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377 Publications visible to you, out of a total of 377
Model prediction and validation of an order mechanism controlling the spatio-temporal phenotype of early hepatocellular carcinoma

Abstract

Not specified

Authors: Stefan Hoehme, Francois Bertaux, William Weens, Bettina Grasl-Kraupp, Jan G. Hengstler, Dirk Drasdo

Date Published: 28th Dec 2017

Publication Type: Not specified

Hepatic Smad7-overexpression causes severe iron overload in the mouse.

Abstract

Not specified

Authors: D. Lai, F. Teng, S. Hammad, J. Werle, T. Maas, A. Teufel, M. U. Muckenthaler, S. Dooley, M. Vujic Spasic

Date Published: 13th Dec 2017

Publication Type: Not specified

Monitoring Membrane Lipidome Turnover by Metabolic (15)N Labeling and Shotgun Ultra-High-Resolution Orbitrap Fourier Transform Mass Spectrometry.

Abstract (Expand)

Lipidomes undergo permanent extensive remodeling, but how the turnover rate differs between lipid classes and molecular species is poorly understood. We employed metabolic (15)N labeling and shotgun … ultra-high-resolution mass spectrometry (sUHR) to quantify the absolute (molar) abundance and determine the turnover rate of glycerophospholipids and sphingolipids by direct analysis of total lipid extracts. sUHR performed on a commercial Orbitrap Elite instrument at the mass resolution of 1.35 x 10(6) (m/z 200) baseline resolved peaks of (13)C isotopes of unlabeled and monoisotopic peaks of (15)N labeled lipids (Deltam = 0.0063 Da). Therefore, the rate of metabolic (15)N labeling of individual lipid species could be determined without compromising the scope, accuracy, and dynamic range of full-lipidome quantitative shotgun profiling. As a proof of concept, we employed sUHR to determine the lipidome composition and fluxes of 62 nitrogen-containing membrane lipids in human hepatoma HepG2 cells.

Authors: K. Schuhmann, K. Srzentic, K. O. Nagornov, H. Thomas, T. Gutmann, U. Coskun, Y. O. Tsybin, A. Shevchenko

Date Published: 5th Dec 2017

Publication Type: Not specified

pSSAlib: The partial-propensity stochastic chemical network simulator

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

Quantitative analysis of hepatic macro- and microvascular alterations during cirrhogenesis in the rat.

Abstract (Expand)

Cirrhosis represents the end-stage of any persistent chronically active liver disease. It is characterized by the complete replacement of normal liver tissue by fibrosis, regenerative nodules, and … complete fibrotic vascularized septa. The resulting angioarchitectural distortion contributes to an increasing intrahepatic vascular resistance, impeding liver perfusion and leading to portal hypertension. To date, knowledge on the dynamically evolving pathological changes of the hepatic vasculature during cirrhogenesis remains limited. More specifically, detailed anatomical data on the vascular adaptations during disease development is lacking. To address this need, we studied the 3D architecture of the hepatic vasculature during induction of cirrhogenesis in a rat model. Cirrhosis was chemically induced with thioacetamide (TAA). At predefined time points, the hepatic vasculature was fixed and visualized using a combination of vascular corrosion casting and deep tissue microscopy. Three-dimensional reconstruction and data-fitting enabled cirrhogenic features to extracted at multiple scales, portraying the impact of cirrhosis on the hepatic vasculature. At the macrolevel, we noticed that regenerative nodules severely compressed pliant venous vessels from 12 weeks of TAA intoxication onwards. Especially hepatic veins were highly affected by this compression, with collapsed vessel segments severely reducing perfusion capabilities. At the microlevel, we discovered zone-specific sinusoidal degeneration, with sinusoids located near the surface being more affected than those in the middle of a liver lobe. Our data shed light on and quantify the evolving angioarchitecture during cirrhogenesis. These findings may prove helpful for future targeted invasive interventions.

Authors: G. Peeters, C. Debbaut, A. Friebel, P. Cornillie, W. H. De Vos, K. Favere, I. Vander Elst, T. Vandecasteele, T. Johann, L. Van Hoorebeke, D. Monbaliu, D. Drasdo, S. Hoehme, W. Laleman, P. Segers

Date Published: 4th Dec 2017

Publication Type: Not specified

Translational learning from clinical studies predicts drug pharmacokinetics across patient populations

Abstract

Not specified

Authors: Markus Krauss, Ute Hofmann, Clemens Schafmayer, Svitlana Igel, Jan Schlender, Christian Mueller, Mario Brosch, Witigo von Schoenfels, Wiebke Erhart, Andreas Schuppert, Michael Block, Elke Schaeffeler, Gabriele Boehmer, Linus Goerlitz, Jan Hoecker, Joerg Lippert, Reinhold Kerb, Jochen Hampe, Lars Kuepfer, Matthias Schwab

