 as a co-receptor of RANTES/CCL5 by the use of mutated syndecan-4 constructs. Our data demonstrate that site-directed mutations in syndecan-4 modify RANTES/CCL5 biological activities in endothelial cells. The SDC4S179A mutant, associated with an induced protein kinase C (PKCα activation, leads to higher RANTES/CCL5 pro-angiogenic effects, whereas the SDC4L188QQ and the SDC4A198del mutants, leading to lower phosphatidylinositol 4,5-bisphosphate (PIP2 binding or to lower PDZ protein binding respectively, are associated with reduced RANTES/CCL5 cellular effects. Moreover, our data highlight that the intracellular domain of SDC-4 is involved in RANTES/CCL5-induced activation of the PKCα signaling pathway and biological effect. As RANTES/CCL5 is involved in various physiopathological processes, the development of a new therapeutic strategy may be reliant on the mechanism by which RANTES/CCL5 exerts its biological activities, for example by targeting the binding of the chemokine to its proteoglycan receptor.

  7. Perturbation Detection Through Modeling of Gene Expression on a Latent Biological Pathway Network: A Bayesian hierarchical approach.

    Science.gov (United States)

    Pham, Lisa M; Carvalho, Luis; Schaus, Scott; Kolaczyk, Eric D

    Cellular response to a perturbation is the result of a dynamic system of biological variables linked in a complex network. A major challenge in drug and disease studies is identifying the key factors of a biological network that are essential in determining the cell's fate. Here our goal is the identification of perturbed pathways from high-throughput gene expression data. We develop a three-level hierarchical model, where (i) the first level captures the relationship between gene expression and biological pathways using confirmatory factor analysis, (ii) the second level models the behavior within an underlying network of pathways induced by an unknown perturbation using a conditional autoregressive model, and (iii) the third level is a spike-and-slab prior on the perturbations. We then identify perturbations through posterior-based variable selection. We illustrate our approach using gene transcription drug perturbation profiles from the DREAM7 drug sensitivity predication challenge data set. Our proposed method identified regulatory pathways that are known to play a causative role and that were not readily resolved using gene set enrichment analysis or exploratory factor models. Simulation results are presented assessing the performance of this model relative to a network-free variant and its robustness to inaccuracies in biological databases.

  8. Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFα inhibitors in patients with rheumatoid arthritis

    DEFF Research Database (Denmark)

    Krintel, Sophine B; Palermo, Giuseppe; Johansen, Julia S;

    2012-01-01

    Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs...... and the possible biological pathways associated with the treatment response to TNFα inhibitors....

  9. Carbon Nanotube Degradation in Macrophages: Live Nanoscale Monitoring and Understanding of Biological Pathway.

    Science.gov (United States)

    Elgrabli, Dan; Dachraoui, Walid; Ménard-Moyon, Cécilia; Liu, Xiao Jie; Bégin, Dominique; Bégin-Colin, Sylvie; Bianco, Alberto; Gazeau, Florence; Alloyeau, Damien

    2015-10-27

    Despite numerous applications, the cellular-clearance mechanism of multiwalled carbon nanotubes (MWCNTs) has not been clearly established yet. Previous in vitro studies showed the ability of oxidative enzymes to induce nanotube degradation. Interestingly, these enzymes have the common capacity to produce reactive oxygen species (ROS). Here, we combined material and life science approaches for revealing an intracellular way taken by macrophages to degrade carbon nanotubes. We report the in situ monitoring of ROS-mediated MWCNT degradation by liquid-cell transmission electron microscopy. Two degradation mechanisms induced by hydroxyl radicals were extracted from these unseen dynamic nanoscale investigations: a non-site-specific thinning process of the walls and a site-specific transversal drilling process on pre-existing defects of nanotubes. Remarkably, similar ROS-induced structural injuries were observed on MWCNTs after aging into macrophages from 1 to 7 days. Beside unraveling oxidative transformations of MWCNT structure, we elucidated an important, albeit not exclusive, biological pathway for MWCNT degradation in macrophages, involving NOX2 complex activation, superoxide production, and hydroxyl radical attack, which highlights the critical role of oxidative stress in cellular processing of MWCNTs.

  10. Endocannabinoid system as a regulator of tumor cell malignancy – biological pathways and clinical significance

    Science.gov (United States)

    Pyszniak, Maria; Tabarkiewicz, Jacek; Łuszczki, Jarogniew J

    2016-01-01

    The endocannabinoid system (ECS) comprises cannabinoid receptors (CBs), endogenous cannabinoids, and enzymes responsible for their synthesis, transport, and degradation of (endo)cannabinoids. To date, two CBs, CB1 and CB2, have been characterized; however, orphan G-protein-coupled receptor GPR55 has been suggested to be the third putative CB. Several different types of cancer present abnormal expression of CBs, as well as other components of ECS, and this has been shown to correlate with the clinical outcome. Although most effects of (endo)cannabinoids are mediated through stimulation of classical CBs, they also interact with several molecules, either prosurvival or proapoptotic molecules. It should be noted that the mode of action of exogenous cannabinoids differs significantly from that of endocannabinoid and results from the studies on their activity both in vivo and in vitro could not be easily compared. This review highlights the main signaling pathways involved in the antitumor activity of cannabinoids and the influence of their activation on cancer cell biology. We also discuss changes in the expression pattern of the ECS in various cancer types that have an impact on disease progression and patient survival. A growing amount of experimental data imply possible exploitation of cannabinoids in cancer therapy. PMID:27486335

  11. Mechanistic pathways and biological roles for receptor-independent activators of G-protein signaling.

    Science.gov (United States)

    Blumer, Joe B; Smrcka, Alan V; Lanier, Stephen M

    2007-03-01

    Signal processing via heterotrimeric G-proteins in response to cell surface receptors is a central and much investigated aspect of how cells integrate cellular stimuli to produce coordinated biological responses. The system is a target of numerous therapeutic agents and plays an important role in adaptive processes of organs; aberrant processing of signals through these transducing systems is a component of various disease states. In addition to G-protein coupled receptor (GPCR)-mediated activation of G-protein signaling, nature has evolved creative ways to manipulate and utilize the Galphabetagamma heterotrimer or Galpha and Gbetagamma subunits independent of the cell surface receptor stimuli. In such situations, the G-protein subunits (Galpha and Gbetagamma) may actually be complexed with alternative binding partners independent of the typical heterotrimeric Galphabetagamma. Such regulatory accessory proteins include the family of regulator of G-protein signaling (RGS) proteins that accelerate the GTPase activity of Galpha and various entities that influence nucleotide binding properties and/or subunit interaction. The latter group of proteins includes receptor-independent activators of G-protein signaling (AGS) proteins that play surprising roles in signal processing. This review provides an overview of our current knowledge regarding AGS proteins. AGS proteins are indicative of a growing number of accessory proteins that influence signal propagation, facilitate cross talk between various types of signaling pathways, and provide a platform for diverse functions of both the heterotrimeric Galphabetagamma and the individual Galpha and Gbetagamma subunits.

  12. Extensive cargo identification reveals distinct biological roles of the 12 importin pathways

    Science.gov (United States)

    Kimura, Makoto; Morinaka, Yuriko; Imai, Kenichiro; Kose, Shingo; Horton, Paul; Imamoto, Naoko

    2017-01-01

    Vast numbers of proteins are transported into and out of the nuclei by approximately 20 species of importin-β family nucleocytoplasmic transport receptors. However, the significance of the multiple parallel transport pathways that the receptors constitute is poorly understood because only limited numbers of cargo proteins have been reported. Here, we identified cargo proteins specific to the 12 species of human import receptors with a high-throughput method that employs stable isotope labeling with amino acids in cell culture, an in vitro reconstituted transport system, and quantitative mass spectrometry. The identified cargoes illuminated the manner of cargo allocation to the receptors. The redundancies of the receptors vary widely depending on the cargo protein. Cargoes of the same receptor are functionally related to one another, and the predominant protein groups in the cargo cohorts differ among the receptors. Thus, the receptors are linked to distinct biological processes by the nature of their cargoes. DOI: http://dx.doi.org/10.7554/eLife.21184.001 PMID:28117667

  13. Genes influencing milk production traits predominantly affect one of four biological pathways

    Directory of Open Access Journals (Sweden)

    Goddard Michael

    2008-01-01

    Full Text Available Abstract In this study we introduce a method that accounts for false positive and false negative results in attempting to estimate the true proportion of quantitative trait loci that affect two different traits. This method was applied to data from a genome scan that was used to detect QTL for three independent milk production traits, Australian Selection Index (ASI, protein percentage (P% and fat percentage corrected for protein percentage (F% – P%. These four different scenarios are attributed to four biological pathways: QTL that (1 increase or decrease total mammary gland production (affecting ASI only; (2 increase or decrease lactose synthesis resulting in the volume of milk being changed but without a change in protein or fat yield (affecting P% only; (3 increase or decrease protein synthesis while milk volume remains relatively constant (affecting ASI and P% in the same direction; (4 increase or decrease fat synthesis while the volume of milk remains relatively constant (affecting F% – P% only. The results indicate that of the positions that detected a gene, most affected one trait and not the others, though a small proportion (2.8% affected ASI and P% in the same direction.

  14. Exposure pathways and biological receptors: baseline data for the canyon uranium mine, Coconino County, Arizona

    Science.gov (United States)

    Hinck, Jo E.; Linder, Greg L.; Darrah, Abigail J.; Drost, Charles A.; Duniway, Michael C.; Johnson, Matthew J.; Méndez-Harclerode, Francisca M.; Nowak, Erika M.; Valdez, Ernest W.; Van Riper, Charles; Wolff, S.W.

    2014-01-01

    Recent restrictions on uranium mining within the Grand Canyon watershed have drawn attention to scientific data gaps in evaluating the possible effects of ore extraction to human populations as well as wildlife communities in the area. Tissue contaminant concentrations, one of the most basic data requirements to determine exposure, are not available for biota from any historical or active uranium mines in the region. The Canyon Uranium Mine is under development, providing a unique opportunity to characterize concentrations of uranium and other trace elements, as well as radiation levels in biota, found in the vicinity of the mine before ore extraction begins. Our study objectives were to identify contaminants of potential concern and critical contaminant exposure pathways for ecological receptors; conduct biological surveys to understand the local food web and refine the list of target species (ecological receptors) for contaminant analysis; and collect target species for contaminant analysis prior to the initiation of active mining. Contaminants of potential concern were identified as arsenic, cadmium, chromium, copper, lead, mercury, nickel, selenium, thallium, uranium, and zinc for chemical toxicity and uranium and associated radionuclides for radiation. The conceptual exposure model identified ingestion, inhalation, absorption, and dietary transfer (bioaccumulation or bioconcentration) as critical contaminant exposure pathways. The biological survey of plants, invertebrates, amphibians, reptiles, birds, and small mammals is the first to document and provide ecological information on .200 species in and around the mine site; this study also provides critical baseline information about the local food web. Most of the species documented at the mine are common to ponderosa pine Pinus ponderosa and pinyon–juniper Pinus–Juniperus spp. forests in northern Arizona and are not considered to have special conservation status by state or federal agencies; exceptions

  15. In-situ time resolved studies of apatite formation pathways - implications for biological and environmental systems

    Science.gov (United States)

    Borkiewicz, O.; Rakovan, J.; Cahill, C. L.

    2006-05-01

    The mineral apatite, Ca5(PO4)3(F,OH,Cl), is of great significance in a variety of fields including life and environmental sciences. Apatite is the main constituent of almost all hard tissues of human body and plays major role in the metabolic processes. Recently, it has gained a considerable amount of attention as a promising candidate for the use in the in-situ metal sequestration of metal ions for environmental remediation, sometimes called phosphate induced metal stabilization (PIMS). We report preliminary results of in-situ time resolved X-ray diffraction studies of apatite formation pathways from aqueous solutions, performed at the X7B beamline of the National Synchrotron Light Source at Brookhaven National Laboratory, Upton, NY. A series of experiments with different Ca/P and liquid/solid ratios in the starting material, and range of temperatures were performed. In the first stage of the experiment, calcium acetate and ammonium phosphate solutions are mixed at room temperature, resulting in the formation of an initial precipitate. The solution is then press-filtered and the remaining slurry, of the desired liquid/solid ratio, is placed inside a heating cell and analyzed within 10 min. of the initial precipitation. The initial precipitate was identified as brushite (CaHPO4 - 2H2O) in all experiments, independent of the initial Ca/P ratio in solution). In the experiment conducted at ambient temperature brushite was the only phase present in the solution/slurry throughout the duration of the analysis. Under the conditions of elevated temperature, however, a sequence of phase transitions, from brushite to apatite with intermediate monetite (CaHPO4) was observed. The pathway of the transitions and the final product was independent of both the Ca/P ratio and the temperature of the reaction. The rate of the transformation, however, increased with increasing temperature. Numerous studies of apatite formation from solution using standard X-ray diffraction experiments

  16. KeyPathwayMiner - De-novo network enrichment by combining multiple OMICS data and biological networks

    DEFF Research Database (Denmark)

    Baumbach, Jan; Alcaraz, Nicolas; Pauling, Josch K.

    We tackle the problem of de-novo pathway extraction. Given a biological network and a set of case-control studies, KeyPathwayMiner efficiently extracts and visualizes all maximal connected sub-networks that contain mainly genes that are dysregulated, e.g., differentially expressed, in most cases...... studied. The exact quantities for ``mainly'' and ``most'' are modeled with two easy-to-interpret parameters that allow the user to control the number of outliers (not dysregulated genes/cases) in the solutions. We developed two slightly varying models that fall into the class of NP-Hard optimization...

  17. Endocannabinoid system as a regulator of tumor cell malignancy – biological pathways and clinical significance

    Directory of Open Access Journals (Sweden)

    Pyszniak M

    2016-07-01

    Full Text Available Maria Pyszniak,1–3 Jacek Tabarkiewicz,1,2 Jarogniew J Łuszczki4,5 1Centre for Innovative Research in Medical and Natural Sciences, Faculty of Medicine, 2Department of Immunology, Faculty of Medicine, University of Rzeszów, Rzeszów, 3Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warszawa, 4Department of Pathophysiology, Medical University of Lublin, 5Isobolographic Analysis Laboratory, Institute of Agricultural Medicine, Lublin, Poland Abstract: The endocannabinoid system (ECS comprises cannabinoid receptors (CBs, endogenous cannabinoids, and enzymes responsible for their synthesis, transport, and degradation of (endocannabinoids. To date, two CBs, CB1 and CB2, have been characterized; however, orphan G-protein-coupled receptor GPR55 has been suggested to be the third putative CB. Several different types of cancer present abnormal expression of CBs, as well as other components of ECS, and this has been shown to correlate with the clinical outcome. Although most effects of (endocannabinoids are mediated through stimulation of classical CBs, they also interact with several molecules, either prosurvival or proapoptotic molecules. It should be noted that the mode of action of exogenous cannabinoids differs significantly from that of endocannabinoid and results from the studies on their activity both in vivo and in vitro could not be easily compared. This review highlights the main signaling pathways involved in the antitumor activity of cannabinoids and the influence of their activation on cancer cell biology. We also discuss changes in the expression pattern of the ECS in various cancer types that have an impact on disease progression and patient survival. A growing amount of experimental data imply possible exploitation of cannabinoids in cancer therapy. Keywords: cannabinoids, cancer, cell signaling, cannabinoid receptor, delta-9-tetrahy­drocannabinol

  18. Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations.

    Science.gov (United States)

    Louissaint, Abner; Schafernak, Kristian T; Geyer, Julia T; Kovach, Alexandra E; Ghandi, Mahmoud; Gratzinger, Dita; Roth, Christine G; Paxton, Christian N; Kim, Sunhee; Namgyal, Chungdak; Morin, Ryan; Morgan, Elizabeth A; Neuberg, Donna S; South, Sarah T; Harris, Marian H; Hasserjian, Robert P; Hochberg, Ephraim P; Garraway, Levi A; Harris, Nancy Lee; Weinstock, David M

    2016-08-25

    Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy number analysis and exome and/or targeted sequencing of 26 PTNFLs (16 pediatric and 10 adult). The most commonly mutated gene in PTNFL was MAP2K1, encoding MEK1, with a mutation frequency of 43%. All MAP2K1 mutations were activating missense mutations localized to exons 2 and 3, which encode negative regulatory and catalytic domains, respectively. Missense mutations in MAPK1 (2/22) and RRAS (1/22) were identified in cases that lacked MAP2K1 mutations. The second most commonly mutated gene in PTNFL was TNFRSF14, with a mutation frequency of 29%, similar to that seen in limited-stage typical FL (P = .35). PTNFL was otherwise genomically bland and specifically lacked recurrent mutations in epigenetic modifiers (eg, CREBBP, KMT2D). Copy number aberrations affected a mean of only 0.5% of PTNFL genomes, compared with 10% of limited-stage typical FL genomes (P < .02). Importantly, the mutational profiles of PTNFLs in children and adults were highly similar. Together, these findings define PTNFL as a biologically and clinically distinct indolent lymphoma of children and adults characterized by a high prevalence of MAPK pathway mutations and a near absence of mutations in epigenetic modifiers.

  19. A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle.

    Directory of Open Access Journals (Sweden)

    Reijo Laaksonen

    Full Text Available BACKGROUND: Aggressive lipid lowering with high doses of statins increases the risk of statin-induced myopathy. However, the cellular mechanisms leading to muscle damage are not known and sensitive biomarkers are needed to identify patients at risk of developing statin-induced serious side effects. METHODOLOGY: We performed bioinformatics analysis of whole genome expression profiling of muscle specimens and UPLC/MS based lipidomics analyses of plasma samples obtained in an earlier randomized trial from patients either on high dose simvastatin (80 mg, atorvastatin (40 mg, or placebo. PRINCIPAL FINDINGS: High dose simvastatin treatment resulted in 111 differentially expressed genes (1.5-fold change and p-value<0.05, while expression of only one and five genes was altered in the placebo and atorvastatin groups, respectively. The Gene Set Enrichment Analysis identified several affected pathways (23 gene lists with False Discovery Rate q-value<0.1 in muscle following high dose simvastatin, including eicosanoid synthesis and Phospholipase C pathways. Using lipidomic analysis we identified previously uncharacterized drug-specific changes in the plasma lipid profile despite similar statin-induced changes in plasma LDL-cholesterol. We also found that the plasma lipidomic changes following simvastatin treatment correlate with the muscle expression of the arachidonate 5-lipoxygenase-activating protein. CONCLUSIONS: High dose simvastatin affects multiple metabolic and signaling pathways in skeletal muscle, including the pro-inflammatory pathways. Thus, our results demonstrate that clinically used high statin dosages may lead to unexpected metabolic effects in non-hepatic tissues. The lipidomic profiles may serve as highly sensitive biomarkers of statin-induced metabolic alterations in muscle and may thus allow us to identify patients who should be treated with a lower dose to prevent a possible toxicity.

  20. DMPD: Lysophospholipid receptors: signaling and biology. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15189145 Lysophospholipid receptors: signaling and biology. Ishii I, Fukushima N, Y...e X, Chun J. Annu Rev Biochem. 2004;73:321-54. (.png) (.svg) (.html) (.csml) Show Lysophospholipid receptors: signaling and biology.... PubmedID 15189145 Title Lysophospholipid receptors: signaling and biology. Authors

  1. DMPD: Type I interferon receptors: biochemistry and biological functions. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17502368 Type I interferon receptors: biochemistry and biological functions. de Wee...(.html) (.csml) Show Type I interferon receptors: biochemistry and biological functions. PubmedID 17502368 T...itle Type I interferon receptors: biochemistry and biological functions. Authors

  2. PathRings: a web-based tool for exploration of ortholog and expression data in biological pathways

    OpenAIRE

    2015-01-01

    Background High-throughput methods are generating biological data on a vast scale. In many instances, genomic, transcriptomic, and proteomic data must be interpreted in the context of signaling and metabolic pathways to yield testable hypotheses. Since humans can interpret visual information rapidly, a means for interactive visual exploration that lets biologists interpret such data in a comprehensive and exploratory manner would be invaluable. However, humans have limited memory capacity. Cu...

  3. A novel approach for discovering condition-specific correlations of gene expressions within biological pathways by using cloud computing technology.

    Science.gov (United States)

    Chang, Tzu-Hao; Wu, Shih-Lin; Wang, Wei-Jen; Horng, Jorng-Tzong; Chang, Cheng-Wei

    2014-01-01

    Microarrays are widely used to assess gene expressions. Most microarray studies focus primarily on identifying differential gene expressions between conditions (e.g., cancer versus normal cells), for discovering the major factors that cause diseases. Because previous studies have not identified the correlations of differential gene expression between conditions, crucial but abnormal regulations that cause diseases might have been disregarded. This paper proposes an approach for discovering the condition-specific correlations of gene expressions within biological pathways. Because analyzing gene expression correlations is time consuming, an Apache Hadoop cloud computing platform was implemented. Three microarray data sets of breast cancer were collected from the Gene Expression Omnibus, and pathway information from the Kyoto Encyclopedia of Genes and Genomes was applied for discovering meaningful biological correlations. The results showed that adopting the Hadoop platform considerably decreased the computation time. Several correlations of differential gene expressions were discovered between the relapse and nonrelapse breast cancer samples, and most of them were involved in cancer regulation and cancer-related pathways. The results showed that breast cancer recurrence might be highly associated with the abnormal regulations of these gene pairs, rather than with their individual expression levels. The proposed method was computationally efficient and reliable, and stable results were obtained when different data sets were used. The proposed method is effective in identifying meaningful biological regulation patterns between conditions.

  4. A Novel Approach for Discovering Condition-Specific Correlations of Gene Expressions within Biological Pathways by Using Cloud Computing Technology

    Directory of Open Access Journals (Sweden)

    Tzu-Hao Chang

    2014-01-01

    Full Text Available Microarrays are widely used to assess gene expressions. Most microarray studies focus primarily on identifying differential gene expressions between conditions (e.g., cancer versus normal cells, for discovering the major factors that cause diseases. Because previous studies have not identified the correlations of differential gene expression between conditions, crucial but abnormal regulations that cause diseases might have been disregarded. This paper proposes an approach for discovering the condition-specific correlations of gene expressions within biological pathways. Because analyzing gene expression correlations is time consuming, an Apache Hadoop cloud computing platform was implemented. Three microarray data sets of breast cancer were collected from the Gene Expression Omnibus, and pathway information from the Kyoto Encyclopedia of Genes and Genomes was applied for discovering meaningful biological correlations. The results showed that adopting the Hadoop platform considerably decreased the computation time. Several correlations of differential gene expressions were discovered between the relapse and nonrelapse breast cancer samples, and most of them were involved in cancer regulation and cancer-related pathways. The results showed that breast cancer recurrence might be highly associated with the abnormal regulations of these gene pairs, rather than with their individual expression levels. The proposed method was computationally efficient and reliable, and stable results were obtained when different data sets were used. The proposed method is effective in identifying meaningful biological regulation patterns between conditions.

  5. Process Simulation of Complex Biological Pathways in Physical Reactive Space and Reformulated for Massively Parallel Computing Platforms.

    Science.gov (United States)

    Ganesan, Narayan; Li, Jie; Sharma, Vishakha; Jiang, Hanyu; Compagnoni, Adriana

    2016-01-01

    Biological systems encompass complexity that far surpasses many artificial systems. Modeling and simulation of large and complex biochemical pathways is a computationally intensive challenge. Traditional tools, such as ordinary differential equations, partial differential equations, stochastic master equations, and Gillespie type methods, are all limited either by their modeling fidelity or computational efficiency or both. In this work, we present a scalable computational framework based on modeling biochemical reactions in explicit 3D space, that is suitable for studying the behavior of large and complex biological pathways. The framework is designed to exploit parallelism and scalability offered by commodity massively parallel processors such as the graphics processing units (GPUs) and other parallel computing platforms. The reaction modeling in 3D space is aimed at enhancing the realism of the model compared to traditional modeling tools and framework. We introduce the Parallel Select algorithm that is key to breaking the sequential bottleneck limiting the performance of most other tools designed to study biochemical interactions. The algorithm is designed to be computationally tractable, handle hundreds of interacting chemical species and millions of independent agents by considering all-particle interactions within the system. We also present an implementation of the framework on the popular graphics processing units and apply it to the simulation study of JAK-STAT Signal Transduction Pathway. The computational framework will offer a deeper insight into various biological processes within the cell and help us observe key events as they unfold in space and time. This will advance the current state-of-the-art in simulation study of large scale biological systems and also enable the realistic simulation study of macro-biological cultures, where inter-cellular interactions are prevalent.

  6. The Glutamate Dehydrogenase Pathway and Its Roles in Cell and Tissue Biology in Health and Disease

    Science.gov (United States)

    Plaitakis, Andreas; Kalef-Ezra, Ester; Kotzamani, Dimitra; Zaganas, Ioannis; Spanaki, Cleanthe

    2017-01-01

    Glutamate dehydrogenase (GDH) is a hexameric enzyme that catalyzes the reversible conversion of glutamate to α-ketoglutarate and ammonia while reducing NAD(P)+ to NAD(P)H. It is found in all living organisms serving both catabolic and anabolic reactions. In mammalian tissues, oxidative deamination of glutamate via GDH generates α-ketoglutarate, which is metabolized by the Krebs cycle, leading to the synthesis of ATP. In addition, the GDH pathway is linked to diverse cellular processes, including ammonia metabolism, acid-base equilibrium, redox homeostasis (via formation of fumarate), lipid biosynthesis (via oxidative generation of citrate), and lactate production. While most mammals possess a single GDH1 protein (hGDH1 in the human) that is highly expressed in the liver, humans and other primates have acquired, via duplication, an hGDH2 isoenzyme with distinct functional properties and tissue expression profile. The novel hGDH2 underwent rapid evolutionary adaptation, acquiring unique properties that enable enhanced enzyme function under conditions inhibitory to its ancestor hGDH1. These are thought to provide a biological advantage to humans with hGDH2 evolution occurring concomitantly with human brain development. hGDH2 is co-expressed with hGDH1 in human brain, kidney, testis and steroidogenic organs, but not in the liver. In human cerebral cortex, hGDH1 and hGDH2 are expressed in astrocytes, the cells responsible for removing and metabolizing transmitter glutamate, and for supplying neurons with glutamine and lactate. In human testis, hGDH2 (but not hGDH1) is densely expressed in the Sertoli cells, known to provide the spermatids with lactate and other nutrients. In steroid producing cells, hGDH1/2 is thought to generate reducing equivalents (NADPH) in the mitochondria for the biosynthesis of steroidal hormones. Lastly, up-regulation of hGDH1/2 expression occurs in cancer, permitting neoplastic cells to utilize glutamine/glutamate for their growth. In

  7. The Glutamate Dehydrogenase Pathway and Its Roles in Cell and Tissue Biology in Health and Disease

    Directory of Open Access Journals (Sweden)

    Andreas Plaitakis

    2017-02-01

    Full Text Available Glutamate dehydrogenase (GDH is a hexameric enzyme that catalyzes the reversible conversion of glutamate to α-ketoglutarate and ammonia while reducing NAD(P+ to NAD(PH. It is found in all living organisms serving both catabolic and anabolic reactions. In mammalian tissues, oxidative deamination of glutamate via GDH generates α-ketoglutarate, which is metabolized by the Krebs cycle, leading to the synthesis of ATP. In addition, the GDH pathway is linked to diverse cellular processes, including ammonia metabolism, acid-base equilibrium, redox homeostasis (via formation of fumarate, lipid biosynthesis (via oxidative generation of citrate, and lactate production. While most mammals possess a single GDH1 protein (hGDH1 in the human that is highly expressed in the liver, humans and other primates have acquired, via duplication, an hGDH2 isoenzyme with distinct functional properties and tissue expression profile. The novel hGDH2 underwent rapid evolutionary adaptation, acquiring unique properties that enable enhanced enzyme function under conditions inhibitory to its ancestor hGDH1. These are thought to provide a biological advantage to humans with hGDH2 evolution occurring concomitantly with human brain development. hGDH2 is co-expressed with hGDH1 in human brain, kidney, testis and steroidogenic organs, but not in the liver. In human cerebral cortex, hGDH1 and hGDH2 are expressed in astrocytes, the cells responsible for removing and metabolizing transmitter glutamate, and for supplying neurons with glutamine and lactate. In human testis, hGDH2 (but not hGDH1 is densely expressed in the Sertoli cells, known to provide the spermatids with lactate and other nutrients. In steroid producing cells, hGDH1/2 is thought to generate reducing equivalents (NADPH in the mitochondria for the biosynthesis of steroidal hormones. Lastly, up-regulation of hGDH1/2 expression occurs in cancer, permitting neoplastic cells to utilize glutamine/glutamate for their growth

  8. The Glutamate Dehydrogenase Pathway and Its Roles in Cell and Tissue Biology in Health and Disease.

    Science.gov (United States)

    Plaitakis, Andreas; Kalef-Ezra, Ester; Kotzamani, Dimitra; Zaganas, Ioannis; Spanaki, Cleanthe

    2017-02-08

    Glutamate dehydrogenase (GDH) is a hexameric enzyme that catalyzes the reversible conversion of glutamate to α-ketoglutarate and ammonia while reducing NAD(P)⁺ to NAD(P)H. It is found in all living organisms serving both catabolic and anabolic reactions. In mammalian tissues, oxidative deamination of glutamate via GDH generates α-ketoglutarate, which is metabolized by the Krebs cycle, leading to the synthesis of ATP. In addition, the GDH pathway is linked to diverse cellular processes, including ammonia metabolism, acid-base equilibrium, redox homeostasis (via formation of fumarate), lipid biosynthesis (via oxidative generation of citrate), and lactate production. While most mammals possess a single GDH1 protein (hGDH1 in the human) that is highly expressed in the liver, humans and other primates have acquired, via duplication, an hGDH2 isoenzyme with distinct functional properties and tissue expression profile. The novel hGDH2 underwent rapid evolutionary adaptation, acquiring unique properties that enable enhanced enzyme function under conditions inhibitory to its ancestor hGDH1. These are thought to provide a biological advantage to humans with hGDH2 evolution occurring concomitantly with human brain development. hGDH2 is co-expressed with hGDH1 in human brain, kidney, testis and steroidogenic organs, but not in the liver. In human cerebral cortex, hGDH1 and hGDH2 are expressed in astrocytes, the cells responsible for removing and metabolizing transmitter glutamate, and for supplying neurons with glutamine and lactate. In human testis, hGDH2 (but not hGDH1) is densely expressed in the Sertoli cells, known to provide the spermatids with lactate and other nutrients. In steroid producing cells, hGDH1/2 is thought to generate reducing equivalents (NADPH) in the mitochondria for the biosynthesis of steroidal hormones. Lastly, up-regulation of hGDH1/2 expression occurs in cancer, permitting neoplastic cells to utilize glutamine/glutamate for their growth. In

  9. Nitric oxide and nitrous oxide turnover in natural and engineered microbial communities: biological pathways, chemical reactions and novel technologies

    Directory of Open Access Journals (Sweden)

    Frank eSchreiber

    2012-10-01

    Full Text Available Nitrous oxide (N2O is an environmentally important atmospheric trace gas because it is an effective greenhouse gas and it leads to ozone depletion through photo-chemical nitric oxide (NO production in the stratosphere. Mitigating its steady increase in atmospheric concentration requires an understanding of the mechanisms that lead to its formation in natural and engineered microbial communities. N2O is formed biologically from the oxidation of hydroxylamine (NH2OH or the reduction of nitrite (NO2- to NO and further to N2O. Our review of the biological pathways for N2O production shows that apparently all organisms and pathways known to be involved in the catabolic branch of microbial N-cycle have the potential to catalyze the reduction of NO2- to NO and the further reduction of NO to N2O, while N2O formation from NH2OH is only performed by ammonia oxidizing bacteria. In addition to biological pathways, we review important chemical reactions that can lead to NO and N2O formation due to the reactivity of NO2-, NH2OH and nitroxyl (HNO. Moreover, biological N2O formation is highly dynamic in response to N-imbalance imposed on a system. Thus, understanding NO formation and capturing the dynamics of NO and N2O build-up are key to understand mechanisms of N2O release. Here, we discuss novel technologies that allow experiments on NO and N2O formation at high temporal resolution, namely NO and N2O microelectrodes and the dynamic analysis of the isotopic signature of N2O with quantum cascade laser based absorption spectroscopy. In addition, we introduce other techniques that use the isotopic composition of N2O to distinguish production pathways and findings that were made with emerging molecular techniques in complex environments. Finally, we discuss how a combination of the presented tools might help to address important open questions on pathways and controls of nitrogen flow through complex microbial communities that eventually lead to N2O build-up.

  10. Integrated pathway-based and network-based analysis of GC-MS rice metabolomics data under diazinon stress to infer affected biological pathways.

    Science.gov (United States)

    Mahdavi, Vahideh; Ghanati, Faezeh; Ghassempour, Alireza

    2016-02-01

    Diazinon insecticide is widely applied in rice (Oryza sativa L.) fields in Iran. However, concerns are now being raised about its potential adverse impacts on rice. In this study, a time-course metabolic change in rice plants was investigated after diazinon treatment using gas chromatography-mass spectrometry (GC-MS) and subsequently three different methods, MetaboAnalyst, MetaboNetwork, and analysis of reporter reactions, as a potential multivariate method were used to find the underlying changes in metabolism with stronger evidence in order to link differentially expressed metabolites to biological pathways. Results clearly showed the similarity of acetylcholinesterase (AChE) of rice plants to that of animals in terms of its inhibitability by diazinon and emphasized that subsequent accumulation of AChE mainly affects the metabolism of osmolites and tricarboxylic acid intermediates subsequent accumulation of ACh mainly affects the metabolism of osmolites and TCA intermediates.

  11. Important biology events and pathways in Brucella infection and implications for novel antibiotic drug targets.

    Science.gov (United States)

    Gao, Guangjun; Xu, Jie

    2013-01-01

    Brucellosis caused by Brucella spp. is a common zoonosis in many parts of the world. Humans are infected through contact with infected animals or their dirty products. Many mechanisms are needed for this successful infection, although the mechanisms are still unclear. Host immune response and some signaling molecules play an important role in the infection event. Bacterial pathogens operate by attacking crucial intracellular pathways or some important molecules in each of these pathways for survival in their hosts. The crucial components (molecules) of immunity or pathway play a critical role in the whole process of Brucella infection. Here we summarize the findings of the Brucella-host interactions' immune system and signaling molecular cascades involved in the TLR-initiated immune response to Brucella spp. infection. The paper serves to deepen our understanding of this complex process and to provide some clues regarding the discovery of drug targets for prevention and control.

  12. Use of a bovine genome array to identify new biological pathways for beef marbling in Hanwoo (Korean Cattle

    Directory of Open Access Journals (Sweden)

    Lim Da-jeong

    2010-11-01

    , which is involved in connective tissue degradation, could play a role in an important biological pathway for building up marbling in cattle. Moreover, ADAMTS4 and TGFβ1could potentially be used as an early biological marker for marbling fat content in the early stages of growth.

  13. A wandering pathway in plant biology: from wildflowers to phototropins to bacterial virulence.

    Science.gov (United States)

    Briggs, Winslow R

    2010-01-01

    The author describes the somewhat convoluted pathway he followed from amateur taxonomy of Minnesota wildflowers to identification of the phototropin family of blue-light receptors. He also mentions individuals who were important in moving his career first into plant taxonomy, then plant development, and finally plant photobiology (and out of music). He emphasizes the many twists and turns a research career can take, including a few that lead to blind ends. He also emphasizes the oscillatory nature of his career-back and forth between the Atlantic and Pacific oceans (with occasional forays to Freiburg, Germany) and back and forth between red-light receptors and blue-light receptors. There is a short intermission in which he describes his longtime relationship with California's Henry W. Coe State Park. Finally, he relates how he followed the unlikely pathway from plant blue-light receptors to a blue-light receptor required to maximize virulence of a bacterial animal pathogen.

  14. Multiple Transcriptome Data Analysis Reveals Biologically Relevant Atopic Dermatitis Signature Genes and Pathways.

    Directory of Open Access Journals (Sweden)

    Debajyoti Ghosh

    Full Text Available Several studies have identified genes that are differentially expressed in atopic dermatitis (AD compared to normal skin. However, there is also considerable variation in the list of differentially expressed genes (DEGs reported by different groups and the exact cause of AD is still not fully understood. Using a rank-based approach, we analyzed gene expression data from five different microarray studies, comprising a total of 127 samples and more than 250,000 transcripts. A total of 89 AD gene expression signatures '89ADGES', including FLG gene, were identified to show dysregulation consistently across these studies. Using a Support Vector Machine, we showed that the '89ADGES' discriminates AD from normal skin with 98% predictive accuracy. Functional annotation of these genes implicated their roles in immune responses (e.g., betadefensin, microseminoprotein, keratinocyte differentiation/epidermal development (e.g., FLG, CORIN, AQP, LOR, KRT16, inflammation (e.g., IL37, IL27RA, CCL18 and lipid metabolism (e.g., AKR1B10, FAD7, FAR2. Subsequently, we validated a subset of signature genes using quantitative PCR in a mouse model. Using a bioinformatic approach, we identified keratinocyte pathway over-represented (P = <0.0006 among the 89 signature genes. Keratinocytes are known to play a major role in barrier function due to their location in the epidermis. Our result suggests that besides immune- mediated pathway, skin barrier pathways such as the keratinocyte differentiation pathway play a key role in AD pathogenesis. A better understanding of the role of keratinocytes in AD will be important for developing novel "barrier therapy" for this disease.

  15. High performance hybrid functional Petri net simulations of biological pathway models on CUDA.

    Science.gov (United States)

    Chalkidis, Georgios; Nagasaki, Masao; Miyano, Satoru

    2011-01-01

    Hybrid functional Petri nets are a wide-spread tool for representing and simulating biological models. Due to their potential of providing virtual drug testing environments, biological simulations have a growing impact on pharmaceutical research. Continuous research advancements in biology and medicine lead to exponentially increasing simulation times, thus raising the demand for performance accelerations by efficient and inexpensive parallel computation solutions. Recent developments in the field of general-purpose computation on graphics processing units (GPGPU) enabled the scientific community to port a variety of compute intensive algorithms onto the graphics processing unit (GPU). This work presents the first scheme for mapping biological hybrid functional Petri net models, which can handle both discrete and continuous entities, onto compute unified device architecture (CUDA) enabled GPUs. GPU accelerated simulations are observed to run up to 18 times faster than sequential implementations. Simulating the cell boundary formation by Delta-Notch signaling on a CUDA enabled GPU results in a speedup of approximately 7x for a model containing 1,600 cells.

  16. Understanding specificity in metabolic pathways--structural biology of human nucleotide metabolism.

    Science.gov (United States)

    Welin, Martin; Nordlund, Pär

    2010-05-21

    Interactions are the foundation of life at the molecular level. In the plethora of activities in the cell, the evolution of enzyme specificity requires the balancing of appropriate substrate affinity with a negative selection, in order to minimize interactions with other potential substrates in the cell. To understand the structural basis for enzyme specificity, the comparison of structural and biochemical data between enzymes within pathways using similar substrates and effectors is valuable. Nucleotide metabolism is one of the largest metabolic pathways in the human cell and is of outstanding therapeutic importance since it activates and catabolises nucleoside based anti-proliferative drugs and serves as a direct target for anti-proliferative drugs. In recent years the structural coverage of the enzymes involved in human nucleotide metabolism has been dramatically improved and is approaching completion. An important factor has been the contribution from the Structural Genomics Consortium (SGC) at Karolinska Institutet, which recently has solved 33 novel structures of enzymes and enzyme domains in human nucleotide metabolism pathways and homologs thereof. In this review we will discuss some of the principles for substrate specificity of enzymes in human nucleotide metabolism illustrated by a selected set of enzyme families where a detailed understanding of the structural determinants for specificity is now emerging.

  17. Understanding specificity in metabolic pathways-Structural biology of human nucleotide metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Welin, Martin [Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm (Sweden); Nordlund, Paer, E-mail: Par.Nordlund@ki.se [Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm (Sweden); Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm (Sweden)

    2010-05-21

    Interactions are the foundation of life at the molecular level. In the plethora of activities in the cell, the evolution of enzyme specificity requires the balancing of appropriate substrate affinity with a negative selection, in order to minimize interactions with other potential substrates in the cell. To understand the structural basis for enzyme specificity, the comparison of structural and biochemical data between enzymes within pathways using similar substrates and effectors is valuable. Nucleotide metabolism is one of the largest metabolic pathways in the human cell and is of outstanding therapeutic importance since it activates and catabolises nucleoside based anti-proliferative drugs and serves as a direct target for anti-proliferative drugs. In recent years the structural coverage of the enzymes involved in human nucleotide metabolism has been dramatically improved and is approaching completion. An important factor has been the contribution from the Structural Genomics Consortium (SGC) at Karolinska Institutet, which recently has solved 33 novel structures of enzymes and enzyme domains in human nucleotide metabolism pathways and homologs thereof. In this review we will discuss some of the principles for substrate specificity of enzymes in human nucleotide metabolism illustrated by a selected set of enzyme families where a detailed understanding of the structural determinants for specificity is now emerging.

  18. A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase

    Directory of Open Access Journals (Sweden)

    Christmas DM

    2011-07-01

    Full Text Available David M Christmas, JP Potokar, Simon JC DaviesAcademic Unit of Psychiatry, School of Social and Community Medicine, University of Bristol, Bristol, UK A presentation relating to this manuscript was made by Dr David Christmas at the 9th International Meeting on Clinical Pharmacology in Psychiatry (9th IMCPP in Copenhagen, Denmark in September 2010Abstract: This article highlights the evidence linking depression to increased inflammatory drive and explores putative mechanisms for the association by reviewing both preclinical and clinical literature. The enzyme indoleamine 2,3-dioxygenase is induced by proinflammatory cytokines and may form a link between immune functioning and altered neurotransmission, which results in depression. Increased indoleamine 2,3-dioxygenase activity may cause both tryptophan depletion and increased neurotoxic metabolites of the kynurenine pathway, two alterations which have been hypothesized to cause depression. The tryptophan-kynurenine pathway is comprehensively described with a focus on the evidence linking metabolite alterations to depression. The use of immune-activated groups at high risk of depression have been used to explore these hypotheses; we focus on the studies involving chronic hepatitis C patients receiving interferon-alpha, an immune activating cytokine. Findings from this work have led to novel strategies for the future development of antidepressants including inhibition of indoleamine 2,3-dioxygenase, moderating the cytokines which activate it, or addressing other targets in the kynurenine pathway.Keywords: depression, inflammation, indoleamine 2,3-dioxygenase, kynurenine, serotonin, tryptophan

  19. Occurrence, pathways and implications of biological production of reactive oxygen species in natural waters

    Science.gov (United States)

    Zhang, T.; Hansel, C. M.; Voelker, B. M.; Lamborg, C. H.

    2014-12-01

    Reactive oxygen species (ROS), such as superoxide (O2-) and hydrogen peroxide (H2O2) play a critical role in the redox cycling of both toxic (e.g., Hg) and nutrient (e.g., Fe) metals. Despite the discovery of extracellular ROS production in various microbial cultures, including fungi, algae and bacteria, photo-dependent processes are generally considered as the predominant source of ROS in natural waters. Here we show that biological production of ROS is ubiquitous and occurs at a significant rate in freshwater and brackish water environments. Water samples were collected from three freshwater and one brackish water ponds in Cape Cod, Massachusetts, USA, periodically from 2012 to 2014. Production of O2- and H2O2 were measured in dark incubations of natural water using a chemiluminescent and a colorimetric probe, respectively. Rates of biological ROS production were obtained by comparing unfiltered with 0.2-μm filtered samples. The role of biological activity in ROS production was confirmed by the cessation of ROS production upon addition of formaldehyde. In surface water, production rates of O2- ranged from undetectable to 96.0 ± 30.0 nmol L-1 h-1, and production rates of H2O2 varied between 9.9 ± 1.3 nmol L-1 h-1 and 145.6 ± 11.2 nmol L-1 h-1. The maximum production rates of both ROS were observed in mid-summer 2013, which coincides with peak biological activity. ROS production in the water from aphotic zone was greater than in the water from photic zone. Thus, non-light dependent biological processes are likely the major contributors to ROS production in this system. Moreover, O2- production appeared to be enhanced by NADH and inhibited by proteinase-K, suggesting the possible involvement of NADH oxidoreductases in this process. The potential role of different microbial communities in ROS production, and the implications of biological ROS production for mercury speciation will also be discussed.

  20. Robust gene signatures from microarray data using genetic algorithms enriched with biological pathway keywords.

    Science.gov (United States)

    Luque-Baena, R M; Urda, D; Gonzalo Claros, M; Franco, L; Jerez, J M

    2014-06-01

    Genetic algorithms are widely used in the estimation of expression profiles from microarrays data. However, these techniques are unable to produce stable and robust solutions suitable to use in clinical and biomedical studies. This paper presents a novel two-stage evolutionary strategy for gene feature selection combining the genetic algorithm with biological information extracted from the KEGG database. A comparative study is carried out over public data from three different types of cancer (leukemia, lung cancer and prostate cancer). Even though the analyses only use features having KEGG information, the results demonstrate that this two-stage evolutionary strategy increased the consistency, robustness and accuracy of a blind discrimination among relapsed and healthy individuals. Therefore, this approach could facilitate the definition of gene signatures for the clinical prognosis and diagnostic of cancer diseases in a near future. Additionally, it could also be used for biological knowledge discovery about the studied disease.

  1. Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology (edited by Gerhard Michal)

    Science.gov (United States)

    Voige, Reviewed By William H.

    2000-02-01

    For decades, a wall chart detailing living organisms' metabolic pathways has been a fixture in many classrooms and laboratories where biochemistry is taught. One of the most popular of those charts first appeared 30 years ago. Now its editor, Gerhard Michal, has produced a book that summarizes metabolism (broadly defined) in graphical and textual formats. The book retains the elegance of the chart. Names of molecules are printed in a crisp, easy-to-read font, and structural formulas are shown with exemplary clarity. Color coding serves multiple purposes: to differentiate enzymes, substrates, cofactors, and effector molecules; to indicate in which group or groups of organisms a reaction has been observed; and to distinguish enzymatic reactions from regulatory effects. The primary advantage of presenting this information in book format is immediately apparent. A typical metabolic chart covers about 2 m2; the book has a total surface area nearly 10 times greater. The extra space is used to add explanatory text to the figures and to include many topics not covered by the traditional definition of metabolism. Examples include replication, transcription, translation, reaction mechanisms for proteolytic enzymes, and the role of chaperones in protein folding. Illustrating these topics is not as straightforward as delineating a metabolic pathway, but the author has done an admirable job of designing figures that clarify these and other aspects of biochemistry and complement the accompanying text. A potential deficiency of book format is the inability to clearly show links between different realms of metabolism: carbohydrate and amino acid pathways, for example. The book overcomes this problem in two ways. A diagrammatic overview of metabolism (with references to applicable sections of the book) is printed inside its front cover, and key compounds (pyruvate, for example) have a distinctive green background to provide a visual link between pathways. (The author compares this

  2. Evaluation of NF-kappaB Pathway Inhibition for Space Radiation Biology Research

    Science.gov (United States)

    Koch, Kristina; Hellweg, Christine; Baumstark-Khan, Christa; Schmitz, Claudia; Lau, Patrick; Testard, Isabelle; Reitz, Guenther

    Radiation is a potentially limiting factor for long term orbital and interplanetary missions. To improve risk estimation and to allow development of appropriate countermeasures, the study of the cellular radiation response is necessary. The anti-apoptotic factor nuclear factor κB (NF-κB) was identified as important modulating factor in the cellular response to heavy ions (Radiat. Res. 164: 527-530, 2005). This transcription factor could improve cellular survival after exposure to high radiation doses and influence the cancer risk of astronauts exposed to low doses of cosmic radiation. Therefore, the inhibition of selected NF-κB pathway compo-nents might help to identify possible pharmacological targets. It is supposed that the ATM kinase mediates the signal from damaged DNA in the nucleus to kinases in the cytoplasm. For liberation of NF-κB and its nuclear translocation, the inhibitor of NF-κB (IκB) has to be degraded in the proteasom. In this work, the efficacy and cytotoxicity of ATM, NF-κB and the proteasome inhibitors were analyzed using recombinant HEK-pNF-κB-d2EGFP/Neo cells. In the recommended concentration range, only the NF-κB inhibitor caffeic acid phenethyl ester (CAPE) displayed considerable cytotoxicity, while the others were not toxic. The inhibition of ATM by KU-55933 suppresses the X-ray and heavy ion (13 C, 35 MeV/u, LET 70 keV/m) induced activation of NF-κB dependent gene expression, indicating the central position of ATM in radiation induced NF-κB activation. CAPE and capsaicin partially inhibited NF-κB acti-vation by the cytokine tumor necrosis factor α. The proteasome inhibitor MG-132 completely abolished the activation and was therefore used for short-term incubation experiments with X-rays. MG-132 suppressed the X-ray induced NF-κB activation in HEK-pNF-κB-d2EGFP/Neo cells entirely. The results lead to the conclusion that ATM and the proteasomal degradation of IκB are essential prerequisites for radiation induced NF

  3. MRMPath and MRMutation, Facilitating Discovery of Mass Transitions for Proteotypic Peptides in Biological Pathways Using a Bioinformatics Approach

    Directory of Open Access Journals (Sweden)

    Chiquito Crasto

    2013-01-01

    Full Text Available Quantitative proteomics applications in mass spectrometry depend on the knowledge of the mass-to-charge ratio (m/z values of proteotypic peptides for the proteins under study and their product ions. MRMPath and MRMutation, web-based bioinformatics software that are platform independent, facilitate the recovery of this information by biologists. MRMPath utilizes publicly available information related to biological pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG database. All the proteins involved in pathways of interest are recovered and processed in silico to extract information relevant to quantitative mass spectrometry analysis. Peptides may also be subjected to automated BLAST analysis to determine whether they are proteotypic. MRMutation catalogs and makes available, following processing, known (mutant variants of proteins from the current UniProtKB database. All these results, available via the web from well-maintained, public databases, are written to an Excel spreadsheet, which the user can download and save. MRMPath and MRMutation can be freely accessed. As a system that seeks to allow two or more resources to interoperate, MRMPath represents an advance in bioinformatics tool development. As a practical matter, the MRMPath automated approach represents significant time savings to researchers.

  4. Bridging from Cells to Cognition in Autism Pathophysiology: Biological Pathways to Defective Brain Function and Plasticity

    Energy Technology Data Exchange (ETDEWEB)

    Anderson, Matthew; Hooker, Brian S.; Herbert, Martha

    2008-01-01

    We review evidence to support the model that autism may begin when a maternal environmental, infectious, or autoantibody insult causes inflammation which increases reactive oxygen species (ROS) production in the fetus, leading to fetal DNA damage (nuclear and mitochondrial), and that these inflammatory and oxidative stressors persist beyond early development (with potential further exacerbations), producing ongoing functional consequences. In organs with a high metabolic demand such as the central nervous system, the continued use of mitochondria with DNA damage may generate additional ROS which will activate the innate immune system leading to more ROS production. Such a mechanism would self-sustain and possibly progressively worsen. The mitochondrial dysfunction and altered redox signal transduction pathways found in autism would conspire to activate both astroglia and microglia. These activated cells can then initiate a broad-spectrum proinflammatory gene response. Neurons may have acquired receptors for these inflammatory signals to inhibit neuronal signaling as a protection from excitotoxic damage during various pathologic insults (e.g., infection). In autism, over-zealous neuroinflammatory responses could not only influence neural developmental processes, but may more significantly impair neural signaling involved in cognition in an ongoing fashion. This model makes specific predictions in patients and experimental animal models and suggests a number of targets sites of intervention. Our model of potentially reversible pathophysiological mechanisms in autism motivates our hope that effective therapies may soon appear on the horizon.

  5. Exceptionally High Rates of Biological Hydrogen Production by Biomimetic In Vitro Synthetic Enzymatic Pathways.

    Science.gov (United States)

    Kim, Eui-Jin; Wu, Chang-Hao; Adams, Michael W W; Zhang, Y-H Percival

    2016-11-02

    Hydrogen production by water splitting energized by biomass sugars is one of the most promising technologies for distributed green H2 production. Direct H2 generation from NADPH, catalysed by an NADPH-dependent, soluble [NiFe]-hydrogenase (SH1) is thermodynamically unfavourable, resulting in slow volumetric productivity. We designed the biomimetic electron transport chain from NADPH to H2 by the introduction of an oxygen-insensitive electron mediator benzyl viologen (BV) and an enzyme (NADPH rubredoxin oxidoreductase, NROR), catalysing electron transport between NADPH and BV. The H2 generation rates using this biomimetic chain increased by approximately five-fold compared to those catalysed only by SH1. The peak volumetric H2 productivity via the in vitro enzymatic pathway comprised of hyperthermophilic glucose 6-phosphate dehydrogenase, 6-phosphogluconolactonase, and 6-phosphogluconate dehydrogenase, NROR, and SH1 was 310 mmol H2 /L h(-1) , the highest rate yet reported. The concept of biomimetic electron transport chains could be applied to both in vitro and in vivo H2 production biosystems and artificial photosynthesis.

  6. Molecular Biology of Hepatitis C Virus: Interactions with the IFN-Betta Signalling Pathway

    Directory of Open Access Journals (Sweden)

    M Sabourighannad

    2005-10-01

    Full Text Available The induction of IFN-β expression is the first stage in the innate anti-viral response. In order to investigate the possible effects of HCV proteins on IFN-β signalling, a baculovirus delivery system was developed to introduce the whole genome of HCV genotype 1b into hepatoma cells. The construct used in this study lacks the 3’UTR which is required for HCV replication, thus enabling us to look at the effects of HCV proteins on the IFN-β signalling pathway without inducing IFN-β expression by virtue of the presence of replicating (double-stranded viral RNA. To facilitate this analysis the expression of the HCV polyprotein was under the control of a tetracycline–responsive promoter coupled to the HCV 5’UTR. As a comparison, we have also generated a recombinant baculovirus containing the culture adapted sub-genomic replicon (FK5.1 also derived from HCV genotype 1b, and a mutant form thereof containing an inactivating mutation within the NS5B (RdRp coding sequence (termed GND. We first confirmed that HepG2 cells were able to mount an effective IFN-β response. As expected, the baculovirus carrying the FK5.1 replicon induced the production of IFN-β as judged by the use of an IFN-β-promoter luciferase reporter construct, whereas the GND baculovirus and the full-length 3’UTR deletant failed to induce luciferase expression. We then proceeded to analyse the effect of the HCV polyprotein on exogenous induction of the IFN-β promoter (by transfecting cells with poly I/C. These studies demonstrated that neither the HCV polyprotein nor the non-structural proteins of HCV (expressed from the replicon had any effect on the dsRNA-mediated induction of IFN-β promoter. Secondly we analysed potential effects on the inhibition of the IFN-β response, using an ISRE-luciferase construct. Again we observed no effect of either the complete polyprotein or the sub-genomic replicon. Lastly, we examined the activation of both IRF-3 and NFκB, two

  7. A systems genetics approach provides a bridge from discovered genetic variants to biological pathways in rheumatoid arthritis.

    Directory of Open Access Journals (Sweden)

    Hirofumi Nakaoka

    biological pathways.

  8. Tannerella forsythia strains display different cell-surface nonulosonic acids: biosynthetic pathway characterization and first insight into biological implications.

    Science.gov (United States)

    Friedrich, Valentin; Janesch, Bettina; Windwarder, Markus; Maresch, Daniel; Braun, Matthias L; Megson, Zoë A; Vinogradov, Evgeny; Goneau, Marie-France; Sharma, Ashu; Altmann, Friedrich; Messner, Paul; Schoenhofen, Ian C; Schäffer, Christina

    2016-12-16

    Tannerella forsythia is an anaerobic, Gram-negative periodontal pathogen. A unique O-linked oligosaccharide decorates the bacterium's cell surface proteins and was shown to modulate the host immune response. In our study, we investigated the biosynthesis of the nonulosonic acid (NulO) present at the terminal position of this glycan. A bioinformatic analysis of T. forsythia genomes revealed a gene locus for the synthesis of pseudaminic acid (Pse) in the type strain ATCC 43037 while strains FDC 92A2 and UB4 possess a locus for the synthesis of legionaminic acid (Leg) instead. In contrast to the NulO in ATCC 43037, which has been previously identified as a Pse derivative (5-N-acetimidoyl-7-N-glyceroyl-3,5,7,9-tetradeoxy-l-glycero-l-manno-NulO), glycan analysis of strain UB4 performed in this study indicated a 350-Da, possibly N-glycolyl Leg (3,5,7,9-tetradeoxy-d-glycero-d-galacto-NulO) derivative with unknown C5,7 N-acyl moieties. We have expressed, purified and characterized enzymes of both NulO pathways to confirm these genes' functions. Using capillary electrophoresis (CE), CE-mass spectrometry and NMR spectroscopy, our studies revealed that Pse biosynthesis in ATCC 43037 essentially follows the UDP-sugar route described in Helicobacter pylori, while the pathway in strain FDC 92A2 corresponds to Leg biosynthesis in Campylobacter jejuni involving GDP-sugar intermediates. To demonstrate that the NulO biosynthesis enzymes are functional in vivo, we created knockout mutants resulting in glycans lacking the respective NulO. Compared to the wild-type strains, the mutants exhibited significantly reduced biofilm formation on mucin-coated surfaces, suggestive of their involvement in host-pathogen interactions or host survival. This study contributes to understanding possible biological roles of bacterial NulOs.

