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377 Publications visible to you, out of a total of 377
matthiaskoenig/sbmlutils: sbmlutils-v0.3.9: python utilities for SBML

Abstract

sbmlutils is a collection of python utilities for working with SBML models implemented on top of libSBML and other libraries available from https://github.com/matthiaskoenig/sbmlutils

Author: Matthias König

Date Published: 1st Mar 2020

Publication Type: Misc

Bile canaliculi remodeling activates YAP via the actin cytoskeleton during liver regeneration.

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

Bile canaliculi remodeling activates YAP via the actin cytoskeleton during liver regeneration

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: Kirstin Meyer, Hernan Morales‐Navarrete, Sarah Seifert, Michaela Wilsch‐Braeuninger, Uta Dahmen, Elly M Tanaka, Lutz Brusch, Yannis Kalaidzidis, Marino Zerial

Date Published: 24th Feb 2020

Publication Type: Not specified

Caveolin-1 Impacts on TGF-beta Regulation of Metabolic Gene Signatures in Hepatocytes.

Abstract (Expand)

Caveolin-1 (CAV1) is a membrane protein associated with metabolism in various cell types. The transforming growth factor beta (TGF-beta) is a pro-fibrogenic cytokine in the liver, but its metabolic … gene signatures remain unclear to date. We have previously shown that CAV1 alters TGF-beta signaling and blocks its pro-apoptotic function. Here, we defined TGF-beta-induced metabolic gene signatures in hepatocytes and assessed whether CAV1 abundance affects TGF-beta control of those metabolic genes. Microarray analyses of primary hepatocytes after TGF-beta stimulation (48 h) showed differential expression of 4224 genes, of which 721 are metabolic genes (adjusted p < 0.001). Functional annotation analysis revealed that TGF-beta mainly suppresses metabolic gene network, including genes involved in glutathione, cholesterol, fatty acid, and amino acid metabolism. TGF-beta also upregulated several genes related to glycan metabolism and ion transport. In contrast to TGF-beta effects, CAV1 knockdown triggered the upregulation of metabolic genes. Immortalized mouse hepatocytes (AML12 cells) were used to validate the gene changes induced by TGF-beta stimulation and CAV1 knockdown. Noteworthy, of the TGF-beta metabolic target genes, CAV1 modulated the expression of 228 (27%). In conclusion, we present several novel metabolic gene signatures of TGF-beta in hepatocytes and show that CAV1 abundance alters almost a third of these genes. These findings could enable a better understanding of TGF-beta function in normal and diseased liver especially where differential CAV1 level is implicated.

Authors: M. Han, Z. C. Nwosu, W. Pioronska, M. P. Ebert, S. Dooley, C. Meyer

Date Published: 22nd Feb 2020

Publication Type: Journal

A novel variant of the (13)C-methacetin liver function breath test that eliminates the confounding effect of individual differences in systemic CO2 kinetics.

Abstract (Expand)

The principle of dynamic liver function breath tests is founded on the administration of a (13)C-labeled drug and subsequent monitoring of (13)CO2 in the breath, quantified as time series delta over … natural baseline (13)CO2 (DOB) liberated from the drug during hepatic CYP-dependent detoxification. One confounding factor limiting the diagnostic value of such tests is that only a fraction of the liberated (13)CO2 is immediately exhaled, while another fraction is taken up by body compartments from which it returns with delay to the plasma. The aims of this study were to establish a novel variant of the methacetin-based breath test LiMAx that allows to estimate and to eliminate the confounding effect of systemic (13)CO2 distribution on the DOB curve and thus enables a more reliable assessment of the hepatic detoxification capacity compared with the conventional LiMAx test. We designed a new test variant (named "2DOB") consisting of two consecutive phases. Phase 1 is initiated by the intravenous administration of (13)C-bicarbonate. Phase 2 starts about 30 min later with the intravenous administration of the (13)C-labelled test drug. Using compartment modelling, the resulting 2-phasic DOB curve yields the rate constants for the irreversible elimination and the reversible exchange of plasma (13)CO2 with body compartments (phase 1) and for the detoxification and exchange of the drug with body compartments (phase 2). We carried out the 2DOB test with the test drug (13)C-methacetin in 16 subjects with chronic liver pathologies and 22 normal subjects, who also underwent the conventional LiMAx test. Individual differences in the systemic CO2 kinetics can lead to deviations up to a factor of 2 in the maximum of DOB curves (coefficient of variation CV approximately 0.2) which, in particular, may hamper the discrimination between subjects with normal or mildly impaired detoxification capacities. The novel test revealed that a significant portion of the drug is not immediately metabolized, but transiently taken up into a storage compartment. Intriguingly, not only the hepatic detoxification rate but also the storage capacity of the drug, turned out to be indicative for a normal liver function. We thus used both parameters to define a scoring function which yielded an excellent disease classification (AUC = 0.95) and a high correlation with the MELD score (RSpearman = 0.92). The novel test variant 2DOB promises a significant improvement in the assessment of impaired hepatic detoxification capacity. The suitability of the test for the reliable characterization of the natural history of chronic liver diseases (fatty liver-fibrosis-cirrhosis) has to be assessed in further studies.

