Publications

21 Publications visible to you, out of a total of 21

Abstract (Expand)

The liver is the central hub for processing and maintaining homeostatic levels of dietary nutrients especially essential amino acids such as tryptophan (Trp). Trp is required not only to sustain protein synthesis but also as a precursor for the production of NAD, neurotransmitters and immunosuppressive metabolites. In light of these roles of Trp and its metabolic products, maintaining homeostatic levels of Trp is essential for health and well-being. The liver regulates global Trp supply by the immunosuppressive enzyme tryptophan-2,3-dioxygenase (TDO2), which degrades Trp down the kynurenine pathway (KP). In the current study, we show that isolated primary hepatocytes when exposed to hypoxic environments, extensively rewire their Trp metabolism by reducing constitutive Tdo2 expression and differentially regulating other Trp pathway enzymes and transporters. Mathematical modelling of Trp metabolism in liver cells under hypoxia predicted decreased flux through the KP while metabolic flux through the tryptamine branch significantly increased. In line, the model also revealed an increased accumulation of tryptamines under hypoxia, at the expense of kynurenines. Metabolic measurements in hypoxic hepatocytes confirmed the predicted reduction in KP metabolites as well as accumulation of tryptamine. Tdo2 expression in cultured primary hepatocytes was reduced upon hypoxia inducible factor (HIF) stabilisation by dimethyloxalylglycine (DMOG), demonstrating that HIFs are involved in the hypoxic downregulation of hepatic Tdo2. DMOG abrogated hepatic luciferase signals in Tdo2 reporter mice, indicating that HIF stability also recapitulates hypoxic rewiring of Trp metabolism in vivo. Also in WT mice HIF stabilization drove homeostatic Trp metabolism away from the KP towards enhanced tryptamine production, leading to enhanced levels of tryptamine in liver, serum and brain. As tryptamines are the most potent hallucinogens known, the observed upregulation of tryptamine in response to hypoxic exposure of hepatocytes may be involved in the generation of hallucinations occurring at high altitude. KP metabolites are known to activate the aryl hydrocarbon receptor (AHR). The AHR-activating properties of tryptamines may explain why immunosuppressive AHR activity is maintained under hypoxia despite downregulation of the KP. In summary our results identify hypoxia as an important factor controlling Trp metabolism in the liver with possible implications for immunosuppressive AHR activation and mental disturbances.

Authors: S. R. Mohapatra, A. Sadik, S. Sharma, G. Poschet, H. M. Gegner, T. V. Lanz, P. Lucarelli, U. Klingmuller, M. Platten, I. Heiland, C. A. Opitz

Date Published: 8th Mar 2021

Publication Type: Journal

Abstract (Expand)

This paper presents a report on outcomes of the 10th Computational Modeling in Biology Network (COMBINE) meeting that was held in Heidelberg, Germany, in July of 2019. The annual event brings together researchers, biocurators and software engineers to present recent results and discuss future work in the area of standards for systems and synthetic biology. The COMBINE initiative coordinates the development of various community standards and formats for computational models in the life sciences. Over the past 10 years, COMBINE has brought together standard communities that have further developed and harmonized their standards for better interoperability of models and data. COMBINE 2019 was co-located with a stakeholder workshop of the European EU-STANDS4PM initiative that aims at harmonized data and model standardization for in silico models in the field of personalized medicine, as well as with the FAIRDOM PALs meeting to discuss findable, accessible, interoperable and reusable (FAIR) data sharing. This report briefly describes the work discussed in invited and contributed talks as well as during breakout sessions. It also highlights recent advancements in data, model, and annotation standardization efforts. Finally, this report concludes with some challenges and opportunities that this community will face during the next 10 years.

Authors: Dagmar Waltemath, Martin Golebiewski, Michael L Blinov, Padraig Gleeson, Henning Hermjakob, Michael Hucka, Esther Thea Inau, Sarah M Keating, Matthias König, Olga Krebs, Rahuman S Malik-Sheriff, David Nickerson, Ernst Oberortner, Herbert M Sauro, Falk Schreiber, Lucian Smith, Melanie I Stefan, Ulrike Wittig, Chris J Myers

Date Published: 29th Jun 2020

Publication Type: Journal

Abstract (Expand)

This special issue of the Journal of Integrative Bioinformatics presents papers related to the 10th COMBINE meeting together with the annual update of COMBINE standards in systems and synthetic biology.Not specified

Authors: Falk Schreiber, Björn Sommer, Tobias Czauderna, Martin Golebiewski, Thomas E. Gorochowski, Michael Hucka, Sarah M. Keating, Matthias König, Chris Myers, David Nickerson, Dagmar Waltemath