  9. Biologic

    CERN Document Server

    Kauffman, L H

    2002-01-01

    In this paper we explore the boundary between biology and the study of formal systems (logic). In the end, we arrive at a summary formalism, a chapter in "boundary mathematics" where there are not only containers but also extainers ><, entities open to interaction and distinguishing the space that they are not. The boundary algebra of containers and extainers is to biologic what boolean algebra is to classical logic. We show how this formalism encompasses significant parts of the logic of DNA replication, the Dirac formalism for quantum mechanics, formalisms for protein folding and the basic structure of the Temperley Lieb algebra at the foundations of topological invariants of knots and links.

  10. A Western Blot-based Investigation of the Yeast Secretory Pathway Designed for an Intermediate-Level Undergraduate Cell Biology Laboratory

    Science.gov (United States)

    Hood-DeGrenier, Jennifer K.

    2008-01-01

    The movement of newly synthesized proteins through the endomembrane system of eukaryotic cells, often referred to generally as the secretory pathway, is a topic covered in most intermediate-level undergraduate cell biology courses. An article previously published in this journal described a laboratory exercise in which yeast mutants defective in…

  11. Lung Cancer Cell Line Screen Links Fanconi Anemia/BRCA Pathway Defects to Increased Relative Biological Effectiveness of Proton Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Qi; Ghosh, Priyanjali; Magpayo, Nicole [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Testa, Mauro; Tang, Shikui [Division of Radiation Physics, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Gheorghiu, Liliana [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Biggs, Peter; Paganetti, Harald [Division of Radiation Physics, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Efstathiou, Jason A. [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Lu, Hsiao-Ming [Division of Radiation Physics, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Held, Kathryn D. [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Willers, Henning, E-mail: hwillers@mgh.harvard.edu [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2015-04-01

    Purpose: Growing knowledge of genomic heterogeneity in cancer, especially when it results in altered DNA damage responses, requires re-examination of the generic relative biological effectiveness (RBE) of 1.1 of protons. Methods and Materials: For determination of cellular radiosensitivity, we irradiated 17 lung cancer cell lines at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer, 2.5 keV/μm). For comparison, 250-kVp X rays and {sup 137}Cs γ-rays were used. To estimate the RBE of protons relative to {sup 60}Co (Co60eq), we assigned an RBE(Co60Eq) of 1.1 to X rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor damage responses. FANCD2 was depleted using RNA interference. Results: Five lung cancer cell lines (29.4%) exhibited reduced clonogenic survival after proton irradiation compared with X-irradiation with the same physical doses. This was confirmed in a 3-dimensional sphere assay. Corresponding proton RBE(Co60Eq) estimates were statistically significantly different from 1.1 (P≤.05): 1.31 to 1.77 (for a survival fraction of 0.5). In 3 of these lines, increased RBE was correlated with alterations in the Fanconi anemia (FA)/BRCA pathway of DNA repair. In Calu-6 cells, the data pointed toward an FA pathway defect, leading to a previously unreported persistence of proton-induced RAD51 foci. The FA/BRCA-defective cells displayed a 25% increase in the size of subnuclear 53BP1 foci 18 hours after proton irradiation. Conclusions: Our cell line screen has revealed variations in proton RBE that are partly due to FA/BRCA pathway defects, suggesting that the use of a generic RBE for cancers should be revisited. We propose that functional biomarkers, such as size of residual 53BP1 foci, may be used to identify cancers with increased sensitivity to proton radiation.

  12. Development of computationally predicted Adverse Outcome Pathway (AOP) networks through data mining and integration of publicly available in vivo, in vitro, phenotype, and biological pathway data

    Science.gov (United States)

    The Adverse Outcome Pathway (AOP) framework is increasingly being adopted as a tool for organizing and summarizing the mechanistic information connecting molecular perturbations by environmental stressors with adverse outcomes relevant for ecological and human health outcomes. Ho...

  13. A Novel Biological Role of α-Mangostin in Modulating Inflammatory Response Through the Activation of SIRT-1 Signaling Pathway.

    Science.gov (United States)

    Franceschelli, Sara; Pesce, Mirko; Ferrone, Alessio; Patruno, Antonia; Pasqualone, Livia; Carlucci, Giuseppe; Ferrone, Vincenzo; Carlucci, Maura; de Lutiis, Maria Anna; Grilli, Alfredo; Felaco, Mario; Speranza, Lorenza

    2016-11-01

    Several studies have shown that xanthones obtained from Garcinia Mangostana (GM) have remarkable biological activities. α-mangostin (α-MG) is the main constituent of the fruit hull of the GM. Several findings have suggested that SIRT-1, a nuclear histone deacetylase, could influence cellular function by the inhibition of NF-kB signaling. ROS can inhibit SIRT-1 activity by initiating oxidative modifications on its cysteine residues, and suppression of SIRT-1 enhances the NF-κB signaling resulting in inflammatory responses. The goals of the present study were to evaluate the quantity of α-MG in the methanolic extract of GM (Vithagroup Spa) and to investigate the activity of this xanthone in U937 cell line and in human monocytes from responsive to inflammatory insult analyzing the possible changes on the activation of SIRT-1 protein via NF-Kb. Cells were treated with the methanolic extract of GM and/or LPS. The chromatographic separation of α-MG was performed by an HPLC analysis. EX 527, a specific SIRT-1 inhibitor, was used to determine if SIRT-1/NfkB signaling pathway might be involved in α-MG action on cells. Our results show that α-MG inhibits p65 acetylation and down-regulates the pro-inflammatory gene products as COX-2, iNOS via SIRT-1 activation. Cells treated with EX 527 showed an up-regulation of NFkB acetylation and an over expression of inducible enzymes and their product of catalysis (NO and PGE2). These results suggest that α-MG may be useful for the development of alternative pharmacological strategies aimed at reducing the inflammatory process. J. Cell. Physiol. 231: 2439-2451, 2016. © 2016 Wiley Periodicals, Inc.

  14. Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation

    Science.gov (United States)

    Guilmatre, Audrey; Dubourg, Christèle; Mosca, Anne-Laure; Legallic, Solenn; Goldenberg, Alice; Drouin-Garraud, Valérie; Layet, Valérie; Rosier, Antoine; Briault, Sylvain; Bonnet-Brilhault, Frédérique; Laumonnier, Frédéric; Odent, Sylvie; Le Vacon, Gael; Joly-Helas, Géraldine; David, Véronique; Bendavid, Claude; Pinoit, Jean-Michel; Henry, Céline; Impallomeni, Caterina; Germano, Eva; Tortorella, Gaetano; Di Rosa, Gabriella; Barthelemy, Catherine; Andres, Christian; Faivre, Laurence; Frébourg, Thierry; Saugier Veber, Pascale; Campion, Dominique

    2009-01-01

    Context Comparative genomic hybridization (array-CGH) studies have suggested that rare copy number variations (CNVs) at numerous loci are involved in the etiology of mental retardation (MR), autism spectrum disorders (ASD) and schizophrenia. Objective The goal of the present paper was (i) to provide an estimate of the collective frequency of a set of recurrent/overlapping CNVs in three different groups of patients as compared with healthy controls and (ii) to assess whether each CNV is present in more than one clinical category. Design, setting and population We have investigated 28 candidate loci previously identified by array-CGH studies for gene dosage alteration in 247 subjects with MR, 260 with ASD, 236 with schizophrenia or schizoaffective disorder and 236 healthy controls. Main outcome measures Collective and individual frequency of the analyzed CNVs in patients as compared with controls. Results Recurrent or overlapping CNVs were found in patients at 40% of the selected loci. We show that the collective frequency of CNVs at these loci is significantly increased in autistic patients, patients with schizophrenia and patients with MR as compared with controls (p= 0.005, p< 0.001 and p= 0.001 respectively, Fisher exact test). Individual significance (p= 0.02) was reached for association between autism and a 350 kb deletion located in 22q11 and spanning the PRODH gene. Conclusions These results support the hypothesis that weakly to moderately recurrent CNVs, either transmitted or occurring de novo, are causing or contributory factors for these diseases. Second, we show that most of these CNVs, which contain genes involved in neurotransmission or synapse formation and maintenance, are present in the 3 pathological conditions, supporting the existence of shared biological pathways between these neurodevelopmental disorders. PMID:19736351

  15. Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

    Energy Technology Data Exchange (ETDEWEB)

    Fukunaga, Satoki [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558 (Japan); Kakehashi, Anna [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Sumida, Kayo; Kushida, Masahiko; Asano, Hiroyuki [Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558 (Japan); Gi, Min [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Wanibuchi, Hideki, E-mail: wani@med.osaka-cu.ac.jp [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan)

    2015-08-01

    To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective of initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis.

  16. RNA-sequencing analysis of TCDD-induced responses in zebrafish liver reveals high relatedness to in vivo mammalian models and conserved biological pathways.

    Directory of Open Access Journals (Sweden)

    Zhi-Hua Li

    Full Text Available TCDD is one of the most persistent environmental toxicants in biological systems and its effect through aryl hydrocarbon receptor (AhR has been well characterized. However, the information on TCDD-induced toxicity in other molecular pathways is rather limited. To fully understand molecular toxicity of TCDD in an in vivo animal model, adult zebrafish were exposed to TCDD at 10 nM for 96 h and the livers were sampled for RNA-sequencing based transcriptomic profiling. A total of 1,058 differently expressed genes were identified based on fold-change>2 and TPM (transcripts per million >10. Among the top 20 up-regulated genes, 10 novel responsive genes were identified and verified by RT-qPCR analysis on independent samples. Transcriptomic analysis indicated several deregulated pathways associated with cell cycle, endocrine disruptors, signal transduction and immune systems. Comparative analyses of TCDD-induced transcriptomic changes between fish and mammalian models revealed that proteomic pathway is consistently up-regulated while calcium signaling pathway and several immune-related pathways are generally down-regulated. Finally, our study also suggested that zebrafish model showed greater similarity to in vivo mammalian models than in vitro models. Our study indicated that the zebrafish is a valuable in vivo model in toxicogenomic analyses for understanding molecular toxicity of environmental toxicants relevant to human health. The expression profiles associated with TCDD could be useful for monitoring environmental dioxin and dioxin-like contamination.

  17. Analysis and prediction of pathways in HeLa cells by integrating biological levels of organization with systems-biology approaches.

    Directory of Open Access Journals (Sweden)

    Juan Carlos Higareda-Almaraz

    Full Text Available It has recently begun to be considered that cancer is a systemic disease and that it must be studied at every level of complexity using many of the currently available approaches, including high-throughput technologies and bioinformatics. To achieve such understanding in cervical cancer, we collected information on gene, protein and phosphoprotein expression of the HeLa cell line and performed a comprehensive analysis of the different signaling pathways, transcription networks and metabolic events in which they participate. A total expression analysis by RNA-Seq of the HeLa cell line showed that 19,974 genes were transcribed. Of these, 3,360 were over-expressed, and 2,129 under-expressed when compared to the NHEK cell line. A protein-protein interaction network was derived from the over-expressed genes and used to identify central elements and, together with the analysis of over-represented transcription factor motifs, to predict active signaling and regulatory pathways. This was further validated by Metal-Oxide Affinity Chromatography (MOAC and Tandem Mass Spectrometry (MS/MS assays which retrieved phosphorylated proteins. The 14-3-3 family members emerge as important regulators in carcinogenesis and as possible clinical targets. We observed that the different over- and under-regulated pathways in cervical cancer could be interrelated through elements that participate in crosstalks, therefore belong to what we term "meta-pathways". Additionally, we highlighted the relations of each one of the differentially represented pathways to one or more of the ten hallmarks of cancer. These features could be maintained in many other types of cancer, regardless of mutations or genomic rearrangements, and favor their robustness, adaptations and the evasion of tissue control. Probably, this could explain why cancer cells are not eliminated by selective pressure and why therapy trials directed against molecular targets are not as effective as expected.

  18. Systems Biology Model of Interactions between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFβ and ATM Signaling

    Energy Technology Data Exchange (ETDEWEB)

    Cucinotta, Francis A [Univ. of Nevada, Las Vegas, NV (United States)

    2016-09-01

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low dose responses and cross-talk between the ATM and TGFβ pathways initiated by low and high LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to crosstalk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental approaches

  19. Systems Biology Model of Interactions Between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFbeta and ATM Signaling

    Energy Technology Data Exchange (ETDEWEB)

    O' Neill, Peter [University of Oxford; Anderson, Jennifer [University of Oxford

    2014-10-02

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low dose responses and cross-talk between the ATM and TGFβ pathways initiated by low and high LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to cross- talk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  20. Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes

    DEFF Research Database (Denmark)

    Pers, Tune H; Timshel, Pascal; Ripke, Stephan;

    2016-01-01

    Over 100 associated genetic loci have been robustly associated with schizophrenia. Gene prioritization and pathway analysis have focused on a priori hypotheses and thus may have been unduly influenced by prior assumptions and missed important causal genes and pathways. Using a data-driven approach...... validate the relevance of the prioritized genes by showing that they are enriched for rare disruptive variants and de novo variants from schizophrenia sequencing studies (odds ratio 1.67, P=0.039), and are enriched for genes encoding members of mouse and human postsynaptic density proteomes (odds ratio 4......, we show that genes in associated loci: (1) are highly expressed in cortical brain areas; (2) are enriched for ion channel pathways (false discovery ratesgenes that are functionally related to each other and hence represent promising candidates for experimental follow up. We...

  1. From Hans Selye’s Discovery of Biological Stress to the Identification of Corticotropin Releasing Factor signaling pathways: Implication in Stress-Related Functional Bowel Diseases

    OpenAIRE

    2008-01-01

    Selye’s pioneer the concept of biological stress in 1936 culminating to the identification of the corticotropin releasing factor (CRF) signaling pathways by Vale’s group in the last two decades. The characterization of the 41 amino-acid CRF and other peptide members of the mammalian CRF family, urocortin 1, urocortin 2 and urocortin 3, the cloning of CRF1 and CRF2 receptors, which display distinct affinity for CRF ligands, combined with the development of selective CRF receptor antagonists en...

  2. Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Takahashi Shinichiro

    2011-04-01

    Full Text Available Abstract FLT3 is a type III receptor tyrosine kinase. Mutations of FLT3 comprise one of the most frequently identified types of genetic alterations in acute myeloid leukemia. One-third of acute myeloid leukemia patients have mutations of this gene, and the majority of these mutations involve an internal tandem duplication in the juxtamembrane region of FLT3, leading to constitutive activation of downstream signaling pathways and aberrant cell growth. This review summarizes the current understanding of the effects of the downstream molecular signaling pathways after FLT3 activation, with a particular focus on the effects on transcription factors. Moreover, this review describes novel FLT3-targeted therapies, as well as efficient combination therapies for FLT3-mutated leukemia cells.

  3. Systems Biology-Based Identification of Crosstalk between E2F Transcription Factors and the Fanconi Anemia Pathway

    Directory of Open Access Journals (Sweden)

    Moe Tategu

    2007-01-01

    Full Text Available Fanconi anemia (FA is an autosomal recessive disorder characterized by congenital abnormalities, bone marrow failure, chromosome fragility, and cancer susceptibility. At least eleven members of the FA gene family have been identified using complementation experiments. Ubiquitin-proteasome has been shown to be a key regulator of FA proteins and their involvement in the repair of DNA damage. Here, we identifi ed a novel functional link between the FA/BRCA pathway and E2F-mediated cell cycle regulome. In silico mining of a transcriptome database and promoter analyses revealed that a significant number of FA gene members were regulated by E2F transcription factors, known to be pivotal regulators of cell cycle progression – as previously described for BRCA1. Our findings suggest that E2Fs partly determine cell fate through the FA/BRCA pathway.

  4. Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes.

    Science.gov (United States)

    Pers, Tune H; Timshel, Pascal; Ripke, Stephan; Lent, Samantha; Sullivan, Patrick F; O'Donovan, Michael C; Franke, Lude; Hirschhorn, Joel N

    2016-03-15

    Over 100 associated genetic loci have been robustly associated with schizophrenia. Gene prioritization and pathway analysis have focused on a priori hypotheses and thus may have been unduly influenced by prior assumptions and missed important causal genes and pathways. Using a data-driven approach, we show that genes in associated loci: (1) are highly expressed in cortical brain areas; (2) are enriched for ion channel pathways (false discovery rates genes that are functionally related to each other and hence represent promising candidates for experimental follow up. We validate the relevance of the prioritized genes by showing that they are enriched for rare disruptive variants and de novo variants from schizophrenia sequencing studies (odds ratio 1.67, P = 0.039), and are enriched for genes encoding members of mouse and human postsynaptic density proteomes (odds ratio 4.56, P = 5.00 × 10(-4); odds ratio 2.60, P = 0.049).The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Author.

  5. The MUC1 oncomucin regulates pancreatic cancer cell biological properties and chemoresistance. Implication of p42–44 MAPK, Akt, Bcl-2 and MMP13 pathways

    Energy Technology Data Exchange (ETDEWEB)

    Tréhoux, Solange; Duchêne, Bélinda; Jonckheere, Nicolas; Van Seuningen, Isabelle, E-mail: isabelle.vanseuningen@inserm.fr

    2015-01-16

    Highlights: • Loss of MUC1 decreases proliferation and tumor growth via β-catenin and p42–44 MAPK. • Inhibition of MUC1 decreases cell migration and invasion through MMP13. • Loss of MUC1 decreases survival and increases apoptosis via Akt and Bcl-2 pathways. • Loss of MUC1 sensitizes cells to gemcitabine and 5-Fluorouracil chemotherapeutic drugs. - Abstract: MUC1 is an oncogenic mucin overexpressed in several epithelial cancers, including pancreatic ductal adenocarcinoma, and is considered as a potent target for cancer therapy. To this aim, we undertook to study MUC1 biological effects on pancreatic cancer cells and identify pathways mediating these effects. Our in vitro experiments indicate that inhibiting MUC1 expression decreases cell proliferation, cell migration and invasion, cell survival and increases cell apoptosis. Moreover, lack of MUC1 in these cells profoundly altered their sensitivity to gemcitabine and 5-Fluorouracil chemotherapeutic drugs. In vivo MUC1-KD cell xenografts in SCID mice grew slower. Altogether, we show that MUC1 oncogenic mucin alters proliferation, migration, and invasion properties of pancreatic cancer cells and that these effects are mediated by p42–44 MAPK, Akt, Bcl-2 and MMP13 pathways.

  6. A Western blot-based investigation of the yeast secretory pathway designed for an intermediate-level undergraduate cell biology laboratory.

    Science.gov (United States)

    Hood-Degrenier, Jennifer K

    2008-01-01

    The movement of newly synthesized proteins through the endomembrane system of eukaryotic cells, often referred to generally as the secretory pathway, is a topic covered in most intermediate-level undergraduate cell biology courses. An article previously published in this journal described a laboratory exercise in which yeast mutants defective in two distinct steps of protein secretion were differentiated using a genetic reporter designed specifically to identify defects in the first step of the pathway, the insertion of proteins into the endoplasmic reticulum (Vallen, 2002). We have developed two versions of a Western blotting assay that serves as a second way of distinguishing the two secretory mutants, which we pair with the genetic assay in a 3-wk laboratory module. A quiz administered before and after students participated in the lab activities revealed significant postlab gains in their understanding of the secretory pathway and experimental techniques used to study it. A second survey administered at the end of the lab module assessed student perceptions of the efficacy of the lab activities; the results of this survey indicated that the experiments were successful in meeting a set of educational goals defined by the instructor.

  7. Regulatory effect of evodiamine on the malignant biological behaviors and Wnt/β-catenin signaling pathway of colorectal cancer cell lines HT29

    Institute of Scientific and Technical Information of China (English)

    Yuan-HuiWang; Zhen-Hua Zhou

    2016-01-01

    Objective:To study the regulatory effect of evodiamine on the malignant biological behaviors and Wnt/β-catenin signaling pathway of colorectal cancer cell lines HT29.Methods:Colorectal cancer cell lines HT29 were cultured and divided into blank control group and evodiamine group, and after different treatment, cell viability, proportion of different cell cycle as well as the contents of VEGFA, VEGFB, VEGFC, MMP3, MMP14, Wnt andβ-catenin were detected.Results: (1) Cell viability: MTT value of evodiamine group was significantly lower than that of blank control group; (2) Cell cycle: proportion of both S phase and G2/M phase of evodiamine group were lower than those of blank control group, and proportion of G0/G1 phase was higher than that of blank control group; (3) VEGF and MMP contents: VEGFA, VEGFB, VEGFC, MMP3 and MMP14 contents of evodiamine group were lower than those of blank control group; (4) Wnt/β-catenin signaling pathway: Wnt andβ-catenin contents of evodiamine group were lower than those of blank control group.Conclusion:Evodiamine can inhibit the proliferation of colorectal cancer cell lines HT29 and down-regulate the expression of VEGF and MMP, and the effect may be achieved by inhibiting the activation of Wnt/β-catenin signaling pathway.

  8. Ultraperformance liquid chromatography-mass spectrometry based comprehensive metabolomics combined with pattern recognition and network analysis methods for characterization of metabolites and metabolic pathways from biological data sets.

    Science.gov (United States)

    Zhang, Ai-hua; Sun, Hui; Han, Ying; Yan, Guang-li; Yuan, Ye; Song, Gao-chen; Yuan, Xiao-xia; Xie, Ning; Wang, Xi-jun

    2013-08-06

    Metabolomics is the study of metabolic changes in biological systems and provides the small molecule fingerprints related to the disease. Extracting biomedical information from large metabolomics data sets by multivariate data analysis is of considerable complexity. Therefore, more efficient and optimizing metabolomics data processing technologies are needed to improve mass spectrometry applications in biomarker discovery. Here, we report the findings of urine metabolomic investigation of hepatitis C virus (HCV) patients by high-throughput ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) coupled with pattern recognition methods (principal component analysis, partial least-squares, and OPLS-DA) and network pharmacology. A total of 20 urinary differential metabolites (13 upregulated and 7 downregulated) were identified and contributed to HCV progress, involve several key metabolic pathways such as taurine and hypotaurine metabolism, glycine, serine and threonine metabolism, histidine metabolism, arginine and proline metabolism, and so forth. Metabolites identified through metabolic profiling may facilitate the development of more accurate marker algorithms to better monitor disease progression. Network analysis validated close contact between these metabolites and implied the importance of the metabolic pathways. Mapping altered metabolites to KEGG pathways identified alterations in a variety of biological processes mediated through complex networks. These findings may be promising to yield a valuable and noninvasive tool that insights into the pathophysiology of HCV and to advance the early diagnosis and monitor the progression of disease. Overall, this investigation illustrates the power of the UPLC-MS platform combined with the pattern recognition and network analysis methods that can engender new insights into HCV pathobiology.

  9. Biological degradation of 4-chlorobenzoic acid by a PCB-metabolizing bacterium through a pathway not involving (chloro)catechol.

    Science.gov (United States)

    Adebusoye, Sunday A

    2017-02-01

    Cupriavidus sp. strain SK-3, previously isolated on polychlorinated biphenyl mixtures, was found to aerobically utilize a wide spectrum of substituted aromatic compounds including 4-fluoro-, 4-chloro- and 4-bromobenzoic acids as a sole carbon and energy source. Other chlorobenzoic acid (CBA) congeners such as 2-, 3-, 2,3-, 2,5-, 3,4- and 3,5-CBA were all rapidly transformed to respective chlorocatechols (CCs). Under aerobic conditions, strain SK-3 grew readily on 4-CBA to a maximum concentration of 5 mM above which growth became impaired and yielded no biomass. Growth lagged significantly at concentrations above 3 mM, however chloride elimination was stoichiometric and generally mirrored growth and substrate consumption in all incubations. Experiments with resting cells, cell-free extracts and analysis of metabolite pools suggest that 4-CBA was metabolized in a reaction exclusively involving an initial hydrolytic dehalogenation yielding 4-hydroxybenzoic acid, which was then hydroxylated to protocatechuic acid (PCA) and subsequently metabolized via the β-ketoadipate pathway. When strain SK-3 was grown on 4-CBA, there was gratuitous induction of the catechol-1,2-dioxygenase and gentisate-1,2-dioxygenase pathways, even if both were not involved in the metabolism of the acid. While activities of the modified ortho- and meta-cleavage pathways were not detectable in all extracts, activity of PCA-3,4-dioxygenase was over ten-times higher than those of catechol-1,2- and gentisate-1,2-dioxygenases. Therefore, the only reason other congeners were not utilized for growth was the accumulation of CCs, suggesting a narrow spectrum of the activity of enzymes downstream of benzoate-1,2-dioxygenase, which exhibited affinity for a number of substituted analogs, and that the metabolic bottlenecks are either CCs or catabolites of the modified ortho-cleavage metabolic route.

  10. Cellular Signaling Pathways in Insulin Resistance-Systems Biology Analyses of Microarray Dataset Reveals New Drug Target Gene Signatures of Type 2 Diabetes Mellitus

    Science.gov (United States)

    Muhammad, Syed Aun; Raza, Waseem; Nguyen, Thanh; Bai, Baogang; Wu, Xiaogang; Chen, Jake

    2017-01-01

    Purpose: Type 2 diabetes mellitus (T2DM) is a chronic and metabolic disorder affecting large set of population of the world. To widen the scope of understanding of genetic causes of this disease, we performed interactive and toxicogenomic based systems biology study to find potential T2DM related genes after cDNA differential analysis. Methods: From the list of 50-differential expressed genes (p < 0.05), we found 9-T2DM related genes using extensive data mapping. In our constructed gene-network, T2DM-related differentially expressed seeder genes (9-genes) are found to interact with functionally related gene signatures (31-genes). The genetic interaction network of both T2DM-associated seeder as well as signature genes generally relates well with the disease condition based on toxicogenomic and data curation. Results: These networks showed significant enrichment of insulin signaling, insulin secretion and other T2DM-related pathways including JAK-STAT, MAPK, TGF, Toll-like receptor, p53 and mTOR, adipocytokine, FOXO, PPAR, P13-AKT, and triglyceride metabolic pathways. We found some enriched pathways that are common in different conditions. We recognized 11-signaling pathways as a connecting link between gene signatures in insulin resistance and T2DM. Notably, in the drug-gene network, the interacting genes showed significant overlap with 13-FDA approved and few non-approved drugs. This study demonstrates the value of systems genetics for identifying 18 potential genes associated with T2DM that are probable drug targets. Conclusions: This integrative and network based approaches for finding variants in genomic data expect to accelerate identification of new drug target molecules for different diseases and can speed up drug discovery outcomes. PMID:28179884

  11. Multivariate imaging-genetics study of MRI gray matter volume and SNPs reveals biological pathways correlated with brain structural differences in Attention Deficit Hyperactivity Disorder

    Directory of Open Access Journals (Sweden)

    Sabin Khadka

    2016-07-01

    Full Text Available Background: Attention Deficit Hyperactivity Disorder (ADHD is a prevalent neurodevelopmental disorder affecting children, adolescents, and adults. Its etiology is not well-understood, but it is increasingly believed to result from diverse pathophysiologies that affect the structure and function of specific brain circuits. Although one of the best-studied neurobiological abnormalities in ADHD is reduced fronto-striatal-cerebellar gray matter volume, its specific genetic correlates are largely unknown. Methods: In this study, T1-weighted MR images of brain structure were collected from 198 adolescents (63 ADHD-diagnosed. A multivariate parallel independent component analysis technique (Para-ICA identified imaging-genetic relationships between regional gray matter volume and single nucleotide polymorphism data. Results: Para-ICA analyses extracted 14 components from genetic data and 9 from MR data. An iterative cross-validation using randomly-chosen sub-samples indicated acceptable stability of these ICA solutions. A series of partial correlation analyses controlling for age, sex, and ethnicity revealed two genotype-phenotype component pairs significantly differed between ADHD and non-ADHD groups, after a Bonferroni correction for multiple comparisons. The brain phenotype component not only included structures frequently found to have abnormally low volume in previous ADHD studies, but was also significantly associated with ADHD differences in symptom severity and performance on cognitive tests frequently found to be impaired in patients diagnosed with the disorder. Pathway analysis of the genotype component identified several different biological pathways linked to these structural abnormalities in ADHD. Conclusions: Some of these pathways implicate well-known dopaminergic neurotransmission and neurodevelopment hypothesized to be abnormal in ADHD. Other more recently implicated pathways included glutamatergic and GABA-eric physiological systems

  12. Biology-oriented synthesis of a natural-product inspired oxepane collection yields a small-molecule activator of the Wnt-pathway.

    Science.gov (United States)

    Basu, Sudipta; Ellinger, Bernhard; Rizzo, Stefano; Deraeve, Céline; Schürmann, Markus; Preut, Hans; Arndt, Hans-Dieter; Waldmann, Herbert

    2011-04-26

    In Biology Oriented Synthesis the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is met by the structurally complex scaffolds of natural products (NPs) selected in evolution. The synthesis of NP-inspired compound collections approaching the complexity of NPs calls for the development of efficient synthetic methods. We have developed a one pot 4-7 step synthesis of mono-, bi-, and tricyclic oxepanes that resemble the core scaffolds of numerous NPs with diverse bioactivities. This sequence entails a ring-closing ene-yne metathesis reaction as key step and makes productive use of polymer-immobilized scavenger reagents. Biological profiling of a corresponding focused compound collection in a reporter gene assay monitoring for Wnt-signaling modulation revealed active Wntepanes. This unique class of small-molecule activators of the Wnt pathway modulates the van-Gogh-like receptor proteins (Vangl), which were previously identified in noncanonical Wnt signaling, and acts in synergy with the canonical activator protein (Wnt-3a).

  13. Recasting developmental evolution in terms of genetic pathway and network evolution ... and the implications for comparative biology.

    Science.gov (United States)

    Wilkins, Adam S

    2005-09-15

    The morphological features of complex organisms are the outcomes of developmental processes. Developmental processes, in turn, reflect the genetic networks that underlie them. Differences in morphology must ultimately, therefore, reflect differences in the underlying genetic networks. A mutation that affects a developmental process does so by affecting either a gene whose product acts as an upstream controlling element, an intermediary connecting link, or as a downstream output of the network that governs the trait's development. Although the immense diversity of gene networks in the animal and plant kingdoms would seem to preclude any general "rules" of network evolution, the material discussed here suggests that the patterns of genetic pathway and network evolution actually fall into a number of discrete modes. The potential utility of this conceptual framework in reconstructing instances of developmental evolution and for comparative neurobiology will be discussed.

  14. Determination of the internalization pathway of photoluminescent nanodiamonds in mammalian cells for biological labeling and optimization of the ?uorescent yield

    CERN Document Server

    Faklaris, Orestis; Irinopoulou, Theano; Tauc, Patrick; Girard, Hugues; Gesset, Celine; Senour, Mohamed; Thorel, Alain; Arnault, Jean-Charles; Boudou, Jean-Paul; Curmi, Patrick A; Treussart, François

    2009-01-01

    Diamond nanoparticles have been recently used as new ?uorescent labels in cells. Their emission relies on color centers embedded in the diamond matrix. In this work we compare the photoluminescence of a single color center embedded in a 30 nm diameter nanodiamond to that to a single dye molecule and demonstrate the perfect photostability of the color centers. We also compare the photoluminescence properties of nanodiamonds prepared under different conditions in order to ?nd the optimal parameters to achieve a high ?uorescence yield. We use these photoluminescent nanodiamonds for HeLa cell labeling and investigate their uptake mechanism. On the one hand by immunostaining the endocytotic vesicles and on the other by transmission electron microscopy observations we study the localization of nanodiamonds in cells. Moreover, by blocking selectively different endocytotic mechanisms we unravel their internalization pathway. We ?nd that nanodiamonds enter the cells by receptor-mediated endocytosis. The results of thi...

  15. Biologics beyond TNF-α inhibitors and the effect of targeting the homologues TL1A-DR3 pathway in chronic inflammatory disorders

    DEFF Research Database (Denmark)

    Tougaard, Peter; Zervides, Kristoffer Alexander; Skov, Søren

    2016-01-01

    A number of anti-tumor necrosis factor alpha (TNF-α) biologics have been developed in recent years, such as adalimumab, etanercept, and infliximab for the treatment of chronic inflammatory disorders like rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis and several other...... novel drugs that target TNF-α signaling are still being developed. Indeed, blockade of this pathway seems so important amongst immune-targets that TNF-α targeted therapies will continue to have a significant role in the treatment of chronic inflammation. However, up to 40% of RA and IBD patients do...... concentrations of TL1A has been demonstrated in patients with various chronic inflammatory disorders. Here, we describe the current knowledge of TL1As immunobiology and present results from human disease, animal models, and pre-clinical intervention studies that point toward development of anti-TL1A therapy...

  16. From Hans Selye's discovery of biological stress to the identification of corticotropin-releasing factor signaling pathways: implication in stress-related functional bowel diseases.

    Science.gov (United States)

    Taché, Yvette; Brunnhuber, Stefan

    2008-12-01

    Selye pioneered the concept of biological stress in 1936, culminating in the identification of the corticotropin-releasing factor (CRF) signaling pathways by Vale's group in the last two decades. The characterization of the 41 amino-acid CRF and other peptide members of the mammalian CRF family, urocortin 1, urocortin 2, and urocortin 3, and the cloning of CRF(1) and CRF(2) receptors, which display distinct affinity for CRF ligands, combined with the development of selective CRF receptor antagonists enable us to unravel the importance of CRF(1) receptor in the stress-related endocrine (activation of pituitary-adrenal axis), behavioral (anxiety/depression, altered feeding), autonomic (activation of sympathetic nervous system), and immune responses. The activation of CRF(1) receptors is also one of the key mechanisms through which various stressors impact the gut to stimulate colonic propulsive motor function and to induce hypersensitivity to colorectal distension as shown by the efficacy of the CRF(1) receptor antagonists in blunting these stress-related components. The importance of CRF(1) signaling pathway in the visceral response to stress in experimental animals provided new therapeutic approaches for treatment of functional bowel disorder such as irritable bowel syndrome, a multifactor functional disorder characterized by altered bowel habits and visceral pain, for which stress has been implicated in the pathophysiology and is associated with anxiety-depression in a subset of patients.

  17. Antioxidant pathways are up-regulated during biological nitrogen fixation to prevent ROS-induced nitrogenase inhibition in Gluconacetobacter diazotrophicus.

    Science.gov (United States)

    Alquéres, Sylvia M C; Oliveira, Jose Henrique M; Nogueira, Eduardo M; Guedes, Helma V; Oliveira, Pedro L; Câmara, Fernando; Baldani, Jose I; Martins, Orlando B

    2010-10-01

    Gluconacetobacter diazotrophicus, an endophyte isolated from sugarcane, is a strict aerobe that fixates N(2). This process is catalyzed by nitrogenase and requires copious amounts of ATP. Nitrogenase activity is extremely sensitive to inhibition by oxygen and reactive oxygen species (ROS). However, the elevated oxidative metabolic rates required to sustain biological nitrogen fixation (BNF) may favor an increased production of ROS. Here, we explored this paradox and observed that ROS levels are, in fact, decreased in nitrogen-fixing cells due to the up-regulation of transcript levels of six ROS-detoxifying genes. A cluster analyses based on common expression patterns revealed the existence of a stable cluster with 99.8% similarity made up of the genes encoding the α-subunit of nitrogenase Mo-Fe protein (nifD), superoxide dismutase (sodA) and catalase type E (katE). Finally, nitrogenase activity was inhibited in a dose-dependent manner by paraquat, a redox cycler that increases cellular ROS levels. Our data revealed that ROS can strongly inhibit nitrogenase activity, and G. diazotrophicus alters its redox metabolism during BNF by increasing antioxidant transcript levels resulting in a lower ROS generation. We suggest that careful controlled ROS production during this critical phase is an adaptive mechanism to allow nitrogen fixation.

  18. Metabolic Reconstruction of Setaria italica: A Systems Biology Approach for Integrating Tissue-Specific Omics and Pathway Analysis of Bioenergy Grasses.

    Science.gov (United States)

    de Oliveira Dal'Molin, Cristiana G; Orellana, Camila; Gebbie, Leigh; Steen, Jennifer; Hodson, Mark P; Chrysanthopoulos, Panagiotis; Plan, Manuel R; McQualter, Richard; Palfreyman, Robin W; Nielsen, Lars K

    2016-01-01

    The urgent need for major gains in industrial crops productivity and in biofuel production from bioenergy grasses have reinforced attention on understanding C4 photosynthesis. Systems biology studies of C4 model plants may reveal important features of C4 metabolism. Here we chose foxtail millet (Setaria italica), as a C4 model plant and developed protocols to perform systems biology studies. As part of the systems approach, we have developed and used a genome-scale metabolic reconstruction in combination with the use of multi-omics technologies to gain more insights into the metabolism of S. italica. mRNA, protein, and metabolite abundances, were measured in mature and immature stem/leaf phytomers, and the multi-omics data were integrated into the metabolic reconstruction framework to capture key metabolic features in different developmental stages of the plant. RNA-Seq reads were mapped to the S. italica resulting for 83% coverage of the protein coding genes of S. italica. Besides revealing similarities and differences in central metabolism of mature and immature tissues, transcriptome analysis indicates significant gene expression of two malic enzyme isoforms (NADP- ME and NAD-ME). Although much greater expression levels of NADP-ME genes are observed and confirmed by the correspondent protein abundances in the samples, the expression of multiple genes combined to the significant abundance of metabolites that participates in C4 metabolism of NAD-ME and NADP-ME subtypes suggest that S. italica may use mixed decarboxylation modes of C4 photosynthetic pathways under different plant developmental stages. The overall analysis also indicates different levels of regulation in mature and immature tissues in carbon fixation, glycolysis, TCA cycle, amino acids, fatty acids, lignin, and cellulose syntheses. Altogether, the multi-omics analysis reveals different biological entities and their interrelation and regulation over plant development. With this study, we demonstrated

  19. Metabolic Reconstruction of Setaria italica: A Systems Biology Approach for Integrating Tissue-Specific Omics and Pathway Analysis of Bioenergy Grasses

    Science.gov (United States)

    de Oliveira Dal'Molin, Cristiana G.; Orellana, Camila; Gebbie, Leigh; Steen, Jennifer; Hodson, Mark P.; Chrysanthopoulos, Panagiotis; Plan, Manuel R.; McQualter, Richard; Palfreyman, Robin W.; Nielsen, Lars K.

    2016-01-01

    The urgent need for major gains in industrial crops productivity and in biofuel production from bioenergy grasses have reinforced attention on understanding C4 photosynthesis. Systems biology studies of C4 model plants may reveal important features of C4 metabolism. Here we chose foxtail millet (Setaria italica), as a C4 model plant and developed protocols to perform systems biology studies. As part of the systems approach, we have developed and used a genome-scale metabolic reconstruction in combination with the use of multi-omics technologies to gain more insights into the metabolism of S. italica. mRNA, protein, and metabolite abundances, were measured in mature and immature stem/leaf phytomers, and the multi-omics data were integrated into the metabolic reconstruction framework to capture key metabolic features in different developmental stages of the plant. RNA-Seq reads were mapped to the S. italica resulting for 83% coverage of the protein coding genes of S. italica. Besides revealing similarities and differences in central metabolism of mature and immature tissues, transcriptome analysis indicates significant gene expression of two malic enzyme isoforms (NADP- ME and NAD-ME). Although much greater expression levels of NADP-ME genes are observed and confirmed by the correspondent protein abundances in the samples, the expression of multiple genes combined to the significant abundance of metabolites that participates in C4 metabolism of NAD-ME and NADP-ME subtypes suggest that S. italica may use mixed decarboxylation modes of C4 photosynthetic pathways under different plant developmental stages. The overall analysis also indicates different levels of regulation in mature and immature tissues in carbon fixation, glycolysis, TCA cycle, amino acids, fatty acids, lignin, and cellulose syntheses. Altogether, the multi-omics analysis reveals different biological entities and their interrelation and regulation over plant development. With this study, we demonstrated

  20. Biological Silicon Stimulates Collagen Type 1 and Osteocalcin Synthesis in Human Osteoblast-Like Cells Through the BMP-2/Smad/RUNX2 Signaling Pathway.

    Science.gov (United States)

    Dong, Meng; Jiao, Guangjun; Liu, Haichun; Wu, Wenliang; Li, Shangzhi; Wang, Qingshi; Xu, Daxia; Li, Xiaofeng; Liu, Huan; Chen, Yunzhen

    2016-10-01

    Silicon is essential for bone formation. A low-silicon diet leads to bone defects, and numerous animal models have demonstrated that silicon supplementation increases bone mineral density (BMD) and reduces bone fragility. However, the exact mechanism of this action has not been characterized. In this study, we aimed to determine the role of biological silicon in the induction of osteoblast differentiation and the possible underlying mechanism. We examined whether orthosilicic acid promotes collagen type 1 (COL-1) and osteocalcin synthesis through the bone morphogenetic protein-2 (BMP-2)/Smad1/5/runt-related transcription factor 2 (RUNX2) signaling pathway by investigating its effect in vitro at several concentrations on COL-1 and osteocalcin synthesis in human osteosarcoma cell lines (MG-63 and U2-OS). The expression of relevant proteins was detected by Western blotting following exposure to noggin, an inhibitor of BMP-2. In MG-63 cells, immunofluorescence methods were applied to detect changes in the expression of BMP-2, phosphorylated Smad1/5 (P-Smad1/5), and RUNX2. Furthermore, rat bone mesenchymal stem cells (BMSCs) were used to determine the effect of orthosilicic acid on osteogenic differentiation. Exposure to 10 μM orthosilicic acid markedly increased the expression of BMP-2, P-Smad1/5, RUNX2, COL-1, and osteocalcin in osteosarcoma cell lines. Enhanced ALP activity and the formation of mineralized nodules were also observed under these conditions. Furthermore, preconditioning with noggin inhibited the silicon-induced upregulation of P-Smad1/5, RUNX2, and COL-1 expression. In conclusion, the BMP-2/Smad1/5/RUNX2 signaling pathway participates in the silicon-mediated induction of COL-1 and osteocalcin synthesis, and orthosilicic acid promotes the osteogenic differentiation of rat BMSCs.

  1. Transcription Adaptation during In Vitro Adipogenesis and Osteogenesis of Porcine Mesenchymal Stem Cells: Dynamics of Pathways, Biological Processes, Up-Stream Regulators, and Gene Networks.

    Directory of Open Access Journals (Sweden)

    Massimo Bionaz

    Full Text Available 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

  2. A Systems Biology Approach to Reveal Putative Host-Derived Biomarkers of Periodontitis by Network Topology Characterization of MMP-REDOX/NO and Apoptosis Integrated Pathways.

    Science.gov (United States)

    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.

  3. Pathway of FeEDTA transformation and its impact on performance of NOx removal in a chemical absorption-biological reduction integrated process.

    Science.gov (United States)

    Li, Wei; Zhao, Jingkai; Zhang, Lei; Xia, Yinfeng; Liu, Nan; Li, Sujing; Zhang, Shihan

    2016-01-01

    A novel chemical absorption-biological reduction (CABR) integrated process, employing ferrous ethylenediaminetetraacetate (Fe(II)EDTA) as a solvent, is deemed as a potential option for NOx removal from the flue gas. Previous work showed that the Fe(II)EDTA concentration was critical for the NOx removal in the CABR process. In this work, the pathway of FeEDTA (Fe(III)/Fe(II)-EDTA) transformation was investigated to assess its impact on the NOx removal in a biofilter. Experimental results revealed that the FeEDTA transformation involved iron precipitation and EDTA degradation. X-ray photoelectron spectroscopy analysis confirmed the iron was precipitated in the form of Fe(OH)3. The iron mass balance analysis showed 44.2% of the added iron was precipitated. The EDTA degradation facilitated the iron precipitation. Besides chemical oxidation, EDTA biodegradation occurred in the biofilter. The addition of extra EDTA helped recover the iron from the precipitation. The transformation of FeEDTA did not retard the NO removal. In addition, EDTA rather than the iron concentration determined the NO removal efficiency.

  4. Differential effect of the expression of TGF-β pathway inhibitors, Smad-7 and Ski, on invasive breast carcinomas: relation to biologic behavior.

    Science.gov (United States)

    Theohari, Irini; Giannopoulou, Ioanna; Magkou, Christina; Nomikos, Alexandros; Melissaris, Savvas; Nakopoulou, Lydia

    2012-02-01

    The aim of our study was to investigate the expression of Smad-7 and Ski proteins in invasive breast carcinomas, to determine their clinicopathological value and their influence on carcinomas biologic behavior. Immunohistochemistry was applied on 150 invasive breast carcinomas to detect the expression of Smad-7 and Ski. Their correlation to clinicopathologic parameters and markers of metastasis was statistically processed using chi-squared test. Overall and disease-free survival was assessed using Kaplan-Meier test and log-rank statistics. Smad-7 was immunodetected in the cytoplasm of cancer cells in 60%, whereas Ski was immunodetected in the cytoplasm and nuclei in 44.5% and 17.6% of the cases, respectively. Smad-7 expression was positively correlated with tumor size, stage, matrix metalloproteinase (MMP)-9, and MMP-14. Cytoplasmic Ski expression was negatively associated with tumor size, stage, and lymph node status, and its nuclear expression was negatively related to histologic grade. Cytoplasmic Ski expression was associated with longer overall and disease-free survival. It appears that two negative regulators of the transforming growth factor-β pathway, Smad-7 and Ski, behave differentially in invasive breast carcinomas. Smad-7 appears to be related with an aggressive phenotype, whereas Ski expression is related to a less aggressive behavior and positively influences patients' survival.

  5. Redox biology in normal cells and cancer: restoring function of the redox/Fyn/c-Cbl pathway in cancer cells offers new approaches to cancer treatment.

    Science.gov (United States)

    Noble, Mark; Mayer-Pröschel, Margot; Li, Zaibo; Dong, Tiefei; Cui, Wanchang; Pröschel, Christoph; Ambeskovic, Ibro; Dietrich, Joerg; Han, Ruolan; Yang, Yin Miranda; Folts, Christopher; Stripay, Jennifer; Chen, Hsing-Yu; Stevens, Brett M

    2015-02-01

    This review discusses a unique discovery path starting with novel findings on redox regulation of precursor cell and signaling pathway function and identification of a new mechanism by which relatively small changes in redox status can control entire signaling networks that regulate self-renewal, differentiation, and survival. The pathway central to this work, the redox/Fyn/c-Cbl (RFC) pathway, converts small increases in oxidative status to pan-activation of the c-Cbl ubiquitin ligase, which controls multiple receptors and other proteins of central importance in precursor cell and cancer cell function. Integration of work on the RFC pathway with attempts to understand how treatment with systemic chemotherapy causes neurological problems led to the discovery that glioblastomas (GBMs) and basal-like breast cancers (BLBCs) inhibit c-Cbl function through altered utilization of the cytoskeletal regulators Cool-1/βpix and Cdc42, respectively. Inhibition of these proteins to restore normal c-Cbl function suppresses cancer cell division, increases sensitivity to chemotherapy, disrupts tumor-initiating cell (TIC) activity in GBMs and BLBCs, controls multiple critical TIC regulators, and also allows targeting of non-TICs. Moreover, these manipulations do not increase chemosensitivity or suppress division of nontransformed cells. Restoration of normal c-Cbl function also allows more effective harnessing of estrogen receptor-α (ERα)-independent activities of tamoxifen to activate the RFC pathway and target ERα-negative cancer cells. Our work thus provides a discovery strategy that reveals mechanisms and therapeutic targets that cannot be deduced by standard genetics analyses, which fail to reveal the metabolic information, isoform shifts, protein activation, protein complexes, and protein degradation critical to our discoveries.

  6. Systematization of the protein sequence diversity in enzymes related to secondary metabolic pathways in plants, in the context of big data biology inspired by the KNApSAcK motorcycle database.

    Science.gov (United States)

    Ikeda, Shun; Abe, Takashi; Nakamura, Yukiko; Kibinge, Nelson; Hirai Morita, Aki; Nakatani, Atsushi; Ono, Naoaki; Ikemura, Toshimichi; Nakamura, Kensuke; Altaf-Ul-Amin, Md; Kanaya, Shigehiko

    2013-05-01

    Biology is increasingly becoming a data-intensive science with the recent progress of the omics fields, e.g. genomics, transcriptomics, proteomics and metabolomics. The species-metabolite relationship database, KNApSAcK Core, has been widely utilized and cited in metabolomics research, and chronological analysis of that research work has helped to reveal recent trends in metabolomics research. To meet the needs of these trends, the KNApSAcK database has been extended by incorporating a secondary metabolic pathway database called Motorcycle DB. We examined the enzyme sequence diversity related to secondary metabolism by means of batch-learning self-organizing maps (BL-SOMs). Initially, we constructed a map by using a big data matrix consisting of the frequencies of all possible dipeptides in the protein sequence segments of plants and bacteria. The enzyme sequence diversity of the secondary metabolic pathways was examined by identifying clusters of segments associated with certain enzyme groups in the resulting map. The extent of diversity of 15 secondary metabolic enzyme groups is discussed. Data-intensive approaches such as BL-SOM applied to big data matrices are needed for systematizing protein sequences. Handling big data has become an inevitable part of biology.

  7. Cellular Signaling Pathways in Insulin Resistance-Systems Biology Analyses of Microarray Dataset Reveals New Drug Target Gene Signatures of Type 2 Diabetes Mellitus.

    Science.gov (United States)

    Muhammad, Syed Aun; Raza, Waseem; Nguyen, Thanh; Bai, Baogang; Wu, Xiaogang; Chen, Jake

    2017-01-01

    Purpose: Type 2 diabetes mellitus (T2DM) is a chronic and metabolic disorder affecting large set of population of the world. To widen the scope of understanding of genetic causes of this disease, we performed interactive and toxicogenomic based systems biology study to find potential T2DM related genes after cDNA differential analysis. Methods: From the list of 50-differential expressed genes (p new drug target molecules for different diseases and can speed up drug discovery outcomes.

  8. Alpha-2-glycoprotein 1(AZGP1 regulates biological behaviors of LoVo cells by down-regulating mTOR signaling pathway and endogenous fatty acid synthesis.

    Directory of Open Access Journals (Sweden)

    Ligong Chang

    Full Text Available AZGP1 is a multifaceted protein associated with lipid mobilization, a process that is regulated by FASN and other metabolic pathways such as mTOR signaling. The active mTOR signaling pathway has been found to be involved in a variety of tumors. However, it remains unclear whether it is involved in the regulation of AZGP1 and FASN. An AZGP1-expressing plasmid was transfected into a human colorectal cancer cell line (LoVo with a low expression of AZGP1. The expression of AZGP1, FASN, eIF4E, p-mTOR, p-S6,and S6K1 were measured by Western blot analysis, and target genes were detected by RT-PCR. Cell proliferation was studied using the MTT and colony formation assays. The analysis of apoptosis and the cell cycle phase were assessed by flow cytometry. The capacity of cell migration was investigated using the transwell migration assay. We found that the expression of AZGP1 was up-regulated while the expression of FASN, eIF4E, p-mTOR, p-S6, and S6K1 were down-regulated in LoVo cells after AZGP1 was expressed. The proliferation of malignant cells was reduced in AZGP1-overexpression cells, which is consistent with an increased in the G2-arrest and apoptosis rate. Furthermore, the migration of AZGP1-overexpression cells was decreased. The overexpression of AZGP1 suppressed the activation of the mTOR pathway and endogenous FASN-regulated fatty acid synthesis, mitigating the malignant phenotype of LoVo cells. Herein, we provide evidence that AZGP1 may constitute a novel tumor suppressor for LoVo colorectal cancer cells.

  9. Alpha-2-glycoprotein 1(AZGP1) regulates biological behaviors of LoVo cells by down-regulating mTOR signaling pathway and endogenous fatty acid synthesis.

    Science.gov (United States)

    Chang, Ligong; Tian, Xiaoqiang; Lu, Yinghui; Jia, Min; Wu, Peng; Huang, Peilin

    2014-01-01

    AZGP1 is a multifaceted protein associated with lipid mobilization, a process that is regulated by FASN and other metabolic pathways such as mTOR signaling. The active mTOR signaling pathway has been found to be involved in a variety of tumors. However, it remains unclear whether it is involved in the regulation of AZGP1 and FASN. An AZGP1-expressing plasmid was transfected into a human colorectal cancer cell line (LoVo) with a low expression of AZGP1. The expression of AZGP1, FASN, eIF4E, p-mTOR, p-S6,and S6K1 were measured by Western blot analysis, and target genes were detected by RT-PCR. Cell proliferation was studied using the MTT and colony formation assays. The analysis of apoptosis and the cell cycle phase were assessed by flow cytometry. The capacity of cell migration was investigated using the transwell migration assay. We found that the expression of AZGP1 was up-regulated while the expression of FASN, eIF4E, p-mTOR, p-S6, and S6K1 were down-regulated in LoVo cells after AZGP1 was expressed. The proliferation of malignant cells was reduced in AZGP1-overexpression cells, which is consistent with an increased in the G2-arrest and apoptosis rate. Furthermore, the migration of AZGP1-overexpression cells was decreased. The overexpression of AZGP1 suppressed the activation of the mTOR pathway and endogenous FASN-regulated fatty acid synthesis, mitigating the malignant phenotype of LoVo cells. Herein, we provide evidence that AZGP1 may constitute a novel tumor suppressor for LoVo colorectal cancer cells.

  10. Quantitative proteomic analysis of HIV-1 infected CD4+ T cells reveals an early host response in important biological pathways: Protein synthesis, cell proliferation, and T-cell activation

    Energy Technology Data Exchange (ETDEWEB)

    Navare, Arti T.; Sova, Pavel; Purdy, David E.; Weiss, Jeffrey M. [Department of Microbiology, University of Washington, Seattle, WA (United States); Wolf-Yadlin, Alejandro [Department of Genome Sciences, University of Washington, Seattle, WA (United States); Korth, Marcus J.; Chang, Stewart T.; Proll, Sean C. [Department of Microbiology, University of Washington, Seattle, WA (United States); Jahan, Tahmina A. [Proteomics Resource, UW Medicine at South Lake Union, Seattle, WA (United States); Krasnoselsky, Alexei L.; Palermo, Robert E. [Department of Microbiology, University of Washington, Seattle, WA (United States); Katze, Michael G., E-mail: honey@uw.edu [Department of Microbiology, University of Washington, Seattle, WA (United States); Washington National Primate Research Center, University of Washington, Seattle, WA (United States)

    2012-07-20

    Human immunodeficiency virus (HIV-1) depends upon host-encoded proteins to facilitate its replication while at the same time inhibiting critical components of innate and/or intrinsic immune response pathways. To characterize the host cell response on protein levels in CD4+ lymphoblastoid SUP-T1 cells after infection with HIV-1 strain LAI, we used mass spectrometry (MS)-based global quantitation with iTRAQ (isobaric tag for relative and absolute quantification). We found 266, 60 and 22 proteins differentially expressed (DE) (P-value{<=}0.05) at 4, 8, and 20 hours post-infection (hpi), respectively, compared to time-matched mock-infected samples. The majority of changes in protein abundance occurred at an early stage of infection well before the de novo production of viral proteins. Functional analyses of these DE proteins showed enrichment in several biological pathways including protein synthesis, cell proliferation, and T-cell activation. Importantly, these early changes before the time of robust viral production have not been described before.

  11. MyD88-dependent and independent pathways of Toll-Like Receptors are engaged in biological activity of Triptolide in ligand-stimulated macrophages

    Directory of Open Access Journals (Sweden)

    Dorn Ruth

    2010-04-01

    Full Text Available Abstract Background Triptolide is a diterpene triepoxide from the Chinese medicinal plant Tripterygium wilfordii Hook F., with known anti-inflammatory, immunosuppressive and anti-cancer properties. Results Here we report the expression profile of immune signaling genes modulated by triptolide in LPS induced mouse macrophages. In an array study triptolide treatment modulated expression of 22.5% of one hundred and ninety five immune signaling genes that included Toll-like receptors (TLRs. TLRs elicit immune responses through their coupling with intracellular adaptor molecules, MyD88 and TRIF. Although it is known that triptolide inhibits NFκB activation and other signaling pathways downstream of TLRs, involvement of TLR cascade in triptolide activity was not reported. In this study, we show that triptolide suppresses expression of proinflammatory downstream effectors induced specifically by different TLR agonists. Also, the suppressive effect of triptolide on TLR-induced NFκB activation was observed when either MyD88 or TRIF was knocked out, confirming that both MyD88 and TRIF mediated NFκB activation may be inhibited by triptolide. Within the TLR cascade triptolide downregulates TLR4 and TRIF proteins. Conclusions This study reveals involvement of TLR signaling in triptolide activity and further increases understanding of how triptolide activity may downregulate NFκB activation during inflammatory conditions.