Date Published: 1st Dec 2017

Publication Type: Not specified

Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage

Abstract (Expand)

Diseases and toxins may lead to death of active liver tissue, resulting in a loss of total clearance capacity at the whole-body level. However, it remains difficult to study, whether the loss of … metabolizing tissue is sufficient to explain loss of metabolic capacity of the liver or whether the surviving tissue undergoes an adaptive response to compensate the loss. To understand the cellular impact of toxic liver damage in an in vivo situation, we here used physiologically-based pharmacokinetic modelling to investigate pharmacokinetics of a specifically designed drug cocktail at three different sampling sites of the body in healthy mice and mice treated with carbon tetrachloride (CCl4). Liver zonation was explicitly quantified in the models through immunostaining of cytochrome P450s enzymes. Comparative analyses between the simulated decrease in clearance capacity and the experimentally measured loss in tissue volume indicated that CCl4-induced impairment of metabolic functions goes beyond the mere loss of metabolically active tissue. The here established integrative modelling strategy hence provides mechanistic insights into functional consequences of toxic liver damage in an in vivo situation, which would not have been accessible by conventional methods.

Authors: Arne Schenk, Ahmed Ghallab, Ute Hofmann, Reham Hassan, Michael Schwarz, Andreas Schuppert, Lars Ole Schwen, Albert Braeuning, Donato Teutonico, Jan G. Hengstler, Lars Kuepfer

Date Published: 1st Dec 2017

Publication Type: Not specified

Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage

Abstract

Not specified

Authors: Arne Schenk, Ahmed Ghallab, Ute Hofmann, Reham Hassan, Michael Schwarz, Andreas Schuppert, Lars Ole Schwen, Albert Braeuning, Donato Teutonico, Jan G. Hengstler, Lars Kuepfer

Date Published: 1st Dec 2017

Publication Type: Not specified

Bio-degradable highly fluorescent conjugated polymer nanoparticles for bio-medical imaging applications

Abstract (Expand)

Conjugated polymer nanoparticles exhibit strong fluorescence and have been applied for biological fluorescence imaging in cell culture and in small animals. However, conjugated polymer particles are … hydrophobic and often chemically inert materials with diameters ranging from below 50 nm to several microns. As such, conjugated polymer nanoparticles cannot be excreted through the renal system. This drawback has prevented their application for clinical bio-medical imaging. Here, we present fully conjugated polymer nanoparticles based on imidazole units. These nanoparticles can be bio-degraded by activated macrophages. Reactive oxygen species induce scission of the conjugated polymer backbone at the imidazole unit, leading to complete decomposition of the particles into soluble low molecular weight fragments. Furthermore, the nanoparticles can be surface functionalized for directed targeting. The approach opens a wide range of opportunities for conjugated polymer particles in the fields of medical imaging, drug-delivery, and theranostics.

Authors: Tatjana Repenko, Anne Rix, Simon Ludwanowski, Dennis Go, Fabian Kiessling, Wiltrud Lederle, Alexander J. C. Kuehne

Date Published: 1st Dec 2017

Publication Type: Not specified

A brief history of COMBINE

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: Not specified

Renal oncocytoma characterized by the defective complex I of the respiratory chain boosts the synthesis of the ROS scavenger glutathione.

Abstract (Expand)

Renal oncocytomas are rare benign tumors of the kidney and characterized by a deficient complex I (CI) enzyme activity of the oxidative phosphorylation (OXPHOS) system caused by mitochondrial DNA (mtDNA) … mutations. Yet, little is known about the underlying molecular mechanisms and alterations of metabolic pathways in this tumor. We compared renal oncocytomas with adjacent matched normal kidney tissues on a global scale by multi-omics approaches, including whole exome sequencing (WES), proteomics, metabolomics, and metabolic pathway simulation. The abundance of proteins localized to mitochondria increased more than 2-fold, the only exception was a strong decrease in the abundance for CI subunits that revealed several pathogenic heteroplasmic mtDNA mutations by WES. We also observed renal oncocytomas to dysregulate main metabolic pathways, shunting away from gluconeogenesis and lipid metabolism. Nevertheless, the abundance of energy carrier molecules such as NAD(+), NADH, NADP, ATP, and ADP were significantly higher in renal oncocytomas. Finally, a substantial 5000-fold increase of the reactive oxygen species scavenger glutathione can be regarded as a new hallmark of renal oncocytoma. Our findings demonstrate that renal oncocytomas undergo a metabolic switch to eliminate ATP consuming processes to ensure a sufficient energy supply for the tumor.