Date Published: 29th Jun 2020

Publication Type: Journal

Abstract (Expand)

The mechanisms of organ size control remain poorly understood. A key question is how cells collectively sense the overall status of a tissue. We addressed this problem focusing on mouse liver regeneration. Using digital tissue reconstruction and quantitative image analysis, we found that the apical surface of hepatocytes forming the bile canalicular network expands concomitant with an increase in F-actin and phospho-myosin, to compensate an overload of bile acids. These changes are sensed by the Hippo transcriptional co-activator YAP, which localizes to apical F-actin-rich regions and translocates to the nucleus in dependence of the integrity of the actin cytoskeleton. This mechanism tolerates moderate bile acid fluctuations under tissue homeostasis, but activates YAP in response to sustained bile acid overload. Using an integrated biophysical-biochemical model of bile pressure and Hippo signaling, we explained this behavior by the existence of a mechano-sensory mechanism that activates YAP in a switch-like manner. We propose that the apical surface of hepatocytes acts as a self-regulatory mechano-sensory system that responds to critical levels of bile acids as readout of tissue status.

Authors: K. Meyer, H. Morales-Navarrete, S. Seifert, M. Wilsch-Braeuninger, U. Dahmen, E. M. Tanaka, L. Brusch, Y. Kalaidzidis, M. Zerial

Date Published: 25th Feb 2020

Publication Type: Journal

Abstract (Expand)

The Hedgehog (Hh) and Wnt/beta-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well.

Authors: E. Kolbe, S. Aleithe, C. Rennert, L. Spormann, F. Ott, D. Meierhofer, R. Gajowski, C. Stopel, S. Hoehme, M. Kucken, L. Brusch, M. Seifert, W. von Schoenfels, C. Schafmayer, M. Brosch, U. Hofmann, G. Damm, D. Seehofer, J. Hampe, R. Gebhardt, M. Matz-Soja

Date Published: 24th Dec 2019

Publication Type: Journal

Abstract (Expand)

Computational systems biology involves integrating heterogeneous datasets in order to generate models. These models can assist with understanding and prediction of biological phenomena. Generating datasets and integrating them into models involves a wide range of scientific expertise. As a result these datasets are often collected by one set of researchers, and exchanged with others researchers for constructing the models. For this process to run smoothly the data and models must be FAIR-findable, accessible, interoperable, and reusable. In order for data and models to be FAIR they must be structured in consistent and predictable ways, and described sufficiently for other researchers to understand them. Furthermore, these data and models must be shared with other researchers, with appropriately controlled sharing permissions, before and after publication. In this chapter we explore the different data and model standards that assist with structuring, describing, and sharing. We also highlight the popular standards and sharing databases within computational systems biology.

Authors: N. J. Stanford, M. Scharm, P. D. Dobson, M. Golebiewski, M. Hucka, V. B. Kothamachu, D. Nickerson, S. Owen, J. Pahle, U. Wittig, D. Waltemath, C. Goble, P. Mendes, J. Snoep

Date Published: 12th Oct 2019

Publication Type: Journal

Abstract (Expand)

This special issue of the Journal of Integrative Bioinformatics presents an overview of COMBINE standards and their latest specifications. The standards cover representation formats for computational modeling in synthetic and systems biology and include BioPAX, CellML, NeuroML, SBML, SBGN, SBOL and SED-ML. The articles in this issue contain updated specifications of SBGN Process Description Level 1 Version 2, SBML Level 3 Core Version 2 Release 2, SBOL Version 2.3.0, and SBOL Visual Version 2.1.

Authors: Falk Schreiber, Björn Sommer, Gary D. Bader, Padraig Gleeson, Martin Golebiewski, Michael Hucka, Sarah M. Keating, Matthias König, Chris Myers, David Nickerson, Dagmar Waltemath

Date Published: 13th Jul 2019

Publication Type: Journal

Abstract (Expand)

Life science researchers use computational models to articulate and test hypotheses about the behavior of biological systems. Semantic annotation is a critical component for enhancing the interoperability and reusability of such models as well as for the integration of the data needed for model parameterization and validation. Encoded as machine-readable links to knowledge resource terms, semantic annotations describe the computational or biological meaning of what models and data represent. These annotations help researchers find and repurpose models, accelerate model composition and enable knowledge integration across model repositories and experimental data stores. However, realizing the potential benefits of semantic annotation requires the development of model annotation standards that adhere to a community-based annotation protocol. Without such standards, tool developers must account for a variety of annotation formats and approaches, a situation that can become prohibitively cumbersome and which can defeat the purpose of linking model elements to controlled knowledge resource terms. Currently, no consensus protocol for semantic annotation exists among the larger biological modeling community. Here, we report on the landscape of current annotation practices among the COmputational Modeling in BIology NEtwork community and provide a set of recommendations for building a consensus approach to semantic annotation.