  12. Classifier Design Given an Uncertainty Class of Feature Distributions via Regularized Maximum Likelihood and the Incorporation of Biological Pathway Knowledge in Steady-State Phenotype Classification.

    Science.gov (United States)

    Esfahani, Mohammad Shahrokh; Knight, Jason; Zollanvari, Amin; Yoon, Byung-Jun; Dougherty, Edward R

    2013-10-01

    Contemporary high-throughput technologies provide measurements of very large numbers of variables but often with very small sample sizes. This paper proposes an optimization-based paradigm for utilizing prior knowledge to design better performing classifiers when sample sizes are limited. We derive approximate expressions for the first and second moments of the true error rate of the proposed classifier under the assumption of two widely-used models for the uncertainty classes; ε-contamination and p-point classes. The applicability of the approximate expressions is discussed by defining the problem of finding optimal regularization parameters through minimizing the expected true error. Simulation results using the Zipf model show that the proposed paradigm yields improved classifiers that outperform traditional classifiers that use only training data. Our application of interest involves discrete gene regulatory networks possessing labeled steady-state distributions. Given prior operational knowledge of the process, our goal is to build a classifier that can accurately label future observations obtained in the steady state by utilizing both the available prior knowledge and the training data. We examine the proposed paradigm on networks containing NF-κB pathways, where it shows significant improvement in classifier performance over the classical data-only approach to classifier design. Companion website: http://gsp.tamu.edu/Publications/supplementary/shahrokh12a.

  13. KeyPathwayMinerWeb

    DEFF Research Database (Denmark)

    List, Markus; Alcaraz, Nicolas; Dissing-Hansen, Martin;

    2016-01-01

    We present KeyPathwayMinerWeb, the first online platform for de novo pathway enrichment analysis directly in the browser. Given a biological interaction network (e.g. protein-protein interactions) and a series of molecular profiles derived from one or multiple OMICS studies (gene expression...

  14. Adenosine Receptors as a Biological Pathway for the Anti-Inflammatory and Beneficial Effects of Low Frequency Low Energy Pulsed Electromagnetic Fields

    Directory of Open Access Journals (Sweden)

    Katia Varani

    2017-01-01

    Full Text Available Several studies explored the biological effects of low frequency low energy pulsed electromagnetic fields (PEMFs on human body reporting different functional changes. Much research activity has focused on the mechanisms of interaction between PEMFs and membrane receptors such as the involvement of adenosine receptors (ARs. In particular, PEMF exposure mediates a significant upregulation of A2A and A3ARs expressed in various cells or tissues involving a reduction in most of the proinflammatory cytokines. Of particular interest is the observation that PEMFs, acting as modulators of adenosine, are able to increase the functionality of the endogenous agonist. By reviewing the scientific literature on joint cells, a double role for PEMFs could be hypothesized in vitro by stimulating cell proliferation, colonization of the scaffold, and production of tissue matrix. Another effect could be obtained in vivo after surgical implantation of the construct by favoring the anabolic activities of the implanted cells and surrounding tissues and protecting the construct from the catabolic effects of the inflammatory status. Moreover, a protective involvement of PEMFs on hypoxia damage in neuron-like cells and an anti-inflammatory effect in microglial cells have suggested the hypothesis of a positive impact of this noninvasive biophysical stimulus.

  15. Adenosine Receptors as a Biological Pathway for the Anti-Inflammatory and Beneficial Effects of Low Frequency Low Energy Pulsed Electromagnetic Fields

    Science.gov (United States)

    Vincenzi, Fabrizio; Ravani, Annalisa; Pasquini, Silvia; Merighi, Stefania; Setti, Stefania; Cadossi, Matteo; Cadossi, Ruggero

    2017-01-01

    Several studies explored the biological effects of low frequency low energy pulsed electromagnetic fields (PEMFs) on human body reporting different functional changes. Much research activity has focused on the mechanisms of interaction between PEMFs and membrane receptors such as the involvement of adenosine receptors (ARs). In particular, PEMF exposure mediates a significant upregulation of A2A and A3ARs expressed in various cells or tissues involving a reduction in most of the proinflammatory cytokines. Of particular interest is the observation that PEMFs, acting as modulators of adenosine, are able to increase the functionality of the endogenous agonist. By reviewing the scientific literature on joint cells, a double role for PEMFs could be hypothesized in vitro by stimulating cell proliferation, colonization of the scaffold, and production of tissue matrix. Another effect could be obtained in vivo after surgical implantation of the construct by favoring the anabolic activities of the implanted cells and surrounding tissues and protecting the construct from the catabolic effects of the inflammatory status. Moreover, a protective involvement of PEMFs on hypoxia damage in neuron-like cells and an anti-inflammatory effect in microglial cells have suggested the hypothesis of a positive impact of this noninvasive biophysical stimulus. PMID:28255202

  16. Feedstock Supply System Design and Economics for Conversion of Lignocellulosic Biomass to Hydrocarbon Fuels: Conversion Pathway: Biological Conversion of Sugars to Hydrocarbons The 2017 Design Case

    Energy Technology Data Exchange (ETDEWEB)

    Kevin Kenney; Kara G. Cafferty; Jacob J. Jacobson; Ian J Bonner; Garold L. Gresham; William A. Smith; David N. Thompson; Vicki S. Thompson; Jaya Shankar Tumuluru; Neal Yancey

    2013-09-01

    The U.S. Department of Energy promotes the production of a range of liquid fuels and fuel blendstocks from lignocellulosic biomass feedstocks by funding fundamental and applied research that advances the state of technology in biomass collection, conversion, and sustainability. As part of its involvement in this program, the Idaho National Laboratory (INL) investigates the feedstock logistics economics and sustainability of these fuels. Between 2000 and 2012, INL conducted a campaign to quantify the economics and sustainability of moving biomass from standing in the field or stand to the throat of the biomass conversion process. The goal of this program was to establish the current costs based on conventional equipment and processes, design improvements to the current system, and to mark annual improvements based on higher efficiencies or better designs. The 2012 programmatic target was to demonstrate a delivered biomass logistics cost of $35/dry ton. This goal was successfully achieved in 2012 by implementing field and process demonstration unit-scale data from harvest, collection, storage, preprocessing, handling, and transportation operations into INL’s biomass logistics model. Looking forward to 2017, the programmatic target is to supply biomass to the conversion facilities at a total cost of $80/dry ton and on specification with in-feed requirements. The goal of the 2017 Design Case is to enable expansion of biofuels production beyond highly productive resource areas by breaking the reliance of cost-competitive biofuel production on a single, abundant, low-cost feedstock. If this goal is not achieved, biofuel plants are destined to be small and/or clustered in select regions of the country that have a lock on low-cost feedstock. To put the 2017 cost target into perspective of past accomplishments of the cellulosic ethanol pathway, the $80 target encompasses total delivered feedstock cost, including both grower payment and logistics costs, while meeting all

  17. Identifying dysregulated pathways in cancers from pathway interaction networks

    Directory of Open Access Journals (Sweden)

    Liu Ke-Qin

    2012-06-01

    Full Text Available Abstract Background Cancers, a group of multifactorial complex diseases, are generally caused by mutation of multiple genes or dysregulation of pathways. Identifying biomarkers that can characterize cancers would help to understand and diagnose cancers. Traditional computational methods that detect genes differentially expressed between cancer and normal samples fail to work due to small sample size and independent assumption among genes. On the other hand, genes work in concert to perform their functions. Therefore, it is expected that dysregulated pathways will serve as better biomarkers compared with single genes. Results In this paper, we propose a novel approach to identify dysregulated pathways in cancer based on a pathway interaction network. Our contribution is three-fold. Firstly, we present a new method to construct pathway interaction network based on gene expression, protein-protein interactions and cellular pathways. Secondly, the identification of dysregulated pathways in cancer is treated as a feature selection problem, which is biologically reasonable and easy to interpret. Thirdly, the dysregulated pathways are identified as subnetworks from the pathway interaction networks, where the subnetworks characterize very well the functional dependency or crosstalk between pathways. The benchmarking results on several distinct cancer datasets demonstrate that our method can obtain more reliable and accurate results compared with existing state of the art methods. Further functional analysis and independent literature evidence also confirm that our identified potential pathogenic pathways are biologically reasonable, indicating the effectiveness of our method. Conclusions Dysregulated pathways can serve as better biomarkers compared with single genes. In this work, by utilizing pathway interaction networks and gene expression data, we propose a novel approach that effectively identifies dysregulated pathways, which can not only be used

  18. Robust de novo pathway enrichment with KeyPathwayMiner 5

    DEFF Research Database (Denmark)

    Alcaraz, Nicolas; List, Markus; Dissing-Hansen, Martin

    2016-01-01

    Identifying functional modules or novel active pathways, recently termed de novo pathway enrichment, is a computational systems biology challenge that has gained much attention during the last decade. Given a large biological interaction network, KeyPathwayMiner extracts connected subnetworks...... several network perturbation techniques and over a range of perturbation degrees. In addition, users may now provide a gold-standard set to determine how enriched extracted pathways are with relevant genes compared to randomized versions of the original network....

  19. Interleukin-17: characteristics, differentiation pathways, signaling and biological functions Interleuquina-17: características, vías de diferenciación, señalización y funciones biológicas

    Directory of Open Access Journals (Sweden)

    Luis Fernando García Moreno

    2007-04-01

    Full Text Available Interleukin-17 is a proinflammatory cytokine with very pleiotropic biological functions. It is secreted by different subsets of activated T cells. Its receptor is found on different cells in a wide range of tissues. IL-17 has been shown to be involved in the development of autoimmune diseases, allograft rejection, cancer, immediate and delayed hypersensitivity responses, and control of infections. IL-17 seems to play an important role in the immune response against Mycobacterium tuberculosis. This review includes the recently elucidated aspects of this cytokine, particularly its molecular characteristics, differentiation pathways, signaling and functions. Interleuquina 17 (IL-17 es una citoquina proinflamatoria con diversas funciones biológicas secretada por varios subtipos de células T activadas. Su receptor se encuentra en los distintos tipos celulares de un amplio rango de tejidos. La IL-17 se ha relacionado con el desarrollo de enfermedades autoinmunes, rechazo de aloinjertos, cáncer, respuestas de hipersensibilidad inmediatas y tardías y control de infecciones, entre ellas la respuesta inmune contra Mycobacterium tuberculosis. Esta revisión pretende abarcar los aspectos hasta ahora elucidados sobre las características, las vías de diferenciación de las células productoras de IL-17, así como la señalización y funciones de ésta.

  20. Molecular neurodegeneration: basic biology and disease pathways

    OpenAIRE

    2014-01-01

    The field of neurodegeneration research has been advancing rapidly over the past few years, and has provided intriguing new insights into the normal physiological functions and pathogenic roles of a wide range of molecules associated with several devastating neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease, and Down syndrome. Recent developments have also facilitated initial efforts to...

  1. Partitioning of genomic variance using biological pathways

    DEFF Research Database (Denmark)

    Edwards, Stefan McKinnon; Janss, Luc; Madsen, Per;

    for complex diseases reveals patterns that provide insight into the genetic architecture of complex traits. Although many genetic variants with small or moderate effects contribute to the overall genetic variation, it appears that multiple independently associated variants are located in the same genes...... diseases. However, the variants identified as being statistically significant have generally explained only a small fraction of the heritable component of the trait. Insufficient modelling of the underlying genetic architecture may in part explain this missing heritability. Evidence collected across GWAS...

  2. Plant synthetic biology.

    Science.gov (United States)

    Liu, Wusheng; Stewart, C Neal

    2015-05-01

    Plant synthetic biology is an emerging field that combines engineering principles with plant biology toward the design and production of new devices. This emerging field should play an important role in future agriculture for traditional crop improvement, but also in enabling novel bioproduction in plants. In this review we discuss the design cycles of synthetic biology as well as key engineering principles, genetic parts, and computational tools that can be utilized in plant synthetic biology. Some pioneering examples are offered as a demonstration of how synthetic biology can be used to modify plants for specific purposes. These include synthetic sensors, synthetic metabolic pathways, and synthetic genomes. We also speculate about the future of synthetic biology of plants.

  3. 基元模式分析在生物网络和途径分析中的应用%Applications of elementary mode analysis in biological network and pathway analysis

    Institute of Scientific and Technical Information of China (English)

    赵权宇; 于水燕; 史吉平

    2013-01-01

    基元模式分析是应用最广泛的代谢途径分析方法.基元模式分析的研究对象从代谢网络发展到信号传导网络;研究尺度从细胞到生物反应器,甚至生态系统;数学描述从稳态分解到动态解析;研究领域从微生物代谢到人类疾病.以下综述了基元模式分析的算法和软件开发现状,以及其在代谢途径与鲁棒性、代谢通量分解、稳态代谢通量分析、动态模型与生物过程模拟、网络结构与调控、菌株设计和信号传导网络等方面的应用.开发新的算法解决组合爆炸问题,探索基元模式与代谢调控的关系以及提高菌株设计算法效率是今后基元模式的重要发展方向.%Elementary mode analysis is the widely applied tool in metabolic pathway analysis.Studies based on elementary mode analysis (EMA) were performed for both metabolic network and signal transduction network.Its analytical objective is from cell to bioreactor,and even ecological system.EMA is available to describe biological behaviors by steady state and dynamic models.Not only microorganism metabolism but also human health could be evaluated by EMA.The algorithms and software for calculating elementary mode (EM) were analyzed.The applications of EMA are reviewed such as special metabolic pathway and robustness of metabolic network,metabolic flux decomposition,metabolic flux analysis at steady state,dynamic model and bioprocess simulation,network structure and regulation,strain design and signal transduction network.Solving combinatorial explosion,exploring the relations between EM and metabolic regulation,and improving the algorithm efficiency of strain design are important issues of EMA in future.

  4. Molecular pathways

    DEFF Research Database (Denmark)

    Cox, Thomas R; Erler, Janine Terra

    2014-01-01

    that 45% of deaths in the developed world are linked to fibrotic disease. Fibrosis and cancer are known to be inextricably linked; however, we are only just beginning to understand the common and overlapping molecular pathways between the two. Here, we discuss what is known about the intersection...... of fibrosis and cancer, with a focus on cancer metastasis, and highlight some of the exciting new potential clinical targets that are emerging from analysis of the molecular pathways associated with these two devastating diseases. Clin Cancer Res; 20(14); 3637-43. ©2014 AACR....

  5. All biology is computational biology

    Science.gov (United States)

    2017-01-01

    Here, I argue that computational thinking and techniques are so central to the quest of understanding life that today all biology is computational biology. Computational biology brings order into our understanding of life, it makes biological concepts rigorous and testable, and it provides a reference map that holds together individual insights. The next modern synthesis in biology will be driven by mathematical, statistical, and computational methods being absorbed into mainstream biological training, turning biology into a quantitative science. PMID:28278152

  6. Logical knowledge representation of regulatory relations in biomedical pathways

    DEFF Research Database (Denmark)

    Zambach, Sine; Hansen, Jens Ulrik

    2010-01-01

    Knowledge on regulatory relations, in for example regulatory pathways in biology, is used widely in experiment design by biomedical researchers and in systems biology. The knowledge has typically either been represented through simple graphs or through very expressive differential equation...

  7. Adverse Outcome Pathway (AOP) Network Development for Fatty Liver

    Science.gov (United States)

    Adverse outcome pathways (AOPs) are descriptive biological sequences that start from a molecular initiating event (MIE) and end with an adverse health outcome. AOPs provide biological context for high throughput chemical testing and further prioritize environmental health risk re...

  8. A Board Game to Assist Pharmacy Students in Learning Metabolic Pathways

    OpenAIRE

    2011-01-01

    Objectives. To develop and evaluate a board game designed to increase students’ enjoyment of learning metabolic pathways; their familiarity with pathway reactions, intermediates, and regulation; and, their understanding of how pathways relate to one another and to selected biological conditions.

  9. Designing pathways

    DEFF Research Database (Denmark)

    Scheuer, John Damm

    2010-01-01

    The theoretical background in this chapter is organizational studies and especially theories about design and design processes in organizations. The concept of design is defined as a particular kind of work aimed at making arrangements in order to change existing situations into desired ones....... The illustrative case example is the introduction of clinical pathways in a psychiatric department. The contribution to a general core of design research is the development of the concept of design work and a critical discussion of the role of technological rules in design work....

  10. Biological computation

    CERN Document Server

    Lamm, Ehud

    2011-01-01

    Introduction and Biological BackgroundBiological ComputationThe Influence of Biology on Mathematics-Historical ExamplesBiological IntroductionModels and Simulations Cellular Automata Biological BackgroundThe Game of Life General Definition of Cellular Automata One-Dimensional AutomataExamples of Cellular AutomataComparison with a Continuous Mathematical Model Computational UniversalitySelf-Replication Pseudo Code Evolutionary ComputationEvolutionary Biology and Evolutionary ComputationGenetic AlgorithmsExample ApplicationsAnalysis of the Behavior of Genetic AlgorithmsLamarckian Evolution Genet

  11. Oxylipin Pathway in Rice and Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    E. Wassim Chehab; John V. Perea; Banu Gopalan; Steve Theg; Katayoon Dehesh

    2007-01-01

    Plants have evolved complex signaling pathways to coordinate responses to developmental and environmental information. The oxylipin pathway is one pivotal lipid-based signaling network, composed of several competing branch pathways, that determines the plant's ability to adapt to various stimuli. Activation of the oxylipin pathway induces the de novo synthesis of biologically active metabolltes called "oxylipins". The relative levels of these metabolltes are a distinct indicator of each plant species and determine the ability of plants to adapt to different stimuli. The two major branches of the oxylipln pathway, allene oxide synthase (AOS) and hydroperoxide lyase (HPL) are responsible for production of the signaling compounds,jasmonates and aldehydes respectively. Here, we compare and contrast the regulation of AOS and HPL branch pathways in rice and Arabidopsis as model monocotyledonous and dicotyledonous systems. These analyses provide new Insights into the evolution of JAs and aldehydes signaling pathways, and the complex network of processes responsible for stress adaptations in monocots and dicots.

  12. Minimal metabolic pathway structure is consistent with associated biomolecular interactions

    DEFF Research Database (Denmark)

    Bordbar, Aarash; Nagarajan, Harish; Lewis, Nathan E.;

    2014-01-01

    Pathways are a universal paradigm for functionally describing cellular processes. Even though advances in high-throughput data generation have transformed biology, the core of our biological understanding, and hence data interpretation, is still predicated on human-defined pathways. Here, we intr...

  13. Synthetic biology and metabolic engineering.

    Science.gov (United States)

    Stephanopoulos, Gregory

    2012-11-16

    Metabolic engineering emerged 20 years ago as the discipline occupied with the directed modification of metabolic pathways for the microbial synthesis of various products. As such, it deals with the engineering (design, construction, and optimization) of native as well as non-natural routes of product synthesis, aided in this task by the availability of synthetic DNA, the core enabling technology of synthetic biology. The two fields, however, only partially overlap in their interest in pathway engineering. While fabrication of biobricks, synthetic cells, genetic circuits, and nonlinear cell dynamics, along with pathway engineering, have occupied researchers in the field of synthetic biology, the sum total of these areas does not constitute a coherent definition of synthetic biology with a distinct intellectual foundation and well-defined areas of application. This paper reviews the origins of the two fields and advances two distinct paradigms for each of them: that of unit operations for metabolic engineering and electronic circuits for synthetic biology. In this context, metabolic engineering is about engineering cell factories for the biological manufacturing of chemical and pharmaceutical products, whereas the main focus of synthetic biology is fundamental biological research facilitated by the use of synthetic DNA and genetic circuits.

  14. Nutritional Systems Biology

    DEFF Research Database (Denmark)

    Jensen, Kasper

    sites of diet on the disease pathway. We propose a framework for interrogating the critical targets in colon cancer process and identifying plant-based dietary interventions as important modifiers using a systems chemical biology approach. The fifth chapter of the thesis is on discovering of novel anti...... number of thoroughly selected targets. Our need for fundamental understanding of the building blocks of the complex biological systems had been the main reason for the reductionist approach that was mainly applied in the past to elucidate these systems. Nowadays, it is widely recognized that systems...... components with biological systems and their connection to health and disease. The database will be enriched with predicted interactions between food components and protein targets, based on their structural and pharmacophore similarity with known small molecule ligands. Further to this, the associations...

  15. [Biological weapons].

    Science.gov (United States)

    Kerwat, K; Becker, S; Wulf, H; Densow, D

    2010-08-01

    Biological weapons are weapons of mass destruction that use pathogens (bacteria, viruses) or the toxins produced by them to target living organisms or to contaminate non-living substances. In the past, biological warfare has been repeatedly used. Anthrax, plague and smallpox are regarded as the most dangerous biological weapons by various institutions. Nowadays it seems quite unlikely that biological warfare will be employed in any military campaigns. However, the possibility remains that biological weapons may be used in acts of bioterrorism. In addition all diseases caused by biological weapons may also occur naturally or as a result of a laboratory accident. Risk assessment with regard to biological danger often proves to be difficult. In this context, an early identification of a potentially dangerous situation through experts is essential to limit the degree of damage.

  16. Systems pharmacology of the nerve growth factor pathway: use of a systems biology model for the identification of key drug targets using sensitivity analysis and the integration of physiology and pharmacology.

    Science.gov (United States)

    Benson, Neil; Matsuura, Tomomi; Smirnov, Sergey; Demin, Oleg; Jones, Hannah M; Dua, Pinky; van der Graaf, Piet H

    2013-04-06

    The nerve growth factor (NGF) pathway is of great interest as a potential source of drug targets, for example in the management of certain types of pain. However, selecting targets from this pathway either by intuition or by non-contextual measures is likely to be challenging. An alternative approach is to construct a mathematical model of the system and via sensitivity analysis rank order the targets in the known pathway, with respect to an endpoint such as the diphosphorylated extracellular signal-regulated kinase concentration in the nucleus. Using the published literature, a model was created and, via sensitivity analysis, it was concluded that, after NGF itself, tropomyosin receptor kinase A (TrkA) was one of the most sensitive druggable targets. This initial model was subsequently used to develop a further model incorporating physiological and pharmacological parameters. This allowed the exploration of the characteristics required for a successful hypothetical TrkA inhibitor. Using these systems models, we were able to identify candidates for the optimal drug targets in the known pathway. These conclusions were consistent with clinical and human genetic data. We also found that incorporating appropriate physiological context was essential to drawing accurate conclusions about important parameters such as the drug dose required to give pathway inhibition. Furthermore, the importance of the concentration of key reactants such as TrkA kinase means that appropriate contextual data are required before clear conclusions can be drawn. Such models could be of great utility in selecting optimal targets and in the clinical evaluation of novel drugs.

  17. Towards Systems Biology of Mycotoxin Regulation

    OpenAIRE

    Christof Rampitsch; Rajagopal Subramaniam

    2013-01-01

    Systems biology is a scientific approach that integrates many scientific disciplines to develop a comprehensive understanding of biological phenomena, thus allowing the prediction and accurate simulation of complex biological behaviors. It may be presumptuous to write about toxin regulation at the level of systems biology, but the last decade of research is leading us closer than ever to this approach. Past research has delineated multiple levels of regulation in the pathways leading to the b...

  18. Molecular Biology and Metabolic Engineering of the Indole Pathway In Catharanthus roseus( L.) G.Don%长春花萜类吲哚生物碱的分子生物学与代谢工程研究

    Institute of Scientific and Technical Information of China (English)

    卢衍; 常凯; 郑月; 许宏宣; 杨春贤

    2012-01-01

    长春花不仅是重要抗癌药物,也是长春碱与长春新碱的唯一来源,并且还包含有其他多种药用成分.近年来,长春花次生代谢得到了广泛的研究,但仍有许多不明之处.该研究对长春花的研究进展进行了综述,详细阐述了长春花萜类吲哚生物碱合成的2大途径(莽草酸途径和萜类途径),介绍了该途径中已克隆的部分基因及相关酶,总结了近年来长春花TIAs研究中的代谢工程策略,以期为长春花萜类吲哚生物碱的后续研究提供参考依据.%Catharanthus roseus is the only source for the powerful antitumor drugs of vinblastine and vincristine, it also contains some other pharmaceutical compounds, Althrough C. roseus has been studied extensively, many details of its alkaloid pathway are still unknown. In this paper, the research advances in C. roseus were reviewed, the indole alkaloid biosynthetic pathways of C. roseus, including shikimic acid pathway and lerpenoid pathway, were expounded in details, the enzymes and genes involved in the indole alkaloid biosynthesis were intro-duced. Finally, the recent research progress of periwinkle TIAs combined with metabolic engineering strategy was summarized. The study aims to offer reference for the follow-up studies on the terpenoids indoles alkaloid of C. roseus.

  19. A markov classification model for metabolic pathways

    Directory of Open Access Journals (Sweden)

    Mamitsuka Hiroshi

    2010-01-01

    Full Text Available Abstract Background This paper considers the problem of identifying pathways through metabolic networks that relate to a specific biological response. Our proposed model, HME3M, first identifies frequently traversed network paths using a Markov mixture model. Then by employing a hierarchical mixture of experts, separate classifiers are built using information specific to each path and combined into an ensemble prediction for the response. Results We compared the performance of HME3M with logistic regression and support vector machines (SVM for both simulated pathways and on two metabolic networks, glycolysis and the pentose phosphate pathway for Arabidopsis thaliana. We use AltGenExpress microarray data and focus on the pathway differences in the developmental stages and stress responses of Arabidopsis. The results clearly show that HME3M outperformed the comparison methods in the presence of increasing network complexity and pathway noise. Furthermore an analysis of the paths identified by HME3M for each metabolic network confirmed known biological responses of Arabidopsis. Conclusions This paper clearly shows HME3M to be an accurate and robust method for classifying metabolic pathways. HME3M is shown to outperform all comparison methods and further is capable of identifying known biologically active pathways within microarray data.

  20. ChemProt: A disease chemical biology database

    DEFF Research Database (Denmark)

    Taboureau, Olivier; Oprea, Tudor I.

    2013-01-01

    The integration of chemistry, biology, and informatics to study drug actions across multiple biological targets, pathways, and biological systems is an emerging paradigm in drug discovery. Rather than reducing a complex system to simplistic models, fields such as chemogenomics and translational...... chemical biology, drug repurposing, and off-target effects prediction....

  1. Is synthetic biology mechanical biology?

    Science.gov (United States)

    Holm, Sune

    2015-12-01

    A widespread and influential characterization of synthetic biology emphasizes that synthetic biology is the application of engineering principles to living systems. Furthermore, there is a strong tendency to express the engineering approach to organisms in terms of what seems to be an ontological claim: organisms are machines. In the paper I investigate the ontological and heuristic significance of the machine analogy in synthetic biology. I argue that the use of the machine analogy and the aim of producing rationally designed organisms does not necessarily imply a commitment to mechanical biology. The ideal of applying engineering principles to biology is best understood as expressing recognition of the machine-unlikeness of natural organisms and the limits of human cognition. The paper suggests an interpretation of the identification of organisms with machines in synthetic biology according to which it expresses a strategy for representing, understanding, and constructing living systems that are more machine-like than natural organisms.

  2. Novel personalized pathway-based metabolomics models reveal key metabolic pathways for breast cancer diagnosis

    DEFF Research Database (Denmark)

    Huang, Sijia; Chong, Nicole; Lewis, Nathan

    2016-01-01

    . Methods: We propose that higher-order functional representation of metabolomics data, such as pathway-based metabolomic features, can be used as robust biomarkers for breast cancer. Towards this, we have developed a new computational method that uses personalized pathway dysregulation scores for disease...... the Curve, a receiver operating characteristic curve) of 0.968 and 0.934, sensitivities of 0.946 and 0.954, and specificities of 0.934 and 0.918. These two metabolomics-based pathway models are further validated by RNA-Seq-based TCGA (The Cancer Genome Atlas) breast cancer data, with AUCs of 0.995 and 0.......993. Moreover, important metabolic pathways, such as taurine and hypotaurine metabolism and the alanine, aspartate, and glutamate pathway, are revealed as critical biological pathways for early diagnosis of breast cancer. Conclusions: We have successfully developed a new type of pathway-based model to study...

  3. Robust de novo pathway enrichment with KeyPathwayMiner 5

    DEFF Research Database (Denmark)

    Alcaraz, Nicolas; List, Markus; Dissing-Hansen, Martin;

    2016-01-01

    Identifying functional modules or novel active pathways, recently termed de novo pathway enrichment, is a computational systems biology challenge that has gained much attention during the last decade. Given a large biological interaction network, KeyPathwayMiner extracts connected subnetworks tha...... several network perturbation techniques and over a range of perturbation degrees. In addition, users may now provide a gold-standard set to determine how enriched extracted pathways are with relevant genes compared to randomized versions of the original network.......Identifying functional modules or novel active pathways, recently termed de novo pathway enrichment, is a computational systems biology challenge that has gained much attention during the last decade. Given a large biological interaction network, KeyPathwayMiner extracts connected subnetworks...... that are enriched for differentially active entities from a series of molecular profiles encoded as binary indicator matrices. Since interaction networks constantly evolve, an important question is how robust the extracted results are when the network is modified. We enable users to study this effect through...

  4. Computational biology

    DEFF Research Database (Denmark)

    Hartmann, Lars Røeboe; Jones, Neil; Simonsen, Jakob Grue

    2011-01-01

    Computation via biological devices has been the subject of close scrutiny since von Neumann’s early work some 60 years ago. In spite of the many relevant works in this field, the notion of programming biological devices seems to be, at best, ill-defined. While many devices are claimed or proved t...

  5. 植物花青素生物合成途径相关基因研究进展及其基因工程修饰%Advances in research of genes involved in anthocyanin biological synthesis in plant and the genetic modification of the pathway

    Institute of Scientific and Technical Information of China (English)

    赵德勇

    2012-01-01

    This paper reviews the advances in research of synthetic genes and regulator genes involved in the anthocyanin biological synthesis process as well as in genetic engineering in regulating the anthocyanin biological synthesis. Anthocyanin biological synthesis process of plants belongs to the secondary metabolic pathway, regulates the expression of key enzymes involved in the pathway, and could hence lead to a reduced or increased yield of target compound. Genetic improvement of plants may be realized through modifying the secondary metabolic process. Anthocyanin accumulation helps the plants to act against the UV Further study on the defense molecular mechanism of the anthocyanin facilitates b with resistance to diseases and adversities. radiation, insects and fungi. reeding of new plant cultivars%对植物花青素生物合成及调控基因的研究进展、基因工程在调控花青素合成途径中的应用进行了综述。植物花青素生物合成属次生代谢途径,对该途径关键酶基因的调控可降低或提高目标化合物的产量,可通过调控植物次生代谢的方式对植物进行遗传改良。对植物通过积累花青素来适应紫外线辐射、防卫害虫及真菌侵害的分子机制进行研究,有助于培育抗病、抗逆的植物新品种。

  6. Cardiovascular toxicities of biological therapies

    DEFF Research Database (Denmark)

    Ryberg, Marianne

    2013-01-01

    The development of biological therapy is based on growing knowledge regarding the molecular changes required in cells for the development and progression of cancer to occur. Molecular targeted therapy is designed to inhibit the major molecular pathways identified as essential for a specific...

  7. Synthetic Biological Engineering of Photosynthesis

    Science.gov (United States)

    2015-11-16

    photosynthesis into artificial metabolic pathways. During the course of the granting period, we also made significant progress on understanding the...compartmentalization of carbon fixation and flux in relationship to photosynthesis and obtained 1. REPORT DATE (DD-MM-YYYY) 4. TITLE AND SUBTITLE...2014 Approved for Public Release; Distribution Unlimited Final Report: Synthetic Biological Engineering of Photosynthesis The views, opinions and/or

  8. Dual inhibition of the PI3K/AKT/mTOR pathway suppresses the growth of leiomyosarcomas but leads to ERK activation through mTORC2: biological and clinical implications.

    Science.gov (United States)

    Fourneaux, Benjamin; Chaire, Vanessa; Lucchesi, Carlo; Karanian, Marie; Pineau, Raphael; Laroche-Clary, Audrey; Italiano, Antoine

    2017-01-31

    The PI3K/AKT/mTOR pathway plays a crucial role in the development of leiomyosarcomas (LMSs). In this study, we tested the efficacy of dual PI3K/mTOR (BEZ235), PI3K (BKM120) and mTOR (everolimus) inhibitors in three human LMS cell lines. In vitro and in vivo studies using LMS cell lines showed that BEZ235 has a significantly higher anti-tumor effect than either BKM120 or everolimus, resulting in a greater reduction in tumor growth and more pronounced inhibitory effects on mitotic activity and PI3K/AKT/mTOR signaling. Strikingly, BEZ235 but neither BKM120 nor everolimus markedly enhanced the ERK pathway. This effect was reproduced by the combination of BKM120 and everolimus, suggesting the involvement of mTORC2 via a PI3K-independent mechanism. Silencing of RICTOR in LMS cells confirmed the role of mTORC2 in the regulation of ERK activity. Combined treatment with BEZ235 and GSK1120212, a potent MEK inhibitor, resulted in synergistic growth inhibition and apoptosis induction in vitro and in vivo. These findings document for the first time that dual PI3K/mTOR inhibition in leiomyosarcomas suppress a negative feedback loop mediated by mTORC2, leading to enhanced ERK pathway activity. Thus, combining a dual PI3K/mTOR inhibitor with MEK inhibitors may be a relevant approach to increase anti-tumor activity and prevent drug resistance in patients with LMS.

  9. Textbook Errors & Misconceptions in Biology: Cell Metabolism.

    Science.gov (United States)

    Storey, Richard D.

    1991-01-01

    The idea that errors and misconceptions in biology textbooks are often slow to be discovered and corrected is discussed. Selected errors, misconceptions, and topics of confusion about cell metabolism are described. Fermentation, respiration, Krebs cycle, pentose phosphate pathway, uniformity of catabolism, and metabolic pathways as models are…

  10. Biological Oceanography

    Science.gov (United States)

    Dyhrman, Sonya

    2004-10-01

    The ocean is arguably the largest habitat on the planet, and it houses an astounding array of life, from microbes to whales. As a testament to this diversity and its importance, the discipline of biological oceanography spans studies of all levels of biological organization, from that of single genes, to organisms, to their population dynamics. Biological oceanography also includes studies on how organisms interact with, and contribute to, essential global processes. Students of biological oceanography are often as comfortable looking at satellite images as they are electron micrographs. This diversity of perspective begins the textbook Biological Oceanography, with cover graphics including a Coastal Zone Color Scanner image representing chlorophyll concentration, an electron micrograph of a dinoflagellate, and a photograph of a copepod. These images instantly capture the reader's attention and illustrate some of the different scales on which budding oceanographers are required to think. Having taught a core graduate course in biological oceanography for many years, Charlie Miller has used his lecture notes as the genesis for this book. The text covers the subject of biological oceanography in a manner that is targeted to introductory graduate students, but it would also be appropriate for advanced undergraduates.

  11. Quantum Biology

    Directory of Open Access Journals (Sweden)

    Alessandro Sergi

    2009-06-01

    Full Text Available A critical assessment of the recent developmentsof molecular biology is presented.The thesis that they do not lead to a conceptualunderstanding of life and biological systems is defended.Maturana and Varela's concept of autopoiesis is briefly sketchedand its logical circularity avoided by postulatingthe existence of underlying living processes,entailing amplification from the microscopic to the macroscopic scale,with increasing complexity in the passage from one scale to the other.Following such a line of thought, the currently accepted model of condensed matter, which is based on electrostatics and short-ranged forces,is criticized. It is suggested that the correct interpretationof quantum dispersion forces (van der Waals, hydrogen bonding, and so onas quantum coherence effects hints at the necessity of includinglong-ranged forces (or mechanisms for them incondensed matter theories of biological processes.Some quantum effects in biology are reviewedand quantum mechanics is acknowledged as conceptually important to biology since withoutit most (if not all of the biological structuresand signalling processes would not even exist. Moreover, it is suggested that long-rangequantum coherent dynamics, including electron polarization,may be invoked to explain signal amplificationprocess in biological systems in general.

  12. Foldit Biology

    Science.gov (United States)

    2015-07-31

    Report 8/1/2013-7/31/2015 4. TITLE AND SUBTITLE Sa. CONTRACT NUMBER Foldit Biology NOOO 14-13-C-0221 Sb. GRANT NUMBER N/A Sc. PROGRAM ELEMENT...Include area code) Unclassified Unclassified Unclassified (206) 616-2660 Zoran Popović Foldit Biology (Task 1, 2, 3, 4) Final Report...Period Covered by the Report August 1, 2013 – July 31, 2015 Date of Report: July 31, 2015 Project Title: Foldit Biology Contract Number: N00014-13

  13. Menstrual Cycle: Basic Biology

    Science.gov (United States)

    Hawkins, Shannon M.; Matzuk, Martin M.

    2010-01-01

    The basic biology of the menstrual cycle is a complex, coordinated sequence of events involving the hypothalamus, anterior pituitary, ovary, and endometrium. The menstrual cycle with all its complexities can be easily perturbed by environmental factors such as stress, extreme exercise, eating disorders, and obesity. Furthermore, genetic influences such as fragile X premutations (Chapter X), X chromosome abnormalities (Chapter X), and galactose-1-phosphate uridyltransferase (GALT) point mutations (galactosemia) also contribute to perturbations of the menstrual cycle. Although not perfect, mouse model have helped to identify and confirm additional components and pathways in menstrual cycle function and dysfunction in humans. PMID:18574203

  14. Dominating biological networks.

    Directory of Open Access Journals (Sweden)

    Tijana Milenković

    Full Text Available Proteins are essential macromolecules of life that carry out most cellular processes. Since proteins aggregate to perform function, and since protein-protein interaction (PPI networks model these aggregations, one would expect to uncover new biology from PPI network topology. Hence, using PPI networks to predict protein function and role of protein pathways in disease has received attention. A debate remains open about whether network properties of "biologically central (BC" genes (i.e., their protein products, such as those involved in aging, cancer, infectious diseases, or signaling and drug-targeted pathways, exhibit some topological centrality compared to the rest of the proteins in the human PPI network.To help resolve this debate, we design new network-based approaches and apply them to get new insight into biological function and disease. We hypothesize that BC genes have a topologically central (TC role in the human PPI network. We propose two different concepts of topological centrality. We design a new centrality measure to capture complex wirings of proteins in the network that identifies as TC those proteins that reside in dense extended network neighborhoods. Also, we use the notion of domination and find dominating sets (DSs in the PPI network, i.e., sets of proteins such that every protein is either in the DS or is a neighbor of the DS. Clearly, a DS has a TC role, as it enables efficient communication between different network parts. We find statistically significant enrichment in BC genes of TC nodes and outperform the existing methods indicating that genes involved in key biological processes occupy topologically complex and dense regions of the network and correspond to its "spine" that connects all other network parts and can thus pass cellular signals efficiently throughout the network. To our knowledge, this is the first study that explores domination in the context of PPI networks.

  15. Fibroblast Growth Factors: Biology, Function, and Application for Tissue Regeneration

    Directory of Open Access Journals (Sweden)

    Ye-Rang Yun

    2010-01-01

    Full Text Available Fibroblast growth factors (FGFs that signal through FGF receptors (FGFRs regulate a broad spectrum of biological functions, including cellular proliferation, survival, migration, and differentiation. The FGF signal pathways are the RAS/MAP kinase pathway, PI3 kinase/AKT pathway, and PLCγ pathway, among which the RAS/MAP kinase pathway is known to be predominant. Several studies have recently implicated the in vitro biological functions of FGFs for tissue regeneration. However, to obtain optimal outcomes in vivo, it is important to enhance the half-life of FGFs and their biological stability. Future applications of FGFs are expected when the biological functions of FGFs are potentiated through the appropriate use of delivery systems and scaffolds. This review will introduce the biology and cellular functions of FGFs and deal with the biomaterials based delivery systems and their current applications for the regeneration of tissues, including skin, blood vessel, muscle, adipose, tendon/ligament, cartilage, bone, tooth, and nerve tissues.

  16. A system-level pathway-phenotype association analysis using synthetic feature random forest.

    Science.gov (United States)

    Pan, Qinxin; Hu, Ting; Malley, James D; Andrew, Angeline S; Karagas, Margaret R; Moore, Jason H

    2014-04-01

    As the cost of genome-wide genotyping decreases, the number of genome-wide association studies (GWAS) has increased considerably. However, the transition from GWAS findings to the underlying biology of various phenotypes remains challenging. As a result, due to its system-level interpretability, pathway analysis has become a popular tool for gaining insights on the underlying biology from high-throughput genetic association data. In pathway analyses, gene sets representing particular biological processes are tested for significant associations with a given phenotype. Most existing pathway analysis approaches rely on single-marker statistics and assume that pathways are independent of each other. As biological systems are driven by complex biomolecular interactions, embracing the complex relationships between single-nucleotide polymorphisms (SNPs) and pathways needs to be addressed. To incorporate the complexity of gene-gene interactions and pathway-pathway relationships, we propose a system-level pathway analysis approach, synthetic feature random forest (SF-RF), which is designed to detect pathway-phenotype associations without making assumptions about the relationships among SNPs or pathways. In our approach, the genotypes of SNPs in a particular pathway are aggregated into a synthetic feature representing that pathway via Random Forest (RF). Multiple synthetic features are analyzed using RF simultaneously and the significance of a synthetic feature indicates the significance of the corresponding pathway. We further complement SF-RF with pathway-based Statistical Epistasis Network (SEN) analysis that evaluates interactions among pathways. By investigating the pathway SEN, we hope to gain additional insights into the genetic mechanisms contributing to the pathway-phenotype association. We apply SF-RF to a population-based genetic study of bladder cancer and further investigate the mechanisms that help explain the pathway-phenotype associations using SEN. The

  17. Biological preconcentrator

    Science.gov (United States)

    Manginell, Ronald P.; Bunker, Bruce C.; Huber, Dale L.

    2008-09-09

    A biological preconcentrator comprises a stimulus-responsive active film on a stimulus-producing microfabricated platform. The active film can comprise a thermally switchable polymer film that can be used to selectively absorb and desorb proteins from a protein mixture. The biological microfabricated platform can comprise a thin membrane suspended on a substrate with an integral resistive heater and/or thermoelectric cooler for thermal switching of the active polymer film disposed on the membrane. The active polymer film can comprise hydrogel-like polymers, such as poly(ethylene oxide) or poly(n-isopropylacrylamide), that are tethered to the membrane. The biological preconcentrator can be fabricated with semiconductor materials and technologies.

  18. A pathway to spirituality.

    Science.gov (United States)

    Shaw, Jon A

    2005-01-01

    The phenomenology of mystical experiences has been described throughout all the ages and in all religions. All mystical traditions identify some sense of union with the absolute as the ultimate spiritual goal. I assume that the pathway to both theistic and secular spirituality and our readiness to seek a solution in a psychological merger with something beyond the self evolves out of our human experience. Spirituality is one of man's strategies for dealing with the limitations of the life cycle, separation and loss, biological fragility, transience, and non-existence. Spirituality may serve as the affective component to a belief system or myth that is not rooted in scientific evidence but is lived as if it is true. Spirituality may take many forms, but I will suggest that in some instances it may serve as a reparative process in which one creates in the external world, through symbolic form, a nuance or facet of an internalized mental representation which has become lost or is no longer available to the self; or it may represent the continuity of the self-representation after death through a self-object merger. Lastly I will illustrate from the writings of two of our greatest poets, Dante Alighieri and William Wordsworth, how their poetry became interwoven with a profound spirituality. In Dante we will see the elaboration of a religious spirituality, while in the writings of Wordsworth a secular spirituality emerges interwoven with nature and belatedly his identification with "tragic man" as his mythos.

  19. Systems biology and cardiac arrhythmias.

    Science.gov (United States)

    Grace, Andrew A; Roden, Dan M

    2012-10-27

    During the past few years, the development of effective, empirical technologies for treatment of cardiac arrhythmias has exceeded the pace at which detailed knowledge of the underlying biology has accumulated. As a result, although some clinical arrhythmias can be cured with techniques such as catheter ablation, drug treatment and prediction of the risk of sudden death remain fairly primitive. The identification of key candidate genes for monogenic arrhythmia syndromes shows that to bring basic biology to the clinic is a powerful approach. Increasingly sophisticated experimental models and methods of measurement, including stem cell-based models of human cardiac arrhythmias, are being deployed to study how perturbations in several biologic pathways can result in an arrhythmia-prone heart. The biology of arrhythmia is largely quantifiable, which allows for systematic analysis that could transform treatment strategies that are often still empirical into management based on molecular evidence.

  20. Biology Notes.

    Science.gov (United States)

    School Science Review, 1981

    1981-01-01

    Outlines a variety of laboratory procedures, techniques, and materials including construction of a survey frame for field biology, a simple tidal system, isolation and applications of plant protoplasts, tropisms, teaching lung structure, and a key to statistical methods for biologists. (DS)

  1. (Biological dosimetry)

    Energy Technology Data Exchange (ETDEWEB)

    Preston, R.J.

    1990-12-17

    The traveler attended the 1st International Conference on Biological Dosimetry in Madrid, Spain. This conference was organized to provide information to a general audience of biologists, physicists, radiotherapists, industrial hygiene personnel and individuals from related fields on the current ability of cytogenetic analysis to provide estimates of radiation dose in cases of occupational or environmental exposure. There is a growing interest in Spain in biological dosimetry because of the increased use of radiation sources for medical and occupational uses, and with this the anticipated and actual increase in numbers of overexposure. The traveler delivered the introductory lecture on Biological Dosimetry: Mechanistic Concepts'' that was intended to provide a framework by which the more applied lectures could be interpreted in a mechanistic way. A second component of the trip was to provide advice with regard to several recent cases of overexposure that had been or were being assessed by the Radiopathology and Radiotherapy Department of the Hospital General Gregorio Maranon'' in Madrid. The traveler had provided information on several of these, and had analyzed cells from some exposed or purportedly exposed individuals. The members of the biological dosimetry group were referred to individuals at REACTS at Oak Ridge Associated Universities for advice on follow-up treatment.

  2. Marine Biology

    Science.gov (United States)

    Dewees, Christopher M.; Hooper, Jon K.

    1976-01-01

    A variety of informational material for a course in marine biology or oceanology at the secondary level is presented. Among the topics discussed are: food webs and pyramids, planktonic blooms, marine life, plankton nets, food chains, phytoplankton, zooplankton, larval plankton and filter feeders. (BT)

  3. Scaffolded biology.

    Science.gov (United States)

    Minelli, Alessandro

    2016-09-01

    Descriptions and interpretations of the natural world are dominated by dichotomies such as organism vs. environment, nature vs. nurture, genetic vs. epigenetic, but in the last couple of decades strong dissatisfaction with those partitions has been repeatedly voiced and a number of alternative perspectives have been suggested, from perspectives such as Dawkins' extended phenotype, Turner's extended organism, Oyama's Developmental Systems Theory and Odling-Smee's niche construction theory. Last in time is the description of biological phenomena in terms of hybrids between an organism (scaffolded system) and a living or non-living scaffold, forming unit systems to study processes such as reproduction and development. As scaffold, eventually, we can define any resource used by the biological system, especially in development and reproduction, without incorporating it as happens in the case of resources fueling metabolism. Addressing biological systems as functionally scaffolded systems may help pointing to functional relationships that can impart temporal marking to the developmental process and thus explain its irreversibility; revisiting the boundary between development and metabolism and also regeneration phenomena, by suggesting a conceptual framework within which to investigate phenomena of regular hypermorphic regeneration such as characteristic of deer antlers; fixing a periodization of development in terms of the times at which a scaffolding relationship begins or is terminated; and promoting plant galls to legitimate study objects of developmental biology.

  4. Biology Notes.

    Science.gov (United States)

    School Science Review, 1984

    1984-01-01

    Presents information on the teaching of nutrition (including new information relating to many current O-level syllabi) and part 16 of a reading list for A- and S-level biology. Also includes a note on using earthworms as a source of material for teaching meiosis. (JN)

  5. WholePathwayScope: a comprehensive pathway-based analysis tool for high-throughput data

    Directory of Open Access Journals (Sweden)

    Cohen Jonathan C

    2006-01-01

    Full Text Available Abstract Background Analysis of High Throughput (HTP Data such as microarray and proteomics data has provided a powerful methodology to study patterns of gene regulation at genome scale. A major unresolved problem in the post-genomic era is to assemble the large amounts of data generated into a meaningful biological context. We have developed a comprehensive software tool, WholePathwayScope (WPS, for deriving biological insights from analysis of HTP data. Result WPS extracts gene lists with shared biological themes through color cue templates. WPS statistically evaluates global functional category enrichment of gene lists and pathway-level pattern enrichment of data. WPS incorporates well-known biological pathways from KEGG (Kyoto Encyclopedia of Genes and Genomes and Biocarta, GO (Gene Ontology terms as well as user-defined pathways or relevant gene clusters or groups, and explores gene-term relationships within the derived gene-term association networks (GTANs. WPS simultaneously compares multiple datasets within biological contexts either as pathways or as association networks. WPS also integrates Genetic Association Database and Partial MedGene Database for disease-association information. We have used this program to analyze and compare microarray and proteomics datasets derived from a variety of biological systems. Application examples demonstrated the capacity of WPS to significantly facilitate the analysis of HTP data for integrative discovery. Conclusion This tool represents a pathway-based platform for discovery integration to maximize analysis power. The tool is freely available at http://www.abcc.ncifcrf.gov/wps/wps_index.php.

  6. Marcadores tumorais no câncer de pulmão: um caminho para a terapia biológica Tumor markers in lung cancer: a pathway to biological therapy

    Directory of Open Access Journals (Sweden)

    FERNANDO AZEVEDO PACHECO

    2002-06-01

    Full Text Available Os avanços recentes na genética e na biologia molecular permitiram a identificação de genes e proteínas produzidos ou superexpressados pelos tumores. Tais produtos, os chamados marcadores tumorais, antes utilizados apenas como ferramentas de diagnóstico e prognóstico, vêm atualmente tomando papel importante no desenvolvimento de novas modalidades de tratamento, direcionadas a quebrar o ciclo biológico da progressão tumoral. Neste artigo, revisa-se o papel de alguns marcadores tumorais tradicionalmente conhecidos (CEA, p53, NSE, K-ras, e descrevem-se a prevalência e a função da superexpressão do receptor do fator de crescimento epidérmico (EGFR e do seu produto protéico (p185neu. Novos agentes têm sido desenvolvidos baseando-se no bloqueio da sinalização iniciada pelo EGFR. Destes, destaca-se o ZD1839 (Iressa, uma droga via oral que inibe de modo reversível e seletivo a atividade tirosina-quinase do EGFR, e que vem demonstrando bons resultados tanto isoladamente quanto em combinação com outros agentes quimioterápicos. Tais avanços devem contribuir de modo significativo no tratamento do câncer, principalmente no carcinoma de pulmão do tipo não-pequenas células.Recent advances in genetics and molecular biology lead to the identification of genes and protein products overexpressed by tumors. Such products, called tumor markers, were previously used only as diagnostic and prognostic tools, but are currently being the target of extensive research, with growing evidence that some of them may have an important role in the development of new treatment modalities, targeting the tumor cell biological cycle. In this article, the authors review the role of some of the traditionally known tumor markers (CEA, p53, NSE, K-ras, and describe the prevalence and the role of the epidermal growth factor receptor (EGFR overexpression and its protein product, p185neu. New drugs have been developed, aiming at the blockade of the signaling

  7. Machine learning methods for metabolic pathway prediction

    Directory of Open Access Journals (Sweden)

    Karp Peter D

    2010-01-01

    Full Text Available Abstract Background A key challenge in systems biology is the reconstruction of an organism's metabolic network from its genome sequence. One strategy for addressing this problem is to predict which metabolic pathways, from a reference database of known pathways, are present in the organism, based on the annotated genome of the organism. Results To quantitatively validate methods for pathway prediction, we developed a large "gold standard" dataset of 5,610 pathway instances known to be present or absent in curated metabolic pathway databases for six organisms. We defined a collection of 123 pathway features, whose information content we evaluated with respect to the gold standard. Feature data were used as input to an extensive collection of machine learning (ML methods, including naïve Bayes, decision trees, and logistic regression, together with feature selection and ensemble methods. We compared the ML methods to the previous PathoLogic algorithm for pathway prediction using the gold standard dataset. We found that ML-based prediction methods can match the performance of the PathoLogic algorithm. PathoLogic achieved an accuracy of 91% and an F-measure of 0.786. The ML-based prediction methods achieved accuracy as high as 91.2% and F-measure as high as 0.787. The ML-based methods output a probability for each predicted pathway, whereas PathoLogic does not, which provides more information to the user and facilitates filtering of predicted pathways. Conclusions ML methods for pathway prediction perform as well as existing methods, and have qualitative advantages in terms of extensibility, tunability, and explainability. More advanced prediction methods and/or more sophisticated input features may improve the performance of ML methods. However, pathway prediction performance appears to be limited largely by the ability to correctly match enzymes to the reactions they catalyze based on genome annotations.

  8. Rhomboids, signalling and cell biology.

    Science.gov (United States)

    Freeman, Matthew

    2016-06-15

    Here, I take a somewhat personal perspective on signalling control, focusing on the rhomboid-like superfamily of proteins that my group has worked on for almost 20 years. As well as describing some of the key and recent advances, I attempt to draw out signalling themes that emerge. One important message is that the genetic and biochemical perspective on signalling has tended to underplay the importance of cell biology. There is clear evidence that signalling pathways exploit the control of intracellular trafficking, protein quality control and degradation and other cell biological phenomena, as important regulatory opportunities.

  9. Regulation of cellular metabolism by the Notch receptor signalling pathway

    OpenAIRE

    2012-01-01

    Seven genes involved in metabolism were tested as direct targets of the Notch signalling pathway. For each gene the occupancy of its enhancers by Su(H), its transcriptional response to Notch pathway and its biological functionality was verified in vitro and in vivo.

  10. Integrative Biological Analysis of the APOE*3-Leiden Transgenic Mouse

    NARCIS (Netherlands)

    Clish, C.B.; Davidov, E.; Oresic, M.; Plasterer, T.N.; Lavine, G.; Londo, T.; Meys, M.; Snell, P.; Stochaj, W.; Adourian, A.; Zhang, X.; Morel, N.; Neumann, E.; Verheij, E.; Vogels, J.T.W.E.; Havekes, L.M.; Afeyan, N.; Regnier, F.; Greef, J. van der; Naylor, S.

    2004-01-01

    Integrative (or systems biology) is a new approach to analyzing biological entities as integrated systems of genetic, genomic, protein, metabolite, cellular, and pathway events that are in flux and interdependent. Here, we demonstrate the application of intregrative biological analysis to a mammalia

  11. Mesoscopic biology

    Indian Academy of Sciences (India)

    G V Shivashankar

    2002-02-01

    In this paper we present a qualitative outlook of mesoscopic biology where the typical length scale is of the order of nanometers and the energy scales comparable to thermal energy. Novel biomolecular machines, governed by coded information at the level of DNA and proteins, operate at these length scales in biological systems. In recent years advances in technology have led to the study of some of the design principles of these machines; in particular at the level of an individual molecule. For example, the forces that operate in molecular interactions, the stochasticity involved in these interactions and their spatio-temporal dynamics are beginning to be explored. Understanding such design principles is opening new possibilities in mesoscopic physics with potential applications.

  12. Industrial systems biology and its impact on synthetic biology of yeast cell factories

    DEFF Research Database (Denmark)

    Fletcher, Eugene; Krivoruchko, Anastasia; Nielsen, Jens

    2016-01-01

    Engineering industrial cell factories to effectively yield a desired product while dealing with industrially relevant stresses is usually the most challenging step in the development of industrial production of chemicals using microbial fermentation processes. Using synthetic biology tools......, microbial cell factories such as Saccharomyces cerevisiae can be engineered to express synthetic pathways for the production of fuels, biopharmaceuticals, fragrances, and food flavors. However, directing fluxes through these synthetic pathways towards the desired product can be demanding due to complex...... regulation or poor gene expression. Systems biology, which applies computational tools and mathematical modeling to understand complex biological networks, can be used to guide synthetic biology design. Here, we present our perspective on how systems biology can impact synthetic biology towards the goal...