Authors: H. G. Holzhutter, T. Wuensch, R. Gajowski, N. Berndt, S. Bulik, D. Meierhofer, M. Stockmann

Date Published: 6th Feb 2020

Publication Type: Not specified

Hepatocyte caveolin-1 modulates metabolic gene profiles and functions in non-alcoholic fatty liver disease.

Abstract (Expand)

Caveolin-1 (CAV1) is a crucial regulator of lipid accumulation and metabolism. Previous studies have shown that global Cav1 deficiency affects lipid metabolism and hepatic steatosis. We aimed to analyze … the consequences of hepatocyte-specific Cav1 knockout under healthy conditions and upon non-alcoholic fatty liver disease (NAFLD) development. Male and female hepatocyte-specific Cav1 knockout (HepCAV1ko) mice were fed a methionine/choline (MCD) deficient diet for 4 weeks. MCD feeding caused severe hepatic steatosis and slight fibrosis. In addition, liver function parameters, i.e., ALT, AST, and GLDH, were elevated, while cholesterol and glucose level were reduced upon MCD feeding. These differences were not affected by hepatocyte-specific Cav1 knockout. Microarray analysis showed strong differences in gene expression profiles of livers from HepCAV1ko mice compared those of global Cav1 knockout animals. Pathway enrichment analysis identified that metabolic alterations were sex-dimorphically regulated by hepatocyte-specific CAV1. In male HepCAV1ko mice, metabolic pathways were suppressed in NAFLD, whereas in female knockout mice induced. Moreover, gender-specific transcription profiles were modulated in healthy animals. In conclusion, our results demonstrate that hepatocyte-specific Cav1 knockout significantly altered gene profiles, did not affect liver steatosis and fibrosis in NAFLD and that gender had severe impact on gene expression patterns in healthy and diseased hepatocyte-specific Cav1 knockout mice.

Authors: M. Han, W. Pioronska, S. Wang, Z. C. Nwosu, C. Sticht, S. Wang, Y. Gao, M. P. Ebert, S. Dooley, C. Meyer

Date Published: 6th Feb 2020

Publication Type: Journal

A quantitative high-resolution computational mechanics cell model for growing and regenerating tissues

Abstract

Not specified

Authors: Paul Van Liedekerke, Johannes Neitsch, Tim Johann, Enrico Warmt, Ismael Gonzàlez-Valverde, Stefan Hoehme, Steffen Grosser, Josef Kaes, Dirk Drasdo

Date Published: 1st Feb 2020

Publication Type: Journal

TGF-β2 silencing to target biliary-derived liver diseases

Abstract

Not specified

Authors: Anne Dropmann, Steven Dooley, Bedair Dewidar, Seddik Hammad, Tatjana Dediulia, Julia Werle, Vanessa Hartwig, Shahrouz Ghafoory, Stefan Woelfl, Hanna Korhonen, Michel Janicot, Katja Wosikowski, Timo Itzel, Andreas Teufel, Detlef Schuppan, Ana Stojanovic, Adelheid Cerwenka, Stefanie Nittka, Albrecht Piiper, Timo Gaiser, Naiara Beraza, Malgorzata Milkiewicz, Piotr Milkiewicz, John G Brain, David E J Jones, Thomas S Weiss, Ulrich M Zanger, Matthias Ebert, Nadja M Meindl-Beinker

Date Published: 28th Jan 2020

Publication Type: Not specified

Ultrasound Time-Harmonic Elastography of the Pancreas: Reference Values and Clinical Feasibility.