Authors: Maxwell Lewis Neal, Matthias König, David Nickerson, Göksel Mısırlı, Reza Kalbasi, Andreas Dräger, Koray Atalag, Vijayalakshmi Chelliah, Michael T Cooling, Daniel L Cook, Sharon Crook, Miguel de Alba, Samuel H Friedman, Alan Garny, John H Gennari, Padraig Gleeson, Martin Golebiewski, Michael Hucka, Nick Juty, Chris Myers, Brett G Olivier, Herbert M Sauro, Martin Scharm, Jacky L Snoep, Vasundra Touré, Anil Wipat, Olaf Wolkenhauer, Dagmar Waltemath

Date Published: 1st Mar 2019

Publication Type: Journal

Abstract (Expand)

Data standards support the reliable exchange of information, the interoperability of tools, and the reproducibility of scientific results. In systems biology standards are agreed ways of structuring, describing, and associating models and data, as well as their respective parts, graphical visualization, and information about applied experimental or computational methods. Such standards also assist with describing how constituent parts interact together, or are linked, and how they are embedded in their environmental and experimental context. Here the focus will be on standards for formatting models and their content, and on metadata checklists and ontologies that support modeling.

Author: Martin Golebiewski

Date Published: 2019

Publication Type: InBook

Abstract

Not specified

Authors: Falk Schreiber, Gary D. Bader, Padraig Gleeson, Martin Golebiewski, Michael Hucka, Sarah M. Keating, Nicolas Le Novère, Chris Myers, David Nickerson, Björn Sommer, Dagmar Waltemath

Date Published: 29th Mar 2018

Publication Type: Journal

Abstract (Expand)

Chemical reaction networks are ubiquitous in biology, and their dynamics is fundamentally stochastic. Here, we present the software library pSSAlib, which provides a complete and concise implementation of the most efficient partial-propensity methods for simulating exact stochastic chemical kinetics. pSSAlib can import models encoded in Systems Biology Markup Language, supports time delays in chemical reactions, and stochastic spatiotemporal reaction-diffusion systems. It also provides tools for statistical analysis of simulation results and supports multiple output formats. It has previously been used for studies of biochemical reaction pathways and to benchmark other stochastic simulation methods. Here, we describe pSSAlib in detail and apply it to a new model of the endocytic pathway in eukaryotic cells, leading to the discovery of a stochastic counterpart of the cut-out switch motif underlying early-to-late endosome conversion. pSSAlib is provided as a stand-alone command-line tool and as a developer API. We also provide a plug-in for the SBMLToolbox. The open-source code and pre-packaged installers are freely available from http://mosaic.mpi-cbg.de.

Authors: Oleksandr Ostrenko, Pietro Incardona, Rajesh Ramaswamy, Lutz Brusch, Ivo F. Sbalzarini

Date Published: 4th Dec 2017

Publication Type: Not specified

Abstract (Expand)

Standards for data exchange are critical to the development of any field. They enable researchers and practitioners to transport information reliably, to apply a variety of tools to their problems, and to reproduce scientific results. Over the past two decades, a range of standards have been developed to facilitate the exchange and reuse of information in the domain of representation and modeling of biological systems. These standards are complementary, so the interactions between their developers increased over time. By the end of the last decade, the community of researchers decided that more interoperability is required between the standards, and that common development is needed to make better use of effort, time, and money devoted to this activity. The COmputational MOdeling in Biology NEtwork (COMBINE) was created to enable the sharing of resources, tools, and other infrastructure. This paper provides a brief history of this endeavor and the challenges that remain.

Authors: Chris J. Myers, Gary Bader, Padraig Gleeson, Martin Golebiewski, Michael Hucka, Nicolas Le Novere, David P. Nickerson, Falk Schreiber, Dagmar Waltemath

Date Published: 1st Dec 2017

Publication Type: InProceedings

Abstract

Not specified

Authors: Wolfgang Müller, Meik Bittkowski, Martin Golebiewski, Renate Kania, Maja Rey, Andreas Weidemann, Ulrike Wittig

Date Published: 1st Mar 2017

Publication Type: Journal

Abstract (Expand)

Standards are essential to the advancement of science and technology. In systems and synthetic biology, numerous standards and associated tools have been developed over the last 16 years. This special issue of the Journal of Integrative Bioinformatics aims to support the exchange, distribution and archiving of these standards, as well as to provide centralised and easily citable access to them.