  13. Industrial systems biology and its impact on synthetic biology of yeast cell factories.

    Science.gov (United States)

    Fletcher, Eugene; Krivoruchko, Anastasia; Nielsen, Jens

    2016-06-01

    Engineering industrial cell factories to effectively yield a desired product while dealing with industrially relevant stresses is usually the most challenging step in the development of industrial production of chemicals using microbial fermentation processes. Using synthetic biology tools, microbial cell factories such as Saccharomyces cerevisiae can be engineered to express synthetic pathways for the production of fuels, biopharmaceuticals, fragrances, and food flavors. However, directing fluxes through these synthetic pathways towards the desired product can be demanding due to complex regulation or poor gene expression. Systems biology, which applies computational tools and mathematical modeling to understand complex biological networks, can be used to guide synthetic biology design. Here, we present our perspective on how systems biology can impact synthetic biology towards the goal of developing improved yeast cell factories. Biotechnol. Bioeng. 2016;113: 1164-1170. © 2015 Wiley Periodicals, Inc.

  14. Marine biology

    Energy Technology Data Exchange (ETDEWEB)

    Thurman, H.V.; Webber, H.H.

    1984-01-01

    This book discusses both taxonomic and ecological topics on marine biology. Full coverage of marine organisms of all five kingdoms is provided, along with interesting and thorough discussion of all major marine habitats. Organization into six major parts allows flexibility. It also provides insight into important topics such as disposal of nuclear waste at sea, the idea that life began on the ocean floor, and how whales, krill, and people interact. A full-color photo chapter reviews questions, and exercises. The contents are: an overview marine biology: fundamental concepts/investigating life in the ocean; the physical ocean, the ocean floor, the nature of water, the nature and motion of ocean water; general ecology, conditions for life in the sea, biological productivity and energy transfer; marine organisms; monera, protista, mycota and metaphyta; the smaller marine animals, the large animals marine habitats, the intertidal zone/benthos of the continental shelf, the photic zone, the deep ocean, the ocean under stress, marine pollution, appendix a: the metric system and conversion factors/ appendix b: prefixes and suffixes/ appendix c: taxonomic classification of common marine organisms, and glossary, and index.

  15. 基于蛋白质互作知识的生物学通路扩充新方法%A novel biological pathway expansion method based on the knowledge of protein-protein interactions

    Institute of Scientific and Technical Information of China (English)

    赵小蕾; 左晓宇; 覃继恒; 梁岩; 张乃尊; 栾奕昭; 饶绍奇

    2014-01-01

    生物学通路被广泛应用于基因功能学研究,但现有的生物学通路知识并不完善,仍需进一步扩充.生物信息学预测为通路扩充提供了一种有效且经济的途径.文章提出了一种融合蛋白质-蛋白质互作知识以及Gene Ontology(GO)数据库信息进行基因通路预测的新方法.首先选取目标基因在蛋白质-蛋白质互作层面上的邻居所在的Kyoto Encyclopedia of Genes and Genomes(KEGG)通路为候选通路,然后通过检验候选通路中的基因是否在与目标基因关联的GO节点富集来判断目标基因的通路归属.分别利用Human Protein Reference Database(HPRD)和Biological General Repository for Interaction Datasets(BioGRID)数据库中的蛋白质-蛋白质互作信息进行预测.结果表明,在两套数据中,随着互作邻居个数的增加,预测的平均准确率(在所有目标基因注释的通路中被成功预测的比例)及相对准确率(在至少有一个注释通路被成功预测的基因集中,所有注释通路均被预测正确的基因所占的比例)均呈现上升趋势.当互作邻居个数达到22时,预测的平均准确率分别达到96.2%(HPRD)和96.3%(BioGRID),而相对准确率分别为93.3%(HPRD)和84.1%(BioGRID).进一步利用新版数据库对旧版数据库中被更新的89个基因进行验证,至少有一个更新通路被预测正确的基因有50个,其中43个基因的更新通路被完全正确预测,相对准确率为86.0%.这些结果显示该方法是一种可靠且有效的通路扩充方法.

  16. Cell biology of neuronal endocytosis.

    Science.gov (United States)

    Parton, R G; Dotti, C G

    1993-09-01

    Endocytosis is the process by which cells take in fluid and components of the plasma membrane. In this way cells obtain nutrients and trophic factors, retrieve membrane proteins for degradation, and sample their environment. In neuronal cells endocytosis is essential for the recycling of membrane after neurotransmitter release and plays a critical role during early developmental stages. Moreover, alterations of the endocytic pathway have been attributed a crucial role in the pathophysiology of certain neurological diseases. Although well characterized at the ultrastructural level, little is known of the dynamics and molecular organization of the neuronal endocytic pathways. In this respect most of our knowledge comes from studies of non-neuronal cells. In this review we will examine the endocytic pathways in neurons from a cell biological viewpoint by making comparisons with non-neuronal cells and in particular with another polarized cell, the epithelial cell.

  17. Subpathway Analysis based on Signaling-Pathway Impact Analysis of Signaling Pathway.

    Directory of Open Access Journals (Sweden)

    Xianbin Li

    Full Text Available Pathway analysis is a common approach to gain insight from biological experiments. Signaling-pathway impact analysis (SPIA is one such method and combines both the classical enrichment analysis and the actual perturbation on a given pathway. Because this method focuses on a single pathway, its resolution generally is not very high because the differentially expressed genes may be enriched in a local region of the pathway. In the present work, to identify cancer-related pathways, we incorporated a recent subpathway analysis method into the SPIA method to form the "sub-SPIA method." The original subpathway analysis uses the k-clique structure to define a subpathway. However, it is not sufficiently flexible to capture subpathways with complex structure and usually results in many overlapping subpathways. We therefore propose using the minimal-spanning-tree structure to find a subpathway. We apply this approach to colorectal cancer and lung cancer datasets, and our results show that sub-SPIA can identify many significant pathways associated with each specific cancer that other methods miss. Based on the entire pathway network in the Kyoto Encyclopedia of Genes and Genomes, we find that the pathways identified by sub-SPIA not only have the largest average degree, but also are more closely connected than those identified by other methods. This result suggests that the abnormality signal propagating through them might be responsible for the specific cancer or disease.

  18. Identification of Metabolic Pathway Systems

    Directory of Open Access Journals (Sweden)

    Sepideh eDolatshahi

    2016-02-01

    Full Text Available The estimation of parameters in even moderately large biological systems is a significant challenge. This challenge is greatly exacerbated if the mathematical formats of appropriate process descriptions are unknown. To address this challenge, the method of dynamic flux estimation (DFE was proposed for the analysis of metabolic time series data. Under ideal conditions, the first phase of DFE yields numerical representations of all fluxes within a metabolic pathway system, either as values at each time point or as plots against their substrates and modulators. However, this numerical result does not reveal the mathematical format of each flux. Thus, the second phase of DFE selects functional formats that are consistent with the numerical trends obtained from the first phase. While greatly facilitating metabolic data analysis, DFE is only directly applicable if the pathway system contains as many dependent variables as fluxes. Because most actual systems contain more fluxes than metabolite pools, this requirement is seldom satisfied. Auxiliary methods have been proposed to alleviate this issue, but they are not general. Here we propose strategies that extend DFE toward general, slightly underdetermined pathway systems.

  19. Identification of Metabolic Pathway Systems.

    Science.gov (United States)

    Dolatshahi, Sepideh; Voit, Eberhard O

    2016-01-01

    The estimation of parameters in even moderately large biological systems is a significant challenge. This challenge is greatly exacerbated if the mathematical formats of appropriate process descriptions are unknown. To address this challenge, the method of dynamic flux estimation (DFE) was proposed for the analysis of metabolic time series data. Under ideal conditions, the first phase of DFE yields numerical representations of all fluxes within a metabolic pathway system, either as values at each time point or as plots against their substrates and modulators. However, this numerical result does not reveal the mathematical format of each flux. Thus, the second phase of DFE selects functional formats that are consistent with the numerical trends obtained from the first phase. While greatly facilitating metabolic data analysis, DFE is only directly applicable if the pathway system contains as many dependent variables as fluxes. Because most actual systems contain more fluxes than metabolite pools, this requirement is seldom satisfied. Auxiliary methods have been proposed to alleviate this issue, but they are not general. Here we propose strategies that extend DFE toward general, slightly underdetermined pathway systems.

  20. Biological Databases

    Directory of Open Access Journals (Sweden)

    Kaviena Baskaran

    2013-12-01

    Full Text Available Biology has entered a new era in distributing information based on database and this collection of database become primary in publishing information. This data publishing is done through Internet Gopher where information resources easy and affordable offered by powerful research tools. The more important thing now is the development of high quality and professionally operated electronic data publishing sites. To enhance the service and appropriate editorial and policies for electronic data publishing has been established and editors of article shoulder the responsibility.

  1. The biology of strigolactones

    KAUST Repository

    Ruyter-Spira, Carolien P.

    2013-02-01

    The strigolactones are rhizosphere signaling molecules as well as a new class of plant hormones with a still increasing number of biological functions being uncovered. Here, we review a recent major breakthrough in our understanding of strigolactone biosynthesis, which has revealed the unexpected simplicity of the originally postulated complex pathway. Moreover, the discovery and localization of a strigolactone exporter sheds new light on putative strigolactone fluxes to the rhizosphere as well as within the plant. The combination of these data with information on the expression and regulation of strigolactone biosynthetic and downstream signaling genes provides new insights into how strigolactones control the many different aspects of plant development and how their rhizosphere signaling role may have evolved. © 2012 Elsevier Ltd.

  2. Perception of biological motion in visual agnosia

    OpenAIRE

    Elisabeth eHuberle; Paul eRupek; Markus eLappe; Hans-Otto eKarnath

    2012-01-01

    Over the past twenty-five years, visual processing has been discussed in the context of the dual stream hypothesis consisting of a ventral (‘what') and a dorsal ('where') visual information processing pathway. Patients with brain damage of the ventral pathway typically present with signs of visual agnosia, the inability to identify and discriminate objects by visual exploration, but show normal perception of motion perception. A dissociation between the perception of biological motion and non...

  3. Biological biomaterials

    Energy Technology Data Exchange (ETDEWEB)

    Jorge-Herrero, E. [Servicio de Cirugia Experimental. Clinica Puerta de Hierro, Madrid (Spain)

    1997-05-01

    There are a number of situations in which substances of biological origin are employed as biomaterials. Most of them are macromolecules derived from isolated connective tissue or the connective tissue itself in membrane form, in both cases, the tissue can be used in its natural form or be chemically treated. In other cases, certain blood vessels can be chemically pretreated and used as vascular prostheses. Proteins such as albumin, collagen and fibrinogen are employed to coat vascular prostheses. Certain polysaccharides have also been tested for use in controlled drug release systems. Likewise, a number of tissues, such as dura mater, bovine pericardium, procine valves and human valves, are used in the preparation of cardiac prostheses. We also use veins from animals or humans in arterial replacement. In none of these cases are the tissues employed dissimilar to the native tissues as they have been chemically modified, becoming a new bio material with different physical and biochemical properties. In short, we find that natural products are being utilized as biomaterials and must be considered as such; thus, it is necessary to study both their chemicobiological and physicomechanical properties. In the present report, we review the current applications, problems and future prospects of some of these biological biomaterials. (Author) 84 refs.

  4. Where Synthetic Biology Meets ET

    Science.gov (United States)

    Rothschild, Lynn J.

    2016-01-01

    Synthetic biology - the design and construction of new biological parts and systems and the redesign of existing ones for useful purposes - has the potential to transform fields from pharmaceuticals to fuels. Our lab has focused on the potential of synthetic biology to revolutionize all three major parts of astrobiology: Where do we come from? Where are we going? and Are we alone? For the first and third, synthetic biology is allowing us to answer whether the evolutionary narrative that has played out on planet earth is likely to have been unique or universal. For example, in our lab we are re-evolving the biosynthetic pathways of amino acids in order to understand potential capabilities of an early organism with a limited repertoire of amino acids and developing techniques for the recovery of metals from spent electronics on other planetary bodies. And what about the limits for life? Can we create organisms that expand the envelope for life? In the future synthetic biology will play an increasing role in human activities both on earth, in fields as diverse as human health and the industrial production of novel bio-composites. Beyond earth, we will rely increasingly on biologically-provided life support, as we have throughout our evolutionary history. In order to do this, the field will build on two of the great contributions of astrobiology: studies of the origin of life and life in extreme environments.

  5. An information-flow-based model with dissipation, saturation and direction for active pathway inference

    Directory of Open Access Journals (Sweden)

    Wu Ling-Yun

    2010-05-01

    Full Text Available Abstract Background Biological systems process the genetic information and environmental signals through pathways. How to map the pathways systematically and efficiently from high-throughput genomic and proteomic data is a challenging open problem. Previous methods design different heuristics but do not describe explicitly the behaviours of the information flow. Results In this study, we propose new concepts of dissipation, saturation and direction to decipher the information flow behaviours in the pathways and thereby infer the biological pathways from a given source to its target. This model takes into account explicitly the common features of the information transmission and provides a general framework to model the biological pathways. It can incorporate different types of bio-molecular interactions to infer the signal transduction pathways and interpret the expression quantitative trait loci (eQTL associations. The model is formulated as a linear programming problem and thus is solved efficiently. Experiments on the real data of yeast indicate that the reproduced pathways are highly consistent with the current knowledge. Conclusions Our model explicitly treats the biological pathways as information flows with dissipation, saturation and direction. The effective applications suggest that the three new concepts may be valid to describe the organization rules of biological pathways. The deduced linear programming should be a promising tool to infer the various biological pathways from the high-throughput data.

  6. pathDIP: an annotated resource for known and predicted human gene-pathway associations and pathway enrichment analysis

    Science.gov (United States)

    Rahmati, Sara; Abovsky, Mark; Pastrello, Chiara; Jurisica, Igor

    2017-01-01

    Molecular pathway data are essential in current computational and systems biology research. While there are many primary and integrated pathway databases, several challenges remain, including low proteome coverage (57%), low overlap across different databases, unavailability of direct information about underlying physical connectivity of pathway members, and high fraction of protein-coding genes without any pathway annotations, i.e. ‘pathway orphans’. In order to address all these challenges, we developed pathDIP, which integrates data from 20 source pathway databases, ‘core pathways’, with physical protein–protein interactions to predict biologically relevant protein–pathway associations, referred to as ‘extended pathways’. Cross-validation determined 71% recovery rate of our predictions. Data integration and predictions increase coverage of pathway annotations for protein-coding genes to 86%, and provide novel annotations for 5732 pathway orphans. PathDIP (http://ophid.utoronto.ca/pathdip) annotates 17 070 protein-coding genes with 4678 pathways, and provides multiple query, analysis and output options. PMID:27899558

  7. Master regulators, regulatory networks, and pathways of glioblastoma subtypes.

    Science.gov (United States)

    Bozdag, Serdar; Li, Aiguo; Baysan, Mehmet; Fine, Howard A

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor. GBM samples are classified into subtypes based on their transcriptomic and epigenetic profiles. Despite numerous studies to better characterize GBM biology, a comprehensive study to identify GBM subtype- specific master regulators, gene regulatory networks, and pathways is missing. Here, we used FastMEDUSA to compute master regulators and gene regulatory networks for each GBM subtype. We also ran Gene Set Enrichment Analysis and Ingenuity Pathway Analysis on GBM expression dataset from The Cancer Genome Atlas Project to compute GBM- and GBM subtype-specific pathways. Our analysis was able to recover some of the known master regulators and pathways in GBM as well as some putative novel regulators and pathways, which will aide in our understanding of the unique biology of GBM subtypes.

  8. Development of Network Analysis and Visualization System for KEGG Pathways

    Directory of Open Access Journals (Sweden)

    Dongmin Seo

    2015-07-01

    Full Text Available Big data refers to informationalization technology for extracting valuable information through the use and analysis of large-scale data and, based on that data, deriving plans for response or predicting changes. With the development of software and devices for next generation sequencing, a vast amount of bioinformatics data has been generated recently. Also, bioinformatics data based big-data technology is rising rapidly as a core technology by the bioinformatician, biologist and big-data scientist. KEGG pathway is bioinformatics data for understanding high-level functions and utilities of the biological system. However, KEGG pathway analysis requires a lot of time and effort because KEGG pathways are high volume and very diverse. In this paper, we proposed a network analysis and visualization system that crawl user interest KEGG pathways, construct a pathway network based on a hierarchy structure of pathways and visualize relations and interactions of pathways by clustering and selecting core pathways from the network. Finally, we construct a pathway network collected by starting with an Alzheimer’s disease pathway and show the results on clustering and selecting core pathways from the pathway network.

  9. Genome-Wide Pathway Analysis Identifies Genetic Pathways Associated with Psoriasis.

    Science.gov (United States)

    Aterido, Adrià; Julià, Antonio; Ferrándiz, Carlos; Puig, Lluís; Fonseca, Eduardo; Fernández-López, Emilia; Dauden, Esteban; Sánchez-Carazo, José Luís; López-Estebaranz, José Luís; Moreno-Ramírez, David; Vanaclocha, Francisco; Herrera, Enrique; de la Cueva, Pablo; Dand, Nick; Palau, Núria; Alonso, Arnald; López-Lasanta, María; Tortosa, Raül; García-Montero, Andrés; Codó, Laia; Gelpí, Josep Lluís; Bertranpetit, Jaume; Absher, Devin; Capon, Francesca; Myers, Richard M; Barker, Jonathan N; Marsal, Sara

    2016-03-01

    Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of this study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 single nucleotide polymorphisms in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR ≤ 2.55 × 10(-2)) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR ≤ 3.46 × 10(-2)). We found genetic pathways that had not been previously associated with psoriasis risk such as retinol metabolism (Pcombined = 1.84 × 10(-4)), the transport of inorganic ions and amino acids (Pcombined = 1.57 × 10(-7)), and post-translational protein modification (Pcombined = 1.57 × 10(-7)). In the latter pathway, MGAT5 showed a strong network centrality, and its association with psoriasis risk was further validated in an additional case-control cohort of 3,429 individuals (P psoriasis susceptibility.

  10. Industrial systems biology.

    Science.gov (United States)

    Otero, José Manuel; Nielsen, Jens

    2010-02-15

    The chemical industry is currently undergoing a dramatic change driven by demand for developing more sustainable processes for the production of fuels, chemicals, and materials. In biotechnological processes different microorganisms can be exploited, and the large diversity of metabolic reactions represents a rich repository for the design of chemical conversion processes that lead to efficient production of desirable products. However, often microorganisms that produce a desirable product, either naturally or because they have been engineered through insertion of heterologous pathways, have low yields and productivities, and in order to establish an economically viable process it is necessary to improve the performance of the microorganism. Here metabolic engineering is the enabling technology. Through metabolic engineering the metabolic landscape of the microorganism is engineered such that there is an efficient conversion of the raw material, typically glucose, to the product of interest. This process may involve both insertion of new enzymes activities, deletion of existing enzyme activities, but often also deregulation of existing regulatory structures operating in the cell. In order to rapidly identify the optimal metabolic engineering strategy the industry is to an increasing extent looking into the use of tools from systems biology. This involves both x-ome technologies such as transcriptome, proteome, metabolome, and fluxome analysis, and advanced mathematical modeling tools such as genome-scale metabolic modeling. Here we look into the history of these different techniques and review how they find application in industrial biotechnology, which will lead to what we here define as industrial systems biology.

  11. Applicability of Computational Systems Biology in Toxicology

    DEFF Research Database (Denmark)

    Kongsbak, Kristine Grønning; Hadrup, Niels; Audouze, Karine Marie Laure

    2014-01-01

    Systems biology as a research field has emerged within the last few decades. Systems biology, often defined as the antithesis of the reductionist approach, integrates information about individual components of a biological system. In integrative systems biology, large data sets from various sources...... and databases are used to model and predict effects of chemicals on, for instance, human health. In toxicology, computational systems biology enables identification of important pathways and molecules from large data sets; tasks that can be extremely laborious when performed by a classical literature search...... be used to establish hypotheses on links between the chemical and human diseases. Such information can also be applied for designing more intelligent animal/cell experiments that can test the established hypotheses. Here, we describe how and why to apply an integrative systems biology method...

  12. On Biology as an Emergent Science

    CERN Document Server

    Noyes, H Pierre

    2007-01-01

    Biology is considered here as an "emergent science" in the sense of Anderson and of Laughlin and Pines. It is demonstrated that a straightforward mathematical definition of "biological system" is useful in showing how biology differs in structure from the lower levels in Anderson's "More is Different" hierarchy. Using cells in a chemostat as a paradigmatic exemplar of a biological system, it is found that a coherent collection of metabolic pathways through a single cell in the chemostat also satisfies the proposed definition of a biological system. This provides a theoretical and mathematical underpinning for Young's fundamental model of biological organization and integration. Evidence for the therapeutic efficacy of Young's method of analysis is provided by preliminary results of clinical trials of a specific application of Young's model to the treatment of cancer cachexia.

  13. Efficient reconstruction of metabolic pathways by bidirectional chemical search.

    Science.gov (United States)

    Félix, Liliana; Rosselló, Francesc; Valiente, Gabriel

    2009-04-01

    One of the main challenges in systems biology is the establishment of the metabolome: a catalogue of the metabolites and biochemical reactions present in a specific organism. Current knowledge of biochemical pathways as stored in public databases such as KEGG, is based on carefully curated genomic evidence for the presence of specific metabolites and enzymes that activate particular biochemical reactions. In this paper, we present an efficient method to build a substantial portion of the artificial chemistry defined by the metabolites and biochemical reactions in a given metabolic pathway, which is based on bidirectional chemical search. Computational results on the pathways stored in KEGG reveal novel biochemical pathways.

  14. Standardization for natural product synthetic biology.

    Science.gov (United States)

    Zhao, Huimin; Medema, Marnix H

    2016-08-27

    Standardization is one of the foundational features of modern-day engineering, and the use of standardized parts and processes is a key element that distinguishes bona fide synthetic biology from traditional genetic engineering. Here, we discuss the role of standardization in natural product synthetic biology, focusing on standardization of data on biosynthetic pathways and gene clusters, as well as the role of standardization in the process of biosynthetic gene cluster engineering.

  15. Synergistic Synthetic Biology: Units in Concert.

    Science.gov (United States)

    Trosset, Jean-Yves; Carbonell, Pablo

    2013-01-01

    Synthetic biology aims at translating the methods and strategies from engineering into biology in order to streamline the design and construction of biological devices through standardized parts. Modular synthetic biology devices are designed by means of an adequate elimination of cross-talk that makes circuits orthogonal and specific. To that end, synthetic constructs need to be adequately optimized through in silico modeling by choosing the right complement of genetic parts and by experimental tuning through directed evolution and craftsmanship. In this review, we consider an additional and complementary tool available to the synthetic biologist for innovative design and successful construction of desired circuit functionalities: biological synergies. Synergy is a prevalent emergent property in biological systems that arises from the concerted action of multiple factors producing an amplification or cancelation effect compared with individual actions alone. Synergies appear in domains as diverse as those involved in chemical and protein activity, polypharmacology, and metabolic pathway complementarity. In conventional synthetic biology designs, synergistic cross-talk between parts and modules is generally attenuated in order to verify their orthogonality. Synergistic interactions, however, can induce emergent behavior that might prove useful for synthetic biology applications, like in functional circuit design, multi-drug treatment, or in sensing and delivery devices. Synergistic design principles are therefore complementary to those coming from orthogonal design and may provide added value to synthetic biology applications. The appropriate modeling, characterization, and design of synergies between biological parts and units will allow the discovery of yet unforeseeable, novel synthetic biology applications.

  16. Perception of biological motion in visual agnosia

    Directory of Open Access Journals (Sweden)

    Elisabeth eHuberle

    2012-08-01

    Full Text Available Over the past twenty-five years, visual processing has been discussed in the context of the dual stream hypothesis consisting of a ventral (‘what' and a dorsal ('where' visual information processing pathway. Patients with brain damage of the ventral pathway typically present with signs of visual agnosia, the inability to identify and discriminate objects by visual exploration, but show normal perception of motion perception. A dissociation between the perception of biological motion and non-biological motion has been suggested: Perception of biological motion might be impaired when 'non-biological' motion perception is intact and vice versa. The impact of object recognition on the perception of biological motion remains unclear. We thus investigated this question in a patient with severe visual agnosia, who showed normal perception of non-biological motion. The data suggested that the patient's perception of biological motion remained largely intact. However, when tested with objects constructed of coherently moving dots (‘Shape-from-Motion’, recognition was severely impaired. The results are discussed in the context of possible mechanisms of biological motion perception.

  17. Perception of biological motion in visual agnosia.

    Science.gov (United States)

    Huberle, Elisabeth; Rupek, Paul; Lappe, Markus; Karnath, Hans-Otto

    2012-01-01

    Over the past 25 years, visual processing has been discussed in the context of the dual stream hypothesis consisting of a ventral ("what") and a dorsal ("where") visual information processing pathway. Patients with brain damage of the ventral pathway typically present with signs of visual agnosia, the inability to identify and discriminate objects by visual exploration, but show normal perception of motion perception. A dissociation between the perception of biological motion and non-biological motion has been suggested: perception of biological motion might be impaired when "non-biological" motion perception is intact and vice versa. The impact of object recognition on the perception of biological motion remains unclear. We thus investigated this question in a patient with severe visual agnosia, who showed normal perception of non-biological motion. The data suggested that the patient's perception of biological motion remained largely intact. However, when tested with objects constructed of coherently moving dots ("Shape-from-Motion"), recognition was severely impaired. The results are discussed in the context of possible mechanisms of biological motion perception.

  18. Structural Biology Fact Sheet

    Science.gov (United States)

    ... Home > Science Education > Structural Biology Fact Sheet Structural Biology Fact Sheet Tagline (Optional) Middle/Main Content Area What is structural biology? Structural biology is a field of science focused ...

  19. Systems biology as an integrated platform for bioinformatics, systems synthetic biology, and systems metabolic engineering.

    Science.gov (United States)

    Chen, Bor-Sen; Wu, Chia-Chou

    2013-10-11

    Systems biology aims at achieving a system-level understanding of living organisms and applying this knowledge to various fields such as synthetic biology, metabolic engineering, and medicine. System-level understanding of living organisms can be derived from insight into: (i) system structure and the mechanism of biological networks such as gene regulation, protein interactions, signaling, and metabolic pathways; (ii) system dynamics of biological networks, which provides an understanding of stability, robustness, and transduction ability through system identification, and through system analysis methods; (iii) system control methods at different levels of biological networks, which provide an understanding of systematic mechanisms to robustly control system states, minimize malfunctions, and provide potential therapeutic targets in disease treatment; (iv) systematic design methods for the modification and construction of biological networks with desired behaviors, which provide system design principles and system simulations for synthetic biology designs and systems metabolic engineering. This review describes current developments in systems biology, systems synthetic biology, and systems metabolic engineering for engineering and biology researchers. We also discuss challenges and future prospects for systems biology and the concept of systems biology as an integrated platform for bioinformatics, systems synthetic biology, and systems metabolic engineering.

  20. Systems Biology as an Integrated Platform for Bioinformatics, Systems Synthetic Biology, and Systems Metabolic Engineering

    Directory of Open Access Journals (Sweden)

    Bor-Sen Chen

    2013-10-01

    Full Text Available Systems biology aims at achieving a system-level understanding of living organisms and applying this knowledge to various fields such as synthetic biology, metabolic engineering, and medicine. System-level understanding of living organisms can be derived from insight into: (i system structure and the mechanism of biological networks such as gene regulation, protein interactions, signaling, and metabolic pathways; (ii system dynamics of biological networks, which provides an understanding of stability, robustness, and transduction ability through system identification, and through system analysis methods; (iii system control methods at different levels of biological networks, which provide an understanding of systematic mechanisms to robustly control system states, minimize malfunctions, and provide potential therapeutic targets in disease treatment; (iv systematic design methods for the modification and construction of biological networks with desired behaviors, which provide system design principles and system simulations for synthetic biology designs and systems metabolic engineering. This review describes current developments in systems biology, systems synthetic biology, and systems metabolic engineering for engineering and biology researchers. We also discuss challenges and future prospects for systems biology and the concept of systems biology as an integrated platform for bioinformatics, systems synthetic biology, and systems metabolic engineering.

  1. Simulating Biological and Non-Biological Motion

    Science.gov (United States)

    Bruzzo, Angela; Gesierich, Benno; Wohlschlager, Andreas

    2008-01-01

    It is widely accepted that the brain processes biological and non-biological movements in distinct neural circuits. Biological motion, in contrast to non-biological motion, refers to active movements of living beings. Aim of our experiment was to investigate the mechanisms underlying mental simulation of these two movement types. Subjects had to…

  2. A Brief Introduction to Chinese Biological Biological

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Chinese Biological Abstracts sponsored by the Library, the Shanghai Institutes for Biological Sciences, the Biological Documentation and Information Network, all of the Chinese Academy of Sciences, commenced publication in 1987 and was initiated to provide access to the Chinese information in the field of biology.

  3. Iron diminishes the in vitro biological effect of vanadium.

    Science.gov (United States)

    Mechanistic pathways underlying inflammatory injury following exposures to vanadium-containing compounds are not defined. We tested the postulate that the in vitro biological effect of vanadium results from its impact on iron homeostasis. Human bronchial epithelial (HBE) cells ex...

  4. Radiotracers For Lipid Signaling Pathways In Biological Systems

    Energy Technology Data Exchange (ETDEWEB)

    Gatley, S. J. [Northeastern Univ., Boston, MA (United States)

    2016-09-26

    The primary focus of this project continues to be the development of radiotracers and radiotracer methodology for studying physiology and biochemistry. The compounds that have been labeled areacylethanolamines and acylglycerols that are, as classes, represented in both in plants and in animals. In the latter, some of these act as ligands for cannabinoid receptors and they are therefore known as endocannabinoids. Cannabinoid receptors are not found in plant genomes so that plants must contain other receptors and signaling systems that use acylethanolamines. Relatively little work has been done on that issue, though acylethanolamines do modulate plant growth and stress resistance, thus possessing obvious relevance to agriculture and energy production. Progress has been described in five peer-reviewed papers and seven meeting abstracts. Preparation of 2-acylglycerol lipid messengers in high purity. A novel enzymatic synthesis was developedthat gave pure 2-acylglycerols free of any rearrrangement to the thermodynamically more stable 1(3)-acylglycerol byproducts. The method utilized 1,3-dibutyryl-2-acylglycerol substrate ethanolysis by a resinimobilized lipase. Thus, pure radiolabeled 2-acylglycerols can now be conveniently prepared just prior to their utilization. These synthetic studies were published in the Journal of Medicinal Chemistry, 2011. Diacylglycerol lipase assay methodology. Diacylglycerol lipases (DAGLs) generate 2- acylglycerols, and are thus potential targets for disease- or growth-modifying agents, by means of reducing formation of 2-acylglycerols. A radioTLC assay of the hydrolysis of radiolabeled diglyceride substrate [1''-carbon-14]2-arachidonoyl-1-stearoyl-sn-glycerol has been implemented, and used to validate a novel, potentially highthroughput fluorescence resonance energy transfer (FRET) based assay. A number of new DAGL inhibitors that have selectivity for DAGLs were synthesized and screened. This work was very recently published in Bioorganic and Medicinal Chemistry Letters.Acylethanolamines. The work initially focused on myristoylethanolamine (MEA) labeled in the acyl moiety with tritium and with carbon-14. Standard coupling conditions were used and gave the desired radiotracers in decent yields. Tritiated product was needed for the search for binding sites of this signaling messenger, and C-14 labeled product for imaging using phosphorimaging screens. Additionally, C-14 MEA was prepared labeled in the ethanolamine moiety. Fluorine-18 labeled acylethanolamines. A multi-step synthesis was performed to obtain unlabeled N-(16- fluorohexadecanoyl)ethanolamide for an HPLC standard via the precursor 16-bromo-N- [2[(tetrahydro-2Hpyran-2-yl)oxy]ethyl]hexadecanoylamide. Near-anhydrous F-18 and the bromo precursor (approximately 2-3 mg) in acetonitrile (0.5 ml) were heated with a PETWave microwave reactor for 10 min at 80 °C. F-18 incorporation was checked using silica-gel TLC (8:92 methanol/chloroform). Deprotection was carried out using TFA. The crude product was purified by semi-preparative ODS HPLC (80:20 AcN/ H2O). The product peak was diluted in water, concentrated on an SPE column, and eluted in 1 mL EtOH. F-18 incorporation to form the THP protected product was >90% with negligible side products observed. Deprotection and HPLC purification proceeded successfully with >99% radiochemical l purity. Brain distribution studies were done in mice. This work was presented at the Society of Nuclear Medicine meeting in June 2012. Subsequent more detailed studies including whole body tissue distribution studies, microPET experiments and radiochromatographic studies were published in ACS Chemical Neurosciences in 2014. Iodine-125 labeled acylethanolamines. The precursor 12-bromo-N-[2[(tetrahydro-2H-pyran-2-yl)oxy]ethyl]dodecanoylamide was prepared and a 1 mg sample was subject to exchange labeling withradioiodide in refluxing acetonitrile for 1 hour. HPLC analysis as above indicated incorporation of about10% of the radioactivity into a compound with the expected retention time of the correspondin

  5. Heavy metal pathways and archives in biological tissue

    Science.gov (United States)

    Orlic, I.; Siegele, R.; Menon, D. D.; Markich, S. J.; Cohen, D. D.; Jeffree, R. A.; McPhail, D. C.; Sarbutt, A.; Stelcer, E.

    2002-05-01

    Nuclear milli and microprobes at the Australian Nuclear Science and Technology Organisation (ANSTO) were used to determine lead accumulation in native Australian plants and animals. Three species of eucalypt plants ( Eucalyptus camaldulensis, Eucalyptus globulus and Eucalyptus lesouefii), one species of salt bush ( Atriplex burbhanyana) and one species each of acacia ( Acacia saligna) and estuarine crocodiles ( Crocodylus porosus) were investigated. Experimentally grown plants were subjected to a nutrient solution with a pH of 5 and spiked with a 200 μmol concentration of Pb. Lead concentrations in leaves of both E. globulus and E. camaldulensis showed an almost exponential decrease from the base of the main vein to the tip. Similarly, Pb concentrations decreased from the main vein to secondary veins. Concentrations of essential elements such as K, Fe, Zn and Br in the main and secondary veins were constant within experimental uncertainty. In contrast, the concentrations of Pb in the leaf veins of E. lesouefii were much lower and showed no systematic pattern. In stem and root samples the highest concentration of Pb was found in roots and stem of E. globulus and A. burbhanyana followed by E. camaldulensis. Some Pb was found in roots of A. saligna and only very low concentration in stem of the same plant. More detailed analysis of thin cross-sectional samples of roots and stem showed that Pb is present in much higher concentration in the growth area of the plant structure (i.e. meristemic region) and in relatively low concentration within the pith region and outer cortex. The osteoderms (dermal bones) of estuarine crocodiles, exposed to lead ammunition in food from the hunting activities of traditional Aboriginal owners, were sampled at two sites in Kakadu National Park, northern Australia. PIXE analyses showed enhanced, but relatively constant, ratios of Pb/Ca in the annual laminations. This was consistent with both their history of long term exposure to elevated anthropogenic Pb sources and the hypothesis that the osteoderm can be used as an archive of the crocodile's exposure to Pb during its life.

  6. Heavy metal pathways and archives in biological tissue

    Energy Technology Data Exchange (ETDEWEB)

    Orlic, I. E-mail: ivo@ansto.gov.au; Siegele, R.; Menon, D.D.; Markich, S.J.; Cohen, D.D.; Jeffree, R.A.; McPhail, D.C.; Sarbutt, A.; Stelcer, E

    2002-05-01

    Nuclear milli and microprobes at the Australian Nuclear Science and Technology Organisation (ANSTO) were used to determine lead accumulation in native Australian plants and animals. Three species of eucalypt plants (Eucalyptus camaldulensis, Eucalyptus globulus and Eucalyptus lesouefii), one species of salt bush (Atriplex burbhanyana) and one species each of acacia (Acacia saligna) and estuarine crocodiles (Crocodylus porosus) were investigated. Experimentally grown plants were subjected to a nutrient solution with a pH of 5 and spiked with a 200 {mu}mol concentration of Pb. Lead concentrations in leaves of both E. globulus and E. camaldulensis showed an almost exponential decrease from the base of the main vein to the tip. Similarly, Pb concentrations decreased from the main vein to secondary veins. Concentrations of essential elements such as K, Fe, Zn and Br in the main and secondary veins were constant within experimental uncertainty. In contrast, the concentrations of Pb in the leaf veins of E. lesouefii were much lower and showed no systematic pattern. In stem and root samples the highest concentration of Pb was found in roots and stem of E. globulus and A. burbhanyana followed by E. camaldulensis. Some Pb was found in roots of A. saligna and only very low concentration in stem of the same plant. More detailed analysis of thin cross-sectional samples of roots and stem showed that Pb is present in much higher concentration in the growth area of the plant structure (i.e. meristemic region) and in relatively low concentration within the pith region and outer cortex. The osteoderms (dermal bones) of estuarine crocodiles, exposed to lead ammunition in food from the hunting activities of traditional Aboriginal owners, were sampled at two sites in Kakadu National Park, northern Australia. PIXE analyses showed enhanced, but relatively constant, ratios of Pb/Ca in the annual laminations. This was consistent with both their history of long term exposure to elevated anthropogenic Pb sources and the hypothesis that the osteoderm can be used as an archive of the crocodile's exposure to Pb during its life.

  7. Toward metabolic engineering in the context of system biology and synthetic biology: advances and prospects.

    Science.gov (United States)

    Liu, Yanfeng; Shin, Hyun-dong; Li, Jianghua; Liu, Long

    2015-02-01

    Metabolic engineering facilitates the rational development of recombinant bacterial strains for metabolite overproduction. Building on enormous advances in system biology and synthetic biology, novel strategies have been established for multivariate optimization of metabolic networks in ensemble, spatial, and dynamic manners such as modular pathway engineering, compartmentalization metabolic engineering, and metabolic engineering guided by genome-scale metabolic models, in vitro reconstitution, and systems and synthetic biology. Herein, we summarize recent advances in novel metabolic engineering strategies. Combined with advancing kinetic models and synthetic biology tools, more efficient new strategies for improving cellular properties can be established and applied for industrially important biochemical production.

  8. Pathway and network analysis of cancer genomes

    DEFF Research Database (Denmark)

    Creixell, Pau; Reimand, Jueri; Haider, Syed

    2015-01-01

    Genomic information on tumors from 50 cancer types cataloged by the International Cancer Genome Consortium (ICGC) shows that only a few well-studied driver genes are frequently mutated, in contrast to many infrequently mutated genes that may also contribute to tumor biology. Hence there has been...... large interest in developing pathway and network analysis methods that group genes and illuminate the processes involved. We provide an overview of these analysis techniques and show where they guide mechanistic and translational investigations....

  9. Discovery of Unclustered Fungal Indole Diterpene Biosynthetic Pathways through Combinatorial Pathway Reassembly in Engineered Yeast.

    Science.gov (United States)

    Tang, Man-Cheng; Lin, Hsiao-Ching; Li, Dehai; Zou, Yi; Li, Jian; Xu, Wei; Cacho, Ralph A; Hillenmeyer, Maureen E; Garg, Neil K; Tang, Yi

    2015-11-01

    The structural diversity and biological activities of fungal indole diterpenes (IDTs) are generated in large part by the IDT cyclases (IDTCs). Identifying different IDTCs from IDT biosynthetic pathways is therefore important toward understanding how these enzymes introduce chemical diversity from a common linear precursor. However, IDTCs involved in the cyclization of the well-known aflavinine subgroup of IDTs have not been discovered. Here, using Saccharomyces cerevisiae as a heterologous host and a phylogenetically guided enzyme mining approach, we combinatorially assembled IDT biosynthetic pathways using IDTCs homologues identified from different fungal hosts. We identified the genetically standalone IDTCs involved in the cyclization of aflavinine and anominine and produced new IDTs not previously isolated. The cyclization mechanisms of the new IDTCs were proposed based on the yeast reconstitution results. Our studies demonstrate heterologous pathway assembly is a useful tool in the reconstitution of unclustered biosynthetic pathways.

  10. PathNet: a tool for pathway analysis using topological information

    Directory of Open Access Journals (Sweden)

    Dutta Bhaskar

    2012-09-01

    Full Text Available Abstract Background Identification of canonical pathways through enrichment of differentially expressed genes in a given pathway is a widely used method for interpreting gene lists generated from high-throughput experimental studies. However, most algorithms treat pathways as sets of genes, disregarding any inter- and intra-pathway connectivity information, and do not provide insights beyond identifying lists of pathways. Results We developed an algorithm (PathNet that utilizes the connectivity information in canonical pathway descriptions to help identify study-relevant pathways and characterize non-obvious dependencies and connections among pathways using gene expression data. PathNet considers both the differential expression of genes and their pathway neighbors to strengthen the evidence that a pathway is implicated in the biological conditions characterizing the experiment. As an adjunct to this analysis, PathNet uses the connectivity of the differentially expressed genes among all pathways to score pathway contextual associations and statistically identify biological relations among pathways. In this study, we used PathNet to identify biologically relevant results in two Alzheimer’s disease microarray datasets, and compared its performance with existing methods. Importantly, PathNet identified de-regulation of the ubiquitin-mediated proteolysis pathway as an important component in Alzheimer’s disease progression, despite the absence of this pathway in the standard enrichment analyses. Conclusions PathNet is a novel method for identifying enrichment and association between canonical pathways in the context of gene expression data. It takes into account topological information present in pathways to reveal biological information. PathNet is available as an R workspace image from http://www.bhsai.org/downloads/pathnet/.

  11. Putative adverse outcome pathways relevant to neurotoxicity

    Science.gov (United States)

    Bal-Price, Anna; Crofton, Kevin M.; Sachana, Magdalini; Shafer, Timothy J.; Behl, Mamta; Forsby, Anna; Hargreaves, Alan; Landesmann, Brigitte; Lein, Pamela J.; Louisse, Jochem; Monnet-Tschudi, Florianne; Paini, Alicia; Rolaki, Alexandra; Schrattenholz, André; Suñol, Cristina; van Thriel, Christoph; Whelan, Maurice; Fritsche, Ellen

    2016-01-01

    The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways. PMID:25605028

  12. The mevalonate pathway in C. Elegans

    Directory of Open Access Journals (Sweden)

    Rauthan Manish

    2011-12-01

    Full Text Available Abstract The mevalonate pathway in human is responsible for the synthesis of cholesterol and other important biomolecules such as coenzyme Q, dolichols and isoprenoids. These molecules are required in the cell for functions ranging from signaling to membrane integrity, protein prenylation and glycosylation, and energy homeostasis. The pathway consists of a main trunk followed by sub-branches that synthesize the different biomolecules. The majority of our knowledge about the mevalonate pathway is currently focused on the cholesterol synthesis branch, which is the target of the cholesterol-lowering statins; less is known about the function and regulation of the non-cholesterol-related branches. To study them, we need a biological system where it is possible to specifically modulate these metabolic branches individually or in groups. The nematode Caenorhabditis elegans (C. elegans is a promising model to study these non-cholesterol branches since its mevalonate pathway seems very well conserved with that in human except that it has no cholesterol synthesis branch. The simple genetic makeup and tractability of C. elegans makes it relatively easy to identify and manipulate key genetic components of the mevalonate pathway, and to evaluate the consequences of tampering with their activity. This general experimental approach should lead to new insights into the physiological roles of the non-cholesterol part of the mevalonate pathway. This review will focus on the current knowledge related to the mevalonate pathway in C. elegans and its possible applications as a model organism to study the non-cholesterol functions of this pathway.

  13. Oxidative stress: Biomarkers and novel therapeutic pathways.

    Science.gov (United States)

    Maiese, Kenneth; Chong, Zhao Zhong; Hou, Jinling; Shang, Yan Chen

    2010-03-01

    Oxidative stress significantly impacts multiple cellular pathways that can lead to the initiation and progression of varied disorders throughout the body. It therefore becomes imperative to elucidate the components and function of novel therapeutic strategies against oxidative stress to further clinical diagnosis and care. In particular, both the growth factor and cytokine erythropoietin (EPO) and members of the mammalian forkhead transcription factors of the O class (FoxOs) may offer the greatest promise for new treatment regimens since these agents and the cellular pathways they oversee cover a range of critical functions that directly influence progenitor cell development, cell survival and degeneration, metabolism, immune function, and cancer cell invasion. Furthermore, both EPO and FoxOs function not only as therapeutic targets, but also as biomarkers of disease onset and progression, since their cellular pathways are closely linked and overlap with several unique signal transduction pathways. However, biological outcome with EPO and FoxOs may sometimes be both unexpected and undesirable that can raise caution for these agents and warrant further investigations. Here we present the exciting as well as complicated role EPO and FoxOs possess to uncover the benefits as well as the risks of these agents for cell biology and clinical care in processes that range from stem cell development to uncontrolled cellular proliferation.

  14. Network biology concepts in complex disease comorbidities

    DEFF Research Database (Denmark)

    Hu, Jessica Xin; Thomas, Cecilia Engel; Brunak, Søren

    2016-01-01

    The co-occurrence of diseases can inform the underlying network biology of shared and multifunctional genes and pathways. In addition, comorbidities help to elucidate the effects of external exposures, such as diet, lifestyle and patient care. With worldwide health transaction data now often being...

  15. Nutritional Systems Biology: Definitions and Approaches

    DEFF Research Database (Denmark)

    Panagiotou, Gianni; Nielsen, Jens

    2009-01-01

    waiting for a predictive knowledge of genetic variation. It is widely recognized that systems and network biology has the potential to increase our understanding of how nutrition influences metabolic pathways and homeostasis, how this regulation is disturbed in a diet-related disease, and to what extent...

  16. Targeting stem cell signaling pathways for drug discovery: advances in the Notch and Wnt pathways.

    Science.gov (United States)

    An, Songzhu Michael; Ding, Qiang; Zhang, Jie; Xie, JingYi; Li, LingSong

    2014-06-01

    Signaling pathways transduce extracellular stimuli into cells through molecular cascades to regulate cellular functions. In stem cells, a small number of pathways, notably those of TGF-β/BMP, Hedgehog, Notch, and Wnt, are responsible for the regulation of pluripotency and differentiation. During embryonic development, these pathways govern cell fate specifications as well as the formation of tissues and organs. In adulthood, their normal functions are important for tissue homeostasis and regeneration, whereas aberrations result in diseases, such as cancer and degenerative disorders. In complex biological systems, stem cell signaling pathways work in concert as a network and exhibit crosstalk, such as the negative crosstalk between Wnt and Notch. Over the past decade, genetic and genomic studies have identified a number of potential drug targets that are involved in stem cell signaling pathways. Indeed, discovery of new targets and drugs for these pathways has become one of the most active areas in both the research community and pharmaceutical industry. Remarkable progress has been made and several promising drug candidates have entered into clinical trials. This review focuses on recent advances in the discovery of novel drugs which target the Notch and Wnt pathways.

  17. Chapter 8: Biological knowledge assembly and interpretation.

    Directory of Open Access Journals (Sweden)

    Ju Han Kim

    Full Text Available Most methods for large-scale gene expression microarray and RNA-Seq data analysis are designed to determine the lists of genes or gene products that show distinct patterns and/or significant differences. The most challenging and rate-liming step, however, is to determine what the resulting lists of genes and/or transcripts biologically mean. Biomedical ontology and pathway-based functional enrichment analysis is widely used to interpret the functional role of tightly correlated or differentially expressed genes. The groups of genes are assigned to the associated biological annotations using Gene Ontology terms or biological pathways and then tested if they are significantly enriched with the corresponding annotations. Unlike previous approaches, Gene Set Enrichment Analysis takes quite the reverse approach by using pre-defined gene sets. Differential co-expression analysis determines the degree of co-expression difference of paired gene sets across different conditions. Outcomes in DNA microarray and RNA-Seq data can be transformed into the graphical structure that represents biological semantics. A number of biomedical annotation and external repositories including clinical resources can be systematically integrated by biological semantics within the framework of concept lattice analysis. This array of methods for biological knowledge assembly and interpretation has been developed during the past decade and clearly improved our biological understanding of large-scale genomic data from the high-throughput technologies.

  18. Cell biology perspectives in phage biology.

    Science.gov (United States)

    Ansaldi, Mireille

    2012-01-01

    Cellular biology has long been restricted to large cellular organisms. However, as the resolution of microscopic methods increased, it became possible to study smaller cells, in particular bacterial cells. Bacteriophage biology is one aspect of bacterial cell biology that has recently gained insight from cell biology. Despite their small size, bacteriophages could be successfully labeled and their cycle studied in the host cells. This review aims to put together, although non-extensively, several cell biology studies that recently pushed the elucidation of key mechanisms in phage biology, such as the lysis-lysogeny decision in temperate phages or genome replication and transcription, one step further.

  19. Curation and Computational Design of Bioenergy-Related Metabolic Pathways

    Energy Technology Data Exchange (ETDEWEB)

    Karp, Peter D. [SRI International, Menlo Park, CA (United States)

    2014-09-12

    Pathway Tools is a systems-biology software package written by SRI International (SRI) that produces Pathway/Genome Databases (PGDBs) for organisms with a sequenced genome. Pathway Tools also provides a wide range of capabilities for analyzing predicted metabolic networks and user-generated omics data. More than 5,000 academic, industrial, and government groups have licensed Pathway Tools. This user community includes researchers at all three DOE bioenergy centers, as well as academic and industrial metabolic engineering (ME) groups. An integral part of the Pathway Tools software is MetaCyc, a large, multiorganism database of metabolic pathways and enzymes that SRI and its academic collaborators manually curate. This project included two main goals: I. Enhance the MetaCyc content of bioenergy-related enzymes and pathways. II. Develop computational tools for engineering metabolic pathways that satisfy specified design goals, in particular for bioenergy-related pathways. In part I, SRI proposed to significantly expand the coverage of bioenergy-related metabolic information in MetaCyc, followed by the generation of organism-specific PGDBs for all energy-relevant organisms sequenced at the DOE Joint Genome Institute (JGI). Part I objectives included: 1: Expand the content of MetaCyc to include bioenergy-related enzymes and pathways. 2: Enhance the Pathway Tools software to enable display of complex polymer degradation processes. 3: Create new PGDBs for the energy-related organisms sequenced by JGI, update existing PGDBs with new MetaCyc content, and make these data available to JBEI via the BioCyc website. In part II, SRI proposed to develop an efficient computational tool for the engineering of metabolic pathways. Part II objectives included: 4: Develop computational tools for generating metabolic pathways that satisfy specified design goals, enabling users to specify parameters such as starting and ending compounds, and preferred or disallowed intermediate compounds

  20. Targeting the hedgehog pathway for gallbladder cancer therapy?

    Science.gov (United States)

    Mittal, Balraj; Yadav, Saurabh

    2016-02-01

    Gallbladder carcinoma is a fatal malignancy of hepatobiliary tract that is generally diagnosed at advanced stages of cancer because of its asymptomatic nature. Advanced GBC tumors are unresectable with poor prognosis. Improvement in GBC patient care requires better understanding of the biological signaling pathways and application of newly discovered drugs for cancer therapy. Herein, we discuss the possibilities and challenges in targeting the hedgehog pathway in gallbladder cancer therapy based on recent developments in the area.

  1. Dissection of the insulin signaling pathway via quantitative phosphoproteomics

    DEFF Research Database (Denmark)

    Krüger, Marcus; Kratchmarova, Irina; Blagoev, Blagoy;

    2008-01-01

    The insulin signaling pathway is of pivotal importance in metabolic diseases, such as diabetes, and in cellular processes, such as aging. Insulin activates a tyrosine phosphorylation cascade that branches to create a complex network affecting multiple biological processes. To understand the full ...... the calcium transporting ATPase SERCA2, supporting a connection to calcium signaling. The combination of quantitative phosphoproteomics with cell culture models provides a powerful strategy to dissect the insulin signaling pathways in intact cells....

  2. Small molecule screening identifies targetable zebrafish pigmentation pathways

    DEFF Research Database (Denmark)

    Colanesi, Sarah; Taylor, Kerrie L; Temperley, Nicholas D

    2012-01-01

    Small molecules complement genetic mutants and can be used to probe pigment cell biology by inhibiting specific proteins or pathways. Here, we present the results of a screen of active compounds for those that affect the processes of melanocyte and iridophore development in zebrafish and investig......Small molecules complement genetic mutants and can be used to probe pigment cell biology by inhibiting specific proteins or pathways. Here, we present the results of a screen of active compounds for those that affect the processes of melanocyte and iridophore development in zebrafish...

  3. [Biology molecular of glioblastomas].

    Science.gov (United States)

    Franco-Hernández, C; Martínez-Glez, V; Rey, J A

    2007-10-01

    Glioblastomas, the most frequent and malignant human brain tumors, may develop de novo (primary glioblastoma) or by progression from low-grade or anapalsic astrocytoma (secondary glioblastoma). The molecular alteration most frequent in these tumor-like types is the loss of heterozygosity on chromosome 10, in which several genes have been identified as tumors suppressor. The TP53/MDM2/P14arf and CDK4/RB1/ P16ink4 genetic pathways involved in cycle control are deregulated in the majority of gliomas as well as genes that promote the cellular division, EGFR. Finally the increase of growth and angiogenics factors is also involved in the development of glioblastomas. One of the objectives of molecular biology in tumors of glial ancestry is to try to find the genetic alterations that allow to approach better the classification of glioblastomas, its evolution prediction and treatment. The new pathmolecular classification of gliomas should improve the old one, especially being concerned about the oncogenesis and heterogeneity of these tumors. It is desirable that this classification had clinical applicability and integrates new molecular findings with some known histological features with pronostic value. In this paper we review the most frequent molecular mechanisms involved in the patogenesis of glioblastomas.

  4. Mesangial cell biology

    Energy Technology Data Exchange (ETDEWEB)

    Abboud, Hanna E., E-mail: Abboud@uthscsa.edu

    2012-05-15

    Mesangial cells originate from the metanephric mesenchyme and maintain structural integrity of the glomerular microvascular bed and mesangial matrix homeostasis. In response to metabolic, immunologic or hemodynamic injury, these cells undergo apoptosis or acquire an activated phenotype and undergo hypertrophy, proliferation with excessive production of matrix proteins, growth factors, chemokines and cytokines. These soluble factors exert autocrine and paracrine effects on the cells or on other glomerular cells, respectively. MCs are primary targets of immune-mediated glomerular diseases such as IGA nephropathy or metabolic diseases such as diabetes. MCs may also respond to injury that primarily involves podocytes and endothelial cells or to structural and genetic abnormalities of the glomerular basement membrane. Signal transduction and oxidant stress pathways are activated in MCs and likely represent integrated input from multiple mediators. Such responses are convenient targets for therapeutic intervention. Studies in cultured MCs should be supplemented with in vivo studies as well as examination of freshly isolated cells from normal and diseases glomeruli. In addition to ex vivo morphologic studies in kidney cortex, cells should be studied in their natural environment, isolated glomeruli or even tissue slices. Identification of a specific marker of MCs should help genetic manipulation as well as selective therapeutic targeting of these cells. Identification of biological responses of MCs that are not mediated by the renin–angiotensin system should help development of novel and effective therapeutic strategies to treat diseases characterized by MC pathology.

  5. Biological warfare agents.

    Science.gov (United States)

    Pohanka, Miroslav; Kuca, Kamil

    2010-01-01

    Biological warfare agents are a group of pathogens and toxins of biological origin that can be potentially misused for military or criminal purposes. The present review attempts to summarize necessary knowledge about biological warfare agents. The historical aspects, examples of applications of these agents such as anthrax letters, biological weapons impact, a summary of biological warfare agents and epidemiology of infections are described. The last section tries to estimate future trends in research on biological warfare agents.