Authors: G. Kurschner, Q. Zhang, R. Clima, Y. Xiao, J. F. Busch, E. Kilic, K. Jung, N. Berndt, S. Bulik, H. G. Holzhutter, G. Gasparre, M. Attimonelli, M. Babu, D. Meierhofer

Date Published: 1st Dec 2017

Publication Type: Not specified

Modeling approaches for hepatic spatial heterogeneity in pharmacokinetic simulations

Abstract (Expand)

The metabolization and excretion of drugs in the liver are spatially heterogeneous processes. This is due to the spatial variability of physiological processes at different length scales of biological … organization in healthy individuals, while many liver diseases further contribute to the heterogeneity. Classical, well-stirred pharmacokinetic models do not represent this heterogeneity, and various modeling approaches capable of representing heterogeneity have been developed recently. These approaches range from mechanistic and physio-geometrically realistic models focusing on specific spatial scales, via continuum models using homogenized physiological and metabolic properties, to integrative multiscale models. Such models could become essential research tools for simulations involving drugs with notable first-pass effects, fast-acting drugs or tracers, and diseased livers.

Authors: Lars Ole Schwen, Lars Kuepfer, Tobias Preusser

Date Published: 29th Nov 2017

Publication Type: Not specified

Computational Modeling in Liver Surgery

Abstract (Expand)

The need for extended liver resection is increasing due to the growing incidence of liver tumors in aging societies. Individualized surgical planning is the key for identifying the optimal resection … strategy and to minimize the risk of postoperative liver failure and tumor recurrence. Current computational tools provide virtual planning of liver resection by taking into account the spatial relationship between the tumor and the hepatic vascular trees, as well as the size of the future liver remnant. However, size and function of the liver are not necessarily equivalent. Hence, determining the future liver volume might misestimate the future liver function, especially in cases of hepatic comorbidities such as hepatic steatosis. A systems medicine approach could be applied, including biological, medical, and surgical aspects, by integrating all available anatomical and functional information of the individual patient. Such an approach holds promise for better prediction of postoperative liver function and hence improved risk assessment. This review provides an overview of mathematical models related to the liver and its function and explores their potential relevance for computational liver surgery. We first summarize key facts of hepatic anatomy, physiology, and pathology relevant for hepatic surgery, followed by a description of the computational tools currently used in liver surgical planning. Then we present selected state-of-the-art computational liver models potentially useful to support liver surgery. Finally, we discuss the main challenges that will need to be addressed when developing advanced computational planning tools in the context of liver surgery.

Authors: Bruno Christ, Uta Dahmen, Karl-Heinz Herrmann, Matthias König, Jürgen R. Reichenbach, Tim Ricken, Jana Schleicher, Lars Ole Schwen, Sebastian Vlaic, Navina Waschinsky

Date Published: 14th Nov 2017

Publication Type: Not specified

Adverse outcome pathways: opportunities, limitations and open questions.

Abstract (Expand)

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory … purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.

Authors: M. Leist, A. Ghallab, R. Graepel, R. Marchan, R. Hassan, S. H. Bennekou, A. Limonciel, M. Vinken, S. Schildknecht, T. Waldmann, E. Danen, B. van Ravenzwaay, H. Kamp, I. Gardner, P. Godoy, F. Y. Bois, A. Braeuning, R. Reif, F. Oesch, D. Drasdo, S. Hohme, M. Schwarz, T. Hartung, T. Braunbeck, J. Beltman, H. Vrieling, F. Sanz, A. Forsby, D. Gadaleta, C. Fisher, J. Kelm, D. Fluri, G. Ecker, B. Zdrazil, A. Terron, P. Jennings, B. van der Burg, S. Dooley, A. H. Meijer, E. Willighagen, M. Martens, C. Evelo, E. Mombelli, O. Taboureau, A. Mantovani, B. Hardy, B. Koch, S. Escher, C. van Thriel, C. Cadenas, D. Kroese, B. van de Water, J. G. Hengstler

Date Published: 19th Oct 2017

Publication Type: Not specified

The level of caveolin-1 expression determines response to TGF-β as a tumour suppressor in hepatocellular carcinoma cells

Abstract

Not specified

Authors: Joaquim Moreno-Càceres, Daniel Caballero-Díaz, Zeribe Chike Nwosu, Christoph Meyer, Judit López-Luque, Andrea Malfettone, Raquel Lastra, Teresa Serrano, Emilio Ramos, Steven Dooley, Isabel Fabregat

Date Published: 12th Oct 2017

Publication Type: Not specified

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