Authors: F. Schreiber, G. D. Bader, P. Gleeson, M. Golebiewski, M. Hucka, N. Le Novere, C. Myers, D. Nickerson, B. Sommer, D. Walthemath

Date Published: 12th Feb 2017

Publication Type: Not specified

Abstract (Expand)

The FAIRDOMHub is a repository for publishing FAIR (Findable, Accessible, Interoperable and Reusable) Data, Operating procedures and Models (https://fairdomhub.org/) for the Systems Biology community. It is a web-accessible repository for storing and sharing systems biology research assets. It enables researchers to organize, share and publish data, models and protocols, interlink them in the context of the systems biology investigations that produced them, and to interrogate them via API interfaces. By using the FAIRDOMHub, researchers can achieve more effective exchange with geographically distributed collaborators during projects, ensure results are sustained and preserved and generate reproducible publications that adhere to the FAIR guiding principles of data stewardship.

Authors: K. Wolstencroft, O. Krebs, J. L. Snoep, N. J. Stanford, F. Bacall, M. Golebiewski, R. Kuzyakiv, Q. Nguyen, S. Owen, S. Soiland-Reyes, J. Straszewski, D. D. van Niekerk, A. R. Williams, L. Malmstrom, B. Rinn, W. Muller, C. Goble

Date Published: 4th Jan 2017

Publication Type: Journal

Abstract (Expand)

Whole-cell (WC) modeling is a promising tool for biological research, bioengineering, and medicine. However, substantial work remains to create accurate, comprehensive models of complex cells. METHODS: We organized the 2015 Whole-Cell Modeling Summer School to teach WC modeling and evaluate the need for new WC modeling standards and software by recoding a recently published WC model in SBML. RESULTS: Our analysis revealed several challenges to representing WC models using the current standards. CONCLUSION: We, therefore, propose several new WC modeling standards, software, and databases. SIGNIFICANCE: We anticipate that these new standards and software will enable more comprehensive models.

Authors: D. Waltemath, J. Karr, F. Bergmann, V. Chelliah, M. Hucka, M. Krantz, W. Liebermeister, P. Mendes, C. Myers, P. Pir, B. Alaybeyoglu, N. Aranganathan, K. Baghalian, A. Bittig, P. Burke, M. Cantarelli, Y. Chew, R. Costa, J. Cursons, T. Czauderna, A. Goldberg, H. Gomez, J. Hahn, T. Hameri, D. Gardiol, D. Kazakiewicz, I. Kiselev, V. Knight-Schrijver, C. Knupfer, M. Konig, D. Lee, A. Lloret-Villas, N. Mandrik, J. Medley, B. Moreau, H. Naderi-Meshkin, S. Palaniappan, D. Priego-Espinosa, M. Scharm, M. Sharma, K. Smallbone, N. Stanford, J. H. Song, T. Theile, M. Tokic, N. Tomar, V. Toure, J. Uhlendorf, T. Varusai, L. Watanabe, F. Wendland, M. Wolfien, J. Yurkovich, Y. Zhu, A. Zardilis, A. Zhukova, F. Schreiber

Date Published: 16th Jun 2016

Publication Type: Not specified

Abstract (Expand)

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and is increasing in prevalence. The pathomechanisms, however, are poorly understood. This study assessed the unexpected role of the Hedgehog pathway in adult liver lipid metabolism. Using transgenic mice with conditional hepatocyte-specific deletion of Smoothened in adult mice, we showed that hepatocellular inhibition of Hedgehog signaling leads to steatosis by altering the abundance of the transcription factors GLI1 and GLI3. This steatotic 'Gli-code' caused the modulation of a complex network of lipogenic transcription factors and enzymes, including SREBP1 and PNPLA3, as demonstrated by microarray analysis and siRNA experiments and could be confirmed in other steatotic mouse models as well as in steatotic human livers. Conversely, activation of the Hedgehog pathway reversed the "Gli-code" and mitigated hepatic steatosis. Collectively, our results reveal that dysfunctions in the Hedgehog pathway play an important role in hepatic steatosis and beyond.