  6. Dynamical Systems and Control Theory Inspired by Molecular Biology

    Science.gov (United States)

    2014-10-02

    in both bacterial and eukaryotic signaling pathways. A common theme in the systems biology literature is that certain systems whose output variables...AFRL-OSR-VA-TR-2014-0282 DYNAMICAL SYSTEMS AND CONTROL THEORY INSPIRED BY MOLECULAR BIOLOGY Eduardo Sontag RUTGERS THE STATE UNIVERSITY OF NEW JERSEY...Standard Form 298 (Re . 8-98) v Prescribed by ANSI Std. Z39.18 DYNAMICAL SYSTEMS AND CONTROL THEORY INSPIRED BY MOLECULAR BIOLOGY AFOSR FA9550-11-1-0247

  7. DMPD: Regulatory pathways in inflammation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17967718 Regulatory pathways in inflammation. Mantovani A, Garlanda C, Locati M, Ro....html) (.csml) Show Regulatory pathways in inflammation. PubmedID 17967718 Title Regulatory pathways in infl... B, Vecchi A. Publication Autoimmun Rev. 2007 Nov;7(1):8-11. Epub 2007 Mar 26. Pathway - PNG File (.png) SVG

  8. Signal transduction pathway profiling of individual tumor samples

    Directory of Open Access Journals (Sweden)

    Peterson Carsten

    2005-06-01

    Full Text Available Abstract Background Signal transduction pathways convey information from the outside of the cell to transcription factors, which in turn regulate gene expression. Our objective is to analyze tumor gene expression data from microarrays in the context of such pathways. Results We use pathways compiled from the TRANSPATH/TRANSFAC databases and the literature, and three publicly available cancer microarray data sets. Variation in pathway activity, across the samples, is gauged by the degree of correlation between downstream targets of a pathway. Two correlation scores are applied; one considers all pairs of downstream targets, and the other considers only pairs without common transcription factors. Several pathways are found to be differentially active in the data sets using these scores. Moreover, we devise a score for pathway activity in individual samples, based on the average expression value of the downstream targets. Statistical significance is assigned to the scores using permutation of genes as null model. Hence, for individual samples, the status of a pathway is given as a sign, + or -, and a p-value. This approach defines a projection of high-dimensional gene expression data onto low-dimensional pathway activity scores. For each dataset and many pathways we find a much larger number of significant samples than expected by chance. Finally, we find that several sample-wise pathway activities are significantly associated with clinical classifications of the samples. Conclusion This study shows that it is feasible to infer signal transduction pathway activity, in individual samples, from gene expression data. Furthermore, these pathway activities are biologically relevant in the three cancer data sets.

  9. Pathways, Networks and Systems Medicine Conferences

    Energy Technology Data Exchange (ETDEWEB)

    Nadeau, Joseph H. [Pacific Northwest Research Institute

    2013-11-25

    The 6th Pathways, Networks and Systems Medicine Conference was held at the Minoa Palace Conference Center, Chania, Crete, Greece (16-21 June 2008). The Organizing Committee was composed of Joe Nadeau (CWRU, Cleveland), Rudi Balling (German Research Centre, Brauschweig), David Galas (Institute for Systems Biology, Seattle), Lee Hood (Institute for Systems Biology, Seattle), Diane Isonaka (Seattle), Fotis Kafatos (Imperial College, London), John Lambris (Univ. Pennsylvania, Philadelphia),Harris Lewin (Univ. of Indiana, Urbana-Champaign), Edison Liu (Genome Institute of Singapore, Singapore), and Shankar Subramaniam (Univ. California, San Diego). A total of 101 individuals from 21 countries participated in the conference: USA (48), Canada (5), France (5), Austria (4), Germany (3), Italy (3), UK (3), Greece (2), New Zealand (2), Singapore (2), Argentina (1), Australia (1), Cuba (1), Denmark (1), Japan (1), Mexico (1), Netherlands (1), Spain (1), Sweden (1), Switzerland (1). With respect to speakers, 29 were established faculty members and 13 were graduate students or postdoctoral fellows. With respect to gender representation, among speakers, 13 were female and 28 were male, and among all participants 43 were female and 58 were male. Program these included the following topics: Cancer Pathways and Networks (Day 1), Metabolic Disease Networks (Day 2), Day 3 ? Organs, Pathways and Stem Cells (Day 3), and Day 4 ? Inflammation, Immunity, Microbes and the Environment (Day 4). Proceedings of the Conference were not published.

  10. Clinical Pathway for Thyroidectomy.

    Science.gov (United States)

    Villar del Moral, Jesús María; Soria Aledo, Víctor; Colina Alonso, Alberto; Flores Pastor, Benito; Gutiérrez Rodríguez, María Teresa; Ortega Serrano, Joaquín; Parra Hidalgo, Pedro; Ros López, Susana

    2015-05-01

    Clinical pathways are care plans applicable to patient care procedures that present variations in practice and a predictable clinical course. They are designed not as a substitute for clinical judgment, but rather as a means to improve the effectiveness and efficiency of the procedures. This clinical pathway is the result of a collaborative work of the Sections of Endocrine Surgery and Quality Management of the Spanish Association of Surgeons. It attempts to provide a framework for standardizing the performance of thyroidectomy, the most frequently performed operation in endocrine surgery. Along with the usual documents of clinical pathways (temporary matrix, variance tracking and information sheets, assessment indicators and a satisfaction questionnaire) it includes a review of the scientific evidence around different aspects of pre, intra and postoperative management. Among others, antibiotic and antithrombotic prophylaxis, preoperative preparation in hyperthyroidism, intraoperative neuromonitoring and systems for obtaining hemostasis are included, along with management of postoperative hypocalcemia.

  11. XTalkDB: a database of signaling pathway crosstalk

    Science.gov (United States)

    Sam, Sarah A.; Teel, Joelle; Tegge, Allison N.; Bharadwaj, Aditya; Murali, T.M.

    2017-01-01

    Analysis of signaling pathways and their crosstalk is a cornerstone of systems biology. Thousands of papers have been published on these topics. Surprisingly, there is no database that carefully and explicitly documents crosstalk between specific pairs of signaling pathways. We have developed XTalkDB (http://www.xtalkdb.org) to fill this very important gap. XTalkDB contains curated information for 650 pairs of pathways from over 1600 publications. In addition, the database reports the molecular components (e.g. proteins, hormones, microRNAs) that mediate crosstalk between a pair of pathways and the species and tissue in which the crosstalk was observed. The XTalkDB website provides an easy-to-use interface for scientists to browse crosstalk information by querying one or more pathways or molecules of interest. PMID:27899583

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

    Science.gov (United States)

    Baker, Ej; Culpepper, C; Philips, C; Bubier, J; Langston, M; Chesler, Ej

    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.

  13. Nutrient shortage triggers the hexosamine biosynthetic pathway via the GCN2-ATF4 signalling pathway.

    Science.gov (United States)

    Chaveroux, Cédric; Sarcinelli, Carmen; Barbet, Virginie; Belfeki, Sofiane; Barthelaix, Audrey; Ferraro-Peyret, Carole; Lebecque, Serge; Renno, Toufic; Bruhat, Alain; Fafournoux, Pierre; Manié, Serge N

    2016-06-03

    The hexosamine biosynthetic pathway (HBP) is a nutrient-sensing metabolic pathway that produces the activated amino sugar UDP-N-acetylglucosamine, a critical substrate for protein glycosylation. Despite its biological significance, little is known about the regulation of HBP flux during nutrient limitation. Here, we report that amino acid or glucose shortage increase GFAT1 production, the first and rate-limiting enzyme of the HBP. GFAT1 is a transcriptional target of the activating transcription factor 4 (ATF4) induced by the GCN2-eIF2α signalling pathway. The increased production of GFAT1 stimulates HBP flux and results in an increase in O-linked β-N-acetylglucosamine protein modifications. Taken together, these findings demonstrate that ATF4 provides a link between nutritional stress and the HBP for the regulation of the O-GlcNAcylation-dependent cellular signalling.

  14. Synthetic biology for CO2 fixation.

    Science.gov (United States)

    Gong, Fuyu; Cai, Zhen; Li, Yin

    2016-11-01

    Recycling of carbon dioxide (CO2) into fuels and chemicals is a potential approach to reduce CO2 emission and fossil-fuel consumption. Autotrophic microbes can utilize energy from light, hydrogen, or sulfur to assimilate atmospheric CO2 into organic compounds at ambient temperature and pressure. This provides a feasible way for biological production of fuels and chemicals from CO2 under normal conditions. Recently great progress has been made in this research area, and dozens of CO2-derived fuels and chemicals have been reported to be synthesized by autotrophic microbes. This is accompanied by investigations into natural CO2-fixation pathways and the rapid development of new technologies in synthetic biology. This review first summarizes the six natural CO2-fixation pathways reported to date, followed by an overview of recent progress in the design and engineering of CO2-fixation pathways as well as energy supply patterns using the concept and tools of synthetic biology. Finally, we will discuss future prospects in biological fixation of CO2.

  15. Pathway analysis of IMC

    DEFF Research Database (Denmark)

    Skrypnyuk, Nataliya; Nielson, Flemming; Pilegaard, Henrik

    2009-01-01

    We present the ongoing work on the pathway analysis of a stochastic calculus. Firstly we present a particular stochastic calculus that we have chosen for our modeling - the Interactive Markov Chains calculus, IMC for short. After that we specify a few restrictions that we have introduced into the......We present the ongoing work on the pathway analysis of a stochastic calculus. Firstly we present a particular stochastic calculus that we have chosen for our modeling - the Interactive Markov Chains calculus, IMC for short. After that we specify a few restrictions that we have introduced...

  16. Synthetic biology, inspired by synthetic chemistry.

    Science.gov (United States)

    Malinova, V; Nallani, M; Meier, W P; Sinner, E K

    2012-07-16

    The topic synthetic biology appears still as an 'empty basket to be filled'. However, there is already plenty of claims and visions, as well as convincing research strategies about the theme of synthetic biology. First of all, synthetic biology seems to be about the engineering of biology - about bottom-up and top-down approaches, compromising complexity versus stability of artificial architectures, relevant in biology. Synthetic biology accounts for heterogeneous approaches towards minimal and even artificial life, the engineering of biochemical pathways on the organismic level, the modelling of molecular processes and finally, the combination of synthetic with nature-derived materials and architectural concepts, such as a cellular membrane. Still, synthetic biology is a discipline, which embraces interdisciplinary attempts in order to have a profound, scientific base to enable the re-design of nature and to compose architectures and processes with man-made matter. We like to give an overview about the developments in the field of synthetic biology, regarding polymer-based analogs of cellular membranes and what questions can be answered by applying synthetic polymer science towards the smallest unit in life, namely a cell.

  17. Correcting ligands, metabolites, and pathways

    Directory of Open Access Journals (Sweden)

    Vriend Gert

    2006-11-01

    Full Text Available Abstract Background A wide range of research areas in bioinformatics, molecular biology and medicinal chemistry require precise chemical structure information about molecules and reactions, e.g. drug design, ligand docking, metabolic network reconstruction, and systems biology. Most available databases, however, treat chemical structures more as illustrations than as a datafield in its own right. Lack of chemical accuracy impedes progress in the areas mentioned above. We present a database of metabolites called BioMeta that augments the existing pathway databases by explicitly assessing the validity, correctness, and completeness of chemical structure and reaction information. Description The main bulk of the data in BioMeta were obtained from the KEGG Ligand database. We developed a tool for chemical structure validation which assesses the chemical validity and stereochemical completeness of a molecule description. The validation tool was used to examine the compounds in BioMeta, showing that a relatively small number of compounds had an incorrect constitution (connectivity only, not considering stereochemistry and that a considerable number (about one third had incomplete or even incorrect stereochemistry. We made a large effort to correct the errors and to complete the structural descriptions. A total of 1468 structures were corrected and/or completed. We also established the reaction balance of the reactions in BioMeta and corrected 55% of the unbalanced (stoichiometrically incorrect reactions in an automatic procedure. The BioMeta database was implemented in PostgreSQL and provided with a web-based interface. Conclusion We demonstrate that the validation of metabolite structures and reactions is a feasible and worthwhile undertaking, and that the validation results can be used to trigger corrections and improvements to BioMeta, our metabolite database. BioMeta provides some tools for rational drug design, reaction searches, and

  18. The cardiopulmonary effects of ambient air pollution and mechanistic pathways: a comparative hierarchical pathway analysis.

    Directory of Open Access Journals (Sweden)

    Ananya Roy

    Full Text Available Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001 and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005. These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours and the hemostasis pathway responds gradually over a 2-3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system.

  19. Combination of Endothelial-Monocyte-Activating Polypeptide-II with Temozolomide Suppress Malignant Biological Behaviors of Human Glioblastoma Stem Cells via miR-590-3p/MACC1 Inhibiting PI3K/AKT/mTOR Signal Pathway

    Science.gov (United States)

    Zhou, Wei; Liu, Libo; Xue, Yixue; Zheng, Jian; Liu, Xiaobai; Ma, Jun; Li, Zhen; Liu, Yunhui

    2017-01-01

    This study aims to investigate the effect of Endothelial-Monocyte-Activating Polypeptide-II (EMAP-II) combined with temozolomide (TMZ) upon glioblastoma stem cells (GSCs) and its possible molecular mechanisms. In this study, combination of EMAP-II with TMZ inhibited cell viability, migration and invasion in GSCs, and autophagy inhibitor 3-methyl adenine (3-MA) and chloroquine (CQ) partly reverse the anti-proliferative effect of the combination treatment. Autophagic vacuoles were formed in GSCs after the combination therapy, accompanied with the up-regulation of LC3-II and Beclin-1 as well as the down-regulation of p62/SQSTM1. Further, miR-590-3p was up-regulated and Metastasis-associated in colon cancer 1 (MACC1) was down-regulated by the combination treatment in GSCs; MiR-590-3p overexpression and MACC1 knockdown up-regulated LC3-II and Beclin-1 as well as down-regulated p62/SQSTM1 in GSCs; MACC1 was identified as a direct target of miR-590-3p, mediating the effects of miR-590-3p in the combination treatment. Furthermore, the combination treatment and MACC1 knockdown decreased p-PI3K, p-Akt, p-mTOR, p-S6 and p-4EBP in GSCs; PI3K/Akt agonist insulin-like growth factor-1(IGF-1) partly blocked the effect of the combination treatment. Moreover, in vivo xenograft models, the mice given stable overexpressed miR-590-3p cells and treated with EMAP-II and TMZ had the smallest tumor sizes, besides, miR-590-3p + EMAP-II + TMZ up-regulated the expression level of miR-590-3p, LC3-II and Beclin-1 as well as down-regulated p62/SQSTM1. In conclusion, these results elucidated anovel molecular mechanism of EMAP-II in combination with TMZ suppressed malignant biological behaviors of GSCs via miR-590-3p/MACC1 inhibiting PI3K/AKT/mTOR signaling pathway, and might provide potential therapeutic approaches for human GSCs.

  20. Pathway-based screening strategy for multitarget inhibitors of diverse proteins in metabolic pathways.

    Directory of Open Access Journals (Sweden)

    Kai-Cheng Hsu

    Full Text Available Many virtual screening methods have been developed for identifying single-target inhibitors based on the strategy of "one-disease, one-target, one-drug". The hit rates of these methods are often low because they cannot capture the features that play key roles in the biological functions of the target protein. Furthermore, single-target inhibitors are often susceptible to drug resistance and are ineffective for complex diseases such as cancers. Therefore, a new strategy is required for enriching the hit rate and identifying multitarget inhibitors. To address these issues, we propose the pathway-based screening strategy (called PathSiMMap to derive binding mechanisms for increasing the hit rate and discovering multitarget inhibitors using site-moiety maps. This strategy simultaneously screens multiple target proteins in the same pathway; these proteins bind intermediates with common substructures. These proteins possess similar conserved binding environments (pathway anchors when the product of one protein is the substrate of the next protein in the pathway despite their low sequence identity and structure similarity. We successfully discovered two multitarget inhibitors with IC50 of <10 µM for shikimate dehydrogenase and shikimate kinase in the shikimate pathway of Helicobacter pylori. Furthermore, we found two selective inhibitors (IC50 of <10 µM for shikimate dehydrogenase using the specific anchors derived by our method. Our experimental results reveal that this strategy can enhance the hit rates and the pathway anchors are highly conserved and important for biological functions. We believe that our strategy provides a great value for elucidating protein binding mechanisms and discovering multitarget inhibitors.

  1. Biological conversion system

    Science.gov (United States)

    Scott, C.D.

    A system for bioconversion of organic material comprises a primary bioreactor column wherein a biological active agent (zymomonas mobilis) converts the organic material (sugar) to a product (alcohol), a rejuvenator column wherein the biological activity of said biological active agent is enhanced, and means for circulating said biological active agent between said primary bioreactor column and said rejuvenator column.

  2. Systems Biology and Stem Cell Pluripotency

    DEFF Research Database (Denmark)

    Mashayekhi, Kaveh; Hall, Vanessa; Freude, Kristine

    2016-01-01

    Recent breakthroughs in stem cell biology have accelerated research in the area of regenerative medicine. Over the past years, it has become possible to derive patient-specific stem cells which can be used to generate different cell populations for potential cell therapy. Systems biological...... modeling of stem cell pluripotency and differentiation have largely been based on prior knowledge of signaling pathways, gene regulatory networks, and epigenetic factors. However, there is a great need to extend the complexity of the modeling and to integrate different types of data, which would further...... improve systems biology and its uses in the field. In this chapter, we first give a general background on stem cell biology and regenerative medicine. Stem cell potency is introduced together with the hierarchy of stem cells ranging from pluripotent embryonic stem cells (ESCs) and induced pluripotent stem...

  3. Developmental systems biology flourishing on new technologies

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Organism development is a systems level process. It has benefited greatly from the recent technological advances in the field of systems biology. DNA microarray, phenome, interactome and transcriptome mapping, the new generation of deep sequencing technologies,and faster and better computational and modeling approaches have opened new frontiers for both systems biologists and developmental biologists to reexamine the old developmental biology questions, such as pattern formation, and to tackle new problems, such as stem cell reprogramming. As showcased in the International Developmental Systems Biology Symposium organized by Chinese Academy of Sciences, developmental systems biology is flourishing in many perspectives, from the evolution of developmental systems, to the underlying genetic and molecular pathways and networks, to the genomic, epigenomic and noncoding levels, to the computational analysis and modeling. We believe that the field will continue to reap rewards into the future with these new approaches.

  4. Clinical pharmacology considerations in biologics development

    Institute of Scientific and Technical Information of China (English)

    Liang ZHAO; Tian-hua REN; Diane D WANG

    2012-01-01

    Biologics,including monoclonal antibodies (mAbs) and other therapeutic proteins such as cytokines and growth hormones,have unique characteristics compared to small molecules.This paper starts from an overview of the pharmacokinetics (PK) of biologics from a mechanistic perspective,the determination of a starting dose for first-in-human(FIH) studies,and dosing regimen optimisation for phase Ⅱ/Ⅲ clinical trials.Subsequently,typical clinical pharmacology issues along the corresponding pathways for biologics development are summarised,including drug-drug interactions,QTc prolongation,immunogenicity,and studies in specific populations.The relationships between the molecular structure of biologics,their pharmacokinetic and pharmacodynamic characteristics,and the corresponding clinical pharmacology strategies are summarised and depicted in a schematic diagram.

  5. Language Based Techniques for Systems Biology

    DEFF Research Database (Denmark)

    Pilegaard, Henrik

    calculi have similarly been used for the study of bio-chemical reactive systems. In this dissertation it is argued that techniques rooted in the theory and practice of programming languages, language based techniques if you will, constitute a strong basis for the investigation of models of biological.......g., the effects of receptor defects or drug delivery mechanisms. The property of sequential realisability. which is closely related to the function of biochemical pathways, is addressed by a variant of traditional Data Flow Analysis (DFA). This so-called ‘Pathway Analysis’ computes safe approximations to the set...

  6. Synthetic biology: insights into biological computation.

    Science.gov (United States)

    Manzoni, Romilde; Urrios, Arturo; Velazquez-Garcia, Silvia; de Nadal, Eulàlia; Posas, Francesc

    2016-04-18

    Organisms have evolved a broad array of complex signaling mechanisms that allow them to survive in a wide range of environmental conditions. They are able to sense external inputs and produce an output response by computing the information. Synthetic biology attempts to rationally engineer biological systems in order to perform desired functions. Our increasing understanding of biological systems guides this rational design, while the huge background in electronics for building circuits defines the methodology. In this context, biocomputation is the branch of synthetic biology aimed at implementing artificial computational devices using engineered biological motifs as building blocks. Biocomputational devices are defined as biological systems that are able to integrate inputs and return outputs following pre-determined rules. Over the last decade the number of available synthetic engineered devices has increased exponentially; simple and complex circuits have been built in bacteria, yeast and mammalian cells. These devices can manage and store information, take decisions based on past and present inputs, and even convert a transient signal into a sustained response. The field is experiencing a fast growth and every day it is easier to implement more complex biological functions. This is mainly due to advances in in vitro DNA synthesis, new genome editing tools, novel molecular cloning techniques, continuously growing part libraries as well as other technological advances. This allows that digital computation can now be engineered and implemented in biological systems. Simple logic gates can be implemented and connected to perform novel desired functions or to better understand and redesign biological processes. Synthetic biological digital circuits could lead to new therapeutic approaches, as well as new and efficient ways to produce complex molecules such as antibiotics, bioplastics or biofuels. Biological computation not only provides possible biomedical and

  7. Translational environmental biology: cell biology informing conservation.

    Science.gov (United States)

    Traylor-Knowles, Nikki; Palumbi, Stephen R

    2014-05-01

    Typically, findings from cell biology have been beneficial for preventing human disease. However, translational applications from cell biology can also be applied to conservation efforts, such as protecting coral reefs. Recent efforts to understand the cell biological mechanisms maintaining coral health such as innate immunity and acclimatization have prompted new developments in conservation. Similar to biomedicine, we urge that future efforts should focus on better frameworks for biomarker development to protect coral reefs.

  8. Notch pathway is dispensable for adipocyte specification.

    Science.gov (United States)

    Nichols, Amy M; Pan, Yonghua; Herreman, An; Hadland, Brandon K; De Strooper, Bart; Kopan, Raphael; Huppert, Stacey S

    2004-09-01

    In the past decade we have witnessed an epidemic of obesity in developed countries. Therefore, understanding the mechanisms involved in regulation of body weight is becoming an increasingly important goal shared by the public and the scientific community. The key to fat deposition is the adipocyte, a specialized cell that plays a critical role in energy balance and appetite regulation. Much of our knowledge of adipogenesis comes from studies using preadipocytic cell lines that have provided important information regarding molecular control of adipocyte differentiation. However, they fall short of revealing how naive cells acquire competence for adipogenesis. Studies in preadipocytes indicate that the Notch pathway plays a role in regulating adipogenesis (Garces et al.: J Biol Chem 272:29729-29734, 1997). Given the known biological functions of Notch in mediating cell fate decisions (Artavanis-Tsakonas et al.: Science 284:770-776, 1999), we wished to test the hypothesis that the Notch pathway is required for this cellular program by examining adipogenesis in several genetic loss-of-function models that encompass the entire pathway. We conclude that the "canonical" Notch signaling pathway is dispensable for adipocyte specification and differentiation from either mesenchymal or epithelial progenitors.

  9. Pathway Analysis: State of the Art

    Science.gov (United States)

    García-Campos, Miguel A.; Espinal-Enríquez, Jesús; Hernández-Lemus, Enrique

    2015-01-01

    Pathway analysis is a set of widely used tools for research in life sciences intended to give meaning to high-throughput biological data. The methodology of these tools settles in the gathering and usage of knowledge that comprise biomolecular functioning, coupled with statistical testing and other algorithms. Despite their wide employment, pathway analysis foundations and overall background may not be fully understood, leading to misinterpretation of analysis results. This review attempts to comprise the fundamental knowledge to take into consideration when using pathway analysis as a hypothesis generation tool. We discuss the key elements that are part of these methodologies, their capabilities and current deficiencies. We also present an overview of current and all-time popular methods, highlighting different classes across them. In doing so, we show the exploding diversity of methods that pathway analysis encompasses, point out commonly overlooked caveats, and direct attention to a potential new class of methods that attempt to zoom the analysis scope to the sample scale. PMID:26733877

  10. Policies built upon pathways

    NARCIS (Netherlands)

    S. Musterd; Z. Kovács

    2013-01-01

    After the general introductions, the first substantive part of this volume (Part II) provides concise research-based discussions of policies developed in recognition of the important role played by the pathways along which city-regions have travelled. Our research has shown that it is highly importa

  11. Dexter energy transfer pathways.

    Science.gov (United States)

    Skourtis, Spiros S; Liu, Chaoren; Antoniou, Panayiotis; Virshup, Aaron M; Beratan, David N

    2016-07-19

    Energy transfer with an associated spin change of the donor and acceptor, Dexter energy transfer, is critically important in solar energy harvesting assemblies, damage protection schemes of photobiology, and organometallic opto-electronic materials. Dexter transfer between chemically linked donors and acceptors is bridge mediated, presenting an enticing analogy with bridge-mediated electron and hole transfer. However, Dexter coupling pathways must convey both an electron and a hole from donor to acceptor, and this adds considerable richness to the mediation process. We dissect the bridge-mediated Dexter coupling mechanisms and formulate a theory for triplet energy transfer coupling pathways. Virtual donor-acceptor charge-transfer exciton intermediates dominate at shorter distances or higher tunneling energy gaps, whereas virtual intermediates with an electron and a hole both on the bridge (virtual bridge excitons) dominate for longer distances or lower energy gaps. The effects of virtual bridge excitons were neglected in earlier treatments. The two-particle pathway framework developed here shows how Dexter energy-transfer rates depend on donor, bridge, and acceptor energetics, as well as on orbital symmetry and quantum interference among pathways.

  12. Computational Systems Chemical Biology

    OpenAIRE

    Oprea, Tudor I.; Elebeoba E. May; Leitão, Andrei; Tropsha, Alexander

    2011-01-01

    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).

  13. Integrative biology identifies shared transcriptional networks in CKD.

    Science.gov (United States)

    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; Kretzler, Matthias

    2014-11-01

    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.

  14. Opportunities and challenges in biological lignin valorization.

    Science.gov (United States)

    Beckham, Gregg T; Johnson, Christopher W; Karp, Eric M; Salvachúa, Davinia; Vardon, Derek R

    2016-12-01

    Lignin is a primary component of lignocellulosic biomass that is an underutilized feedstock in the growing biofuels industry. Despite the fact that lignin depolymerization has long been studied, the intrinsic heterogeneity of lignin typically leads to heterogeneous streams of aromatic compounds, which in turn present significant technical challenges when attempting to produce lignin-derived chemicals where purity is often a concern. In Nature, microorganisms often encounter this same problem during biomass turnover wherein powerful oxidative enzymes produce heterogeneous slates of aromatics compounds. Some microbes have evolved metabolic pathways to convert these aromatic species via 'upper pathways' into central intermediates, which can then be funneled through 'lower pathways' into central carbon metabolism in a process we dubbed 'biological funneling'. This funneling approach offers a direct, biological solution to overcome heterogeneity problems in lignin valorization for the modern biorefinery. Coupled to targeted separations and downstream chemical catalysis, this concept offers the ability to produce a wide range of molecules from lignin. This perspective describes research opportunities and challenges ahead for this new field of research, which holds significant promise towards a biorefinery concept wherein polysaccharides and lignin are treated as equally valuable feedstocks. In particular, we discuss tailoring the lignin substrate for microbial utilization, host selection for biological funneling, ligninolytic enzyme-microbe synergy, metabolic engineering, expanding substrate specificity for biological funneling, and process integration, each of which presents key challenges. Ultimately, for biological solutions to lignin valorization to be viable, multiple questions in each of these areas will need to be addressed, making biological lignin valorization a multidisciplinary, co-design problem.

  15. What can causal networks tell us about metabolic pathways?

    Directory of Open Access Journals (Sweden)

    Rachael Hageman Blair

    Full Text Available Graphical models describe the linear correlation structure of data and have been used to establish causal relationships among phenotypes in genetic mapping populations. Data are typically collected at a single point in time. Biological processes on the other hand are often non-linear and display time varying dynamics. The extent to which graphical models can recapitulate the architecture of an underlying biological processes is not well understood. We consider metabolic networks with known stoichiometry to address the fundamental question: "What can causal networks tell us about metabolic pathways?". Using data from an Arabidopsis Bay[Formula: see text]Sha population and simulated data from dynamic models of pathway motifs, we assess our ability to reconstruct metabolic pathways using graphical models. Our results highlight the necessity of non-genetic residual biological variation for reliable inference. Recovery of the ordering within a pathway is possible, but should not be expected. Causal inference is sensitive to subtle patterns in the correlation structure that may be driven by a variety of factors, which may not emphasize the substrate-product relationship. We illustrate the effects of metabolic pathway architecture, epistasis and stochastic variation on correlation structure and graphical model-derived networks. We conclude that graphical models should be interpreted cautiously, especially if the implied causal relationships are to be used in the design of intervention strategies.

  16. Influence of Delta-like ligand 4/Notch signal transduction pathway upon the biological behavior of human umbilical vein endothelial cells%Delta样分子4/Notch信号途径对人脐静脉内皮细胞生物学行为的影响

    Institute of Scientific and Technical Information of China (English)

    陈凛; 吕伟; 卫勃; 王宁; 李涛

    2009-01-01

    Objective To study the influence of inhibiting Delta-like ligand 4 (Dll4)/Notch signal transduction pathway upon the biological behavior of human umbilical vein endothelial cells (HUVEC). Methods Used rAAV vectors expressing an active small interfering RNA (siRNA) (vector 6) targeting the Dll4 (rAAV-Dll4-shRNA) to infect HUVEC. And an empty plasmid (rAAV-EGFP) was infected into the same cell line as control group. The stable transfection and expression of Dll4 mRNA in HUVEC were determined by semi-quantitative RT-PCR. The protein expression of Dll4 was examined by Western blotting. Distribution of cell cycle was assessed by flow cytometry. The cell growth was analyzed by MTT assay. HUVEC were separated by type Ⅰ collagen and cultured in a three-dimensional culture system for tubule like structure (TLS) formation. Results Compared with the negative control cells, semi-quantitative RT-PCR and Western blotting showed the expression of Dll4 mRNA (0.636±0.082, 0.972±0.022 vs 0.948± 0.046) and protein (0.632±0.052, 2.016±0.048 vs 1.946±0.066) were down-regulated in the stable cell (P=0.024, 0.033). The rAAV vectors expressing an active small interfering RNA (siRNA) targeting the Dll4 effectively stimulated HUVEC cell growth and proliferation while empty plasmid had no such specific effect. The proliferation index of experimental group was (39.9±2.2) % versus untreated group (25.7± 4. 5)% (P=0.036). TLS formation was significantly induced by rAAV vector. And the average length of TIN were more than those of control group (12.5±0.5, 8.7±7.7, 8.5±3.0, P=0.028). Conclusion The inhibiting Dll4/Notch signal transduction pathway stimulates the proliferation of HUVEC and facilitates the angiogenesis. Interference with Dll4/Notch signaling may be particularly desirable in tumors with highly induced Dll4/Notch pathway.%目的 特异性阻断Delta样分子4(Dll)4/Notch信号途径,观察其对细胞生物学行为的影响.方法 将自行构建的含短发夹样

  17. Oxidative stress response pathways: Fission yeast as archetype

    DEFF Research Database (Denmark)

    Papadakis, Manos A.; Workman, Christopher

    2015-01-01

    Schizosaccharomyces pombe is a popular model eukaryotic organism to study diverse aspects of mammalian biology, including responses to cellular stress triggered by redox imbalances within its compartments. The review considers the current knowledge on the signaling pathways that govern the transc...

  18. Efficient key pathway mining: combining networks and OMICS data.

    Science.gov (United States)

    Alcaraz, Nicolas; Friedrich, Tobias; Kötzing, Timo; Krohmer, Anton; Müller, Joachim; Pauling, Josch; Baumbach, Jan

    2012-07-01

    Systems biology has emerged over the last decade. Driven by the advances in sophisticated measurement technology the research community generated huge molecular biology data sets. These comprise rather static data on the interplay of biological entities, for instance protein-protein interaction network data, as well as quite dynamic data collected for studying the behavior of individual cells or tissues in accordance with changing environmental conditions, such as DNA microarrays or RNA sequencing. Here we bring the two different data types together in order to gain higher level knowledge. We introduce a significantly improved version of the KeyPathwayMiner software framework. Given a biological network modelled as a graph and a set of expression studies, KeyPathwayMiner efficiently finds and visualizes connected sub-networks where most components are expressed in most cases. It finds all maximal connected sub-networks where all nodes but k exceptions are expressed in all experimental studies but at most l exceptions. We demonstrate the power of the new approach by comparing it to similar approaches with gene expression data previously used to study Huntington's disease. In addition, we demonstrate KeyPathwayMiner's flexibility and applicability to non-array data by analyzing genome-scale DNA methylation profiles from colorectal tumor cancer patients. KeyPathwayMiner release 2 is available as a Cytoscape plugin and online at http://keypathwayminer.mpi-inf.mpg.de.

  19. Diversity in Pathways to Common Childhood Disruptive Behavior Disorders

    Science.gov (United States)

    Martel, Michelle M.; Nikolas, Molly; Jernigan, Katherine; Friderici, Karen; Nigg, Joel T.

    2012-01-01

    Oppositional-Defiant Disorder (ODD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are highly comorbid, a phenomenon thought to be due to shared etiological factors and mechanisms. Little work has attempted to chart multiple-level-of-analysis pathways (i.e., simultaneously including biological, environmental, and trait influences) to ODD and…

  20. Computational tools for the synthetic design of biochemical pathways

    NARCIS (Netherlands)

    Medema, Marnix H.; van Raaphorst, Renske; Takano, Eriko; Breitling, Rainer

    2012-01-01

    As the field of synthetic biology is developing, the prospects for de novo design of biosynthetic pathways are becoming more and more realistic. Hence, there is an increasing need for computational tools that can support these efforts. A range of algorithms has been developed that can be used to ide

  1. Osteoarthritis year in review 2013: biology.

    Science.gov (United States)

    Loeser, R F

    2013-10-01

    The purpose of this review was to present highlights from the published literature on the topic of the biology of osteoarthritis (OA). A PubMed search was conducted in order to locate original research manuscripts published since the last OARSI meeting in 2012. From review of the published literature, common themes emerged as active areas of research over the past year including studies in the areas of epigenetics, Wnt signaling, the role of inflammatory pathways in OA, lubricin, fibroblast growth factor signaling, and studies on OA biology in bone. Key findings in these areas were summarized and implications for future therapies were discussed.

  2. Polyketide stereocontrol: a study in chemical biology

    Science.gov (United States)

    2017-01-01

    The biosynthesis of reduced polyketides in bacteria by modular polyketide synthases (PKSs) proceeds with exquisite stereocontrol. As the stereochemistry is intimately linked to the strong bioactivity of these molecules, the origins of stereochemical control are of significant interest in attempts to create derivatives of these compounds by genetic engineering. In this review, we discuss the current state of knowledge regarding this key aspect of the biosynthetic pathways. Given that much of this information has been obtained using chemical biology tools, work in this area serves as a showcase for the power of this approach to provide answers to fundamental biological questions.

  3. Biological elimination phosphorus; Eliminacion biologia de fosforo

    Energy Technology Data Exchange (ETDEWEB)

    Carrera, J.; Vicent, T.; Lafuente, J. [Universitat Autonoma de Barcelona (Spain)

    2000-07-01

    Phosphorus is the main limiting nutrient in the eutrophication process, and therefore its removal from the aquatic medium is indispensable. Biological Phosphorous Removal is a more efficient and convenient process compared with the classical chemical precipitation, due to a reduction of chemical reagents and sludge production. Moreover, it represents energy save since the sludge produced can be reused for agriculture purposes. In this paper bibliographic hypothesis about the metabolic pathways of the phosphorous accumulating organisms are widely and accurate reviewed and the above mentioned environmental benefits of the Biological Phosphorous Removal are reported. (Author) 22 refs.

  4. Programmable genetic circuits for pathway engineering.

    Science.gov (United States)

    Hoynes-O'Connor, Allison; Moon, Tae Seok

    2015-12-01

    Synthetic biology has the potential to provide decisive advances in genetic control of metabolic pathways. However, there are several challenges that synthetic biologists must overcome before this vision becomes a reality. First, a library of diverse and well-characterized sensors, such as metabolite-sensing or condition-sensing promoters, must be constructed. Second, robust programmable circuits that link input conditions with a specific gene regulation response must be developed. Finally, multi-gene targeting strategies must be integrated with metabolically relevant sensors and complex, robust logic. Achievements in each of these areas, which employ the CRISPR/Cas system, in silico modeling, and dynamic sensor-regulators, among other tools, provide a strong basis for future research. Overall, the future for synthetic biology approaches in metabolic engineering holds immense promise.

  5. Using Biological-Control Research in the Classroom to Promote Scientific Inquiry & Literacy

    Science.gov (United States)

    Richardson, Matthew L.; Richardson, Scott L.; Hall, David G.

    2012-01-01

    Scientists researching biological control should engage in education because translating research programs into classroom activities is a pathway to increase scientific literacy among students. Classroom activities focused on biological control target all levels of biological organization and can be cross-disciplinary by drawing from subject areas…

  6. Pathway elucidation and metabolic engineering of specialized plant metabolites

    DEFF Research Database (Denmark)

    Salomonsen, Bo

    , these projects have increased revenues on fermentative production of several biochemicals. The use of systems biology is, however, not limited to microorganisms. Recent advances in biotechnology methods have provided a wealth of data within functional genomics, metabolomics, transcriptomics, proteomics...... and fluxomics for a considerable number of organisms. Unfortunately, transferring the wealth of data to valuable information for metabolic engineering purposes is a non-obvious task. This PhD thesis describes a palate of tools used in generation of cell factories for production of specialized plant metabolites......, namely the plant defense compounds camalexin and glucosinolates. The thesis shows methodologies for elucidation of biosynthesis pathways and describes how to transfer obtained knowledge of metabolic pathways to other organisms through establishment of a synthetic biology platform. Through pathway...

  7. Applicability of computational systems biology in toxicology.

    Science.gov (United States)

    Kongsbak, Kristine; Hadrup, Niels; Audouze, Karine; Vinggaard, Anne Marie

    2014-07-01

    Systems biology as a research field has emerged within the last few decades. Systems biology, often defined as the antithesis of the reductionist approach, integrates information about individual components of a biological system. In integrative systems biology, large data sets from various sources and databases are used to model and predict effects of chemicals on, for instance, human health. In toxicology, computational systems biology enables identification of important pathways and molecules from large data sets; tasks that can be extremely laborious when performed by a classical literature search. However, computational systems biology offers more advantages than providing a high-throughput literature search; it may form the basis for establishment of hypotheses on potential links between environmental chemicals and human diseases, which would be very difficult to establish experimentally. This is possible due to the existence of comprehensive databases containing information on networks of human protein-protein interactions and protein-disease associations. Experimentally determined targets of the specific chemical of interest can be fed into these networks to obtain additional information that can be used to establish hypotheses on links between the chemical and human diseases. Such information can also be applied for designing more intelligent animal/cell experiments that can test the established hypotheses. Here, we describe how and why to apply an integrative systems biology method in the hypothesis-generating phase of toxicological research.

  8. Altered Pathway Analyzer: A gene expression dataset analysis tool for identification and prioritization of differentially regulated and network rewired pathways

    Science.gov (United States)

    Kaushik, Abhinav; Ali, Shakir; Gupta, Dinesh

    2017-01-01

    Gene connection rewiring is an essential feature of gene network dynamics. Apart from its normal functional role, it may also lead to dysregulated functional states by disturbing pathway homeostasis. Very few computational tools measure rewiring within gene co-expression and its corresponding regulatory networks in order to identify and prioritize altered pathways which may or may not be differentially regulated. We have developed Altered Pathway Analyzer (APA), a microarray dataset analysis tool for identification and prioritization of altered pathways, including those which are differentially regulated by TFs, by quantifying rewired sub-network topology. Moreover, APA also helps in re-prioritization of APA shortlisted altered pathways enriched with context-specific genes. We performed APA analysis of simulated datasets and p53 status NCI-60 cell line microarray data to demonstrate potential of APA for identification of several case-specific altered pathways. APA analysis reveals several altered pathways not detected by other tools evaluated by us. APA analysis of unrelated prostate cancer datasets identifies sample-specific as well as conserved altered biological processes, mainly associated with lipid metabolism, cellular differentiation and proliferation. APA is designed as a cross platform tool which may be transparently customized to perform pathway analysis in different gene expression datasets. APA is freely available at http://bioinfo.icgeb.res.in/APA. PMID:28084397

  9. The structural biology of patellamide biosynthesis.

    Science.gov (United States)

    Koehnke, Jesko; Bent, Andrew F; Houssen, Wael E; Mann, Greg; Jaspars, Marcel; Naismith, James H

    2014-12-01

    The biosynthetic pathways for patellamide and related natural products have recently been studied by structural biology. These pathways produce molecules that have a complex framework and exhibit a diverse array of activity due to the variability of the amino acids that are found in them. As these molecules are difficult to synthesize chemically, exploitation of their properties has been modest. The patellamide pathway involves amino acid heterocyclization, peptide cleavage, peptide macrocyclization, heterocycle oxidation and epimerization; closely related products are also prenylated. Enzyme activities have been identified for all these transformations except epimerization, which may be spontaneous. This review highlights the recent structural and mechanistic work on amino acid heterocyclization, peptide cleavage and peptide macrocyclization. This work should help in using the enzymes to produce novel analogs of the natural products enabling an exploitation of their properties.

  10. Enhanced C30 carotenoid production in Bacillus subtilis by systematic overexpression of MEP pathway genes

    NARCIS (Netherlands)

    Xue, Dan; Abdallah, Ingy I.; de Haan, Ilse E.M.; Sibbald, Mark J.J.B.; Quax, Wim J.

    2015-01-01

    Creating novel biosynthetic pathways and modulating the synthesis of important compounds are one of the hallmarks of synthetic biology. Understanding the key parameters controlling the flux of chemicals throughout a metabolic pathway is one of the challenges ahead. Isoprenoids are the most functiona

  11. Synthetic biology approaches to fluorinated polyketides.

    Science.gov (United States)

    Thuronyi, Benjamin W; Chang, Michelle C Y

    2015-03-17

    The catalytic diversity of living systems offers a broad range of opportunities for developing new methods to produce small molecule targets such as fuels, materials, and pharmaceuticals. In addition to providing cost-effective and renewable methods for large-scale commercial processes, the exploration of the unusual chemical phenotypes found in living organisms can also enable the expansion of chemical space for discovery of novel function by combining orthogonal attributes from both synthetic and biological chemistry. In this context, we have focused on the development of new fluorine chemistry using synthetic biology approaches. While fluorine has become an important feature in compounds of synthetic origin, the scope of biological fluorine chemistry in living systems is limited, with fewer than 20 organofluorine natural products identified to date. In order to expand the diversity of biosynthetically accessible organofluorines, we have begun to develop methods for the site-selective introduction of fluorine into complex natural products by engineering biosynthetic machinery to incorporate fluorinated building blocks. To gain insight into how both enzyme active sites and metabolic pathways can be evolved to manage and select for fluorinated compounds, we have studied one of the only characterized natural hosts for organofluorine biosynthesis, the soil microbe Streptomyces cattleya. This information provides a template for designing engineered organofluorine enzymes, pathways, and hosts and has allowed us to initiate construction of enzymatic and cellular pathways for the production of fluorinated polyketides.

  12. Resetting Biological Clocks

    Science.gov (United States)

    Winfree, Arthur T.

    1975-01-01

    Reports on experiments conducted on two biological clocks, in organisms in the plant and animal kingdoms, which indicate that biological oscillation can be arrested by a single stimulus of a definite strength delivered at the proper time. (GS)

  13. Biology is simple.

    Science.gov (United States)

    Newman, Tim

    2015-12-30

    This paper explores the potential for simplicity to reveal new biological understanding. Borrowing selectively from physics thinking, and contrasting with Crick's reductionist philosophy, the author argues that greater emphasis on simplicity is necessary to advance biology and its applications.

  14. Biology of Blood

    Science.gov (United States)

    ... here for the Professional Version Home Blood Disorders Biology of Blood Overview of Blood Resources In This ... Version. DOCTORS: Click here for the Professional Version Biology of Blood Overview of Blood Components of Blood ...

  15. Pathway analysis of bladder cancer genome-wide association study identifies novel pathways involved in bladder cancer development

    Science.gov (United States)

    Chen, Meng; Rothman, Nathaniel; Ye, Yuanqing; Gu, Jian; Scheet, Paul A.; Huang, Maosheng; Chang, David W.; Dinney, Colin P.; Silverman, Debra T.; Figueroa, Jonine D.; Chanock, Stephen J.; Wu, Xifeng

    2016-01-01

    Genome-wide association studies (GWAS) are designed to identify individual regions associated with cancer risk, but only explain a small fraction of the inherited variability. Alternative approach analyzing genetic variants within biological pathways has been proposed to discover networks of susceptibility genes with additional effects. The gene set enrichment analysis (GSEA) may complement and expand traditional GWAS analysis to identify novel genes and pathways associated with bladder cancer risk. We selected three GSEA methods: Gen-Gen, Aligator, and the SNP Ratio Test to evaluate cellular signaling pathways involved in bladder cancer susceptibility in a Texas GWAS population. The candidate genetic polymorphisms from the significant pathway selected by GSEA were validated in an independent NCI GWAS. We identified 18 novel pathways (P < 0.05) significantly associated with bladder cancer risk. Five of the most promising pathways (P ≤ 0.001 in any of the three GSEA methods) among the 18 pathways included two cell cycle pathways and neural cell adhesion molecule (NCAM), platelet-derived growth factor (PDGF), and unfolded protein response pathways. We validated the candidate polymorphisms in the NCI GWAS and found variants of RAPGEF1, SKP1, HERPUD1, CACNB2, CACNA1C, CACNA1S, COL4A2, SRC, and CACNA1C were associated with bladder cancer risk. Two CCNE1 variants, rs8102137 and rs997669, from cell cycle pathways showed the strongest associations; the CCNE1 signal at 19q12 has already been reported in previous GWAS. These findings offer additional etiologic insights highlighting the specific genes and pathways associated with bladder cancer development. GSEA may be a complementary tool to GWAS to identify additional loci of cancer susceptibility.

  16. [Biology of cancer metastasis].

    Science.gov (United States)

    Robert, Jacques

    2013-04-01

    Metastatic dissemination represents the true cause of the malignant character of cancers. Its targeting is much more difficult than that of cell proliferation, because metastasis, like angiogenesis, involves a number of complex interactions between tumour and stroma; the contribution of adhesion and motility pathways is added to that of proliferation and survival pathways. Long distance extension, discontinuous in respect to the primitive tumour, is a major feature of cancer and the main cause of patients' death. Cancer cells use two main dissemination pathways: the lymphatic pathway, leading to the invasion of the lymph nodes draining the organs where the tumour evolves; and the blood pathway, leading to the invasion of distant organs such as liver, brain, bone or lung. Metastasis is inscribed within the properties of the primitive tumour, as shown by the comparative molecular analysis of the primitive tumour and its own metastases: their similarity is always more important than what could be expected from the general activation of "metastasis genes" or the inhibition of "metastasis suppressor genes". Among the signalling pathways involved in metastasis, one can mention the integrin pathway, the transforming growth factor beta (TGFβ) pathway, the chemokine pathway, the dependence receptor pathway and many others. These pathways allow the possibility of therapeutic targeting, thanks to therapeutic antibodies or small molecules inhibiting the kinases involved in these signalling pathways, but not a single properly anti-metastatic drug has yet been proposed: the complexity and the diversity of the processes allowing metastasis emergence, as well as the fact that the activation mechanisms are more often epigenetic than genetic and are generally physiological processes misled by the malignant cell, render especially difficult the therapeutic approach of metastasis.

  17. Designing synthetic biology.

    Science.gov (United States)

    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.

  18. BIOLOGICAL FOUNDATIONS OF LANGUAGE.

    Science.gov (United States)

    LENNEBERG, ERIC H.

    THE RELATIONSHIP BETWEEN BIOLOGY AND LANGUAGE IS EXPLORED IN THIS VOLUME. THE AUTHOR BELIEVES THAT "LANGUAGE IS THE MANIFESTATION OF SPECIES-SPECIFIC COGNITIVE PROPENSITIES. IT IS THE CONSEQUENCE OF THE BIOLOGICAL PECULIARITIES THAT MAKE A HUMAN TYPE OF COGNITION POSSIBLE." IN ATTEMPTING TO "REINSTATE THE CONCEPT OF THE BIOLOGICAL BASIS OF…

  19. Biology Myth-Killers

    Science.gov (United States)

    Lampert, Evan

    2014-01-01

    "Biology Myth-Killers" is an activity designed to identify and correct common misconceptions for high school and college introductory biology courses. Students identify common myths, which double as biology misconceptions, and use appropriate sources to share the "truth" about the myths. This learner-centered activity is a fun…

  20. Lessons learned from mice deficient in lectin complement pathway molecules

    DEFF Research Database (Denmark)

    Genster, Ninette Benthien; Takahashi, Minoru; Sekine, Hideharu;

    2014-01-01

    The lectin pathway of the complement system is initiated when the pattern-recognition molecules, mannose-binding lectin (MBL), ficolins or collectin-11, bind to invading pathogens or damaged host cells. This leads to activation of MBL/ficolin/collectin-11 associated serine proteases (MASPs), which...... in turn activate downstream complement components, ultimately leading to elimination of the pathogen. Mice deficient in the key molecules of lectin pathway of complement have been generated in order to build knowledge of the molecular mechanisms of the lectin pathway in health and disease. Despite...... in complement activation, pathogen infection, coagulation, host tissue injury and developmental biology have been revealed by in vivo investigations. This review provides an overview of the mice deficient in lectin pathway molecules and highlights some of the most important findings that have resulted from...

  1. Hippo and rassf1a Pathways: A Growing Affair

    Directory of Open Access Journals (Sweden)

    Francesca Fausti

    2012-01-01

    Full Text Available First discovered in Drosophila, the Hippo pathway regulates the size and shape of organ development. Its discovery and study have helped to address longstanding questions in developmental biology. Central to this pathway is a kinase cascade leading from the tumor suppressor Hippo (Mst1 and Mst2 in mammals to the Yki protein (YAP and TAZ in mammals, a transcriptional coactivator of target genes involved in cell proliferation, survival, and apoptosis. A dysfunction of the Hippo pathway activity is frequently detected in human cancers. Recent studies have highlighted that the Hippo pathway may play an important role in tissue homoeostasis through the regulation of stem cells, cell differentiation, and tissue regeneration. Recently, the impact of RASSF proteins on Hippo signaling potentiating its proapoptotic activity has been addressed, thus, providing further evidence for Hippo's key role in mammalian tumorigenesis as well as other important diseases.

  2. Improving Carbon Fixation Pathways

    OpenAIRE

    Ducat, Daniel C.; Silver, Pamela A

    2012-01-01

    A recent resurgence in basic and applied research on photosynthesis has been driven in part by recognition that fulfilling future food and energy requirements will necessitate improvements in crop carbon-fixation efficiencies. Photosynthesis in traditional terrestrial crops is being reexamined in light of molecular strategies employed by photosynthetic microbes to enhance the activity of the Calvin cycle. Synthetic biology is well-situated to provide original approaches for compartmentalizing...

  3. Integrating interactive computational modeling in biology curricula.

    Directory of Open Access Journals (Sweden)

    Tomáš Helikar

    2015-03-01

    Full Text Available While the use of computer tools to simulate complex processes such as computer circuits is normal practice in fields like engineering, the majority of life sciences/biological sciences courses continue to rely on the traditional textbook and memorization approach. To address this issue, we explored the use of the Cell Collective platform as a novel, interactive, and evolving pedagogical tool to foster student engagement, creativity, and higher-level thinking. Cell Collective is a Web-based platform used to create and simulate dynamical models of various biological processes. Students can create models of cells, diseases, or pathways themselves or explore existing models. This technology was implemented in both undergraduate and graduate courses as a pilot study to determine the feasibility of such software at the university level. First, a new (In Silico Biology class was developed to enable students to learn biology by "building and breaking it" via computer models and their simulations. This class and technology also provide a non-intimidating way to incorporate mathematical and computational concepts into a class with students who have a limited mathematical background. Second, we used the technology to mediate the use of simulations and modeling modules as a learning tool for traditional biological concepts, such as T cell differentiation or cell cycle regulation, in existing biology courses. Results of this pilot application suggest that there is promise in the use of computational modeling and software tools such as Cell Collective to provide new teaching methods in biology and contribute to the implementation of the "Vision and Change" call to action in undergraduate biology education by providing a hands-on approach to biology.

  4. Integrating interactive computational modeling in biology curricula.

    Science.gov (United States)

    Helikar, Tomáš; Cutucache, Christine E; Dahlquist, Lauren M; Herek, Tyler A; Larson, Joshua J; Rogers, Jim A

    2015-03-01

    While the use of computer tools to simulate complex processes such as computer circuits is normal practice in fields like engineering, the majority of life sciences/biological sciences courses continue to rely on the traditional textbook and memorization approach. To address this issue, we explored the use of the Cell Collective platform as a novel, interactive, and evolving pedagogical tool to foster student engagement, creativity, and higher-level thinking. Cell Collective is a Web-based platform used to create and simulate dynamical models of various biological processes. Students can create models of cells, diseases, or pathways themselves or explore existing models. This technology was implemented in both undergraduate and graduate courses as a pilot study to determine the feasibility of such software at the university level. First, a new (In Silico Biology) class was developed to enable students to learn biology by "building and breaking it" via computer models and their simulations. This class and technology also provide a non-intimidating way to incorporate mathematical and computational concepts into a class with students who have a limited mathematical background. Second, we used the technology to mediate the use of simulations and modeling modules as a learning tool for traditional biological concepts, such as T cell differentiation or cell cycle regulation, in existing biology courses. Results of this pilot application suggest that there is promise in the use of computational modeling and software tools such as Cell Collective to provide new teaching methods in biology and contribute to the implementation of the "Vision and Change" call to action in undergraduate biology education by providing a hands-on approach to biology.

  5. Cytoplasmic permeation pathway of neurotransmitter transporters.

    Science.gov (United States)

    Rudnick, Gary

    2011-09-06

    Ion-coupled solute transporters are responsible for transporting nutrients, ions, and signaling molecules across a variety of biological membranes. Recent high-resolution crystal structures of several transporters from protein families that were previously thought to be unrelated show common structural features indicating a large structural family representing transporters from all kingdoms of life. This review describes studies that led to an understanding of the conformational changes required for solute transport in this family. The first structure in this family showed the bacterial amino acid transporter LeuT, which is homologous to neurotransmitter transporters, in an extracellularly oriented conformation with a molecule of leucine occluded at the substrate site. Studies with the mammalian serotonin transporter identified positions, buried in the LeuT structure, that defined a potential pathway leading from the cytoplasm to the substrate binding site. Modeling studies utilized an inverted structural repeat within the LeuT crystal structure to predict the conformation of LeuT in which the cytoplasmic permeation pathway, consisting of positions identified in SERT, was open for diffusion of the substrate to the cytoplasm. From the difference between the model and the crystal structures, a simple "rocking bundle" mechanism was proposed, in which a four-helix bundle changed its orientation with respect to the rest of the protein to close the extracellular pathway and open the cytoplasmic one. Subsequent crystal structures from structurally related proteins provide evidence supporting this model for transport.

  6. Illuminating the Reaction Pathways of Viromimetic Assembly

    Science.gov (United States)

    2017-01-01

    The coassembly of well-defined biological nanostructures relies on a delicate balance between attractive and repulsive interactions between biomolecular building blocks. Viral capsids are a prototypical example, where coat proteins exhibit not only self-interactions but also interact with the cargo they encapsulate. In nature, the balance between antagonistic and synergistic interactions has evolved to avoid kinetic trapping and polymorphism. To date, it has remained a major challenge to experimentally disentangle the complex kinetic reaction pathways that underlie successful coassembly of biomolecular building blocks in a noninvasive approach with high temporal resolution. Here we show how macromolecular force sensors, acting as a genome proxy, allow us to probe the pathways through which a viromimetic protein forms capsids. We uncover the complex multistage process of capsid assembly, which involves recruitment and complexation, followed by allosteric growth of the proteinaceous coat. Under certain conditions, the single-genome particles condense into capsids containing multiple copies of the template. Finally, we derive a theoretical model that quantitatively describes the kinetics of recruitment and growth. These results shed new light on the origins of the pathway complexity in biomolecular coassembly.

  7. Translational Targeted Proteomics Profiling of Mitochondrial Energy Metabolic Pathways in Mouse and Human Samples

    NARCIS (Netherlands)

    Wolters, Justina C.; Ciapaite, Jolita; van Eunen, Karen; Niezen-Koning, Klary E.; Matton, Alix; Porte, Robert J.; Horvatovich, Peter; Bakker, Barbara M.; Bischoff, Rainer; Permentier, Hjalmar P.

    2016-01-01

    Absolute measurements of protein abundance are important in the understanding of biological processes and the precise computational modeling of biological pathways. We developed targeted LC-MS/MS assays in the selected reaction monitoring (SRM) mode to quantify over 50 mitochondrial proteins in a si

  8. A mathematical model of the mating signal transduction pathway in the yeast Saccharomyces cerevisiae. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Thomas Ivan Milac

    1998-09-14

    Outline of two major goals in my proposal for this fellowship. First goal having no previous training in biology, was to become knowledgeable of the paradigms, experimental techniques, and current research interests of molecular biology. Second goal was to construct a mathematical model of the mating signal transduction pathway in the yeast Saccharomyces cerevisiae.