Abstract (Expand)

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a very low 5-year survival rate of 8%. The aims of this study are to determine reference values and physiologic … confounders in healthy pancreas and to assess the diagnostic accuracy of ultrasound time-harmonic elastography (THE) in the detection of PDAC. MATERIALS AND METHODS: From March 2017 through May 2019, a total of 54 study participants with healthy pancreas (n = 33, CTR) or PDAC (n = 21) were prospectively enrolled. Repeatability of THE was tested in a CTR subgroup (n = 5) undergoing repeat measurement on 4 different days. Interobserver variability was analyzed in 10 healthy volunteers. Age-matched and sex-matched subgroups of CTR (n = 13) and PDAC (n = 13) were compared. In participants with histopathologically proven PDAC, measurements were performed separately in tumorous (PDAC-T) and nontumorous pancreatic tissue (PDAC-NT). Diagnostic performance of pancreatic THE was assessed by receiver operating characteristic curve analysis. RESULTS: Time-harmonic elastography was highly repeatable (intraclass correlation coefficient, 0.99), and interobserver agreement was excellent (intraclass correlation coefficient, 0.97). Shear wave speed (SWS) of PDAC-T (mean [95% confidence interval] in meters per second, 1.88 +/- 0.07 [1.84-1.92]) was higher than SWS of CTR (1.63 +/- 0.04 [1.60-1.66], P < 0.001) and PDAC-NT (1.59 +/- 0.03 [1.57-1.61], P < 0.001). The exploratory diagnostic performance of THE in separating PDAC-T was excellent (area under the receiver operating characteristic curve, 1.0). Tumorous pancreatic ductal adenocarcinoma was distinguished from CTR and PDAC-NT with cutoff values of 1.73 m/s and 1.70 m/s, respectively. CONCLUSIONS: Pancreatic ultrasound THE has high repeatability and provides excellent imaging contrast based on SWS, allowing detection of PDAC without overlap to nontumorous pancreatic tissue.

Authors: C. Burkhardt, H. Tzschatzsch, R. Schmuck, M. Bahra, C. Jurgensen, U. Pelzer, B. Hamm, J. Braun, I. Sack, S. R. Marticorena Garcia

Date Published: 28th Jan 2020

Publication Type: Journal

Executable Simulation Model of the Liver

Abstract (Expand)

To address the issue of reproducibility in computational modeling we developed the concept of an executable simulation model (EXSIMO). An EXSIMO combines model, data and code with the execution environment … to run the computational analysis in an automated manner using tools from software engineering. Key components are i) models, data and code for the computational analysis; ii) tests for models, data and code; and iii) an automation layer to run tests and execute the analysis. An EXSIMO combines version control, model, data, units, annotations, analysis, reports, execution environment, testing, continuous integration and release. We applied the concept to perform a replication study of a computational analysis of hepatic glucose metabolism in the liver. The corresponding EXSIMO is available from https://github.com/matthiaskoenig/exsimo.

Author: Matthias König

Date Published: 6th Jan 2020

Publication Type: Unpublished

An environment for sustainable research software in Germany and beyond: current state, open challenges, and call for action

Abstract (Expand)

Research software has become a central asset in academic research. It optimizes existing and enables new research methods, implements and embeds research knowledge, and constitutes an essential research … product in itself. Research software must be sustainable in order to understand, replicate, reproduce, and build upon existing research or conduct new research effectively. In other words, software must be available, discoverable, usable, and adaptable to new needs, both now and in the future. Research software therefore requires an environment that supports sustainability. Hence, a change is needed in the way research software development and maintenance are currently motivated, incentivized, funded, structurally and infrastructurally supported, and legally treated. Failing to do so will threaten the quality and validity of research. In this paper, we identify challenges for research software sustainability in Germany and beyond, in terms of motivation, selection, research software engineering personnel, funding, infrastructure, and legal aspects. Besides researchers, we specifically address political and academic decision-makers to increase awareness of the importance and needs of sustainable research software practices. In particular, we recommend strategies and measures to create an environment for sustainable research software, with the ultimate goal to ensure that software-driven research is valid, reproducible and sustainable, and that software is recognized as a first class citizen in research.

Authors: Hartwig Anzt, Felix Bach, Stephan Druskat, Frank Löffler, Axel Loewe, Bernhard Y. Renard, Gunnar Seemann, Alexander Struck, Elke Achhammer, Piush Aggarwal, Franziska Appel, Michael Bader, Lutz Brusch, Christian Busse, Gerasimos Chourdakis, Piotr Wojciech Dabrowski, Peter Ebert, Bernd Flemisch, Sven Friedl, Bernadette Fritzsch, Maximilian D. Funk, Volker Gast, Florian Goth, Jean-Noël Grad, Sibylle Hermann, Florian Hohmann, Stephan Janosch, Dominik Kutra, Jan Linxweiler, Thilo Muth, Wolfgang Peters-Kottig, Fabian Rack, Fabian H.C. Raters, Stephan Rave, Guido Reina, Malte Reißig, Timo Ropinski, Joerg Schaarschmidt, Heidi Seibold, Jan P. Thiele, Benjamin Uekermann, Stefan Unger, Rudolf Weeber