Authors: Madlen Matz-Soja, Christiane Rennert, Kristin Schönefeld, Susanne Aleithe, Jan Boettger, Wolfgang Schmidt-Heck, Thomas S Weiss, Amalya Hovhannisyan, Sebastian Zellmer, Nora Klöting, Angela Schulz, Jürgen Kratzsch, Reinhardt Guthke, Rolf Gebhardt

Date Published: 17th May 2016

Publication Type: Not specified

Abstract (Expand)

Reconstructing and understanding the Human Physiome virtually is a complex mathematical problem, and a highly demanding computational challenge. Mathematical models spanning from the molecular level through to whole populations of individuals must be integrated, then personalized. This requires interoperability with multiple disparate and geographically separated data sources, and myriad computational software tools. Extracting and producing knowledge from such sources, even when the databases and software are readily available, is a challenging task. Despite the difficulties, researchers must frequently perform these tasks so that available knowledge can be continually integrated into the common framework required to realize the Human Physiome. Software and infrastructures that support the communities that generate these, together with their underlying standards to format, describe and interlink the corresponding data and computer models, are pivotal to the Human Physiome being realized. They provide the foundations for integrating, exchanging and re-using data and models efficiently, and correctly, while also supporting the dissemination of growing knowledge in these forms. In this paper, we explore the standards, software tooling, repositories and infrastructures that support this work, and detail what makes them vital to realizing the Human Physiome.

Authors: D. Nickerson, K. Atalag, B. de Bono, J. Geiger, C. Goble, S. Hollmann, J. Lonien, W. Muller, B. Regierer, N. J. Stanford, M. Golebiewski, P. Hunter

Date Published: 7th Apr 2016

Publication Type: Not specified

Abstract (Expand)

Kinetic data of biochemical reactions are essential for the creation of kinetic models of biochemical networks. One of the main resources of such information is SABIO-RK, a curated database for kinetic data of biochemical reactions and their related information. Despite the importance for computational modelling there has been no simple solution to visualize the kinetic data from SABIO-RK. In this work, I present cy3sabiork, an app for querying and visualization of kinetic data from SABIO-RK in Cytoscape. The kinetic information is accessible via a combination of graph structure and annotations of nodes, with provided information consisting of: (I) reaction details, enzyme and organism; (II) kinetic law, formula, parameters; (III) experimental conditions; (IV) publication; (V) additional annotations. cy3sabiork creates an intuitive visualization of kinetic entries in form of a species-reaction-kinetics graph, which reflects the reaction-centered approach of SABIO-RK. Kinetic entries can be imported in SBML format from either the SABIO-RK web interface or via web service queries. The app allows for easy comparison of kinetic data, visual inspection of the elements involved in the kinetic record and simple access to the annotation information of the kinetic record. I applied cy3sabiork in the computational modelling of galactose metabolism in the human liver.

Author: Matthias König

Date Published: 2016

Publication Type: Not specified

Abstract (Expand)

Morpheus is a modeling environment for the simulation and integration of cell-based models with ordinary differential equations and reaction-diffusion systems. It allows rapid development of multiscale models in biological terms and mathematical expressions rather than programming code. Its graphical user interface supports the entire workflow from model construction and simulation to visualization, archiving and batch processing.

Authors: J. Starruss, W. de Back, L. Brusch, A. Deutsch

Date Published: No date defined

Publication Type: Not specified

Abstract (Expand)

Bile, the central metabolic product of the liver, is transported by the bile canaliculi network. The impairment of bile flow in cholestatic liver diseases has urged a demand for insights into its regulation. Here, we developed a predictive 3D multi-scale model that simulates fluid dynamic properties successively from the subcellular to the tissue level. The model integrates the structure of the bile canalicular network in the mouse liver lobule, as determined by high-resolution confocal and serial block-face scanning electron microscopy, with measurements of bile transport by intravital microscopy. The combined experiment-theory approach revealed spatial heterogeneities of biliary geometry and hepatocyte transport activity. Based on this, our model predicts gradients of bile velocity and pressure in the liver lobule. Validation of the model predictions by pharmacological inhibition of Rho kinase demonstrated a requirement of canaliculi contractility for bile flow in vivo. Our model can be applied to functionally characterize liver diseases and quantitatively estimate biliary transport upon drug-induced liver injury.

Authors: K. Meyer, O. Ostrenko, G. Bourantas, H. Morales-Navarrete, N. Porat-Shliom, F. Segovia-Miranda, H. Nonaka, A. Ghaemi, J. M. Verbavatz, L. Brusch, I. Sbalzarini, Y. Kalaidzidis, R. Weigert, M. Zerial

Date Published: No date defined

Publication Type: Not specified

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