  9. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

    DEFF Research Database (Denmark)

    O'Dushlaine, Colm; Rossin, Lizzy; Lee, Phil H.

    2015-01-01

    Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from ...

  10. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

    NARCIS (Netherlands)

    O'Dushlaine, Colm; Rossin, Lizzy; Lee, Phil H.; Duncan, Laramie; Parikshak, Neelroop N.; Newhouse, Stephen; Ripke, Stephan; Neale, Benjamin M.; Purcell, Shaun M.; Posthuma, Danielle; Nurnberger, John I.; Lee, S. Hong; Faraone, Stephen V.; Perlis, Roy H.; Mowry, Bryan J.; Thapar, Anita; Goddard, Michael E.; Witte, John S.; Absher, Devin; Agartz, Ingrid; Akil, Huda; Amin, Farooq; Andreassen, Ole A.; Anjorin, Adebayo; Anney, Richard; Anttila, Verneri; Arking, Dan E.; Asherson, Philip; Azevedo, Maria H.; Backlund, Lena; Badner, Judith A.; Bailey, Anthony J.; Banaschewski, Tobias; Barchas, Jack D.; Barnes, Michael R.; Barrett, Thomas B.; Bass, Nicholas; Battaglia, Agatino; Bauer, Michael; Bayes, Monica; Bellivier, Frank; Bergen, Sarah E.; Berrettini, Wade; Betancur, Catalina; Bettecken, Thomas; Biederman, Joseph; Binder, Elisabeth B.; Black, Donald W.; Blackwood, Douglas H. R.; Bloss, Cinnamon S.; Boehnke, Michael; Boomsma, Dorret I.; Breuer, Rene; Bruggeman, Richard; Cormican, Paul; Buccola, Nancy G.; Buitelaar, Jan K.; Bunney, William E.; Buxbaum, Joseph D.; Byerley, William F.; Byrne, Enda M.; Caesar, Sian; Cahn, Wiepke; Cantor, Rita M.; Casas, Miguel; Chakravarti, Aravinda; Chambert, Kimberly; Choudhury, Khalid; Cichon, Sven; Mattheisen, Manuel; Cloninger, C. Robert; Collier, David A.; Cook, Edwin H.; Coon, Hilary; Cormand, Bru; Corvin, Aiden; Coryell, William H.; Craig, David W.; Craig, Ian W.; Crosbie, Jennifer; Cuccaro, Michael L.; Curtis, David; Czamara, Darina; Datta, Susmita; Dawson, Geraldine; Day, Richard; De Geus, Eco J.; Degenhardt, Franziska; Djurovic, Srdjan; Donohoe, Gary J.; Doyle, Alysa E.; Duan, Jubao; Dudbridge, Frank; Duketis, Eftichia; Ebstein, Richard P.; Edenberg, Howard J.; Elia, Josephine; Ennis, Sean; Etain, Bruno; Fanous, Ayman; Farmer, Anne E.; Ferrier, I. Nicol; Flicldnger, Matthew; Fombonne, Eric; Foroud, Tatiana; Frank, Josef; Franke, Barbara; Fraser, Christine; Freedman, Robert; Freimer, Nelson B.; Freitag, Christine M.; Friedl, Marion; Frisen, Louise; Gailagher, Louise; Gejman, Pablo V.; Georgieva, Lyudmila; Gershon, Elliot S.; Giegling, Ina; Gill, Michael; Gordon, Scott D.; Gordon-Smith, Katherine; Green, Elaine K.; Greenwood, Tiffany A.; Grice, Dorothy E.; Gross, Magdalena; Grozeva, Detelina; Guan, Weihua; Gurling, Hugh; De Haan, Lieuwe; Haines, Jonathan L.; Hakonarson, Hakon; Hallmayer, Joachim; Hamilton, Steven P.; Hamshere, Marian L.; Hansen, Thomas F.; Hartmann, Annette M.; Hautzinger, Martin; Heath, Andrew C.; Henders, Anjali K.; Herms, Stefan; Hickie, Ian B.; Hipolito, Maria; Hoefels, Susanne; Holsboer, Florian; Hoogendijk, Witte J.; Hottenga, Jouke-Jan; Hultman, Christina M.; Hus, Vanessa; Ingason, Andres; Ising, Marcus; Jamain, Stephane; Jones, Edward G.; Jones, Ian; Jones, Lisa; Tzeng, Jung-Ying; Kaehler, Anna K.; Kahn, Rene S.; Kandaswamy, Radhika; Keller, Matthew C.; Kennedy, James L.; Kenny, Elaine; Kent, Lindsey; Kim, Yunjung; Kirov, George K.; Klauck, Sabine M.; Klei, Lambertus; Knowles, James A.; Kohli, Martin A.; Koller, Daniel L.; Konte, Bettina; Korszun, Ania; Krabbendam, Lydia; Krasucki, Robert; Kuntsi, Jonna; Kwan, Phoenix; Landen, Mikael; Laengstroem, Niklas; Lathrop, Mark; Lawrence, Jacob; Lawson, William B.; Leboyer, Marion; Ledbetter, David H.; Lencz, Todd; Lesch, Klaus-Peter; Levinson, Douglas F.; Lewis, Cathryn M.; Li, Jun; Lichtenstein, Paul; Lieberman, Jeffrey A.; Lin, Dan-Yu; Linszen, Don H.; Liu, Chunyu; Lohoff, Falk W.; Loo, Sandra K.; Lord, Catherine; Lowe, Jennifer K.; Lucae, Susanne; MacIntyre, Donald J.; Madden, Pamela A. F.; Maestrini, Elena; Magnusson, Patrik K. E.; Mahon, Pamela B.; Maier, Wolfgang; Malhotra, Anil K.; Mane, Shrikant M.; Martin, Christa L.; Martin, Nicholas G.; Matthews, Keith; Mattingsdal, Morten; McCarroll, Steven A.; McGhee, Kevin A.; McGough, James J.; McGrath, Patrick J.; McGuffin, Peter; McInnis, Melvin G.; McIntosh, Andrew; McKinney, Rebecca; McLean, Alan W.; McMahon, Francis J.; McMahon, William M.; McQuillin, Andrew; Medeiros, Helena; Medland, Sarah E.; Meier, Sandra; Melle, Ingrid; Meng, Fan; Meyer, Jobst; Middeldorp, Christel M.; Middleton, Lefkos; Milanova, Vihra; Miranda, Ana; Monaco, Anthony P.; Montgomery, Grant W.; Moran, Jennifer L.; Moreno-De-Luca, Daniel; Morken, Gunnar; Morris, Derek W.; Morrow, Eric M.; Moskvina, Valentina; Muglia, Pierandrea; Muehleisen, Thomas W.; Muir, Walter J.; Mueller-Myhsok, Bertram; Murtha, Michael; Myers, Richard M.; Myin-Germeys, Inez; Neale, Michael C.; Nelson, Stan F.; Nievergelt, Caroline M.; Nikolov, Ivan; Nimgaonkar, Vishwajit; Nolen, Willem A.; Noethen, Markus M.; Nwulia, Evaristus A.; Nyholt, Dale R.; Oades, Robert D.; Olincy, Ann; Oliveira, Guiomar; Olsen, Line; Ophoff, Roel A.; Osby, Urban; Owen, Michael J.; Palotie, Aarno; Parr, Jeremy R.; Paterson, Andrew D.; Pato, Carlos N.; Pato, Michele T.; Penninx, Brenda W.; Pergadia, Michele L.; Pericak-Vance, Margaret A.; Pickard, Benjamin S.; Pimm, Jonathan; Piven, Joseph; Potash, James B.; Poustka, Fritz; Propping, Peter; Puri, Vinay; Quested, Digby J.; Quinn, Emma M.; Ramos-Quiroga, Josep Antoni; Rasmussen, Henrik B.; Raychaudhuri, Soumya; Rehnstroem, Karola; Reif, Andreas; Ribases, Marta; Rice, John P.; Rietschel, Marcella; Roeder, Kathryn; Roeyers, Herbert; Rothenberger, Aribert; Rouleau, Guy; Ruderfer, Douglas; Rujescu, Dan; Sanders, Alan R.; Sanders, Stephan J.; Santangelo, Susan L.; Sergeant, Joseph A.; Schachar, Russell; Schalling, Martin; Schatzberg, Alan F.; Scheftner, William A.; Schellenberg, Gerard D.; Scherer, Stephen W.; Schork, Nicholas J.; Schulze, Thomas G.; Schumacher, Johannes; Schwarz, Markus; Scolnick, Edward; Scott, Laura J.; Shi, Jianxin; Shilling, Paul D.; Shyn, Stanley I.; Silverman, Jeremy M.; Slager, Susan L.; Smalley, Susan L.; Smit, Johannes H.; Smith, Erin N.; Sonuga-Barke, Edmund J. S.; Cair, David St.; State, Matthew; Steffens, Michael; Steinhausen, Hans-Christoph; Strauss, John S.; Strohmaier, Jana; Stroup, T. Scott; Sutdiffe, James S.; Szatmari, Peter; Szelinger, Szabocls; Thirumalai, Srinivasa; Thompson, Robert C.; Todorov, Alexandre A.; Tozzi, Federica; Treutlein, Jens; Uhr, Manfred; Van den Oord, Edwin J. C. G.; Van Grootheest, Gerard; Van Os, Jim; Vicente, Astrid M.; Vieland, Veronica J.; Vincent, John B.; Visscher, Peter M.; Walsh, Christopher A.; Wassink, Thomas H.; Watson, Stanley J.; Weissman, Myrna M.; Werge, Thomas; Wienker, Thomas F.; Wijsman, Ellen M.; Willemsen, Gonneke; Williams, Nigel; Willsey, A. Jeremy; Witt, Stephanie H.; Xu, Wei; Young, Allan H.; Yu, Timothy W.; Zammit, Stanley; Zandi, Peter P.; Zhang, Peng; Zitman, Frans G.; Zoellner, Sebastian; Devlin, Bernie; Kelsoe, John R.; Sklar, Pamela; Daly, Mark J.; O'Donovan, Michael C.; Craddock, Nicholas; Kendler, Kenneth S.; Weiss, Lauren A.; Wray, Naomi R.; Zhao, Zhaoming; Geschwind, Daniel H.; Sullivan, Patrick F.; Smoller, Jordan W.; Holmans, Peter A.; Breen, Gerome

    2015-01-01

    Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from ove

  11. Additive manufacturing of biologically-inspired materials.

    Science.gov (United States)

    Studart, André R

    2016-01-21

    Additive manufacturing (AM) technologies offer an attractive pathway towards the fabrication of functional materials featuring complex heterogeneous architectures inspired by biological systems. In this paper, recent research on the use of AM approaches to program the local chemical composition, structure and properties of biologically-inspired materials is reviewed. A variety of structural motifs found in biological composites have been successfully emulated in synthetic systems using inkjet-based, direct-writing, stereolithography and slip casting technologies. The replication in synthetic systems of design principles underlying such structural motifs has enabled the fabrication of lightweight cellular materials, strong and tough composites, soft robots and autonomously shaping structures with unprecedented properties and functionalities. Pushing the current limits of AM technologies in future research should bring us closer to the manufacturing capabilities of living organisms, opening the way for the digital fabrication of advanced materials with superior performance, lower environmental impact and new functionalities.

  12. Computational systems biology in cancer brain metastasis.

    Science.gov (United States)

    Peng, Huiming; Tan, Hua; Zhao, Weiling; Jin, Guangxu; Sharma, Sambad; Xing, Fei; Watabe, Kounosuke; Zhou, Xiaobo

    2016-01-01

    Brain metastases occur in 20-40% of patients with advanced malignancies. A better understanding of the mechanism of this disease will help us to identify novel therapeutic strategies. In this review, we will discuss the systems biology approaches used in this area, including bioinformatics and mathematical modeling. Bioinformatics has been used for identifying the molecular mechanisms driving brain metastasis and mathematical modeling methods for analyzing dynamics of a system and predicting optimal therapeutic strategies. We will illustrate the strategies, procedures, and computational techniques used for studying systems biology in cancer brain metastases. We will give examples on how to use a systems biology approach to analyze a complex disease. Some of the approaches used to identify relevant networks, pathways, and possibly biomarkers in metastasis will be reviewed into details. Finally, certain challenges and possible future directions in this area will also be discussed.

  13. Principles of biological therapy in psoriasis.

    Science.gov (United States)

    Caca Biljanovska, N; V'lckova Laskoska, M

    2013-01-01

    Psoriasis is a chronic, systemic T-cell mediated autoimmune skin disease, potentially associated with arthritis. The new understanding of immunopathogenesis and inflammatory cytokine pathways was actually the rationale for developing and introducing biological drugs in the treatment of moderate to severe psoriasis and psoriatic arthritis. Different from the traditional systemic drugs that impact the entire immune system, bio-logics target only specific points of the immune system. This review focuses on five biologics which target either T-cells (alefacept) or TNF-alpha (etanercept, adalimumab and infliximab) or interleukin IL-12/IL-23 (ustekinumab)--their efficacy, safety, patient monitoring and recommended dosage. The purpose of the treatment guidelines presented here is to provide a high standard of continuing care of psoriasis and psoriatic arthritis patients.

  14. Computational systems chemical biology.

    Science.gov (United States)

    Oprea, Tudor I; May, Elebeoba E; Leitão, Andrei; Tropsha, Alexander

    2011-01-01

    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) (Nat Chem Biol 3: 447-450, 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.

  15. Quantum biological information theory

    CERN Document Server

    Djordjevic, Ivan B

    2016-01-01

    This book is a self-contained, tutorial-based introduction to quantum information theory and quantum biology. It serves as a single-source reference to the topic for researchers in bioengineering, communications engineering, electrical engineering, applied mathematics, biology, computer science, and physics. The book provides all the essential principles of the quantum biological information theory required to describe the quantum information transfer from DNA to proteins, the sources of genetic noise and genetic errors as well as their effects. Integrates quantum information and quantum biology concepts; Assumes only knowledge of basic concepts of vector algebra at undergraduate level; Provides a thorough introduction to basic concepts of quantum information processing, quantum information theory, and quantum biology; Includes in-depth discussion of the quantum biological channel modelling, quantum biological channel capacity calculation, quantum models of aging, quantum models of evolution, quantum models o...

  16. Mapping Nursing Pathways

    Directory of Open Access Journals (Sweden)

    Melanie Birks

    2015-09-01

    Full Text Available Articulated education pathways between the vocational education training sector and universities provide opportunities for students wishing to progress to higher qualifications. Enrolled nurses seeking to advance their career in nursing can choose to enter baccalaureate degree programs through such alternative entry routes. Awarding of credit for prior studies is dependent on accurate assessment of the existing qualification against that which is sought. This study employed a modified Delphi method to inform the development of an evidence-based, structured approach to mapping the pathway from the nationally consistent training package of the Diploma of Nursing to the diversity of baccalaureate nursing programs across Australia. The findings of this study reflect the practical nature of the role of the enrolled nurse, particularly the greater emphasis placed on direct care activities as opposed to those related to professional development and the generation and use of evidence. These findings provide a valuable summative overview of the relationship between the Diploma of Nursing and the expectations of the registered nurse role.

  17. A Skyline Plugin for Pathway-Centric Data Browsing

    Energy Technology Data Exchange (ETDEWEB)

    Degan, Michael G.; Ryadinskiy, Lillian; Fujimoto, Grant M.; Wilkins, Christopher S.; Lichti, Cheryl F.; Payne, Samuel H.

    2016-08-16

    For targeted proteomics to be broadly adopted in biological laboratories as a routine experimental protocol, wet-bench biologists must be able to approach SRM assay design in the same way they approach biological experimental design. Most often, biological hypotheses are envisioned in a set of protein interactions, networks and pathways. We present a plugin for the popular Skyline tool that presents public mass spectrometry data in a pathway-centric view to assist users in browsing available data and determining how to design quantitative experiments. Selected proteins and their underlying mass spectra are imported to Skyline for further assay design (transition selection). The same plugin can be used for hypothesis-drive DIA data analysis, again utilizing the pathway view to help narrow down the set of proteins which will be investigated. The plugin is backed by the PNNL Biodiversity Library, a corpus of 3 million peptides from >100 organisms, and the draft human proteome. Users can upload personal data to the plugin to use the pathway navigation prior to importing their own data into Skyline.

  18. A Skyline Plugin for Pathway-Centric Data Browsing

    Science.gov (United States)

    Degan, Michael G.; Ryadinskiy, Lillian; Fujimoto, Grant M.; Wilkins, Christopher S.; Lichti, Cheryl F.; Payne, Samuel H.

    2016-08-01

    For targeted proteomics to be broadly adopted in biological laboratories as a routine experimental protocol, wet-bench biologists must be able to approach selected reaction monitoring (SRM) and parallel reaction monitoring (PRM) assay design in the same way they approach biological experimental design. Most often, biological hypotheses are envisioned in a set of protein interactions, networks, and pathways. We present a plugin for the popular Skyline tool that presents public mass spectrometry data in a pathway-centric view to assist users in browsing available data and determining how to design quantitative experiments. Selected proteins and their underlying mass spectra are imported to Skyline for further assay design (transition selection). The same plugin can be used for hypothesis-driven data-independent acquisition (DIA) data analysis, again utilizing the pathway view to help narrow down the set of proteins that will be investigated. The plugin is backed by the Pacific Northwest National Laboratory (PNNL) Biodiversity Library, a corpus of 3 million peptides from >100 organisms, and the draft human proteome. Users can upload personal data to the plugin to use the pathway navigation prior to importing their own data into Skyline.

  19. A Skyline Plugin for Pathway-Centric Data Browsing

    Science.gov (United States)

    Degan, Michael G.; Ryadinskiy, Lillian; Fujimoto, Grant M.; Wilkins, Christopher S.; Lichti, Cheryl F.; Payne, Samuel H.

    2016-11-01

    For targeted proteomics to be broadly adopted in biological laboratories as a routine experimental protocol, wet-bench biologists must be able to approach selected reaction monitoring (SRM) and parallel reaction monitoring (PRM) assay design in the same way they approach biological experimental design. Most often, biological hypotheses are envisioned in a set of protein interactions, networks, and pathways. We present a plugin for the popular Skyline tool that presents public mass spectrometry data in a pathway-centric view to assist users in browsing available data and determining how to design quantitative experiments. Selected proteins and their underlying mass spectra are imported to Skyline for further assay design (transition selection). The same plugin can be used for hypothesis-driven data-independent acquisition (DIA) data analysis, again utilizing the pathway view to help narrow down the set of proteins that will be investigated. The plugin is backed by the Pacific Northwest National Laboratory (PNNL) Biodiversity Library, a corpus of 3 million peptides from >100 organisms, and the draft human proteome. Users can upload personal data to the plugin to use the pathway navigation prior to importing their own data into Skyline.

  20. Partitioning of genomic variance using prior biological information

    DEFF Research Database (Denmark)

    Edwards, Stefan McKinnon; Janss, Luc; Madsen, Per;

    2013-01-01

    that the associated genetic variants are enriched for genes that are connected in biol ogical pathways or for likely functional effects on genes. These biological findings provide valuable insight for developing better genomic models. These are statistical models for predicting complex trait phenotypes on the basis...... of single nucleotide polymorphism (SNP) data and trait phenotypes and can account for a much larger fraction of the heritable component of the trait. A disadvantage is that this “black box” modelling approach does not provide any insight into the biological mechanisms underlying the trait. We propose...... to open the “black box” by building SNP set genomic models that evaluate the collective action of multiple SNPs in genes, biological pathways or other external biological findings on the trait phenotype. As a proof of concept we have tested the modelling framework on susceptibility to mastitis in dairy...

  1. Synthetic biology: applying biological circuits beyond novel therapies.

    Science.gov (United States)

    Dobrin, Anton; Saxena, Pratik; Fussenegger, Martin

    2016-04-18

    Synthetic biology, an engineering, circuit-driven approach to biology, has developed whole new classes of therapeutics. Unfortunately, these advances have thus far been undercapitalized upon by basic researchers. As discussed herein, using synthetic circuits, one can undertake exhaustive investigations of the endogenous circuitry found in nature, develop novel detectors and better temporally and spatially controlled inducers. One could detect changes in DNA, RNA, protein or even transient signaling events, in cell-based systems, in live mice, and in humans. Synthetic biology has also developed inducible systems that can be induced chemically, optically or using radio waves. This induction has been re-wired to lead to changes in gene expression, RNA stability and splicing, protein stability and splicing, and signaling via endogenous pathways. Beyond simple detectors and inducible systems, one can combine these modalities and develop novel signal integration circuits that can react to a very precise pre-programmed set of conditions or even to multiple sets of precise conditions. In this review, we highlight some tools that were developed in which these circuits were combined such that the detection of a particular event automatically triggered a specific output. Furthermore, using novel circuit-design strategies, circuits have been developed that can integrate multiple inputs together in Boolean logic gates composed of up to 6 inputs. We highlight the tools available and what has been developed thus far, and highlight how some clinical tools can be very useful in basic science. Most of the systems that are presented can be integrated together; and the possibilities far exceed the number of currently developed strategies.

  2. Small RNA biology is systems biology.

    Science.gov (United States)

    Jost, Daniel; Nowojewski, Andrzej; Levine, Erel

    2011-01-01

    During the last decade small regulatory RNA (srRNA) emerged as central players in the regulation of gene expression in all kingdoms of life. Multiple pathways for srRNA biogenesis and diverse mechanisms of gene regulation may indicate that srRNA regulation evolved independently multiple times. However, small RNA pathways share numerous properties, including the ability of a single srRNA to regulate multiple targets. Some of the mechanisms of gene regulation by srRNAs have significant effect on the abundance of free srRNAs that are ready to interact with new targets. This results in indirect interactions among seemingly unrelated genes, as well as in a crosstalk between different srRNA pathways. Here we briefly review and compare the major srRNA pathways, and argue that the impact of srRNA is always at the system level. We demonstrate how a simple mathematical model can ease the discussion of governing principles. To demonstrate these points we review a few examples from bacteria and animals.

  3. Pathway analysis of smoking quantity in multiple GWAS identifies cholinergic and sensory pathways.

    Directory of Open Access Journals (Sweden)

    Oscar Harari

    Full Text Available Cigarette smoking is a common addiction that increases the risk for many diseases, including lung cancer and chronic obstructive pulmonary disease. Genome-wide association studies (GWAS have successfully identified and validated several susceptibility loci for nicotine consumption and dependence. However, the trait variance explained by these genes is only a small fraction of the estimated genetic risk. Pathway analysis complements single marker methods by including biological knowledge into the evaluation of GWAS, under the assumption that causal variants lie in functionally related genes, enabling the evaluation of a broad range of signals. Our approach to the identification of pathways enriched for multiple genes associated with smoking quantity includes the analysis of two studies and the replication of common findings in a third dataset. This study identified pathways for the cholinergic receptors, which included SNPs known to be genome-wide significant; as well as novel pathways, such as genes involved in the sensory perception of smell, that do not contain any single SNP that achieves that stringent threshold.

  4. Genome-wide association study knowledge-driven pathway analysis of alcohol dependence implicates the calcium signaling pathway

    Institute of Scientific and Technical Information of China (English)

    Li Danni; Li Jinming; Guo Yanfang

    2014-01-01

    Background Alcohol dependence (AD) is a serious and common public health problem.The identification of genes that contribute to the AD variation will improve our understanding of the genetic mechanism underlying this complex disease.Previous genome-wide association studies (GWAS) and candidate gene genetic association studies identified individual genes as candidates for alcohol phenotypes,but efforts to generate an integrated view of accumulative genetic variants and pathways under alcohol drinking are lacking.Methods We applied enrichment gene set analysis to existing genetic association results to identify pertinent pathways to AD in this study.A total of 1 438 SNPs (P <1.0×10-3) associated to alcohol drinking related traits have been collected from 31 studies (10 candidate gene association studies,19 GWAS of SNPs,and 2 GWAS of copy number variants).Results Among all of the KEGG pathways,the calcium signaling pathway (hsa04020) showed the most significant enrichment of associations (21 genes) to alcohol consumption phenotypes (P=5.4×10-5).Furthermore,the calcium signaling pathway is the only pathway that turned out to be significant after multiple test adjustments,achieving Bonferroni P value of 0.8×10-3 and FDR value of 0.6×10-2,respectively.Interestingly,the calcium signaling pathway was previously found to be essential to regulate brain function,and genes in this pathway link to a depressive effect of alcohol consumption on the body.Conclusions Our findings,together with previous biological evidence,suggest the importance of gene polymorphisms of calcium signaling pathway to AD susceptibility.Still,further investigations are warranted to uncover the role of this pathway in AD and related traits.

  5. Use of logic theory in understanding regulatory pathway signaling in response to infection.

    Science.gov (United States)

    Watterson, Steven; Ghazal, Peter

    2010-02-01

    Biological pathways link the molecular and cellular levels of biological activity and perform complex information processing seamlessly. Systems biology aims to combine an understanding of the cause-effect relationships of each individual interaction to build an understanding of the function of whole pathways. Therapies that target the 'host' biological processes in infectious diseases are often limited to the use of vaccines and biologics rather than small molecules. The development of host drug targets for small molecules is constrained by a limited knowledge of the underlying role of each target, particularly its potential to cause harmful side effects after targeting. By considering the combinatorial complexity of pathways from the outset, we can develop modeling tools that are better suited to analyzing large pathways, enabling us to identify new causal relationships. This could lead to new drug target strategies that beneficially disrupt host-pathogen interactions, minimizing the number of side effects. We introduce logic theory as part of a pathway modeling approach that can provide a new framework for understanding pathways and refine 'host-based' drug target identification strategies.

  6. Standard biological parts knowledgebase.

    Science.gov (United States)

    Galdzicki, Michal; Rodriguez, Cesar; Chandran, Deepak; Sauro, Herbert M; Gennari, John H

    2011-02-24

    We have created the Knowledgebase of Standard Biological Parts (SBPkb) as a publically accessible Semantic Web resource for synthetic biology (sbolstandard.org). The SBPkb allows researchers to query and retrieve standard biological parts for research and use in synthetic biology. Its initial version includes all of the information about parts stored in the Registry of Standard Biological Parts (partsregistry.org). SBPkb transforms this information so that it is computable, using our semantic framework for synthetic biology parts. This framework, known as SBOL-semantic, was built as part of the Synthetic Biology Open Language (SBOL), a project of the Synthetic Biology Data Exchange Group. SBOL-semantic represents commonly used synthetic biology entities, and its purpose is to improve the distribution and exchange of descriptions of biological parts. In this paper, we describe the data, our methods for transformation to SBPkb, and finally, we demonstrate the value of our knowledgebase with a set of sample queries. We use RDF technology and SPARQL queries to retrieve candidate "promoter" parts that are known to be both negatively and positively regulated. This method provides new web based data access to perform searches for parts that are not currently possible.

  7. Standard biological parts knowledgebase.

    Directory of Open Access Journals (Sweden)

    Michal Galdzicki

    Full Text Available We have created the Knowledgebase of Standard Biological Parts (SBPkb as a publically accessible Semantic Web resource for synthetic biology (sbolstandard.org. The SBPkb allows researchers to query and retrieve standard biological parts for research and use in synthetic biology. Its initial version includes all of the information about parts stored in the Registry of Standard Biological Parts (partsregistry.org. SBPkb transforms this information so that it is computable, using our semantic framework for synthetic biology parts. This framework, known as SBOL-semantic, was built as part of the Synthetic Biology Open Language (SBOL, a project of the Synthetic Biology Data Exchange Group. SBOL-semantic represents commonly used synthetic biology entities, and its purpose is to improve the distribution and exchange of descriptions of biological parts. In this paper, we describe the data, our methods for transformation to SBPkb, and finally, we demonstrate the value of our knowledgebase with a set of sample queries. We use RDF technology and SPARQL queries to retrieve candidate "promoter" parts that are known to be both negatively and positively regulated. This method provides new web based data access to perform searches for parts that are not currently possible.

  8. The extracellular matrix of plants: Molecular, cellular and developmental biology

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-12-31

    A symposium entitled ``The Extracellular Matrix of Plants: Molecular, Cellular and Developmental Biology was held in Tamarron, Colorado, March 15--21, 1996. The following topics were explored in addresses by 43 speakers: structure and biochemistry of cell walls; biochemistry, molecular biology and biosynthesis of lignin; secretory pathway and synthesis of glycoproteins; biosynthesis of matrix polysaccharides, callose and cellulose; role of the extracellular matrix in plant growth and development; plant cell walls in symbiosis and pathogenesis.

  9. A case study in pathway knowledgebase verification

    Directory of Open Access Journals (Sweden)

    Shah Nigam H

    2006-04-01

    Full Text Available Abstract Background Biological databases and pathway knowledgebases are proliferating rapidly. We are developing software tools for computer-aided hypothesis design and evaluation, and we would like our tools to take advantage of the information stored in these repositories. But before we can reliably use a pathway knowledgebase as a data source, we need to proofread it to ensure that it can fully support computer-aided information integration and inference. Results We design a series of logical tests to detect potential problems we might encounter using a particular knowledgebase, the Reactome database, with a particular computer-aided hypothesis evaluation tool, HyBrow. We develop an explicit formal language from the language implicit in the Reactome data format and specify a logic to evaluate models expressed using this language. We use the formalism of finite model theory in this work. We then use this logic to formulate tests for desirable properties (such as completeness, consistency, and well-formedness for pathways stored in Reactome. We apply these tests to the publicly available Reactome releases (releases 10 through 14 and compare the results, which highlight Reactome's steady improvement in terms of decreasing inconsistencies. We also investigate and discuss Reactome's potential for supporting computer-aided inference tools. Conclusion The case study described in this work demonstrates that it is possible to use our model theory based approach to identify problems one might encounter using a knowledgebase to support hypothesis evaluation tools. The methodology we use is general and is in no way restricted to the specific knowledgebase employed in this case study. Future application of this methodology will enable us to compare pathway resources with respect to the generic properties such resources will need to possess if they are to support automated reasoning.

  10. PLANT ISOFLAVONES: BIOSYNHTESIS, DETECTION AND BIOLOGICAL PROPERTIES

    Directory of Open Access Journals (Sweden)

    V. D. Naumenko

    2013-10-01

    Full Text Available Biological properties, chemical structures and biosynthesis pathways of plant isoflavones, especially soybean isoflavones (daidzein, genistein and glycitein are reviewed. The structures of isoflavones, and their aglicone and glucosides (glycosides forms as well as isoflavone biosynthesis pathways are described. General information about the advanced methods for the detection of isoflavones and their conjugates are considered. The importance of the profiling of isoflavones, flavonoids and their conjugates by means of analytical tools and methods to dissolve some questions in biology and medicine is discussed. The review provides data on the major isoflavone content in some vegetable crops and in the tissues of different soybean varieties. Health benefits and treatment or preventive properties of isoflavones for cancer, cardiovascular, endocrine diseases and metabolic disorders are highlighted. The mechanisms that may explain their positive biological effects are considered. The information on the application of advanced technologies to create new plant forms producing isoflavonoids with a predicted level of isoflavones, which is the most favorable for the treatment is given. The possibilities to use the metabolic engineering for the increasing of accumulation and synthesis of isoflavones at the non-legume crops such as tobacco, Arabidopsis and maize are considered. The examples how the plant tissues, which are not naturally produced of the isoflavones, can obtain potential for the synthesis of biologically active compounds via inducing of the activity of the introduced enzyme isoflavon synthase, are given. Specific biochemical pathways for increasing the synthesis of isoflavone genistein in Arabidopsis thaliana tissues are discussed. It is concluded that plant genetic engineering which is focused on modification of the secondary metabolites contain in plant tissues, enables to create the new crop varieties with improved agronomic properties and

  11. Biology of Healthy Aging and Longevity.

    Science.gov (United States)

    Carmona, Juan José; Michan, Shaday

    2016-01-01

    As human life expectancy is prolonged, age-related diseases are thriving. Aging is a complex multifactorial process of molecular and cellular decline that affects tissue function over time, rendering organisms frail and susceptible to disease and death. Over the last decades, a growing body of scientific literature across different biological models, ranging from yeast, worms, flies, and mice to primates, humans and other long-lived animals, has contributed greatly towards identifying conserved biological mechanisms that ward off structural and functional deterioration within living systems. Collectively, these data offer powerful insights into healthy aging and longevity. For example, molecular integrity of the genome, telomere length, epigenetic landscape stability, and protein homeostasis are all features linked to "youthful" states. These molecular hallmarks underlie cellular functions associated with aging like mitochondrial fitness, nutrient sensing, efficient intercellular communication, stem cell renewal, and regenerative capacity in tissues. At present, calorie restriction remains the most robust strategy for extending health and lifespan in most biological models tested. Thus, pathways that mediate the beneficial effects of calorie restriction by integrating metabolic signals to aging processes have received major attention, such as insulin/insulin growth factor-1, sirtuins, mammalian target of rapamycin, and 5' adenosine monophosphate-activated protein kinase. Consequently, small-molecule targets of these pathways have emerged in the impetuous search for calorie restriction mimetics, of which resveratrol, metformin, and rapamycin are the most extensively studied. A comprehensive understanding of the molecular and cellular mechanisms that underlie age-related deterioration and repair, and how these pathways interconnect, remains a major challenge for uncovering interventions to slow human aging while extending molecular and physiological youthfulness

  12. Allicin: Chemistry and Biological Properties

    Directory of Open Access Journals (Sweden)

    Jan Borlinghaus

    2014-08-01

    Full Text Available Allicin (diallylthiosulfinate is a defence molecule from garlic (Allium sativum L. with a broad range of biological activities. Allicin is produced upon tissue damage from the non-proteinogenic amino acid alliin (S-allylcysteine sulfoxide in a reaction that is catalyzed by the enzyme alliinase. Current understanding of the allicin biosynthetic pathway will be presented in this review. Being a thiosulfinate, allicin is a reactive sulfur species (RSS and undergoes a redox-reaction with thiol groups in glutathione and proteins that is thought to be essential for its biological activity. Allicin is physiologically active in microbial, plant and mammalian cells. In a dose-dependent manner allicin can inhibit the proliferation of both bacteria and fungi or kill cells outright, including antibiotic-resistant strains like methicillin-resistant Staphylococcus aureus (MRSA. Furthermore, in mammalian cell lines, including cancer cells, allicin induces cell-death and inhibits cell proliferation. In plants allicin inhibits seed germination and attenuates root-development. The majority of allicin’s effects are believed to be mediated via redox-dependent mechanisms. In sub-lethal concentrations, allicin has a variety of health-promoting properties, for example cholesterol- and blood pressure-lowering effects that are advantageous for the cardio-vascular system. Clearly, allicin has wide-ranging and interesting applications in medicine and (green agriculture, hence the detailed discussion of its enormous potential in this review. Taken together, allicin is a fascinating biologically active compound whose properties are a direct consequence of the molecule’s chemistry.

  13. Pathways to Global Markets

    DEFF Research Database (Denmark)

    Smith, David E.; Mitry, Darryl J.

    2011-01-01

    . An important case study is McDonald‘s corporation, the world‘s largest fast food restaurant chain. This company has employed divergent marketing and economic strategies in both domestic and the international markets to become a leader in the global marketplace. An overview of the company‘s background......, organizational structures, mission and vision illustrate McDonald‘s strategic focus on its proactive evolution from a small drive-through operation to a global fast-food giant. The strategy is based on its ability to adapt to the cultural differences of the markets that McDonald‘s serves while preserving its......For marketing and economic researchers, an important aspect of globalization is the degree to which various consumer behavior dimensions and consumption patterns in different parts of the world are becoming similar, and how multinational companies have identified pathways to global success...

  14. Branching processes in biology

    CERN Document Server

    Kimmel, Marek

    2015-01-01

    This book provides a theoretical background of branching processes and discusses their biological applications. Branching processes are a well-developed and powerful set of tools in the field of applied probability. The range of applications considered includes molecular biology, cellular biology, human evolution and medicine. The branching processes discussed include Galton-Watson, Markov, Bellman-Harris, Multitype, and General Processes. As an aid to understanding specific examples, two introductory chapters, and two glossaries are included that provide background material in mathematics and in biology. The book will be of interest to scientists who work in quantitative modeling of biological systems, particularly probabilists, mathematical biologists, biostatisticians, cell biologists, molecular biologists, and bioinformaticians. The authors are a mathematician and cell biologist who have collaborated for more than a decade in the field of branching processes in biology for this new edition. This second ex...

  15. A literature mining-based approach for identification of cellular pathways associated with chemoresistance in cancer.

    Science.gov (United States)

    Oh, Jung Hun; Deasy, Joseph O

    2016-05-01

    Chemoresistance is a major obstacle to the successful treatment of many human cancer types. Increasing evidence has revealed that chemoresistance involves many genes and multiple complex biological mechanisms including cancer stem cells, drug efflux mechanism, autophagy and epithelial-mesenchymal transition. Many studies have been conducted to investigate the possible molecular mechanisms of chemoresistance. However, understanding of the biological mechanisms in chemoresistance still remains limited. We surveyed the literature on chemoresistance-related genes and pathways of multiple cancer types. We then used a curated pathway database to investigate significant chemoresistance-related biological pathways. In addition, to investigate the importance of chemoresistance-related markers in protein-protein interaction networks identified using the curated database, we used a gene-ranking algorithm designed based on a graph-based scoring function in our previous study. Our comprehensive survey and analysis provide a systems biology-based overview of the underlying mechanisms of chemoresistance.

  16. Chemical Biology is.....

    OpenAIRE

    2007-01-01

    Chemical Biology is a relatively new field, and as such is not yet simply or succinctly defined. It includes such a wide range of fundamental problems that this commentary could only include just a few snapshots of potential areas of interest. Overarching themes and selected recent successes and ideas in chemical biology are described to illustrate broadly the scope of the field, but should not be taken as exhaustive. The Chemical Biology Section of Chemistry Central Journal is pleased to rec...

  17. Biological detector and method

    Energy Technology Data Exchange (ETDEWEB)

    Sillerud, Laurel; Alam, Todd M.; McDowell, Andrew F.

    2015-11-24

    A biological detector includes a conduit for receiving a fluid containing one or more magnetic nanoparticle-labeled, biological objects to be detected and one or more permanent magnets or electromagnet for establishing a low magnetic field in which the conduit is disposed. A microcoil is disposed proximate the conduit for energization at a frequency that permits detection by NMR spectroscopy of whether the one or more magnetically-labeled biological objects is/are present in the fluid.

  18. Biological detector and method

    Science.gov (United States)

    Sillerud, Laurel; Alam, Todd M; McDowell, Andrew F

    2014-04-15

    A biological detector includes a conduit for receiving a fluid containing one or more magnetic nanoparticle-labeled, biological objects to be detected and one or more permanent magnets or electromagnet for establishing a low magnetic field in which the conduit is disposed. A microcoil is disposed proximate the conduit for energization at a frequency that permits detection by NMR spectroscopy of whether the one or more magnetically-labeled biological objects is/are present in the fluid.

  19. Biological Individuality of Man

    Science.gov (United States)

    1974-12-01

    RECIPIENT’S CAT * LOO NUMBER Biological Individuality of Man 5 TlrPE OF REPORT a PERIOD COVERED Technical « PERFORMING ORO REPORT...Variability 13 A. Background , 13 B. Slatistictl Approaches to Biological Variability 13 C. Genetic Aspects of Biological Variability . 14 III...ioiological determinants of individuality. Only recently, have genetic infaienccs been investigated and the potentialities for future control of bio

  20. Biological detector and method

    Science.gov (United States)

    Sillerud, Laurel; Alam, Todd M; McDowell, Andrew F

    2013-02-26

    A biological detector includes a conduit for receiving a fluid containing one or more magnetic nanoparticle-labeled, biological objects to be detected and one or more permanent magnets or electromagnet for establishing a low magnetic field in which the conduit is disposed. A microcoil is disposed proximate the conduit for energization at a frequency that permits detection by NMR spectroscopy of whether the one or more magnetically-labeled biological objects is/are present in the fluid.

  1. Gene expression meta-analysis identifies metastatic pathways and transcription factors in breast cancer

    DEFF Research Database (Denmark)

    Thomassen, Mads; Tan, Qihua; Kruse, Torben

    2008-01-01

    tumors compared to non-metastasizing tumors. Meta-analysis has been used to determine overrepresentation of pathways and transcription factors targets, concordant deregulated in metastasizing breast tumors, in several data sets. RESULTS: The major findings are upregulation of cell cycle pathways...... system, angiogenesis, DNA repair and several signal transduction pathways are associated to metastasis. Finally several transcription factors e.g. E2F, NFY, and YY1 are identified as being involved in metastasis. CONCLUSIONS: By pathway meta-analysis many biological mechanisms beyond major...... studies. Besides classification of outcome, these global expression patterns may reflect biological mechanisms involved in metastasis of breast cancer. Our purpose has been to investigate pathways and transcription factors involved in metastasis by use of gene expression data sets. METHODS: We have...

  2. KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases.

    Science.gov (United States)

    Xie, Chen; Mao, Xizeng; Huang, Jiaju; Ding, Yang; Wu, Jianmin; Dong, Shan; Kong, Lei; Gao, Ge; Li, Chuan-Yun; Wei, Liping

    2011-07-01

    High-throughput experimental technologies often identify dozens to hundreds of genes related to, or changed in, a biological or pathological process. From these genes one wants to identify biological pathways that may be involved and diseases that may be implicated. Here, we report a web server, KOBAS 2.0, which annotates an input set of genes with putative pathways and disease relationships based on mapping to genes with known annotations. It allows for both ID mapping and cross-species sequence similarity mapping. It then performs statistical tests to identify statistically significantly enriched pathways and diseases. KOBAS 2.0 incorporates knowledge across 1327 species from 5 pathway databases (KEGG PATHWAY, PID, BioCyc, Reactome and Panther) and 5 human disease databases (OMIM, KEGG DISEASE, FunDO, GAD and NHGRI GWAS Catalog). KOBAS 2.0 can be accessed at http://kobas.cbi.pku.edu.cn.

  3. A binary classifier for prediction of the types of metabolic pathway of chemicals.

    Science.gov (United States)

    Fang, Yemin; Chen, Lei

    2016-12-15

    The study of metabolic pathway is one of the most important fields in biochemistry. Good comprehension of the metabolic pathway system is helpful to uncover the mechanism of some fundamental biological processes. Because chemicals are part of the main components of the metabolic pathway, correct identification of which metabolic pathways a given chemical can participate in is an important step for understanding the metabolic pathway system. Most previous methods only considered the chemical information, which tried to deal with a multi-label classification problem of assigning chemicals to proper metabolic pathways. In this study, the pathway information was also employed, thereby transforming the problem into a binary classification problem of identifying the pair of chemicals and metabolic pathways, i.e., a chemical and a metabolic pathway was paired as a sample to be considered in this study. To construct the prediction model, the association between chemical pathway type pairs was evaluated by integrating the association between chemicals and association between pathway types. The support vector machine was adopted as the prediction engine. The extensive tests show that the constructed model yields good performance with total prediction accuracy around 0.878. Furthermore, the comparison results indicate that our model is quite effective and suitable for the identification of whether a given chemical can participate in a given metabolic pathway.

  4. SPATIAL: A System-level PAThway Impact AnaLysis approach

    Science.gov (United States)

    Bokanizad, Behzad; Tagett, Rebecca; Ansari, Sahar; Helmi, B. Hoda; Draghici, Sorin

    2016-01-01

    The goal of pathway analysis is to identify the pathways that are significantly impacted when a biological system is perturbed, e.g. by a disease or drug. Current methods treat pathways as independent entities. However, many signals are constantly sent from one pathway to another, essentially linking all pathways into a global, system-wide complex. In this work, we propose a set of three pathway analysis methods based on the impact analysis, that performs a system-level analysis by considering all signals between pathways, as well as their overlaps. Briefly, the global system is modeled in two ways: (i) considering the inter-pathway interaction exchange for each individual pathways, and (ii) combining all individual pathways to form a global, system-wide graph. The third analysis method is a hybrid of these two models. The new methods were compared with DAVID, GSEA, GSA, PathNet, Crosstalk and SPIA on 23 GEO data sets involving 19 tissues investigated in 12 conditions. The results show that both the ranking and the P-values of the target pathways are substantially improved when the analysis considers the system-wide dependencies and interactions between pathways. PMID:27193997

  5. Chemical space and biology.

    Science.gov (United States)

    Dobson, Christopher M

    2004-12-16

    Chemical space--which encompasses all possible small organic molecules, including those present in biological systems--is vast. So vast, in fact, that so far only a tiny fraction of it has been explored. Nevertheless, these explorations have greatly enhanced our understanding of biology, and have led to the development of many of today's drugs. The discovery of new bioactive molecules, facilitated by a deeper understanding of the nature of the regions of chemical space that are relevant to biology, will advance our knowledge of biological processes and lead to new strategies to treat disease.

  6. Polythiophenes in biological applications.

    Science.gov (United States)

    Sista, Prakash; Ghosh, Koushik; Martinez, Jennifer S; Rocha, Reginaldo C

    2014-01-01

    Polythiophene and its derivatives have shown tremendous potential for interfacing electrically conducting polymers with biological applications. These semiconducting organic polymers are relatively soft, conduct electrons and ions, have low cytotoxicity, and can undergo facile chemical modifications. In addition, the reduction in electrical impedance of electrodes coated with polythiophenes may prove to be invaluable for a stable and permanent connection between devices and biological tissues. This review article focuses on the synthesis and some key applications of polythiophenes in multidisciplinary areas at the interface with biology. These polymers have shown tremendous potential in biological applications such as diagnostics, therapy, drug delivery, imaging, implant devices and artificial organs.

  7. An overview of the non-mevalonate pathway for terpenoid biosynthesis in plants

    Indian Academy of Sciences (India)

    Vinod Shanker Dubey; Ritu Bhalla; Rajesh Luthra

    2003-09-01

    Terpenoids are known to have many important biological and physiological functions. Some of them are also known for their pharmaceutical significance. In the late nineties after the discovery of a novel non-mevalonate (non-MVA) pathway, the whole concept of terpenoid biosynthesis has changed. In higher plants, the conventional acetate-mevalonate (Ac-MVA) pathway operates mainly in the cytoplasm and mitochondria and synthesizes sterols, sesquiterpenes and ubiquinones predominantly. The plastidic non-MVA pathway however synthesizes hemi-, mono-, sesqui- and di-terpenes, along with carotenoids and phytol chain of chlorophyll. In this paper, recent developments on terpenoids biosynthesis are reviewed with respect to the non-MVA pathway.

  8. Modelling and simulation of signal transductions in an apoptosis pathway by using timed Petri nets

    Indian Academy of Sciences (India)

    Chen Li; Qi-Wei Ge; Mitsuru Nakata; Hiroshi Matsuno; Satoru Miyano

    2007-01-01

    This paper first presents basic Petri net components representing molecular interactions and mechanisms of signalling pathways, and introduces a method to construct a Petri net model of a signalling pathway with these components. Then a simulation method of determining the delay time of transitions, by using timed Petri nets – i.e. the time taken in firing of each transition – is proposed based on some simple principles that the number of tokens flowed into a place is equivalent to the number of tokens flowed out. Finally, the availability of proposed method is confirmed by observing signalling transductions in biological pathways through simulation experiments of the apoptosis signalling pathways as an example.

  9. Systems biology of ageing and longevity.

    Science.gov (United States)

    Kirkwood, Thomas B L

    2011-01-12

    Ageing is intrinsically complex, being driven by multiple causal mechanisms. Each mechanism tends to be partially supported by data indicating that it has a role in the overall cellular and molecular pathways underlying the ageing process. However, the magnitude of this role is usually modest. The systems biology approach combines (i) data-driven modelling, often using the large volumes of data generated by functional genomics technologies, and (ii) hypothesis-driven experimental studies to investigate causal pathways and identify their parameter values in an unusually quantitative manner, which enables the contributions of individual mechanisms and their interactions to be better understood, and allows for the design of experiments explicitly to test the complex predictions arising from such models. A clear example of the success of the systems biology approach in unravelling the complexity of ageing can be seen in recent studies on cell replicative senescence, revealing interactions between mitochondrial dysfunction, telomere erosion and DNA damage. An important challenge also exists in connecting the network of (random) damage-driven proximate mechanisms of ageing with the higher level (genetically specified) signalling pathways that influence longevity. This connection is informed by actions of natural selection on the determinants of ageing and longevity.

  10. The biology of cancer stem cells.

    Science.gov (United States)

    Lobo, Neethan A; Shimono, Yohei; Qian, Dalong; Clarke, Michael F

    2007-01-01

    Cancers originally develop from normal cells that gain the ability to proliferate aberrantly and eventually turn malignant. These cancerous cells then grow clonally into tumors and eventually have the potential to metastasize. A central question in cancer biology is, which cells can be transformed to form tumors? Recent studies elucidated the presence of cancer stem cells that have the exclusive ability to regenerate tumors. These cancer stem cells share many characteristics with normal stem cells, including self-renewal and differentiation. With the growing evidence that cancer stem cells exist in a wide array of tumors, it is becoming increasingly important to understand the molecular mechanisms that regulate self-renewal and differentiation because corruption of genes involved in these pathways likely participates in tumor growth. This new paradigm of oncogenesis has been validated in a growing list of tumors. Studies of normal and cancer stem cells from the same tissue have shed light on the ontogeny of tumors. That signaling pathways such as Bmi1 and Wnt have similar effects in normal and cancer stem cell self-renewal suggests that common molecular pathways regulate both populations. Understanding the biology of cancer stem cells will contribute to the identification of molecular targets important for future therapies.

  11. WISB: Warwick Integrative Synthetic Biology Centre.

    Science.gov (United States)

    McCarthy, John

    2016-06-15

    Synthetic biology promises to create high-impact solutions to challenges in the areas of biotechnology, human/animal health, the environment, energy, materials and food security. Equally, synthetic biologists create tools and strategies that have the potential to help us answer important fundamental questions in biology. Warwick Integrative Synthetic Biology (WISB) pursues both of these mutually complementary 'build to apply' and 'build to understand' approaches. This is reflected in our research structure, in which a core theme on predictive biosystems engineering develops underpinning understanding as well as next-generation experimental/theoretical tools, and these are then incorporated into three applied themes in which we engineer biosynthetic pathways, microbial communities and microbial effector systems in plants. WISB takes a comprehensive approach to training, education and outreach. For example, WISB is a partner in the EPSRC/BBSRC-funded U.K. Doctoral Training Centre in synthetic biology, we have developed a new undergraduate module in the subject, and we have established five WISB Research Career Development Fellowships to support young group leaders. Research in Ethical, Legal and Societal Aspects (ELSA) of synthetic biology is embedded in our centre activities. WISB has been highly proactive in building an international research and training network that includes partners in Barcelona, Boston, Copenhagen, Madrid, Marburg, São Paulo, Tartu and Valencia.

  12. Hyperpolarized NMR Probes for Biological Assays

    Directory of Open Access Journals (Sweden)

    Sebastian Meier

    2014-01-01

    Full Text Available During the last decade, the development of nuclear spin polarization enhanced (hyperpolarized molecular probes has opened up new opportunities for studying the inner workings of living cells in real time. The hyperpolarized probes are produced ex situ, introduced into biological systems and detected with high sensitivity and contrast against background signals using high resolution NMR spectroscopy. A variety of natural, derivatized and designed hyperpolarized probes has emerged for diverse biological studies including assays of intracellular reaction progression, pathway kinetics, probe uptake and export, pH, redox state, reactive oxygen species, ion concentrations, drug efficacy or oncogenic signaling. These probes are readily used directly under natural conditions in biofluids and are often directly developed and optimized for cellular assays, thus leaving little doubt about their specificity and utility under biologically relevant conditions. Hyperpolarized molecular probes for biological NMR spectroscopy enable the unbiased detection of complex processes by virtue of the high spectral resolution, structural specificity and quantifiability of NMR signals. Here, we provide a survey of strategies used for the selection, design and use of hyperpolarized NMR probes in biological assays, and describe current limitations and developments.

  13. Measuring the evolutionary rewiring of biological networks.

    Directory of Open Access Journals (Sweden)

    Chong Shou

    Full Text Available 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.

  14. Systems Biology for Organotypic Cell Cultures

    Energy Technology Data Exchange (ETDEWEB)

    Grego, Sonia [RTI International, Research Triangle Park, NC (United States); Dougherty, Edward R. [Texas A & M Univ., College Station, TX (United States); Alexander, Francis J. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Auerbach, Scott S. [National Inst. of Environmental Health Sciences, Research Triangle Park, NC (United States); Berridge, Brian R. [GlaxoSmithKline, Research Triangle Park, NC (United States); Bittner, Michael L. [Translational Genomics Research Inst., Phoenix, AZ (United States); Casey, Warren [National Inst. of Environmental Health Sciences, Research Triangle Park, NC (United States); Cooley, Philip C. [RTI International, Research Triangle Park, NC (United States); Dash, Ajit [HemoShear Therapeutics, Charlottesville, VA (United States); Ferguson, Stephen S. [National Inst. of Environmental Health Sciences, Research Triangle Park, NC (United States); Fennell, Timothy R. [RTI International, Research Triangle Park, NC (United States); Hawkins, Brian T. [RTI International, Research Triangle Park, NC (United States); Hickey, Anthony J. [RTI International, Research Triangle Park, NC (United States); Kleensang, Andre [Johns Hopkins Univ., Baltimore, MD (United States). Center for Alternatives to Animal Testing; Liebman, Michael N. [IPQ Analytics, Kennett Square, PA (United States); Martin, Florian [Phillip Morris International, Neuchatel (Switzerland); Maull, Elizabeth A. [National Inst. of Environmental Health Sciences, Research Triangle Park, NC (United States); Paragas, Jason [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Qiao, Guilin [Defense Threat Reduction Agency, Ft. Belvoir, VA (United States); Ramaiahgari, Sreenivasa [National Inst. of Environmental Health Sciences, Research Triangle Park, NC (United States); Sumner, Susan J. [RTI International, Research Triangle Park, NC (United States); Yoon, Miyoung [The Hamner Inst. for Health Sciences, Research Triangle Park, NC (United States); ScitoVation, Research Triangle Park, NC (United States)

    2016-08-04

    Translating in vitro biological data into actionable information related to human health holds the potential to improve disease treatment and risk assessment of chemical exposures. While genomics has identified regulatory pathways at the cellular level, translation to the organism level requires a multiscale approach accounting for intra-cellular regulation, inter-cellular interaction, and tissue/organ-level effects. Tissue-level effects can now be probed in vitro thanks to recently developed systems of three-dimensional (3D), multicellular, “organotypic” cell cultures, which mimic functional responses of living tissue. However, there remains a knowledge gap regarding interactions across different biological scales, complicating accurate prediction of health outcomes from molecular/genomic data and tissue responses. Systems biology aims at mathematical modeling of complex, non-linear biological systems. We propose to apply a systems biology approach to achieve a computational representation of tissue-level physiological responses by integrating empirical data derived from organotypic culture systems with computational models of intracellular pathways to better predict human responses. Successful implementation of this integrated approach will provide a powerful tool for faster, more accurate and cost-effective screening of potential toxicants and therapeutics. On September 11, 2015, an interdisciplinary group of scientists, engineers, and clinicians gathered for a workshop in Research Triangle Park, North Carolina, to discuss this ambitious goal. Participants represented laboratory-based and computational modeling approaches to pharmacology and toxicology, as well as the pharmaceutical industry, government, non-profits, and academia. Discussions focused on identifying critical system perturbations to model, the computational tools required, and the experimental approaches best suited to generating key data. This consensus report summarizes the discussions held.

  15. Pathway-based analysis tools for complex diseases: a review.

    Science.gov (United States)

    Jin, Lv; Zuo, Xiao-Yu; Su, Wei-Yang; Zhao, Xiao-Lei; Yuan, Man-Qiong; Han, Li-Zhen; Zhao, Xiang; Chen, Ye-Da; Rao, Shao-Qi

    2014-10-01

    Genetic studies are traditionally based on single-gene analysis. The use of these analyses can pose tremendous challenges for elucidating complicated genetic interplays involved in complex human diseases. Modern pathway-based analysis provides a technique, which allows a comprehensive understanding of the molecular mechanisms underlying complex diseases. Extensive studies utilizing the methods and applications for pathway-based analysis have significantly advanced our capacity to explore large-scale omics data, which has rapidly accumulated in biomedical fields. This article is a comprehensive review of the pathway-based analysis methods-the powerful methods with the potential to uncover the biological depths of the complex diseases. The general concepts and procedures for the pathway-based analysis methods are introduced and then, a comprehensive review of the major approaches for this analysis is presented. In addition, a list of available pathway-based analysis software and databases is provided. Finally, future directions and challenges for the methodological development and applications of pathway-based analysis techniques are discussed. This review will provide a useful guide to dissect complex diseases.