Date Published: 2020

Publication Type: Not specified

matthiaskoenig/exsimo: exsimo-v0.3.2 - EXecutable SImulation MOdels

Abstract (Expand)

EXSIMO: EXecutable SImulation MOdel; Data, model and code for executable simulation model of hepatic glucose metabolism Reports: https://matthiaskoenig.github.io/exsimo/ Docker images: …: https://hub.docker.com/r/matthiaskoenig/exsimo Github releases: https://github.com/matthiaskoenig/exsimo/releases

Author: Matthias König

Date Published: 2020

Publication Type: Misc

Resection of hepatic and pulmonary metastasis from metastatic esophageal and gastric cancer: a nationwide study.

Abstract (Expand)

The standard of care for gastroesophageal cancer patients with hepatic or pulmonary metastases is best supportive care or palliative chemotherapy. Occasionally, patients can be selected for curative … treatment instead. This study aimed to evaluate patients who underwent a resection of hepatic or pulmonary metastasis with curative intent. The Dutch national registry for histo- and cytopathology was used to identify these patients. Data were retrieved from the individual patient files. Kaplan-Meier survival analysis was performed. Between 1991 and 2016, 32,057 patients received a gastrectomy or esophagectomy for gastroesophageal cancer in the Netherlands. Of these patients, 34 selected patients received a resection of hepatic metastasis (n = 19) or pulmonary metastasis (n = 15) in 21 different hospitals. Only 4 patients received neoadjuvant therapy before metastasectomy. The majority of patients had solitary, metachronous metastases. After metastasectomy, grade 3 (Clavien-Dindo) complications occurred in 7 patients and mortality in 1 patient. After resection of hepatic metastases, the median potential follow-up time was 54 months. Median overall survival (OS) was 28 months and the 1-, 3-, and 5- year OS was 84%, 41%, and 31%, respectively. After pulmonary metastases resection, the median potential follow-up time was 80 months. The median OS was not reached and the 1-, 3-, and 5- year OS was 67%, 53%, and 53%, respectively. In selected patients with gastroesophageal cancer with hepatic or pulmonary metastases, metastasectomy was performed with limited morbidity and mortality and offered a 5-year OS of 31-53%. Further prospective studies are required.

Authors: M. F. J. Seesing, A. van der Veen, H. J. F. Brenkman, H. B. A. C. Stockmann, G. A. P. Nieuwenhuijzen, C. Rosman, F. J. H. van den Wildenberg, M. I. van Berge Henegouwen, P. van Duijvendijk, B. P. L. Wijnhoven, J. H. M. B. Stoot, M. Lacle, J. P. Ruurda, R. van Hillegersberg

Date Published: 31st Dec 2019

Publication Type: Not specified

Kinetic modelling of quantitative proteome data predicts metabolic reprogramming of liver cancer

Abstract

Not specified

Authors: Nikolaus Berndt, Antje Egners, Guido Mastrobuoni, Olga Vvedenskaya, Athanassios Fragoulis, Aurélien Dugourd, Sascha Bulik, Matthias Pietzke, Chris Bielow, Rob van Gassel, Steven W. Olde Damink, Merve Erdem, Julio Saez-Rodriguez, Hermann-Georg Holzhütter, Stefan Kempa, Thorsten Cramer

Date Published: 10th Dec 2019

Publication Type: Not specified

Three-dimensional spatially resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression.

Abstract (Expand)

Early disease diagnosis is key to the effective treatment of diseases. Histopathological analysis of human biopsies is the gold standard to diagnose tissue alterations. However, this approach has low … resolution and overlooks 3D (three-dimensional) structural changes resulting from functional alterations. Here, we applied multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD). We identified a set of morphometric cellular and tissue parameters correlated with disease progression, and discover profound topological defects in the 3D bile canalicular (BC) network. Personalized biliary fluid dynamic simulations predicted an increased pericentral biliary pressure and micro-cholestasis, consistent with elevated cholestatic biomarkers in patients' sera. Our spatially resolved models of human liver tissue can contribute to high-definition medicine by identifying quantitative multiparametric cellular and tissue signatures to define disease progression and provide new insights into NAFLD pathophysiology.

Authors: F. Segovia-Miranda, H. Morales-Navarrete, M. Kucken, V. Moser, S. Seifert, U. Repnik, F. Rost, M. Brosch, A. Hendricks, S. Hinz, C. Rocken, D. Lutjohann, Y. Kalaidzidis, C. Schafmayer, L. Brusch, J. Hampe, M. Zerial

Date Published: 2nd Dec 2019

Publication Type: Not specified

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