  16. Pathway-based Analysis Tools for Complex Diseases: A Review

    Directory of Open Access Journals (Sweden)

    Lv Jin

    2014-10-01

    Full Text Available Genetic studies are traditionally based on single-gene analysis. The use of these analyses can pose tremendous challenges for elucidating complicated genetic interplays involved in complex human diseases. Modern pathway-based analysis provides a technique, which allows a comprehensive understanding of the molecular mechanisms underlying complex diseases. Extensive studies utilizing the methods and applications for pathway-based analysis have significantly advanced our capacity to explore large-scale omics data, which has rapidly accumulated in biomedical fields. This article is a comprehensive review of the pathway-based analysis methods—the powerful methods with the potential to uncover the biological depths of the complex diseases. The general concepts and procedures for the pathway-based analysis methods are introduced and then, a comprehensive review of the major approaches for this analysis is presented. In addition, a list of available pathway-based analysis software and databases is provided. Finally, future directions and challenges for the methodological development and applications of pathway-based analysis techniques are discussed. This review will provide a useful guide to dissect complex diseases.

  17. Biology Library Workbook.

    Science.gov (United States)

    Miller, Constance; And Others

    A library skills workbook provides college biology students with an introduction to biological library resources. Divided into two sections, the first contains explanations of the various steps in the library research process. The second consists of exercises keyed to the explanatory chapters of the first section. (RAA)

  18. Homosexuality, biology, and ideology.

    Science.gov (United States)

    Haumann, G

    1995-01-01

    This paper critically examines the complex relationships and interdependencies between biological theories on homosexuality and sociosexual ideologies. It challenges the privileged status of biology as the ultimate authority on homosexuality. This status is based on the belief that biology is a value-free science. On the contrary, this essay shows how unacknowledged assumptions and culturally bound patterns of thinking about sexuality taint biological research. Sociosexual ideologies are defined as principles that organize the ways we express our sexualities and the way we theorize about them in biology. The following ideologies are identified: (1) sexuality-as-heterosexuality, (2) sexuality-as-reproduction, (3) sexual dualism (male vs. female), and (4) the view the homosexuality is a sexual inversion. The process by which these ideologies are incorporated into biology is two-fold: (1) as a projective act from society onto nature and (2) as a reflective act from nature back into society. It is further argued that biological knowledge of homosexuality resulting from that process can be used for diverse political interests. Finally, it is proposed that since biological theories on homosexuality are inseparable from the context of their paradigmatic origin, it is possible that new theories could be derived from new ideologies.

  19. Psoriasis : implications of biologics

    NARCIS (Netherlands)

    Lecluse, L.L.A.

    2010-01-01

    Since the end of 2004 several specific immunomodulating therapies: ‘biologic response modifiers’ or ‘biologics’ have been registered for moderate to severe psoriasis in Europe. This thesis is considering the implications of the introduction of the biologics for psoriasis patients, focusing on safety

  20. Biological Macromolecule Crystallization Database

    Science.gov (United States)

    SRD 21 Biological Macromolecule Crystallization Database (Web, free access)   The Biological Macromolecule Crystallization Database and NASA Archive for Protein Crystal Growth Data (BMCD) contains the conditions reported for the crystallization of proteins and nucleic acids used in X-ray structure determinations and archives the results of microgravity macromolecule crystallization studies.

  1. Experimenting with Mathematical Biology

    Science.gov (United States)

    Sanft, Rebecca; Walter, Anne

    2016-01-01

    St. Olaf College recently added a Mathematical Biology concentration to its curriculum. The core course, Mathematics of Biology, was redesigned to include a wet laboratory. The lab classes required students to collect data and implement the essential modeling techniques of formulation, implementation, validation, and analysis. The four labs…

  2. Introduction to systems biology

    NARCIS (Netherlands)

    Bruggeman, F.J.; Hornberg, J.J.; Boogerd, F.C.; Westerhoff, H.V.; Boogerd, F.C.; Bruggeman, F.J.; Hofmeyr, J.H.S.; Westerhoff, H.V.

    2007-01-01

    The developments in the molecular biosciences have made possible a shift to combined molecular and system-level approaches to biological research under the name of Systems Biology. It integrates many types of molecular knowledge, which can best be achieved by the synergistic use of models and experi

  3. Frontiers in mathematical biology

    CERN Document Server

    1994-01-01

    Volume 100, which is the final volume of the LNBM series serves to commemorate the acievements in two decades of this influential collection of books in mathematical biology. The contributions, by the leading mathematical biologists, survey the state of the art in the subject, and offer speculative, philosophical and critical analyses of the key issues confronting the field. The papers address fundamental issues in cell and molecular biology, organismal biology, evolutionary biology, population ecology, community and ecosystem ecology, and applied biology, plus the explicit and implicit mathematical challenges. Cross-cuttting issues involve the problem of variation among units in nonlinear systems, and the related problems of the interactions among phenomena across scales of space, time and organizational complexity.

  4. Space biology research development

    Science.gov (United States)

    Bonting, Sjoerd L.

    1993-01-01

    The purpose of the Search for Extraterrestrial Intelligence (SETI) Institute is to conduct and promote research related activities regarding the search for extraterrestrial life, particularly intelligent life. Such research encompasses the broad discipline of 'Life in the Universe', including all scientific and technological aspects of astronomy and the planetary sciences, chemical evolution, the origin of life, biological evolution, and cultural evolution. The primary purpose was to provide funding for the Principal Investigator to collaborate with the personnel of the SETI Institute and the NASA-Ames Research center in order to plan and develop space biology research on and in connection with Space Station Freedom; to promote cooperation with the international partners in the space station; to conduct a study on the use of biosensors in space biology research and life support system operation; and to promote space biology research through the initiation of an annual publication 'Advances in Space Biology and Medicine'.

  5. Optics of Biological Particles

    CERN Document Server

    Hoekstra, Alfons; Videen, Gorden

    2007-01-01

    This book covers the optics of single biological particles, both theory and experiment, with emphasis on Elastic Light Scattering and Fluorescence. It deals with the optics of bacteria (bio-aerosols), marine particles (selected phytoplankton communities) and red and white blood cells. Moreover, there are dedicated chapters on a general theory for scattering by a cell, and modelling and simulation of scattering by inhomogeneous biological cells. Finally, one chapter is dedicated to astro-biological signatures, discussing the possibilities for detecting non-terrestrial biological material. The volume has up-to-date discussions on new experimental and numerical techniques, and many examples of applications of these techniques in real-life systems, as used to detect and characterize e.g. biological warfare agents or human blood cells.

  6. Biological sample collector

    Science.gov (United States)

    Murphy, Gloria A.

    2010-09-07

    A biological sample collector is adapted to a collect several biological samples in a plurality of filter wells. A biological sample collector may comprise a manifold plate for mounting a filter plate thereon, the filter plate having a plurality of filter wells therein; a hollow slider for engaging and positioning a tube that slides therethrough; and a slide case within which the hollow slider travels to allow the tube to be aligned with a selected filter well of the plurality of filter wells, wherein when the tube is aligned with the selected filter well, the tube is pushed through the hollow slider and into the selected filter well to sealingly engage the selected filter well and to allow the tube to deposit a biological sample onto a filter in the bottom of the selected filter well. The biological sample collector may be portable.

  7. Co-production of hydrogen and ethanol from glucose by modification of glycolytic pathways in Escherichia coli - from Embden-Meyerhof-Parnas pathway to pentose phosphate pathway.

    Science.gov (United States)

    Seol, Eunhee; Sekar, Balaji Sundara; Raj, Subramanian Mohan; Park, Sunghoon

    2016-02-01

    Hydrogen (H2) production from glucose by dark fermentation suffers from the low yield. As a solution to this problem, co-production of H2 and ethanol, both of which are good biofuels, has been suggested. To this end, using Escherichia coli, activation of pentose phosphate (PP) pathway, which can generate more NADPH than the Embden-Meyhof-Parnas (EMP) pathway, was attempted. Overexpression of two key enzymes in the branch nodes of the glycolytic pathway, Zwf and Gnd, significantly improved the co-production of H2 and ethanol with concomitant reduction of pyruvate secretion. Gene expression analysis and metabolic flux analysis (MFA) showed that, upon overexpression of Zwf and Gnd, glucose assimilation through the PP pathway, compared with that of the EMP or Entner-Doudoroff (ED) pathway, was greatly enhanced. The maximum co-production yields were 1.32 mol H2 mol(-1) glucose and 1.38 mol ethanol mol(-1) glucose, respectively. It is noteworthy that the glycolysis and the amount of NAD(P)H formed under anaerobic conditions could be altered by modifying (the activity of) several key enzymes. Our strategy could be applied for the development of industrial strains for biological production of reduced chemicals and biofuels which suffers from lack of reduced co-factors.

  8. Applied Developmental Biology: Making Human Pancreatic Beta Cells for Diabetics.

    Science.gov (United States)

    Melton, Douglas A

    2016-01-01

    Understanding the genes and signaling pathways that determine the differentiation and fate of a cell is a central goal of developmental biology. Using that information to gain mastery over the fates of cells presents new approaches to cell transplantation and drug discovery for human diseases including diabetes.

  9. Evolution of the TOR Pathway.

    NARCIS (Netherlands)

    Dam, T.J.P. van; Zwartkruis, F.J.; Bos, J.L.; Snel, B.

    2011-01-01

    The TOR kinase is a major regulator of growth in eukaryotes. Many components of the TOR pathway are implicated in cancer and metabolic diseases in humans. Analysis of the evolution of TOR and its pathway may provide fundamental insight into the evolution of growth regulation in eukaryotes and provid

  10. Autism: Many Genes, Common Pathways?

    OpenAIRE

    Geschwind, Daniel H.

    2008-01-01

    Autism is a heterogeneous neurodevelopmental syndrome with a complex genetic etiology. It is still not clear whether autism comprises a vast collection of different disorders akin to intellectual disability or a few disorders sharing common aberrant pathways. Unifying principles among cases of autism are likely to be at the level of brain circuitry in addition to molecular pathways.

  11. Autism: many genes, common pathways?

    Science.gov (United States)

    Geschwind, Daniel H

    2008-10-31

    Autism is a heterogeneous neurodevelopmental syndrome with a complex genetic etiology. It is still not clear whether autism comprises a vast collection of different disorders akin to intellectual disability or a few disorders sharing common aberrant pathways. Unifying principles among cases of autism are likely to be at the level of brain circuitry in addition to molecular pathways.

  12. Biogenetic Pathways for Marine Terpenoids

    Institute of Scientific and Technical Information of China (English)

    郑其煌; 苏镜娱; 黄起鹏; 王植材; 刘璇; 高碧; 曾陇梅; 郑德炫

    1994-01-01

    A reasonable theoretical elucidation of biogenetic pathways is given for marine ter-penoids——halogenated terpenoids,cernbranolides and tetracyclic tetraterpenoids in marine organisms ac-cording to biogenesis,and the possibility of studying biogenetic pathways by chemical synthesis and molecu-lar probe method is discussed.

  13. Novel protein regulates ERK pathway

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ The ERK (extracellular signal-regulated kinase) pathway plays a critical role in the vital processes of living cells such as proliferation and differentiation.Recently, CAS scientists in Shanghai have discovered a novel mechanism of spatial regulation on ERK pathway. The result was published in the 4 September issue of the Proceedings of National Academy of Sciences(PNAS).

  14. Uveitis as a Result of MAP Kinase Pathway Inhibition

    Directory of Open Access Journals (Sweden)

    Lavnish Joshi

    2013-11-01

    Full Text Available We report the case of a patient treated with dabrafenib and trametinib (mitogen-activated protein kinase pathway inhibitors for stage 3b cutaneous melanoma who developed bilateral uveitis. Although there have been reports of ocular side effects with this class of drugs, uveitis has not been previously reported to the best of our knowledge. This case indicates the wide range of side effects that can be seen with the newer targeted biological therapies.

  15. The Hippo tumor suppressor pathway: a brainstorming workshop.

    Science.gov (United States)

    Blandino, Giovanni; Shaul, Yosef; Strano, Sabrina; Sudol, Marius; Yaffe, Michael

    2009-11-03

    Researchers from around the world met for two days in April this year in Rome, Italy, to discuss progress in the rapidly developing field of Hippo signaling, which is relevant to cancer and the control of organ size. Most of the participants presented data related to previously uncharacterized proteins that physically and functionally interact with known components of the Hippo pathway and regulate its biological output.

  16. kpath: integration of metabolic pathway linked data.

    Science.gov (United States)

    Navas-Delgado, Ismael; García-Godoy, María Jesús; López-Camacho, Esteban; Rybinski, Maciej; Reyes-Palomares, Armando; Medina, Miguel Ángel; Aldana-Montes, José F

    2015-01-01

    In the last few years, the Life Sciences domain has experienced a rapid growth in the amount of available biological databases. The heterogeneity of these databases makes data integration a challenging issue. Some integration challenges are locating resources, relationships, data formats, synonyms or ambiguity. The Linked Data approach partially solves the heterogeneity problems by introducing a uniform data representation model. Linked Data refers to a set of best practices for publishing and connecting structured data on the Web. This article introduces kpath, a database that integrates information related to metabolic pathways. kpath also provides a navigational interface that enables not only the browsing, but also the deep use of the integrated data to build metabolic networks based on existing disperse knowledge. This user interface has been used to showcase relationships that can be inferred from the information available in several public databases.

  17. Pathways to psychosis in cannabis abuse.

    Science.gov (United States)

    Shrivastava, Amresh; Johnston, Megan; Terpstra, Kristen; Bureau, Yves

    2015-04-01

    Cannabis has been implicated as a risk factor for the development of schizophrenia, but the exact biological mechanisms remain unclear. In this review, we attempt to understand the neurobiological pathways that link cannabis use to schizophrenia. This has been an area of great debate; despite similarities between cannabis users and schizophrenia patients, the evidence is not sufficient to establish cause-and-effect. There have been advances in the understanding of the mechanisms of cannabis dependence as well as the role of the cannabinoid system in the development of psychosis and schizophrenia. The neurobiological mechanisms associated with the development of psychosis and effects from cannabis use may be similar but remain elusive. In order to better understand these associations, this paper will show common neurobiological and neuroanatomical changes as well as common cognitive dysfunction in cannabis users and patients of schizophrenia. We conclude that epidemiologic evidence highlights potential causal links; however, neurobiological evidence for causality remains weak.

  18. DC-ATLAS : a systems biology resource to dissect receptor specific signal transduction in dendritic cells

    NARCIS (Netherlands)

    Cavalieri, D.; Rivero, D.; Beltrame, L.; Buschow, S.I.; Calura, E.; Rizzetto, L.; Gessani, S.; Gauzzi, M.C.; Reith, W.; Baur, A.; Bonaiuti, R.; Brandizi, M.; Filippo, C. De; D'Oro, U.; Draghici, S.; Dunand-Sauthier, I.; Gatti, E.; Granucci, F.; Gundel, M.; Kramer, M.; Kuka, M.; Lanyi, A.; Melief, C.J.; Montfoort, N. van; Ostuni, R.; Pierre, P.; Popovici, R.; Rajnavolgyi, E.; Schierer, S.; Schuler, G.; Soumelis, V.; Splendiani, A.; Stefanini, I.; Torcia, M.G.; Zanoni, I.; Zollinger, R.; Figdor, C.G.; Austyn, J.M.

    2010-01-01

    BACKGROUND: The advent of Systems Biology has been accompanied by the blooming of pathway databases. Currently pathways are defined generically with respect to the organ or cell type where a reaction takes place. The cell type specificity of the reactions is the foundation of immunological research,

  19. Refining the quantitative pathway of the Pathways to Mathematics model.

    Science.gov (United States)

    Sowinski, Carla; LeFevre, Jo-Anne; Skwarchuk, Sheri-Lynn; Kamawar, Deepthi; Bisanz, Jeffrey; Smith-Chant, Brenda

    2015-03-01

    In the current study, we adopted the Pathways to Mathematics model of LeFevre et al. (2010). In this model, there are three cognitive domains--labeled as the quantitative, linguistic, and working memory pathways--that make unique contributions to children's mathematical development. We attempted to refine the quantitative pathway by combining children's (N=141 in Grades 2 and 3) subitizing, counting, and symbolic magnitude comparison skills using principal components analysis. The quantitative pathway was examined in relation to dependent numerical measures (backward counting, arithmetic fluency, calculation, and number system knowledge) and a dependent reading measure, while simultaneously accounting for linguistic and working memory skills. Analyses controlled for processing speed, parental education, and gender. We hypothesized that the quantitative, linguistic, and working memory pathways would account for unique variance in the numerical outcomes; this was the case for backward counting and arithmetic fluency. However, only the quantitative and linguistic pathways (not working memory) accounted for unique variance in calculation and number system knowledge. Not surprisingly, only the linguistic pathway accounted for unique variance in the reading measure. These findings suggest that the relative contributions of quantitative, linguistic, and working memory skills vary depending on the specific cognitive task.

  20. Eliciting maize defense pathways aboveground attracts belowground biocontrol agents

    Science.gov (United States)

    Filgueiras, Camila Cramer; Willett, Denis S.; Pereira, Ramom Vasconcelos; Moino Junior, Alcides; Pareja, Martin; Duncan, Larry W.

    2016-01-01

    Plant defense pathways mediate multitrophic interactions above and belowground. Understanding the effects of these pathways on pests and natural enemies above and belowground holds great potential for designing effective control strategies. Here we investigate the effects of aboveground stimulation of plant defense pathways on the interactions between corn, the aboveground herbivore adult Diabrotica speciosa, the belowground herbivore larval D. speciosa, and the subterranean ento-mopathogenic nematode natural enemy Heterorhabditis amazonensis. We show that adult D. speciosa recruit to aboveground herbivory and methyl salicylate treatment, that larval D. speciosa are relatively indiscriminate, and that H. amazonensis en-tomopathogenic nematodes recruit to corn fed upon by adult D. speciosa. These results suggest that entomopathogenicnematodes belowground can be highly attuned to changes in the aboveground parts of plants and that biological control can be enhanced with induced plant defense in this and similar systems. PMID:27811992

  1. Exploring two plant hosts for expression of diterpenoid pathway genes

    DEFF Research Database (Denmark)

    Bach, Søren Spanner

    by humanity in biopharmaceuticals or as industrial bioproducts. Yields and purity of diterpenoids purified from natural sources or made by chemical synthesis are generally insufficient for large-volume or high-end applications, thus alternative sources are needed. Synthetic biology, where heterologous pathways...... have been reconstructed in host production organisms is an attractive lternative, which holds the promise to enable a scalable, costeffective and table supply of natural products. Knowledge about the genes and mechanisms nvolved in the original pathway is a prerequisite for such heterologous production...... is compatible with native codon usage, and through the conserved mechanisms of protein targeting and posttranslational odifications, has the capacity to produce functional enzymes. To further explore plant based expression and characterization of diterpenoid pathway genes, two different plant expression hosts...

  2. Cellular metabolic and autophagic pathways: traffic control by redox signaling.

    Science.gov (United States)

    Dodson, Matthew; Darley-Usmar, Victor; Zhang, Jianhua

    2013-10-01

    It has been established that the key metabolic pathways of glycolysis and oxidative phosphorylation are intimately related to redox biology through control of cell signaling. Under physiological conditions glucose metabolism is linked to control of the NADH/NAD redox couple, as well as providing the major reductant, NADPH, for thiol-dependent antioxidant defenses. Retrograde signaling from the mitochondrion to the nucleus or cytosol controls cell growth and differentiation. Under pathological conditions mitochondria are targets for reactive oxygen and nitrogen species and are critical in controlling apoptotic cell death. At the interface of these metabolic pathways, the autophagy-lysosomal pathway functions to maintain mitochondrial quality and generally serves an important cytoprotective function. In this review we will discuss the autophagic response to reactive oxygen and nitrogen species that are generated from perturbations of cellular glucose metabolism and bioenergetic function.

  3. Targeting the PI3K/Akt pathway in prostate cancer: challenges and opportunities (review).

    Science.gov (United States)

    Toren, Paul; Zoubeidi, Amina

    2014-11-01

    The PI3K/Akt pathway is an actively pursued therapeutic target in oncology. In prostate cancer, the activation of this pathway appears to be characteristic of many aggressive prostate cancers. Further, activation of the PI3K/Akt pathway is more frequently observed as prostate cancer progresses toward a resistant, metastatic disease. Signalling from this pathway activates numerous survival, growth, metabolic and metastatic functions characteristic of aggressive cancer. Biomarkers of this pathway have correlated activation of this pathway to high grade disease and higher risk of disease progression. Therefore there is significant interest in developing effective strategies to target this pathway in prostate cancer. In this review, we discuss the pre-clinical and clinical data relevant to targeting of the PI3K/Akt pathway in prostate cancer. In particular, we review the rationale and relevance of co-targeting approaches against the PI3K/Akt pathway. It is anticipated that through an improved understanding of the biology of the PI3K/Akt pathway in prostate cancer, relevant biomarkers and rationale combination therapies will optimize targeting of this pathway to improve outcomes among patients with aggressive prostate cancer.

  4. Correlation between oncogenic mutations and parameter sensitivity of the apoptosis pathway model.

    Directory of Open Access Journals (Sweden)

    Jia Chen

    2014-01-01

    Full Text Available One of the major breakthroughs in oncogenesis research in recent years is the discovery that, in most patients, oncogenic mutations are concentrated in a few core biological functional pathways. This discovery indicates that oncogenic mechanisms are highly related to the dynamics of biologic regulatory networks, which govern the behaviour of functional pathways. Here, we propose that oncogenic mutations found in different biological functional pathways are closely related to parameter sensitivity of the corresponding networks. To test this hypothesis, we focus on the DNA damage-induced apoptotic pathway--the most important safeguard against oncogenesis. We first built the regulatory network that governs the apoptosis pathway, and then translated the network into dynamics equations. Using sensitivity analysis of the network parameters and comparing the results with cancer gene mutation spectra, we found that parameters that significantly affect the bifurcation point correspond to high-frequency oncogenic mutations. This result shows that the position of the bifurcation point is a better measure of the functionality of a biological network than gene expression levels of certain key proteins. It further demonstrates the suitability of applying systems-level analysis to biological networks as opposed to studying genes or proteins in isolation.

  5. Carotenoids as signaling molecules in cardiovascular biology

    Directory of Open Access Journals (Sweden)

    Abolfazl Barzegari

    2014-09-01

    Full Text Available Oxidative stress and inflammation play important roles in the etiology of cardiovascular disease (CVD. Thus, natural antioxidant carotenoids existing in fruits and vegetables could have a significant role in the prevention of CVD. Nevertheless,clinical data are conflicting about the positive effect of some antioxidant carotenoids in reducing cardiovascular morbidity and mortality. Many biological actions of carotenoids have been attributed to their antioxidant effect; however, the precise mechanism by which carotenoids produce their beneficial effects is still under discussion. They might modulate molecular pathways involved in cell proliferation, acting at Akt, tyrosine kinases, mitogen activated protein kinase (MAP kinase and growth factor signaling cascades. Screening for a promising cardiovascular protective carotenoids therefore might be performed in vitro and in vivo with caution in cross-interaction with other molecules involved in signaling pathways especially those affecting microRNAs, performing a role in molecular modulation of cardiovascular cells.

  6. Flavonoids: Biosynthesis, Biological functions and Biotechnological applications

    Directory of Open Access Journals (Sweden)

    Maria Lorena eFalcone Ferreyra

    2012-09-01

    Full Text Available Flavonoids are widely distributed secondary metabolites with different metabolic functions in plants. The elucidation of the biosynthetic pathways, as well as their regulation by MYB, bHLH and WD40-type transcription factors, has allowed metabolic engineering of plants through the manipulation of the different final products with valuable applications. The present review describes the regulation of flavonoid biosynthesis, as well as the biological functions of flavonoids in plants, such as in defense against UV-B radiation and pathogen infection, nodulation, pollen fertility. In addition, we discuss different strategies and achievements through the genetic engineering of flavonoid biosynthesis with implication in the industry and the combinatorial biosynthesis in microorganisms by the reconstruction of the pathway to obtain high amounts of specific compounds.

  7. Pathways Intern Report

    Science.gov (United States)

    Bell, Evan A.

    2015-01-01

    During my time at NASA, I worked with the Granular Mechanics and Regolith Organization (GMRO), better known as Swamp Works. The goal of the lab is to find ways to utilize resources found after the astronaut or robot has landed on another planet or asteroid. This concept is known as in-situ resource utilization and it is critical to long term missions such as those to Mars. During my time here I worked on the Asteroid and Lava Tube Free Flyer project (ALTFF). A lava tube, such as the one shown in figure 1, is a long tear drop shaped cavern that is produced when molten lava tunnels through the surrounding rock creating large unground pathways. Before mining for resources on Mars or on asteroids, a sampling mission must be done to scout out useful resource deposits. ALTFF's goal is to provide a low cost, autonomous scout robot that can sample the surface and return to the mother ship or lander for further processing of the samples. The vehicle will be looking for water ice in the regolith that can be processed into either potable water, hydrogen and oxygen fuel, or a binder material for 3D printing. By using a low cost craft to sample, there is much less risk to the more expensive mother ship or lander. While my main task was the construction of a simulation environment to test control code in and the construction of the asteroid free flyer prototype, there were other tasks that I performed relating to the ALTFF project.

  8. Managing biological diversity

    Science.gov (United States)

    Samson, Fred B.; Knopf, Fritz L.

    1993-01-01

    Biological diversity is the variety of life and accompanying ecological processes (Off. Technol. Assess. 1987, Wilcove and Samson 1987, Keystone 1991). Conservation of biological diversity is a major environmental issue (Wilson 1988, Counc. Environ. Quality 1991). The health and future of the earth's ecological systems (Lubchenco et al. 1991), global climate change (Botkin 1990), and an ever-increasing rate in loss of species, communities, and ecological systems (Myers 1990) are among issues drawing biological diversity to the mainstream of conservation worldwide (Int. Union Conserv. Nat. and Nat. Resour. [IUCN] et al. 1991). The legal mandate for conserving biological diversity is now in place (Carlson 1988, Doremus 1991). More than 19 federal laws govern the use of biological resources in the United States (Rein 1991). The proposed National Biological Diversity Conservation and Environmental Research Act (H.R. 585 and S.58) notes the need for a national biological diversity policy, would create a national center for biological diversity research, and recommends a federal interagency strategy for ecosystem conservation. There are, however, hard choices ahead for the conservation of biological diversity, and biologists are grappling with how to set priorities in research and management (Roberts 1988). We sense disillusion among field biologists and managers relative to how to operationally approach the seemingly overwhelming charge of conserving biological diversity. Biologists also need to respond to critics like Hunt (1991) who suggest a tree farm has more biological diversity than an equal area of old-growth forest. At present, science has played only a minor role in the conservation of biological diversity (Weston 1992) with no unified approach available to evaluate strategies and programs that address the quality and quantity of biological diversity (Murphy 1990, Erwin 1992). Although actions to conserve biological diversity need to be clearly defined by

  9. Biological and Chemical Security

    Energy Technology Data Exchange (ETDEWEB)

    Fitch, P J

    2002-12-19

    The LLNL Chemical & Biological National Security Program (CBNP) provides science, technology and integrated systems for chemical and biological security. Our approach is to develop and field advanced strategies that dramatically improve the nation's capabilities to prevent, prepare for, detect, and respond to terrorist use of chemical or biological weapons. Recent events show the importance of civilian defense against terrorism. The 1995 nerve gas attack in Tokyo's subway served to catalyze and focus the early LLNL program on civilian counter terrorism. In the same year, LLNL began CBNP using Laboratory-Directed R&D investments and a focus on biodetection. The Nunn-Lugar-Domenici Defense Against Weapons of Mass Destruction Act, passed in 1996, initiated a number of U.S. nonproliferation and counter-terrorism programs including the DOE (now NNSA) Chemical and Biological Nonproliferation Program (also known as CBNP). In 2002, the Department of Homeland Security was formed. The NNSA CBNP and many of the LLNL CBNP activities are being transferred as the new Department becomes operational. LLNL has a long history in national security including nonproliferation of weapons of mass destruction. In biology, LLNL had a key role in starting and implementing the Human Genome Project and, more recently, the Microbial Genome Program. LLNL has over 1,000 scientists and engineers with relevant expertise in biology, chemistry, decontamination, instrumentation, microtechnologies, atmospheric modeling, and field experimentation. Over 150 LLNL scientists and engineers work full time on chemical and biological national security projects.

  10. New insights into Reelin-mediated signaling pathways

    Directory of Open Access Journals (Sweden)

    Gum Hwa eLee

    2016-05-01

    Full Text Available Reelin, a multifunctional extracellular protein that is important for mammalian brain development and function, is secreted by different cell types in the prenatal or postnatal brain. The spatiotemporal regulation of Reelin expression and distribution during development relates to its multifaceted function in the brain. Prenatally Reelin controls neuronal radial migration and proper positioning in cortical layers, whereas postnatally Reelin promotes neuronal maturation, synaptic formation and plasticity. The molecular mechanisms underlying the distinct biological functions of Reelin during and after brain development involve unique and overlapping signaling pathways that are activated following Reelin binding to its cell surface receptors. Distinct Reelin ligand isoforms, such as the full-length protein or fragments generated by proteolytic cleavage differentially affect the activity of downstream signaling pathways. In this review, we discuss recent advances in our understanding of the signaling transduction pathways activated by Reelin that regulate different aspects of brain development and function. A core signaling machinery, including ApoER2/VLDLR receptors, Src/Fyn kinases, and the adaptor protein Dab1, participates in all known aspects of Reelin biology. However, distinct downstream mechanisms, such as the Crk/Rap1 pathway and cell adhesion molecules, play crucial roles in the control of neuronal migration, whereas the PI3K/Akt/mTOR pathway appears to be more important for dendrite and spine development. Finally, the NMDAR and an unidentified receptor contribute to the activation of the MEK/Erk1/2 pathway leading to the upregulation of genes involved in synaptic plasticity and learning. This knowledge may provide new insight into neurodevelopmental or neurodegenerative disorders that are associated with Reelin dysfunction.

  11. Modularized study of human calcium signalling pathway

    Indian Academy of Sciences (India)

    Losiana Nayak; Rajat K De

    2007-08-01

    Signalling pathways are complex biochemical networks responsible for reg ulation of numerous cellular functions. These networks function by serial and successive interactions among a large number of vital biomolecules and chemical compounds. For deciphering and analysing the underlying mechanism of such networks, a modularized study is quite helpful. Here we propose an algorithm for modularization of calcium signalling pathway of H. sapiens. The idea that ``a node whose function is dependant on maximum number of other nodes tends to be the center of a sub network” is used to divide a large signalling network into smaller sub networks. Inclusion of node(s) into sub networks(s) is dependant on the outdegree of the node(s). Here outdegree of a node refers to the number of re lations of the considered node lying outside the constructed sub network. Node(s) having more than c relations lying outside the expanding subnetwork have to be excluded from it. Here is a specified variable based on user preference, which is finally fixed during adjustments of created subnetworks, so that certain biological significance can be conferred on them.

  12. Explorations into Chemical Reactions and Biochemical Pathways.

    Science.gov (United States)

    Gasteiger, Johann

    2016-12-01

    A brief overview of the work in the research group of the present author on extracting knowledge from chemical reaction data is presented. Methods have been developed to calculate physicochemical effects at the reaction site. It is shown that these physicochemical effects can quite favourably be used to derive equations for the calculation of data on gas phase reactions and on reactions in solution such as aqueous acidity of alcohols or carboxylic acids or the hydrolysis of amides. Furthermore, it is shown that these physicochemical effects are quite effective for assigning reactions into reaction classes that correspond to chemical knowledge. Biochemical reactions constitute a particularly interesting and challenging task for increasing our understanding of living species. The BioPath.Database is a rich source of information on biochemical reactions and has been used for a variety of applications of chemical, biological, or medicinal interests. Thus, it was shown that biochemical reactions can be assigned by the physicochemical effects into classes that correspond to the classification of enzymes by the EC numbers. Furthermore, 3D models of reaction intermediates can be used for searching for novel enzyme inhibitors. It was shown in a combined application of chemoinformatics and bioinformatics that essential pathways of diseases can be uncovered. Furthermore, a study showed that bacterial flavor-forming pathways can be discovered.

  13. Survival associated pathway identification with group Lp penalized global AUC maximization

    Directory of Open Access Journals (Sweden)

    Liu Zhenqiu

    2010-08-01

    Full Text Available Abstract It has been demonstrated that genes in a cell do not act independently. They interact with one another to complete certain biological processes or to implement certain molecular functions. How to incorporate biological pathways or functional groups into the model and identify survival associated gene pathways is still a challenging problem. In this paper, we propose a novel iterative gradient based method for survival analysis with group Lp penalized global AUC summary maximization. Unlike LASSO, Lp (p 1. We first extend Lp for individual gene identification to group Lp penalty for pathway selection, and then develop a novel iterative gradient algorithm for penalized global AUC summary maximization (IGGAUCS. This method incorporates the genetic pathways into global AUC summary maximization and identifies survival associated pathways instead of individual genes. The tuning parameters are determined using 10-fold cross validation with training data only. The prediction performance is evaluated using test data. We apply the proposed method to survival outcome analysis with gene expression profile and identify multiple pathways simultaneously. Experimental results with simulation and gene expression data demonstrate that the proposed procedures can be used for identifying important biological pathways that are related to survival phenotype and for building a parsimonious model for predicting the survival times.

  14. Identification of molecular markers related to human alveolar bone cells and pathway analysis in diabetic patients.

    Science.gov (United States)

    Sun, X; Ren, Q H; Bai, L; Feng, Q

    2015-10-28

    Alveolar bone osteoblasts are widely used in dental and related research. They are easily affected by systemic diseases such as diabetes. However, the mechanism of diabetes-induced alveolar bone absorption remains unclear. This study systematically explored the changes in human alveolar bone cell-related gene expression and biological pathways, which may facilitate the investigation of its mechanism. Alveolar bone osteoblasts isolated from 5 male diabetics and 5 male healthy adults were cultured. Total RNA was extracted from these cells and subjected to gene microarray analysis. Differentially expressed genes were screened, and a gene interaction network was constructed. An enrichment pathway analysis was simultaneously performed on differentially expressed genes to identify the biological pathways associated with changes in the alveolar bone cells of diabetic humans. In total, we identified 147 mRNAs that were differentially expressed in diabetic alveolar bone cells (than in the normal cells; 91 upregulated and 36 downregulated mRNAs). The constructed co-expression network showed 3 pairs of significantly-expressed genes. High-enrichment pathway analysis identified 8 pathways that were affected by changes in gene expression; three of the significant pathways were related to metabolism (inositol phosphate metabolism, propanoate metabolism, and pyruvate metabolism). Here, we identified a few potential genes and biological pathways for the diagnosis and treatment of alveolar bone cells in diabetic patients.

  15. Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks

    Science.gov (United States)

    Zhang, Jingyu; Tian, Xiao-Jun; Xing, Jianhua

    2016-01-01

    Epithelial-to-mesenchymal transition (EMT) is a key step in development, wound healing, and cancer development. It involves cooperation of signaling pathways, such as transformation growth factor-β (TGF-β), Sonic Hedgehog (SHH), and WNT pathways. These signaling pathways crosstalk to each other and converge to key transcription factors (e.g., SNAIL1) to initialize and maintain the process of EMT. The functional roles of multi-signaling pathway crosstalks in EMT are sophisticated and, thus, remain to be explored. In this review, we focused on three major signal transduction pathways that promote or regulate EMT in carcinoma. We discussed the network structures, and provided a brief overview of the current therapy strategies and drug development targeted to these three signal transduction pathways. Finally, we highlighted systems biology approaches that can accelerate the process of deconstructing complex networks and drug discovery. PMID:27043642

  16. Modular and Stochastic Approaches to Molecular Pathway Models of ATM, TGF beta, and WNT Signaling

    Science.gov (United States)

    Cucinotta, Francis A.; O'Neill, Peter; Ponomarev, Artem; Carra, Claudio; Whalen, Mary; Pluth, Janice M.

    2009-01-01

    Deterministic pathway models that describe the biochemical interactions of a group of related proteins, their complexes, activation through kinase, etc. are often the basis for many systems biology models. Low dose radiation effects present a unique set of challenges to these models including the importance of stochastic effects due to the nature of radiation tracks and small number of molecules activated, and the search for infrequent events that contribute to cancer risks. We have been studying models of the ATM, TGF -Smad and WNT signaling pathways with the goal of applying pathway models to the investigation of low dose radiation cancer risks. Modeling challenges include introduction of stochastic models of radiation tracks, their relationships to more than one substrate species that perturb pathways, and the identification of a representative set of enzymes that act on the dominant substrates. Because several pathways are activated concurrently by radiation the development of modular pathway approach is of interest.

  17. Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks.

    Science.gov (United States)

    Zhang, Jingyu; Tian, Xiao-Jun; Xing, Jianhua

    2016-03-28

    Epithelial-to-mesenchymal transition (EMT) is a key step in development, wound healing, and cancer development. It involves cooperation of signaling pathways, such as transformation growth factor-β (TGF-β), Sonic Hedgehog (SHH), and WNT pathways. These signaling pathways crosstalk to each other and converge to key transcription factors (e.g., SNAIL1) to initialize and maintain the process of EMT. The functional roles of multi-signaling pathway crosstalks in EMT are sophisticated and, thus, remain to be explored. In this review, we focused on three major signal transduction pathways that promote or regulate EMT in carcinoma. We discussed the network structures, and provided a brief overview of the current therapy strategies and drug development targeted to these three signal transduction pathways. Finally, we highlighted systems biology approaches that can accelerate the process of deconstructing complex networks and drug discovery.

  18. Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks

    Directory of Open Access Journals (Sweden)

    Jingyu Zhang

    2016-03-01

    Full Text Available Epithelial-to-mesenchymal transition (EMT is a key step in development, wound healing, and cancer development. It involves cooperation of signaling pathways, such as transformation growth factor-β (TGF-β, Sonic Hedgehog (SHH, and WNT pathways. These signaling pathways crosstalk to each other and converge to key transcription factors (e.g., SNAIL1 to initialize and maintain the process of EMT. The functional roles of multi-signaling pathway crosstalks in EMT are sophisticated and, thus, remain to be explored. In this review, we focused on three major signal transduction pathways that promote or regulate EMT in carcinoma. We discussed the network structures, and provided a brief overview of the current therapy strategies and drug development targeted to these three signal transduction pathways. Finally, we highlighted systems biology approaches that can accelerate the process of deconstructing complex networks and drug discovery.

  19. Pathway Analysis Using Genome-Wide Association Study Data for Coronary Restenosis – A Potential Role for the PARVB Gene

    Science.gov (United States)

    Verschuren, Jeffrey J. W.; Trompet, Stella; Sampietro, M. Lourdes; Heijmans, Bastiaan T.; Koch, Werner; Kastrati, Adnan; Houwing-Duistermaat, Jeanine J.; Slagboom, P. Eline; Quax, Paul H. A.; Jukema, J. Wouter

    2013-01-01

    Background Coronary restenosis after percutaneous coronary intervention (PCI) still remains a significant limitation of the procedure. The causative mechanisms of restenosis have not yet been fully identified. The goal of the current study was to perform gene-set analysis of biological pathways related to inflammation, proliferation, vascular function and transcriptional regulation on coronary restenosis to identify novel genes and pathways related to this condition. Methods The GENetic DEterminants of Restenosis (GENDER) databank contains genotypic data of 556,099SNPs of 295 cases with restenosis and 571 matched controls. Fifty-four pathways, related to known restenosis-related processes, were selected. Gene-set analysis was performed using PLINK, GRASS and ALIGATOR software. Pathways with a p<0.01 were fine-mapped and significantly associated SNPs were analyzed in an independent replication cohort. Results Six pathways (cell-extracellular matrix (ECM) interactions pathway, IL2 signaling pathway, IL6 signaling pathway, platelet derived growth factor pathway, vitamin D receptor pathway and the mitochondria pathway) were significantly associated in one or two of the software packages. Two SNPs in the cell-ECM interactions pathway were replicated in an independent restenosis cohort. No replication was obtained for the other pathways. Conclusion With these results we demonstrate a potential role of the cell-ECM interactions pathway in the development of coronary restenosis. These findings contribute to the increasing knowledge of the genetic etiology of restenosis formation and could serve as a hypothesis-generating effort for further functional studies. PMID:23950981

  20. Mechanistic Effects of Calcitriol in Cancer Biology

    Directory of Open Access Journals (Sweden)

    Lorenza Díaz

    2015-06-01

    Full Text Available Besides its classical biological effects on calcium and phosphorus homeostasis, calcitriol, the active vitamin D metabolite, has a broad variety of actions including anticancer effects that are mediated either transcriptionally and/or via non-genomic pathways. In the context of cancer, calcitriol regulates the cell cycle, induces apoptosis, promotes cell differentiation and acts as anti-inflammatory factor within the tumor microenvironment. In this review, we address the different mechanisms of action involved in the antineoplastic effects of calcitriol.

  1. Wnt Signaling in Cancer Stem Cell Biology.

    Science.gov (United States)

    de Sousa E Melo, Felipe; Vermeulen, Louis

    2016-06-27

    Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt signaling levels identify stem-like tumor cells that are responsible for fueling tumor growth. As therapeutic targeting of these tumor stem cells is an intense area of investigation, a concise understanding on how Wnt activity relates to cancer stem cell traits is needed. This review attempts at summarizing the intricacies between Wnt signaling and cancer stem cell biology with a special emphasis on colorectal cancer.

  2. Unraveling pancreatic islet biology by quantitative proteomics

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Jianying; Dann, Geoffrey P.; Liew, Chong W.; Smith, Richard D.; Kulkarni, Rohit N.; Qian, Weijun

    2011-08-01

    The pancreatic islets of Langerhans play a critical role in maintaining blood glucose homeostasis by secreting insulin and several other important peptide hormones. Impaired insulin secretion due to islet dysfunction is linked to the pathogenesis underlying both Type 1 and Type 2 diabetes. Over the past 5 years, emerging proteomic technologies have been applied to dissect the signaling pathways that regulate islet functions and gain an understanding of the mechanisms of islet dysfunction relevant to diabetes. Herein, we briefly review some of the recent quantitative proteomic studies involving pancreatic islets geared towards gaining a better understanding of islet biology relevant to metabolic diseases.

  3. Protein design for pathway engineering.

    Science.gov (United States)

    Eriksen, Dawn T; Lian, Jiazhang; Zhao, Huimin

    2014-02-01

    Design and construction of biochemical pathways has increased the complexity of biosynthetically-produced compounds when compared to single enzyme biocatalysis. However, the coordination of multiple enzymes can introduce a complicated set of obstacles to overcome in order to achieve a high titer and yield of the desired compound. Metabolic engineering has made great strides in developing tools to optimize the flux through a target pathway, but the inherent characteristics of a particular enzyme within the pathway can still limit the productivity. Thus, judicious protein design is critical for metabolic and pathway engineering. This review will describe various strategies and examples of applying protein design to pathway engineering to optimize the flux through the pathway. The proteins can be engineered for altered substrate specificity/selectivity, increased catalytic activity, reduced mass transfer limitations through specific protein localization, and reduced substrate/product inhibition. Protein engineering can also be expanded to design biosensors to enable high through-put screening and to customize cell signaling networks. These strategies have successfully engineered pathways for significantly increased productivity of the desired product or in the production of novel compounds.

  4. [New synthetic and biologic treatments for spondylarthritis].

    Science.gov (United States)

    Zufferey, Pascal

    2016-03-09

    The only biological treatments recognized and reimbursed for spondylarthritis in Switzerland are anti TNF. Other effective agents in rheumatoid arthritis were found to be of little use in this indication. Fortunately, in recent years appeared biological molecules blocking cytokines involved in new pathways of inflammation in particular that of IL7. They have been very effective against psoriasis and have a high potential in psoriatic arthritis and spondylarthritis. In parallel, synthetic small molecules capable of modulating the production of intracellular cytokines begin to be marketed. They also are potentially active in the same rheumatic diseases. The purpose of this article is to review these new drugs, in particular to review the progress of their development and commercialization status.

  5. Candidate pathway based analysis for cleft lip with or without cleft palate.

    Science.gov (United States)

    Zhang, Tian-Xiao; Beaty, Terri H; Ruczinski, Ingo

    2012-01-06

    The objective of this research was to identify potential biological pathways associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and to explore the potential biological mechanisms underlying these associated pathways on risk of NSCL/P. This project was based on the dataset of a previously published genome-wide association (GWA) study on NSCL/P (Beaty et al. 2010). Case-parent trios used here originated from an international consortium (The Gene, Environment Association Studies consortium, GENEVA) formed in 2007. A total of 5,742 individuals from 1,908 CL/P case-parents trios (1,591 complete trios and 317 incomplete trios where one parent was missing) were collected and genotyped using the Illumina Human610-Quad array. Candidate pathways were selected using a list of 356 genes that may be related to oral clefts. In total, 42 candidate pathways, which included 1,564 genes and 40,208 SNPs were tested. Using a pathway-based analysis approach proposed by Wang et al (2007), we conducted a permutation-based test to assess the statistical significance of the nominal p-values of 42 candidate pathways. The analysis revealed several pathways yielding nominally significant p-values. However, controlling for the family wise error rate, none of these pathways could retain statistical significance. Nominal p-values of these pathways were concentrated at the lower tail of the distribution, with more than expected low p-values. A permutation based test for examining this type of distribution pattern yielded an overall p-value of 0.029. Thus, while this pathway-based analysis did not yield a clear significant result for any particular pathway, we conclude that one or more of the genes and pathways considered here likely do play a role in oral clefting.

  6. Thermodynamics of Biological Processes

    Science.gov (United States)

    Garcia, Hernan G.; Kondev, Jane; Orme, Nigel; Theriot, Julie A.; Phillips, Rob

    2012-01-01

    There is a long and rich tradition of using ideas from both equilibrium thermodynamics and its microscopic partner theory of equilibrium statistical mechanics. In this chapter, we provide some background on the origins of the seemingly unreasonable effectiveness of ideas from both thermodynamics and statistical mechanics in biology. After making a description of these foundational issues, we turn to a series of case studies primarily focused on binding that are intended to illustrate the broad biological reach of equilibrium thinking in biology. These case studies include ligand-gated ion channels, thermodynamic models of transcription, and recent applications to the problem of bacterial chemotaxis. As part of the description of these case studies, we explore a number of different uses of the famed Monod–Wyman–Changeux (MWC) model as a generic tool for providing a mathematical characterization of two-state systems. These case studies should provide a template for tailoring equilibrium ideas to other problems of biological interest. PMID:21333788

  7. Hammond Bay Biological Station

    Data.gov (United States)

    Federal Laboratory Consortium — Hammond Bay Biological Station (HBBS), located near Millersburg, Michigan, is a field station of the USGS Great Lakes Science Center (GLSC). HBBS was established by...

  8. Enhanced Biological Sampling Data

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This is a database of a variety of biological, reproductive, and energetic data collected from fish on the continental shelf in the northwest Atlantic Ocean. Species...

  9. Chemistry and biology data

    Data.gov (United States)

    U.S. Environmental Protection Agency — Chemical monitoring data and biological data from field collected samples. This dataset is associated with the following publication: Biales , A., D. Denton , D....

  10. Laboratory of Biological Modeling

    Data.gov (United States)

    Federal Laboratory Consortium — The Laboratory of Biological Modeling is defined by both its methodologies and its areas of application. We use mathematical modeling in many forms and apply it to...

  11. Laboratory of Biological Modeling

    Data.gov (United States)

    Federal Laboratory Consortium — The Laboratory of Biological Modeling is defined by both its methodologies and its areas of application. We use mathematical modeling in many forms and apply it to a...

  12. Precision Measurement in Biology

    Science.gov (United States)

    Quake, Stephen

    Is biology a quantitative science like physics? I will discuss the role of precision measurement in both physics and biology, and argue that in fact both fields can be tied together by the use and consequences of precision measurement. The elementary quanta of biology are twofold: the macromolecule and the cell. Cells are the fundamental unit of life, and macromolecules are the fundamental elements of the cell. I will describe how precision measurements have been used to explore the basic properties of these quanta, and more generally how the quest for higher precision almost inevitably leads to the development of new technologies, which in turn catalyze further scientific discovery. In the 21st century, there are no remaining experimental barriers to biology becoming a truly quantitative and mathematical science.

  13. Biological satellite Kosmos-936

    Science.gov (United States)

    Vedeshin, L. A.

    1978-01-01

    A description is given of physiological experiments performed on the biological satellite Kosmos-936. Other experiments to determine the electrostatic and dielectric responses to the effects of cosmic radiation are discussed.

  14. Fishery Biology Database (AGDBS)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Basic biological data are the foundation on which all assessments of fisheries resources are built. These include parameters such as the size and age composition of...

  15. Large Pelagics Biological Survey

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Large Pelagics Biological Survey (LPBS) collects additional length and weight information and body parts such as otoliths, caudal vertebrae, dorsal spines, and...

  16. Vibrations, Quanta and Biology

    CERN Document Server

    Huelga, S F

    2013-01-01

    Quantum biology is an emerging field of research that concerns itself with the experimental and theoretical exploration of non-trivial quantum phenomena in biological systems. In this tutorial overview we aim to bring out fundamental assumptions and questions in the field, identify basic design principles and develop a key underlying theme -- the dynamics of quantum dynamical networks in the presence of an environment and the fruitful interplay that the two may enter. At the hand of three biological phenomena whose understanding is held to require quantum mechanical processes, namely excitation and charge transfer in photosynthetic complexes, magneto-reception in birds and the olfactory sense, we demonstrate that this underlying theme encompasses them all, thus suggesting its wider relevance as an archetypical framework for quantum biology.

  17. Mechanical Biological Treatment

    DEFF Research Database (Denmark)

    Bilitewski, B-; Oros, Christiane; Christensen, Thomas Højlund

    2011-01-01

    or residual waste (after some recyclables removed at the source). The concept was originally to reduce the amount of waste going to landfill, but MBT technologies are today also seen as plants recovering fuel as well as material fractions. As the name suggests the technology combines mechanical treatment......The basic processes and technologies of composting and anaerobic digestion, as described in the previous chapters, are usually used for specific or source-separated organic waste flows. However, in the 1990s mechanical biological waste treatment technologies (MBT) were developed for unsorted...... technologies (screens, sieves, magnets, etc.) with biological technologies (composting, anaerobic digestion). Two main technologies are available: Mechanical biological pretreatment (MBP), which first removes an RDF fraction and then biologically treats the remaining waste before most of it is landfilled...

  18. Multiscale Biological Materials

    DEFF Research Database (Denmark)

    Frølich, Simon

    example of biological design. We investigated the architecture of A. simplex and found that an advanced hierarchical biomineralized structure acts as the interface between soft musculature and a stiff substrate, thus securing underwater attachment. In bone, the mechanical properties of the material......, and the nanoscale response of bone in compression. Lastly, a framework for the investigation of biological design principles has been developed. The framework combines parametric modeling, multi-material 3D-printing, and direct mechanical testing to efficiently screen large parameter spaces of biological design. We......Materials formed by organisms, also known as biological materials, exhibit outstanding structural properties. The range of materials formed in nature is remarkable and their functions include support, protection, motion, sensing, storage, and maintenance of physiological homeostasis. These complex...

  19. [Systems biology of cancer].

    Science.gov (United States)

    Barillot, Emmanuel; Calzone, Laurence; Zinovyev, Andrei

    2009-01-01

    Cancer Systems Biology is now accepted and recognized as a promising field both in biological and clinical research. It relies on a rigorous formalization of regulation networks into precise and unambiguous languages. It provides both detailed and modular views of the complex biological system of interest (which in cancer research is typically an interaction network governing essential cellular events such as proliferation, differentiation, cell death...) in order to facilitate the interpretation of molecular profiles of tumors. The translation of these networks into mathematical models allows prediction of the evolution of the system in time and under certain perturbations. As a result, it can not only propose specific target points for pharmaceutical purposes, but also anticipate the evolution of tumors as well as their classifications. These characteristics emphasize the important role of Systems Biology of Cancer in the future of biomedical research.

  20. Insecticides and Biological Control

    Science.gov (United States)

    Furness, G. O.

    1972-01-01

    Use of insecticides has been questioned due to their harmful effects on edible items. Biological control of insects along with other effective practices for checking spread of parasites on crops are discussed. (PS)

  1. The Wnt and Notch signalling pathways in the developing cochlea : Formation of hair cells and induction of regenerative potential

    NARCIS (Netherlands)

    Zak, Magdalena; Klis, Sjaak F L; Grolman, Wilko

    2015-01-01

    The Wnt and Notch signalling pathways control proliferation, specification, and cell fate choices during embryonic development and in adult life. Hence, there is much interest in both signalling pathways in the context of stem cell biology and tissue regeneration. In the developing ear, the Wnt and

  2. Jasmonate Signal Pathway in Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    Xiao-Yi Shan; Zhi-Long Wang; Daoxin Xie

    2007-01-01

    Jasmonates (JAs), which include jasmonic acid and its cyclopentane derivatives are synthesized from the octadecanoid pathway and widely distributed throughout the plant kingdom. JAs modulate the expression of numerous genes and mediate responses to stress, wounding, insect attack, pathogen infection, and UV damage. They also affect a variety of processes in many plant developmental processes. The JA signal pathway involves two important events: the biosynthesis of JA and the transduction of JA signal. Several important Arabidopsis mutants in jasmonate signal pathway were described in this review.

  3. Self-correcting maps of molecular pathways.

    Directory of Open Access Journals (Sweden)

    Andrey Rzhetsky

    Full Text Available Reliable and comprehensive maps of molecular pathways are indispensable for guiding complex biomedical experiments. Such maps are typically assembled from myriads of disparate research reports and are replete with inconsistencies due to variations in experimental conditions and/or errors. It is often an intractable task to manually verify internal consistency over a large collection of experimental statements. To automate large-scale reconciliation efforts, we propose a random-arcs-and-nodes model where both nodes (tissue-specific states of biological molecules and arcs (interactions between them are represented with random variables. We show how to obtain a non-contradictory model of a molecular network by computing the joint distribution for arc and node variables, and then apply our methodology to a realistic network, generating a set of experimentally testable hypotheses. This network, derived from an automated analysis of over 3,000 full-text research articles, includes genes that have been hypothetically linked to four neurological disorders: Alzheimer's disease, autism, bipolar disorder, and schizophrenia. We estimated that approximately 10% of the published molecular interactions are logically incompatible. Our approach can be directly applied to an array of diverse problems including those encountered in molecular biology, ecology, economics, politics, and sociology.

  4. Nestedness across biological scales

    Science.gov (United States)

    Marquitti, Flavia M. D.; Raimundo, Rafael L. G.; Sebastián-González, Esther; Coltri, Patricia P.; Perez, S. Ivan; Brandt, Débora Y. C.; Nunes, Kelly; Daura-Jorge, Fábio G.; Floeter, Sergio R.; Guimarães, Paulo R.

    2017-01-01

    Biological networks pervade nature. They describe systems throughout all levels of biological organization, from molecules regulating metabolism to species interactions that shape ecosystem dynamics. The network thinking revealed recurrent organizational patterns in complex biological systems, such as the formation of semi-independent groups of connected elements (modularity) and non-random distributions of interactions among elements. Other structural patterns, such as nestedness, have been primarily assessed in ecological networks formed by two non-overlapping sets of elements; information on its occurrence on other levels of organization is lacking. Nestedness occurs when interactions of less connected elements form proper subsets of the interactions of more connected elements. Only recently these properties began to be appreciated in one-mode networks (where all elements can interact) which describe a much wider variety of biological phenomena. Here, we compute nestedness in a diverse collection of one-mode networked systems from six different levels of biological organization depicting gene and protein interactions, complex phenotypes, animal societies, metapopulations, food webs and vertebrate metacommunities. Our findings suggest that nestedness emerge independently of interaction type or biological scale and reveal that disparate systems can share nested organization features characterized by inclusive subsets of interacting elements with decreasing connectedness. We primarily explore the implications of a nested structure for each of these studied systems, then theorize on how nested networks are assembled. We hypothesize that nestedness emerges across scales due to processes that, although system-dependent, may share a general compromise between two features: specificity (the number of interactions the elements of the system can have) and affinity (how these elements can be connected to each other). Our findings suggesting occurrence of nestedness

  5. Biological Parameters of Impact

    Science.gov (United States)

    1965-09-01

    zone between no effect and gross injury or death . For example, the pilot who survives an aircraft crash, but who is injured or unconscious so that he...Biological effects were limited to one incidence of bradycardia (116 t36 t and three instances of premature ventricular contractions. However. subjeCtiY" I...R.F.Chandler INTRODUCTION -Investigation of the biological effects of abrupt acceleration (impact) was stimulated by the advent of technical advances

  6. Systems cell biology.

    Science.gov (United States)

    Mast, Fred D; Ratushny, Alexander V; Aitchison, John D

    2014-09-15

    Systems cell biology melds high-throughput experimentation with quantitative analysis and modeling to understand many critical processes that contribute to cellular organization and dynamics. Recently, there have been several advances in technology and in the application of modeling approaches that enable the exploration of the dynamic properties of cells. Merging technology and computation offers an opportunity to objectively address unsolved cellular mechanisms, and has revealed emergent properties and helped to gain a more comprehensive and fundamental understanding of cell biology.

  7. Alpha2-Adrenergic Receptors and Breast Tumor Stroma: A Novel Pathway Driving Breast Cancer Growth and Metastasis

    Science.gov (United States)

    2015-10-01

    1 AWARD NUMBER: W81XWH-13-1-0439 TITLE: Alpha2-Adrenergic Receptors and Breast Tumor Stroma: A Novel Pathway Driving Breast Cancer Growth and...treatment of breast cancer often experience severe and chronic psychological stress. The sympathetic nervous system (SNS) is an important pathway by which...Sephton SE, McDonald PG, et al. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer . 2006;6:240-8. 3

  8. Can the natural diversity of quorum sensing advance synthetic biology?

    Directory of Open Access Journals (Sweden)

    Rene Michele Davis

    2015-03-01

    Full Text Available Quorum-sensing networks enable bacteria to sense and respond to chemical signals produced by neighboring bacteria. They are widespread: over one hundred morphologically and genetically distinct species of eubacteria are known to use quorum sensing to control gene expression. This diversity suggests the potential to use natural protein variants to engineer parallel, input-specific, cell-cell communication pathways. However, only three distinct signaling pathways, Lux, Las, and Rhl, have been adapted for and broadly used in engineered systems. The paucity of unique quorum-sensing systems and their propensity for crosstalk limits the usefulness of our current quorum-sensing toolkit. This review discusses the need for more signaling pathways, roadblocks to using multiple pathways in parallel, and strategies for expanding the quorum-sensing toolbox for synthetic biology.

  9. Opportunities and challenges in biological lignin valorization

    Energy Technology Data Exchange (ETDEWEB)

    Beckham, Gregg T.; Johnson, Christopher W.; Karp, Eric M.; Salvachúa, Davinia; Vardon, Derek R.

    2016-12-01

    Lignin is a primary component of lignocellulosic biomass that is an underutilized feedstock in the growing biofuels industry. Despite the fact that lignin depolymerization has long been studied, the intrinsic heterogeneity of lignin typically leads to heterogeneous streams of aromatic compounds, which in turn present significant technical challenges when attempting to produce lignin-derived chemicals where purity is often a concern. In Nature, microorganisms often encounter this same problem during biomass turnover wherein powerful oxidative enzymes produce heterogeneous slates of aromatics compounds. Some microbes have evolved metabolic pathways to convert these aromatic species via ‘upper pathways’ into central intermediates, which can then be funneled through ‘lower pathways’ into central carbon metabolism in a process we dubbed ‘biological funneling’. This funneling approach offers a direct, biological solution to overcome heterogeneity problems in lignin valorization for the modern biorefinery. Coupled to targeted separations and downstream chemical catalysis, this concept offers the ability to produce a wide range of molecules from lignin. This perspective describes research opportunities and challenges ahead for this new field of research, which holds significant promise towards a biorefinery concept wherein polysaccharides and lignin are treated as equally valuable feedstocks. In particular, we discuss tailoring the lignin substrate for microbial utilization, host selection for biological funneling, ligninolytic enzyme–microbe synergy, metabolic engineering, expanding substrate specificity for biological funneling, and process integration, each of which presents key challenges. Ultimately, for biological solutions to lignin valorization to be viable, multiple questions in each of these areas will need to be addressed, making biological lignin valorization a multidisciplinary, co-design problem.

  10. Biological Based Risk Assessment for Space Exploration

    Science.gov (United States)

    Cucinotta, Francis A.

    2011-01-01

    Exposures from galactic cosmic rays (GCR) - made up of high-energy protons and high-energy and charge (HZE) nuclei, and solar particle events (SPEs) - comprised largely of low- to medium-energy protons are the primary health concern for astronauts for long-term space missions. Experimental studies have shown that HZE nuclei produce both qualitative and quantitative differences in biological effects compared to terrestrial radiation, making risk assessments for cancer and degenerative risks, such as central nervous system effects and heart disease, highly uncertain. The goal for space radiation protection at NASA is to be able to reduce the uncertainties in risk assessments for Mars exploration to be small enough to ensure acceptable levels of risks are not exceeded and to adequately assess the efficacy of mitigation measures such as shielding or biological countermeasures. We review the recent BEIR VII and UNSCEAR-2006 models of cancer risks and their uncertainties. These models are shown to have an inherent 2-fold uncertainty as defined by ratio of the 95% percent confidence level to the mean projection, even before radiation quality is considered. In order to overcome the uncertainties in these models, new approaches to risk assessment are warranted. We consider new computational biology approaches to modeling cancer risks. A basic program of research that includes stochastic descriptions of the physics and chemistry of radiation tracks and biochemistry of metabolic pathways, to emerging biological understanding of cellular and tissue modifications leading to cancer is described.

  11. Teaching Biochemical Pathways Using Concept Maps

    Directory of Open Access Journals (Sweden)

    Simon Brown

    2013-08-01

    expected to help and, eventually, everyone will be the volunteer. Thereafter, I act as moderator, provide support to any nervous students and, very rarely, offer some clarification, correction or suggestion. The sessions are very lively and highly productive. We usually spend one week going over the details of the reactions in all the pathways we have considered, and in the next tutorial we generate a simpler outline of the reactions and superimpose the regulation of the pathways. In addition to the generation of a coherent overview of the pathways and processes, the advantages of this approach include instant feedback on the suggestions made by students (often provided by other students; real discussion of the biochemistry; identification of particular points of difficulty; the voluntary inclusion of almost every student, which gives me some indication of those who might be struggling; and laughter. The feedback is consistently positive and students actually ask when the sessions are going to happen as we approach the end of semester. A similar approach works just as well when summarizing a semester’s work on cell and molecular biology.

  12. Applications of genetically-encoded biosensors for the construction and control of biosynthetic pathways.

    Science.gov (United States)

    Michener, Joshua K; Thodey, Kate; Liang, Joe C; Smolke, Christina D

    2012-05-01

    Cells are filled with biosensors, molecular systems that measure the state of the cell and respond by regulating host processes. In much the same way that an engineer would monitor a chemical reactor, the cell uses these sensors to monitor changing intracellular environments and produce consistent behavior despite the variable environment. While natural systems derive a clear benefit from pathway regulation, past research efforts in engineering cellular metabolism have focused on introducing new pathways and removing existing pathway regulation. Synthetic biology is a rapidly growing field that focuses on the development of new tools that support the design, construction, and optimization of biological systems. Recent advances have been made in the design of genetically-encoded biosensors and the application of this class of molecular tools for optimizing and regulating heterologous pathways. Biosensors to cellular metabolites can be taken directly from natural systems, engineered from natural sensors, or constructed entirely in vitro. When linked to reporters, such as antibiotic resistance markers, these metabolite sensors can be used to report on pathway productivity, allowing high-throughput screening for pathway optimization. Future directions will focus on the application of biosensors to introduce feedback control into metabolic pathways, providing dynamic control strategies to increase the efficient use of cellular resources and pathway reliability.

  13. FDA 101: Regulating Biological Products

    Science.gov (United States)

    ... Products For Consumers Home For Consumers Consumer Updates FDA 101: Regulating Biological Products Share Tweet Linkedin Pin ... field. back to top What biological products does FDA regulate? The Center for Biologics Evaluation and Research ( ...

  14. Multiple pathways regulate shoot branching

    Directory of Open Access Journals (Sweden)

    Catherine eRameau

    2015-01-01

    Full Text Available Shoot branching patterns result from the spatio-temporal regulation of axillary bud outgrowth. Numerous endogenous, developmental and environmental factors are integrated at the bud and plant levels to determine numbers of growing shoots. Multiple pathways that converge to common integrators are most probably involved. We propose several pathways involving not only the classical hormones auxin, cytokinins and strigolactones, but also other signals with a strong influence on shoot branching such as gibberellins, sugars or molecular actors of plant phase transition. We also deal with recent findings about the molecular mechanisms and the pathway involved in the response to shade as an example of an environmental signal controlling branching. We propose the TCP transcription factor TB1/BRC1 and the polar auxin transport stream in the stem as possible integrators of these pathways. We finally discuss how modeling can help to represent this highly dynamic system by articulating knowledges and hypothesis and calculating the phenotype properties they imply.

  15. Molecular Biology of Esophageal Cancer

    Institute of Scientific and Technical Information of China (English)

    HuanXi; JanBrabender; RalfMetzger; PaulM.Schneider

    2004-01-01

    There have been many new developments in our understanding of esophageal carcinoma biology over the past several years. Information regarding both of the major forms of this disease, adenocarcinoma and squamous cell carcinoma, has accumulated in conjunction with data on precursor conditions such as Barrett's esophagus. Interesting and promising findings have included overexpression of proto-oncogenes,loss of heterozygosity at multiple chromosomal loci, tumor suppressor gene inactivation, epigenetic silencing by DNA methylation, and mutations and deletions involving the tumor suppressor gene p53. Important cancer pathways, the cyclin kinase inhibitor cascade and the DNA mismatch repair process, implicated in the genesis of multiple tumor types have also been inculpated in esophageal carcinogenesis. Alterations in the p16 and p15 cyclin kinase inhibitors including point mutations and homozygous deletions have been reported in primary esophageal tumors. Further developments in the field of molecular carcinogenesis of esophageal malignancies promise to yield improvements in prevention, early detection, prognostic categorization, and perhaps gene-based therapy of this deadly disease.

  16. Developmental defects in zebrafish for classification of EGF pathway inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Pruvot, Benoist; Curé, Yoann; Djiotsa, Joachim; Voncken, Audrey; Muller, Marc, E-mail: m.muller@ulg.ac.be

    2014-01-15

    One of the major challenges when testing drug candidates targeted at a specific pathway in whole animals is the discrimination between specific effects and unwanted, off-target effects. Here we used the zebrafish to define several developmental defects caused by impairment of Egf signaling, a major pathway of interest in tumor biology. We inactivated Egf signaling by genetically blocking Egf expression or using specific inhibitors of the Egf receptor function. We show that the combined occurrence of defects in cartilage formation, disturbance of blood flow in the trunk and a decrease of myelin basic protein expression represent good indicators for impairment of Egf signaling. Finally, we present a classification of known tyrosine kinase inhibitors according to their specificity for the Egf pathway. In conclusion, we show that developmental indicators can help to discriminate between specific effects on the target pathway from off-target effects in molecularly targeted drug screening experiments in whole animal systems. - Highlights: • We analyze the functions of Egf signaling on zebrafish development. • Genetic blocking of Egf expression causes cartilage, myelin and circulatory defects. • Chemical inhibition of Egf receptor function causes similar defects. • Developmental defects can reveal the specificity of Egf pathway inhibitors.

  17. Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

    Science.gov (United States)

    Traglia, Michela; Tsang, Kathryn; Bearden, Carrie E.; Rauen, Katherine A.

    2017-01-01

    Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10−16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway. PMID:28076348

  18. AraPath: a knowledgebase for pathway analysis in Arabidopsis

    Science.gov (United States)

    Lai, Liming; Liberzon, Arthur; Hennessey, Jason; Jiang, Gaixin; Qi, Jianli; Mesirov, Jill P.; Ge, Steven X.

    2012-01-01

    Summary: Studying plants using high-throughput genomics technologies is becoming routine, but interpretation of genome-wide expression data in terms of biological pathways remains a challenge, partly due to the lack of pathway databases. To create a knowledgebase for plant pathway analysis, we collected 1683 lists of differentially expressed genes from 397 gene-expression studies, which constitute a molecular signature database of various genetic and environmental perturbations of Arabidopsis. In addition, we extracted 1909 gene sets from various sources such as Gene Ontology, KEGG, AraCyc, Plant Ontology, predicted target genes of microRNAs and transcription factors, and computational gene clusters defined by meta-analysis. With this knowledgebase, we applied Gene Set Enrichment Analysis to an expression profile of cold acclimation and identified expected functional categories and pathways. Our results suggest that the AraPath database can be used to generate specific, testable hypotheses regarding plant molecular pathways from gene expression data. Availability: http://bioinformatics.sdstate.edu/arapath/ Contact: gexijin@gmail.com Supplementary Information: Supplementary data are available at Bioinformatics online. PMID:22760305

  19. Problems in evaluating radiation dose via terrestrial and aquatic pathways.

    Science.gov (United States)

    Vaughan, B E; Soldat, J K; Schreckhise, R G; Watson, E C; McKenzie, D H

    1981-12-01

    This review is concerned with exposure risk and the environmental pathways models used for predictive assessment of radiation dose. Exposure factors, the adequacy of available data, and the model subcomponents are critically reviewed from the standpoint of absolute error propagation. Although the models are inherently capable of better absolute accuracy, a calculated dose is usually overestimated by from two to six orders of magnitude, in practice. The principal reason for so large an error lies in using "generic" concentration ratios in situations where site specific data are needed. Major opinion of the model makers suggests a number midway between these extremes, with only a small likelihood of ever underestimating the radiation dose. Detailed evaluations are made of source considerations influencing dose (i.e., physical and chemical status of released material); dispersal mechanisms (atmospheric, hydrologic and biotic vector transport); mobilization and uptake mechanisms (i.e., chemical and other factors affecting the biological availability of radioelements); and critical pathways. Examples are shown of confounding in food-chain pathways, due to uncritical application of concentration ratios. Current thoughts of replacing the critical pathways approach to calculating dose with comprehensive model calculations are also shown to be ill-advised, given present limitations in the comprehensive data base. The pathways models may also require improved parametrization, as they are not at present structured adequately to lend themselves to validation. The extremely wide errors associated with predicting exposure stand in striking contrast to the error range associated with the extrapolation of animal effects data to the human being.

  20. The Oxylipin Pathway in Arabidopsis

    OpenAIRE

    Creelman, Robert A.; Mulpuri, Rao

    2002-01-01

    Oxylipins are acyclic or cyclic oxidation products derived from the catabolism of fatty acids which regulate many defense and developmental pathways in plants. The dramatic increase in the volume of publications and reviews on these compounds since 1997 documents the increasing interest in this compound and its role in plants. Research on this topic has solidified our understanding of the chemistry and biosynthetic pathways for oxylipin production. However, more information is still needed on...

  1. An editor for pathway drawing and data visualization in the Biopathways Workbench

    Directory of Open Access Journals (Sweden)

    Li Joshua

    2009-10-01

    Full Text Available Abstract Background Pathway models serve as the basis for much of systems biology. They are often built using programs designed for the purpose. Constructing new models generally requires simultaneous access to experimental data of diverse types, to databases of well-characterized biological compounds and molecular intermediates, and to reference model pathways. However, few if any software applications provide all such capabilities within a single user interface. Results The Pathway Editor is a program written in the Java programming language that allows de-novo pathway creation and downloading of LIPID MAPS (Lipid Metabolites and Pathways Strategy and KEGG lipid metabolic pathways, and of measured time-dependent changes to lipid components of metabolism. Accessed through Java Web Start, the program downloads pathways from the LIPID MAPS Pathway database (Pathway as well as from the LIPID MAPS web server http://www.lipidmaps.org. Data arises from metabolomic (lipidomic, microarray, and protein array experiments performed by the LIPID MAPS consortium of laboratories and is arranged by experiment. Facility is provided to create, connect, and annotate nodes and processes on a drawing panel with reference to database objects and time course data. Node and interaction layout as well as data display may be configured in pathway diagrams as desired. Users may extend diagrams, and may also read and write data and non-lipidomic KEGG pathways to and from files. Pathway diagrams in XML format, containing database identifiers referencing specific compounds and experiments, can be saved to a local file for subsequent use. The program is built upon a library of classes, referred to as the Biopathways Workbench, that convert between different file formats and database objects. An example of this feature is provided in the form of read/construct/write access to models in SBML (Systems Biology Markup Language contained in the local file system. Conclusion

  2. Pathway analysis of genome-wide association datasets of personality traits.

    Science.gov (United States)

    Kim, H-N; Kim, B-H; Cho, J; Ryu, S; Shin, H; Sung, J; Shin, C; Cho, N H; Sung, Y A; Choi, B-O; Kim, H-L

    2015-04-01

    Although several genome-wide association (GWA) studies of human personality have been recently published, genetic variants that are highly associated with certain personality traits remain unknown, due to difficulty reproducing results. To further investigate these genetic variants, we assessed biological pathways using GWA datasets. Pathway analysis using GWA data was performed on 1089 Korean women whose personality traits were measured with the Revised NEO Personality Inventory for the 5-factor model of personality. A total of 1042 pathways containing 8297 genes were included in our study. Of these, 14 pathways were highly enriched with association signals that were validated in 1490 independent samples. These pathways include association of: Neuroticism with axon guidance [L1 cell adhesion molecule (L1CAM) interactions]; Extraversion with neuronal system and voltage-gated potassium channels; Agreeableness with L1CAM interaction, neurotransmitter receptor binding and downstream transmission in postsynaptic cells; and Conscientiousness with the interferon-gamma and platelet-derived growth factor receptor beta polypeptide pathways. Several genes that contribute to top-ranked pathways in this study were previously identified in GWA studies or by pathway analysis in schizophrenia or other neuropsychiatric disorders. Here we report the first pathway analysis of all five personality traits. Importantly, our analysis identified novel pathways that contribute to understanding the etiology of personality traits.

  3. Biology of ageing

    DEFF Research Database (Denmark)

    Rattan, Suresh

    2015-01-01

    Living systems owe their survival and health to a series of complex biochemical pathways of maintenance and repair. These defense systems create the homeodynamic space of an individual, which is characterized by stress tolerance, molecular damage control and continuous remodeling. Ageing, age...

  4. Profiling of molecular pathways regulated by microRNA 601.

    Science.gov (United States)

    Ohdaira, Hiroaki; Nakagawa, Hiroki; Yoshida, Kenichi

    2009-12-01

    MicroRNAs (miRNAs) have been implicated in complex vertebrate developmental and pathological systems as a versatile class of molecules involved in the regulation of various biological processes and molecular pathways. To elucidate the role of miRNAs in human somatic cells, an understanding of the molecular framework regulated by individual miRNA is essential. In this study, we examined the effect of hsa-miR-601 on gene expression changes in human lung cancer cells A549. To achieve this, DNA microarray and global pathway analyses were performed on hsa-miR-601 introduced cells for two successive days. Gene ontology analysis revealed that the effect of hsa-miR-601 over-represented the negative regulation of translation/translational initiation, whereas GenMAPP analysis revealed that several characteristic pathways were changed in hsa-miR-601 introduced A549 cells compared to control short RNA introduced cells. Among them, up-regulation of actin cytoskeleton and down-regulation of Fas-induced apoptosis pathway occurred on two successive days after hsa-miR-601 introduction. Using a luciferase reporter assay, we also showed that hsa-miR-601 specifically repressed nuclear factor-kappaB (NF-kappaB) transcription factor-dependent reporter expression, a key component of the immune-oncogenesis pathway. These findings suggest that hsa-miR-601 could affect a variety of signaling pathways accompanying orchestrated gene expression changes. Our results argue that individual miRNAs affect complex regulation of cellular signaling pathways.

  5. Eukaryotic nucleotide excision repair: from understanding mechanisms to influencing biology

    Institute of Scientific and Technical Information of China (English)

    Sarah C Shuck; Emily A Short; John J Turchi

    2008-01-01

    Repair of bulky DNA adducts by the nucleotide excision repair (NER) pathway is one of the more versatile DNA repair pathways for the removal of DNA lesions. There are two subsets of the NER pathway, global genomic-NER (GG-NER) and transcription-coupled NER (TC-NER), which differ only in the step involving recognition of the DNA lesion. Following recognition of the damage, the sub-pathways then converge for the incision/excision steps and subsequent gap filling and ligation steps. This review will focus on the GGR sub-pathway of NER while the TCR sub-pathway will be covered in another article in this issue. The ability of the NER pathway to repair a wide array of adducts stems, in part, from the mechanisms involved in the initial recognition step of the damaged DNA and results in NER impacting an equally wide array of human physiological responses and events. In this review, the impact of NER on carcinogenesis, neurological function, sensitivity to environmental factors and sensitivity to cancer therapeutics will be discussed. The knowledge generated in our understanding of the NER pathway over the past 40 years has resulted from advances in the fields of animal model systems, mammalian genetics and in vitro biochemistry, as well as from reconstitution studies and structural analyses of the proteins and enzymes that participate in this pathway. Each of these avenues of research has contributed significantly to our understanding of how the NER pathway works and how alterations in NER activity, both positive and negative, influence human biology.

  6. Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling.

    Science.gov (United States)

    Wen, Ya; Alshikho, Mohamad J; Herbert, Martha R

    2016-01-01

    We used established databases in standard ways to systematically characterize gene ontologies, pathways and functional linkages in the large set of genes now associated with autism spectrum disorders (ASDs). These conditions are particularly challenging--they lack clear pathognomonic biological markers, they involve great heterogeneity across multiple levels (genes, systemic biological and brain characteristics, and nuances of behavioral manifestations)-and yet everyone with this diagnosis meets the same defining behavioral criteria. Using the human gene list from Simons Foundation Autism Research Initiative (SFARI) we performed gene set enrichment analysis with the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database, and then derived a pathway network from pathway-pathway functional interactions again in reference to KEGG. Through identifying the GO (Gene Ontology) groups in which SFARI genes were enriched, mapping the coherence between pathways and GO groups, and ranking the relative strengths of representation of pathway network components, we 1) identified 10 disease-associated and 30 function-associated pathways 2) revealed calcium signaling pathway and neuroactive ligand-receptor interaction as the most enriched, statistically significant pathways from the enrichment analysis, 3) showed calcium signaling pathways and MAPK signaling pathway to be interactive hubs with other pathways and also to be involved with pervasively present biological processes, 4) found convergent indications that the process "calcium-PRC (protein kinase C)-Ras-Raf-MAPK/ERK" is likely a major contributor to ASD pathophysiology, and 5) noted that perturbations associated with KEGG's category of environmental information processing were common. These findings support the idea that ASD-associated genes may contribute not only to core features of ASD themselves but also to vulnerability to other chronic and systemic problems potentially including cancer, metabolic conditions

  7. Functionally reciprocal mutations of the prolactin signalling pathway define hairy and slick cattle.

    Science.gov (United States)

    Littlejohn, Mathew D; Henty, Kristen M; Tiplady, Kathryn; Johnson, Thomas; Harland, Chad; Lopdell, Thomas; Sherlock, Richard G; Li, Wanbo; Lukefahr, Steven D; Shanks, Bruce C; Garrick, Dorian J; Snell, Russell G; Spelman, Richard J; Davis, Stephen R

    2014-12-18

    Lactation, hair development and homeothermy are characteristic evolutionary features that define mammals from other vertebrate species. Here we describe the discovery of two autosomal dominant mutations with antagonistic, pleiotropic effects on all three of these biological processes, mediated through the prolactin signalling pathway. Most conspicuously, mutations in prolactin (PRL) and its receptor (PRLR) have an impact on thermoregulation and hair morphology phenotypes, giving prominence to this pathway outside of its classical roles in lactation.

  8. Using pathway modules as targets for assay development in xenobiotic screening.

    Science.gov (United States)

    Judson, Richard S; Mortensen, Holly M; Shah, Imran; Knudsen, Thomas B; Elloumi, Fathi

    2012-02-01

    Toxicology and pharmaceutical research is increasingly making use of high throughout-screening (HTS) methods to assess the effects of chemicals on molecular pathways, cells and tissues. Whole-genome microarray analysis provides broad information on the response of biological systems to chemical exposure, but is not practical to use when thousands of chemicals need to be evaluated at multiple doses and time points, as well as across different tissues, species and life-stages. A useful alternative approach is to identify a focused set of genes that can give a coarse picture of systems-level responses and that can be scaled to the evaluation of thousands of chemicals and diverse biological contexts. We demonstrate a computational approach to select in vitro expression assay targets that are informative and broadly distributed in biological pathway space, using the concept of pathway modularity. Canonical pathways are decomposed into subnetworks (modules) of functionally-related genes based on rules such as co-regulated expression, protein-protein interactions, and coordinated physiological activity. Pathway modules are constructed using these rules but are then restricted by the bounds of canonical pathways. We demonstrate this approach using a subset of genes associated with tumor development and cancer progression. Target genes were identified for assay development, and then validated by using independent, published microarray data. The result is a targeted set of genes that are sensitive predictors of whether a chemical will perturb each pathway module. These selected genes could then form the basis for a battery to test for pathway-chemical interactions under many biological contexts using throughput expression-based assays.

  9. MouseCyc: a curated biochemical pathways database for the laboratory mouse

    OpenAIRE

    Evsikov, Alexei V.; Dolan, Mary E.; Genrich, Michael P; Patek, Emily; Bult, Carol J.

    2009-01-01

    Linking biochemical genetic data to the reference genome for the laboratory mouse is important for comparative physiology and for developing mouse models of human biology and disease. We describe here a new database of curated metabolic pathways for the laboratory mouse called MouseCyc . MouseCyc has been integrated with genetic and genomic data for the laboratory mouse available from the Mouse Genome Informatics database and with pathway data from other organisms, including human.

  10. Stochastic Methods in Biology

    CERN Document Server

    Kallianpur, Gopinath; Hida, Takeyuki

    1987-01-01

    The use of probabilistic methods in the biological sciences has been so well established by now that mathematical biology is regarded by many as a distinct dis­ cipline with its own repertoire of techniques. The purpose of the Workshop on sto­ chastic methods in biology held at Nagoya University during the week of July 8-12, 1985, was to enable biologists and probabilists from Japan and the U. S. to discuss the latest developments in their respective fields and to exchange ideas on the ap­ plicability of the more recent developments in stochastic process theory to problems in biology. Eighteen papers were presented at the Workshop and have been grouped under the following headings: I. Population genetics (five papers) II. Measure valued diffusion processes related to population genetics (three papers) III. Neurophysiology (two papers) IV. Fluctuation in living cells (two papers) V. Mathematical methods related to other problems in biology, epidemiology, population dynamics, etc. (six papers) An important f...

  11. Biological warfare agents

    Directory of Open Access Journals (Sweden)

    Duraipandian Thavaselvam

    2010-01-01

    Full Text Available The recent bioterrorist attacks using anthrax spores have emphasized the need to detect and decontaminate critical facilities in the shortest possible time. There has been a remarkable progress in the detection, protection and decontamination of biological warfare agents as many instrumentation platforms and detection methodologies are developed and commissioned. Even then the threat of biological warfare agents and their use in bioterrorist attacks still remain a leading cause of global concern. Furthermore in the past decade there have been threats due to the emerging new diseases and also the re-emergence of old diseases and development of antimicrobial resistance and spread to new geographical regions. The preparedness against these agents need complete knowledge about the disease, better research and training facilities, diagnostic facilities and improved public health system. This review on the biological warfare agents will provide information on the biological warfare agents, their mode of transmission and spread and also the detection systems available to detect them. In addition the current information on the availability of commercially available and developing technologies against biological warfare agents has also been discussed. The risk that arise due to the use of these agents in warfare or bioterrorism related scenario can be mitigated with the availability of improved detection technologies.

  12. Information Complexity and Biology

    Science.gov (United States)

    Bagnoli, Franco; Bignone, Franco A.; Cecconi, Fabio; Politi, Antonio

    Kolmogorov contributed directly to Biology in essentially three problems: the analysis of population dynamics (Lotka-Volterra equations), the reaction-diffusion formulation of gene spreading (FKPP equation), and some discussions about Mendel's laws. However, the widely recognized importance of his contribution arises from his work on algorithmic complexity. In fact, the limited direct intervention in Biology reflects the generally slow growth of interest of mathematicians towards biological issues. From the early work of Vito Volterra on species competition, to the slow growth of dynamical systems theory, contributions to the study of matter and the physiology of the nervous system, the first 50-60 years have witnessed important contributions, but as scattered pieces apparently uncorrelated, and in branches often far away from Biology. Up to the 40' it is hard to see the initial loose build up of a convergence, for those theories that will become mainstream research by the end of the century, and connected by the study of biological systems per-se.

  13. Systems Biology Graphical Notation: Process Description language Level 1 Version 1.3.

    Science.gov (United States)

    Moodie, Stuart; Le Novère, Nicolas; Demir, Emek; Mi, Huaiyu; Villéger, Alice

    2015-09-04

    The Systems Biological Graphical Notation (SBGN) is an international community effort for standardized graphical representations of biological pathways and networks. The goal of SBGN is to provide unambiguous pathway and network maps for readers with different scientific backgrounds as well as to support efficient and accurate exchange of biological knowledge between different research communities, industry, and other players in systems biology. Three SBGN languages, Process Description (PD), Entity Relationship (ER) and Activity Flow (AF), allow for the representation of different aspects of biological and biochemical systems at different levels of detail. The SBGN Process Description language represents biological entities and processes between these entities within a network. SBGN PD focuses on the mechanistic description and temporal dependencies of biological interactions and transformations. The nodes (elements) are split into entity nodes describing, e.g., metabolites, proteins, genes and complexes, and process nodes describing, e.g., reactions and associations. The edges (connections) provide descriptions of relationships (or influences) between the nodes, such as consumption, production, stimulation and inhibition. Among all three languages of SBGN, PD is the closest to metabolic and regulatory pathways in biological literature and textbooks, but its well-defined semantics offer a superior precision in expressing biological knowledge.

  14. Integrative analysis of RUNX1 downstream pathways and target genes

    Directory of Open Access Journals (Sweden)

    Liu Marjorie

    2008-07-01

    Full Text Available Abstract Background The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML. The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia. Results Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1 cell lines with RUNX1 mutations from FPD-AML patients, 2 over-expression of RUNX1 and CBFβ, and 3 Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBFβ. A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation, microtubule dynamics and possibly genetic stability. In addition, analysis of the regulatory regions of the differentially expressed genes has for the first time systematically identified numerous potential novel RUNX1 target genes. Conclusion This work is the first large-scale study attempting to identify the genetic networks regulated by RUNX1, a master regulator in the development of the hematopoietic system and leukemia. The biological pathways and target genes controlled by RUNX1 will have considerable importance in disease

  15. Fostering synergy between cell biology and systems biology

    OpenAIRE

    2015-01-01

    In the shared pursuit of elucidating detailed mechanisms of cell function, systems biology presents a natural complement to ongoing efforts in cell biology. Systems biology aims to characterize biological systems through integrated and quantitative modeling of cellular information. The process of model building and analysis provides value through synthesizing and cataloging information about cells and molecules; predicting mechanisms and identifying generalizable themes; generating hypotheses...

  16. Informing biological design by integration of systems and synthetic biology.

    Science.gov (United States)

    Smolke, Christina D; Silver, Pamela A

    2011-03-18

    Synthetic biology aims to make the engineering of biology faster and more predictable. In contrast, systems biology focuses on the interaction of myriad components and how these give rise to the dynamic and complex behavior of biological systems. Here, we examine the synergies between these two fields.

  17. Introduction: Applying Chemical Biology to Ion Channels.

    Science.gov (United States)

    Pless, Stephan A; Ahern, Christopher A

    2015-01-01

    Ion channels are membrane-spanning proteins that control the flow of ions across biological membranes through an aqueous pathway. The opening or closing of this pore can be controlled by a myriad of physiological inputs (voltage, ligands, temperature, metabolites, pH), which in turn allow for the controlled flux of ions across membranes, resulting in the generation of minute electrical signals. The functional implications of ion channel function on physiological processes are vast. Electrical impulses, in the form of action potentials or diverse chemo-electrical signals, coordinate the syncytium of the heart beat, support a myriad of neuronal communication pathways, insulin secretion, and are central to the immune response, with more roles being discovered virtually everyday. Thus, ion channel function is a biophysical process that is central to biological life at many levels. And with over 500 channel-forming subunits known today in humans, this large class of proteins is also increasingly recognised as important drug targets, as inherited or acquired ion channel dysfunction are known causes of disease.

  18. Pathway analysis of kidney cancer using proteomics and metabolic profiling

    Directory of Open Access Journals (Sweden)

    Fiehn Oliver

    2006-11-01

    Full Text Available Abstract Background Renal cell carcinoma (RCC is the sixth leading cause of cancer death and is responsible for 11,000 deaths per year in the US. Approximately one-third of patients present with disease which is already metastatic and for which there is currently no adequate treatment, and no biofluid screening tests exist for RCC. In this study, we have undertaken a comprehensive proteomic analysis and subsequently a pathway and network approach to identify biological processes involved in clear cell RCC (ccRCC. We have used these data to investigate urinary markers of RCC which could be applied to high-risk patients, or to those being followed for recurrence, for early diagnosis and treatment, thereby substantially reducing mortality of this disease. Results Using 2-dimensional electrophoresis and mass spectrometric analysis, we identified 31 proteins which were differentially expressed with a high degree of significance in ccRCC as compared to adjacent non-malignant tissue, and we confirmed some of these by immunoblotting, immunohistochemistry, and comparison to published transcriptomic data. When evaluated by several pathway and biological process analysis programs, these proteins are demonstrated to be involved with a high degree of confidence (p values Conclusion Extensive pathway and network analysis allowed for the discovery of highly significant pathways from a set of clear cell RCC samples. Knowledge of activation of these processes will lead to novel assays identifying their proteomic and/or metabolomic signatures in biofluids of patient at high risk for this disease; we provide pilot data for such a urinary bioassay. Furthermore, we demonstrate how the knowledge of networks, processes, and pathways altered in kidney cancer may be used to influence the choice of optimal therapy.

  19. ERβ induces the differentiation of cultured osteoblasts by both Wnt/β-catenin signaling pathway and estrogen signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Yin, Xinhua [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China); Wang, Xiaoyuan [Department of Nephrology, Xi An Honghui Hospital, Xi an (China); Hu, Xiongke; Chen, Yong; Zeng, Kefeng [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China); Zhang, Hongqi, E-mail: zhq9699@126.com [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China)

    2015-07-01

    Although 17β-estradial (E2) is known to stimulate bone formation, the underlying mechanisms are not fully understood. Recent studies have implicated the Wnt/β-catenin pathway as a major signaling cascade in bone biology. The interactions between Wnt/β-catenin signaling pathway and estrogen signaling pathways have been reported in many tissues. In this study, E2 significantly increased the expression of β-catenin by inducing phosphorylations of GSK3β at serine 9. ERβ siRNAs were transfected into MC3T3-E1 cells and revealed that ERβ involved E2-induced osteoblasts proliferation and differentiation via Wnt/β-catenin signaling. The osteoblast differentiation genes (BGP, ALP and OPN) and proliferation related gene (cyclin D1) expression were significantly induced by E2-mediated ERβ. Furthermore immunofluorescence and immunoprecipitation analysis demonstrated that E2 induced the accumulation of β-catenin protein in the nucleus which leads to interaction with T-cell-specific transcription factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors. Taken together, these findings suggest that E2 promotes osteoblastic proliferation and differentiation by inducing proliferation-related and differentiation-related gene expression via ERβ/GSK-3β-dependent Wnt/β-catenin signaling pathway. Our findings provide novel insights into the mechanisms of action of E2 in osteoblastogenesis. - Highlights: • 17β-estradial (E2) promotes GSK3-β phosphorylation. • E2 activates the Wnt/β-catenin signaling pathway. • The Wnt/β-catenin signaling pathway interacts with estrogen signaling pathways. • E2-mediated ER induced osteoblast differentiation and proliferation related genes expression.

  20. Biological applications of nanobiotechnology.

    Science.gov (United States)

    de Morais, Michele Greque; Martins, Vilásia Guimarães; Steffens, Daniela; Pranke, Patricia; da Costa, Jorge Alberto Vieira

    2014-01-01

    Nanotechnology is a multidisciplinary field that covers a vast and diverse array of devices derived from engineering, physics, chemistry, and biology. Nanotechnology has opened up by rapid advances in science and technology, creating new opportunities for advances in the fields of medicine, electronics, foods, and the environment. Nanoscale structures and materials (nanoparticles, nanowires, nanofibers, nanotubes) have been explored in many biological applications (biosensing, biological separation, molecular imaging, anticancer therapy) because their novel properties and functions differ drastically from their bulk counterparts. Their high volume/surface ratio, improved solubility, and multifunctionality open many new possibilities. The objective of this review is to describe the potential benefits and impacts of the nanobiotechnology in different areas.

  1. Epigenetics: Biology's Quantum Mechanics

    Directory of Open Access Journals (Sweden)

    Richard A Jorgensen

    2011-04-01

    Full Text Available The perspective presented here is that modern genetics is at a similar stage of development as were early formulations of quantum mechanics theory in the 1920's and that in 2010 we are at the dawn of a new revolution in genetics that promises to enrich and deepen our understanding of the gene and the genome. The interrelationships and interdependence of two views of the gene - the molecular biological view and the epigenetic view - are explored, and it is argued that the classical molecular biological view is incomplete without incorporation of the epigenetic perspective and that in a sense the molecular biological view has been evolving to include the epigenetic view. Intriguingly, this evolution of the molecular view toward the broader and more inclusive epigenetic view of the gene has an intriguing, if not precise, parallel in the evolution of concepts of atomic physics from Newtonian mechanics to quantum mechanics that are interesting to consider.

  2. Epigenetics: Biology's Quantum Mechanics.

    Science.gov (United States)

    Jorgensen, Richard A

    2011-01-01

    The perspective presented here is that modern genetics is at a similar stage of development as were early formulations of quantum mechanics theory in the 1920s and that in 2010 we are at the dawn of a new revolution in genetics that promises to enrich and deepen our understanding of the gene and the genome. The interrelationships and interdependence of two views of the gene - the molecular biological view and the epigenetic view - are explored, and it is argued that the classical molecular biological view is incomplete without incorporation of the epigenetic perspective and that in a sense the molecular biological view has been evolving to include the epigenetic view. Intriguingly, this evolution of the molecular view toward the broader and more inclusive epigenetic view of the gene has an intriguing, if not precise, parallel in the evolution of concepts of atomic physics from Newtonian mechanics to quantum mechanics that are interesting to consider.

  3. [Biologics in SLE].

    Science.gov (United States)

    Karonitsch, Thomas; Aringer, Martin

    2015-01-01

    Biologics have become indispensable in the last decade in the treatment of the more common rheumatic diseases. For treating systemic lupus erythematodes (SLE), B-cell depletion, albeit off-label, has been a well-accepted strategy in severe and refractory disease. Unexpectedly, however, the results of the first randomized controlled rituximab trials in SLE were negative. New trials with improved study protocols are ongoing, which should resolve this issue. In 2012, with the approval of belimumab, SLE finally entered the era of approved biological therapies. The anti-Blys/BAFF antibody belimumab showed prevention of SLE flares, glucocorticoid sparing, and significant improvement in the quality of life of SLE patients, in part by drastically reducing immune complex mediated fatigue. Positive reports on further targeting approaches give hope that additional biological agents will be available for SLE therapy soon.

  4. Biological therapy of psoriasis

    Directory of Open Access Journals (Sweden)

    Sivamani Raja

    2010-01-01

    Full Text Available The treatment of psoriasis has undergone a revolution with the advent of biologic therapies, including infliximab, etanercept, adalimumab, efalizumab, and alefacept. These medications are designed to target specific components of the immune system and are a major technological advancement over traditional immunosuppressive medications. These usually being well tolerated are being found useful in a growing number of immune-mediated diseases, psoriasis being just one example. The newest biologic, ustekinumab, is directed against the p40 subunit of the IL-12 and IL-23 cytokines. It has provided a new avenue of therapy for an array of T-cell-mediated diseases. Biologics are generally safe; however, there has been concern over the risk of lymphoma with use of these agents. All anti-TNF-α agents have been associated with a variety of serious and "routine" opportunistic infections.

  5. Biological Soft Robotics.

    Science.gov (United States)

    Feinberg, Adam W

    2015-01-01

    In nature, nanometer-scale molecular motors are used to generate force within cells for diverse processes from transcription and transport to muscle contraction. This adaptability and scalability across wide temporal, spatial, and force regimes have spurred the development of biological soft robotic systems that seek to mimic and extend these capabilities. This review describes how molecular motors are hierarchically organized into larger-scale structures in order to provide a basic understanding of how these systems work in nature and the complexity and functionality we hope to replicate in biological soft robotics. These span the subcellular scale to macroscale, and this article focuses on the integration of biological components with synthetic materials, coupled with bioinspired robotic design. Key examples include nanoscale molecular motor-powered actuators, microscale bacteria-controlled devices, and macroscale muscle-powered robots that grasp, walk, and swim. Finally, the current challenges and future opportunities in the field are addressed.

  6. Biological therapy and dentistry

    Science.gov (United States)

    Radfar, Lida; Ahmadabadi, Roshanak E; Masood, Farah; Scofield, R Hal

    2016-01-01

    In recent years, a new class of drugs has revolutionized the treatment of autoimmune, allergic, infectious and many more diseases. These drugs are classified into three groups, cytokines, monoclonal antibodies and fusion proteins. Biological drugs have less side effects compared to conventional drugs, and may target special damaged cells, but not all the cells. There may be side effects such as infection, hypersensitivity, hematological disorders, cancer, hepatotoxicity and neurological disorders, but there is not enough evidence or long term studies of the mechanism of action and side effects of these drugs. Patients on biological therapy may need some special consideration in dentistry. This paper is a review regarding the classification, mechanism of action and side effects of these drugs, and dental consideration for patients on biological therapy. PMID:26372436

  7. The biology of personality.

    Science.gov (United States)

    Mulder, R

    1992-09-01

    Historically, models of personality have generally postulated, or assumed, a link with biology. This century has witnessed a major revision of these ideas with both behavioural and psychoanalytic theorists emphasising life experiences as being largely responsible for behaviour as adults. Challenges to this assumption of the overwhelming importance of life experiences are reviewed. An extensive body of data now exists suggesting that biology contributes significantly to individual variability. This biological contribution occurs at a relatively low level in the central nervous system, best defined as temperament. Further research has suffered from the lack of a cohesive psychobiological model. Cloninger's tridimensional theory of personality is presented as a model which attempts to bridge the gap between theoretical temperamental traits, neurotransmitter function and clinical psychiatry. It is to be hoped that new theoretical models will be formulated which will focus on the importance of temperamental variables in psychiatric disorders.

  8. A simple biosynthetic pathway for large product generation from small substrate amounts

    Science.gov (United States)

    Djordjevic, Marko; Djordjevic, Magdalena

    2012-10-01

    A recently emerging discipline of synthetic biology has the aim of constructing new biosynthetic pathways with useful biological functions. A major application of these pathways is generating a large amount of the desired product. However, toxicity due to the possible presence of toxic precursors is one of the main problems for such production. We consider here the problem of generating a large amount of product from a potentially toxic substrate. To address this, we propose a simple biosynthetic pathway, which can be induced in order to produce a large number of the product molecules, by keeping the substrate amount at low levels. Surprisingly, we show that the large product generation crucially depends on fast non-specific degradation of the substrate molecules. We derive an optimal induction strategy, which allows as much as three orders of magnitude increase in the product amount through biologically realistic parameter values. We point to a recently discovered bacterial immune system (CRISPR/Cas in E. coli) as a putative example of the pathway analysed here. We also argue that the scheme proposed here can be used not only as a stand-alone pathway, but also as a strategy to produce a large amount of the desired molecules with small perturbations of endogenous biosynthetic pathways.

  9. Systems biology approaches to understand natural products biosynthesis

    Directory of Open Access Journals (Sweden)

    Cuauhtemoc eLicona-Cassani

    2015-12-01

    Full Text Available Actinomycetes populate soils and aquatic sediments which impose biotic and abiotic challenges for their survival. As a result, actinomycetes metabolism and genomes have evolved to produce an overwhelming diversity of specialized molecules. Polyketides, non-ribosomal peptides, post-translationally modified peptides, lactams and terpenes are well known bioactive natural products with enormous industrial potential. Accessing such biological diversity has proven difficult due to the complex regulation of cellular metabolism in actinomycetes and to the sparse knowledge of their physiology. The past decade, however, has seen the development of omics technologies that have significantly contributed to our better understanding of their biology. Key observations have contributed towards a shift in the exploitation of actinomycetes biology, such as using their full genomic potential, activating entire pathways through key metabolic elicitors and pathway engineering to improve biosynthesis. Here, we review recent efforts devoted to achieving enhanced discovery, activation and manipulation of natural product biosynthetic pathways in model actinomycetes using genome-scale biological datasets.

  10. 7th Annual Systems Biology Symposium: Systems Biology and Engineering

    Energy Technology Data Exchange (ETDEWEB)

    Galitski, Timothy P.

    2008-04-01

    Systems biology recognizes the complex multi-scale organization of biological systems, from molecules to ecosystems. The International Symposium on Systems Biology has been hosted by the Institute for Systems Biology in Seattle, Washington, since 2002. The annual two-day event gathers the most influential researchers transforming biology into an integrative discipline investingating complex systems. Engineering and application of new technology is a central element of systems biology. Genome-scale, or very small-scale, biological questions drive the enigneering of new technologies, which enable new modes of experimentation and computational analysis, leading to new biological insights and questions. Concepts and analytical methods in engineering are now finding direct applications in biology. Therefore, the 2008 Symposium, funded in partnership with the Department of Energy, featured global leaders in "Systems Biology and Engineering."

  11. Selection platforms for directed evolution in synthetic biology.

    Science.gov (United States)

    Tizei, Pedro A G; Csibra, Eszter; Torres, Leticia; Pinheiro, Vitor B

    2016-08-15

    Life on Earth is incredibly diverse. Yet, underneath that diversity, there are a number of constants and highly conserved processes: all life is based on DNA and RNA; the genetic code is universal; biology is limited to a small subset of potential chemistries. A vast amount of knowledge has been accrued through describing and characterizing enzymes, biological processes and organisms. Nevertheless, much remains to be understood about the natural world. One of the goals in Synthetic Biology is to recapitulate biological complexity from simple systems made from biological molecules-gaining a deeper understanding of life in the process. Directed evolution is a powerful tool in Synthetic Biology, able to bypass gaps in knowledge and capable of engineering even the most highly conserved biological processes. It encompasses a range of methodologies to create variation in a population and to select individual variants with the desired function-be it a ligand, enzyme, pathway or even whole organisms. Here, we present some of the basic frameworks that underpin all evolution platforms and review some of the recent contributions from directed evolution to synthetic biology, in particular methods that have been used to engineer the Central Dogma and the genetic code.

  12. [Cybernetics and biology].

    Science.gov (United States)

    Vasil'ev, G F

    2013-01-01

    Owing to methodical disadvantages, the theory of control still lacks the potential for the analysis of biological systems. To get the full benefit of the method in addition to the algorithmic model of control (as of today the only used model in the theory of control) a parametric model of control is offered to employ. The reasoning for it is explained. The approach suggested provides the possibility to use all potential of the modern theory of control for the analysis of biological systems. The cybernetic approach is shown taking a system of the rise of glucose concentration in blood as an example.

  13. PAC research in biology

    Energy Technology Data Exchange (ETDEWEB)

    Chain, C. Y., E-mail: yamil@fisica.unlp.edu.ar [Universidad Nacional de La Plata, IFLP (Argentina); Ceolin, M. [Instituto de Investigaciones Fisicoquimicas Teoricas y Aplicadas, Dto de Quimica, Fac. Cs. Exactas, UNLP (Argentina); Pasquevich, A. F. [Universidad Nacional de La Plata, IFLP (Argentina)

    2008-01-15

    In this paper possible applications of the Perturbed Angular Correlations (PAC) technique in Biology are considered. Previous PAC experiments in biology are globally analyzed. All the work that appears in the literature has been grouped in a few research lines, just to make the analysis and discussion easy. The commonly used radioactive probes are listed and the experimental difficulties are analyzed. We also report applications of {sup 181}Hf and {sup 111}In isotopes in life sciences other than their use in PAC. The possibility of extending these studies using the PAC technique is discussed.

  14. Biological and Pharmaceutical Nanomaterials

    Science.gov (United States)

    Kumar, Challa S. S. R.

    2006-01-01

    This first comprehensive yet concise overview of all important classes of biological and pharmaceutical nanomaterials presents in one volume the different kinds of natural biological compounds that form nanomaterials or that may be used to purposefully create them. This unique single source of information brings together the many articles published in specialized journals, which often remain unseen by members of other, related disciplines. Covering pharmaceutical, nucleic acid, peptide and DNA-Chitosan nanoparticles, the book focuses on those innovative materials and technologies needed for the continued growth of medicine, healthcare, pharmaceuticals and human wellness. For chemists, biochemists, cell biologists, materials scientists, biologists, and those working in the pharmaceutical and chemical industries.

  15. Pivotal role of the muscle-contraction pathway in cryptorchidism and evidence for genomic connections with cardiomyopathy pathways in RASopathies

    KAUST Repository

    Cannistraci, Carlo

    2013-02-14

    Background: Cryptorchidism is the most frequent congenital disorder in male children; however the genetic causes of cryptorchidism remain poorly investigated. Comparative integratomics combined with systems biology approach was employed to elucidate genetic factors and molecular pathways underlying testis descent. Methods. Literature mining was performed to collect genomic loci associated with cryptorchidism in seven mammalian species. Information regarding the collected candidate genes was stored in MySQL relational database. Genomic view of the loci was presented using Flash GViewer web tool (http://gmod.org/wiki/Flashgviewer/). DAVID Bioinformatics Resources 6.7 was used for pathway enrichment analysis. Cytoscape plug-in PiNGO 1.11 was employed for protein-network-based prediction of novel candidate genes. Relevant protein-protein interactions were confirmed and visualized using the STRING database (version 9.0). Results. The developed cryptorchidism gene atlas includes 217 candidate loci (genes, regions involved in chromosomal mutations, and copy number variations) identified at the genomic, transcriptomic, and proteomic level. Human orthologs of the collected candidate loci were presented using a genomic map viewer. The cryptorchidism gene atlas is freely available online: http://www.integratomics-time.com/cryptorchidism/. Pathway analysis suggested the presence of twelve enriched pathways associated with the list of 179 literature-derived candidate genes. Additionally, a list of 43 network-predicted novel candidate genes was significantly associated with four enriched pathways. Joint pathway analysis of the collected and predicted candidate genes revealed the pivotal importance of the muscle-contraction pathway in cryptorchidism and evidence for genomic associations with cardiomyopathy pathways in RASopathies. Conclusions: The developed gene atlas represents an important resource for the scientific community researching genetics of cryptorchidism. The

  16. Pathway analysis of expression-related SNPs on genome-wide association study of basal cell carcinoma

    Science.gov (United States)

    Li, Xin; Liang, Liming; De Vivo, Immaculata; Tang, Jean Y.; Han, Jiali

    2016-01-01

    Genome-wide association studies (GWASs) have primarily focused on the association between individual genetic markers and risk of disease. We applied a novel approach that integrates skin expression-related single-nucleotide polymorphisms (eSNPs) and pathway analysis for GWAS of basal cell carcinoma (BCC) to identify potential novel biological pathways. We evaluated the associations between 70,932 skin eSNPs and risk of BCC among 2,323 cases and 7,275 controls of European ancestry, and then assigned them to the pathways defined by KEGG, GO, and BioCarta databases. Three KEGG pathways (colorectal cancer, actin cytoskeleton, and BCC), two GO pathways (cellular component disassembly in apoptosis, and nucleus organization), and four BioCarta pathways (Ras signaling, T cell receptor signaling, natural killer cell-mediated cytotoxicity, and links between Pyk2 and Map Kinases) showed significant association with BCC risk with p-value<0.05 and FDR<0.2. These pathways also ranked at top in sensitivity analyses. Two positive controls in KEGG, the hedgehog pathway and the BCC pathway, showed significant association with BCC risk in both main and sensitivity analyses. Our results indicate that SNPs that are undetectable by conventional GWASs are significantly associated with BCC when tested as pathways. Biological studies of these gene groups suggest their potential roles in the etiology of BCC. PMID:27367190

  17. Incorporation of enzyme concentrations into FBA and identification of optimal metabolic pathways

    Directory of Open Access Journals (Sweden)

    Mukhopadhyay Subhasis

    2008-07-01

    Full Text Available Abstract Background In the present article, we propose a method for determining optimal metabolic pathways in terms of the level of concentration of the enzymes catalyzing various reactions in the entire metabolic network. The method, first of all, generates data on reaction fluxes in a pathway based on steady state condition. A set of constraints is formulated incorporating weighting coefficients corresponding to concentration of enzymes catalyzing reactions in the pathway. Finally, the rate of yield of the target metabolite, starting with a given substrate, is maximized in order to identify an optimal pathway through these weighting coefficients. Results The effectiveness of the present method is demonstrated on two synthetic systems existing in the literature, two pentose phosphate, two glycolytic pathways, core carbon metabolism and a large network of carotenoid biosynthesis pathway of various organisms belonging to different phylogeny. A comparative study with the existing extreme pathway analysis also forms a part of this investigation. Biological relevance and validation of the results are provided. Finally, the impact of the method on metabolic engineering is explained with a few examples. Conclusions The method may be viewed as determining an optimal set of enzymes that is required to get an optimal metabolic pathway. Although it is a simple one, it has been able to identify a carotenoid biosynthesis pathway and the optimal pathway of core carbon metabolic network that is closer to some earlier investigations than that obtained by the extreme pathway analysis. Moreover, the present method has identified correctly optimal pathways for pentose phosphate and glycolytic pathways. It has been mentioned using some examples how the method can suitably be used in the context of metabolic engineering.

  18. Systems biology in animal sciences

    NARCIS (Netherlands)

    Woelders, H.; Pas, te M.F.W.; Bannink, A.; Veerkamp, R.F.; Smits, M.A.

    2011-01-01

    Systems biology is a rapidly expanding field of research and is applied in a number of biological disciplines. In animal sciences, omics approaches are increasingly used, yielding vast amounts of data, but systems biology approaches to extract understanding from these data of biological processes an

  19. Cell-free synthetic biology for environmental sensing and remediation.

    Science.gov (United States)

    Karig, David K

    2017-02-19

    The fields of biosensing and bioremediation leverage the phenomenal array of sensing and metabolic capabilities offered by natural microbes. Synthetic biology provides tools for transforming these fields through complex integration of natural and novel biological components to achieve sophisticated sensing, regulation, and metabolic function. However, the majority of synthetic biology efforts are conducted in living cells, and concerns over releasing genetically modified organisms constitute a key barrier to environmental applications. Cell-free protein expression systems offer a path towards leveraging synthetic biology, while preventing the spread of engineered organisms in nature. Recent efforts in the areas of cell-free approaches for sensing, regulation, and metabolic pathway implementation, as well as for preserving and deploying cell-free expression components, embody key steps towards realizing the potential of cell-free systems for environmental sensing and remediation.

  20. Pareto Optimal Design for Synthetic Biology.

    Science.gov (United States)

    Patanè, Andrea; Santoro, Andrea; Costanza, Jole; Carapezza, Giovanni; Nicosia, Giuseppe

    2015-08-01

    Recent advances in synthetic biology call for robust, flexible and efficient in silico optimization methodologies. We present a Pareto design approach for the bi-level optimization problem associated to the overproduction of specific metabolites in Escherichia coli. Our method efficiently explores the high dimensional genetic manipulation space, finding a number of trade-offs between synthetic and biological objectives, hence furnishing a deeper biological insight to the addressed problem and important results for industrial purposes. We demonstrate the computational capabilities of our Pareto-oriented approach comparing it with state-of-the-art heuristics in the overproduction problems of i) 1,4-butanediol, ii) myristoyl-CoA, i ii) malonyl-CoA , iv) acetate and v) succinate. We show that our algorithms are able to gracefully adapt and scale to more complex models and more biologically-relevant simulations of the genetic manipulations allowed. The Results obtained for 1,4-butanediol overproduction significantly outperform results previously obtained, in terms of 1,4-butanediol to biomass formation ratio and knock-out costs. In particular overproduction percentage is of +662.7%, from 1.425 mmolh⁻¹gDW⁻¹ (wild type) to 10.869 mmolh⁻¹gDW⁻¹, with a knockout cost of 6. Whereas, Pareto-optimal designs we have found in fatty acid optimizations strictly dominate the ones obtained by the other methodologies, e.g., biomass and myristoyl-CoA exportation improvement of +21.43% (0.17 h⁻¹) and +5.19% (1.62 mmolh⁻¹gDW⁻¹), respectively. Furthermore CPU time required by our heuristic approach is more than halved. Finally we implement pathway oriented sensitivity analysis, epsilon-dominance analysis and robustness analysis to enhance our biological understanding of the problem and to improve the optimization algorithm capabilities.