Manlio Vinciguerra

Projects: COVID-19 Disease Map

Institutions: The International Clinical Research Center of St. Anne's University Hospital Brno

https://orcid.org/0000-0002-1768-3894
PoLiMeR_user Martines_data project_administrator

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: Heidelberg Institute for Theoretical Studies (HITS gGmbH)

Patrick Schrauwen

Projects: HUMET Startup

Institutions: University Maastricht

https://orcid.org/0000-0002-0973-847X
Matthias König project_administratorasset_housekeeperasset_gatekeeper

Projects: Kinetics on the move - Workshop 2016, Multi-Scale Models for Personalized Liver Function Tests (LiSyM-MM-PLF), FAIRDOM user meeting, COMBINE Multicellular Modelling, FAIRDOM & LiSyM & de.NBI Data Structuring Training

Institutions: Charité University Medicine Berlin, Humboldt-Universität zu Berlin, Humboldt University Berlin

https://orcid.org/0000-0003-1725-179X
RaDR Image Machine Learning Analysis – Data Attached
No description specified

Submitter: Dikshant Pradhan

Assay type: Experimental Assay Type

Technology type: Technology Type

Investigation: MIT SRP

Study: Excision of mutagenic replication-blocking lesi...

GPT Assay – Data Attached
No description specified

Submitter: Dikshant Pradhan

Assay type: Experimental Assay Type

Technology type: Technology Type

Investigation: MIT SRP

Study: Excision of mutagenic replication-blocking lesi...

Tissue Lysis – Metadata
No description specified

Submitter: Dikshant Pradhan

Assay type: Experimental Assay Type

Technology type: Technology Type

Investigation: MIT SRP

Study: Excision of mutagenic replication-blocking lesi...

Mass Spectrometry Processing – Data Linked
No description specified

Submitter: Dikshant Pradhan

Assay type: Experimental Assay Type

Technology type: Technology Type

Investigation: MIT SRP

Study: Excision of mutagenic replication-blocking lesi...

Mass Spectrometry – Data Linked
No description specified

Submitter: Dikshant Pradhan

Assay type: Experimental Assay Type

Technology type: Technology Type

Investigation: MIT SRP

Study: Excision of mutagenic replication-blocking lesi...

Tissue Imaging – Metadata
No description specified

Submitter: Dikshant Pradhan

Assay type: Experimental Assay Type

Technology type: Technology Type

Investigation: MIT SRP

Study: Excision of mutagenic replication-blocking lesi...

Mouse Necropsy – Metadata
No description specified

Submitter: Dikshant Pradhan

Assay type: Experimental Assay Type

Technology type: Technology Type

Investigation: MIT SRP

Study: Excision of mutagenic replication-blocking lesi...

Liver RNA-seq data for in vivo VII

RNA-seq data for In vivo 7 samples. Only 32 RNA samples from liver of male fish sequenced. Illumina poly(A)-RNA sequencing at UiB GCF, as in Yadetie et al., 2018.

Submitter: Fekadu Yadetie

Assay type: RNA-seq

Technology type: Next generation sequencing

Investigation: 1 hidden item

Study: 1 hidden item

A network-based approach reveals the dysregulated transcriptional regulation in non-alcoholic fatty liver disease.

Abstract (Expand)

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide. We performed network analysis to investigate the dysregulated biological processes in the disease … progression and revealed the molecular mechanism underlying NAFLD. Based on network analysis, we identified a highly conserved disease-associated gene module across three different NAFLD cohorts and highlighted the predominant role of key transcriptional regulators associated with lipid and cholesterol metabolism. In addition, we revealed the detailed metabolic differences between heterogeneous NAFLD patients through integrative systems analysis of transcriptomic data and liver-specific genome-scale metabolic model. Furthermore, we identified transcription factors (TFs), including SREBF2, HNF4A, SREBF1, YY1, and KLF13, showing regulation of hepatic expression of genes in the NAFLD-associated modules and validated the TFs using data generated from a mouse NAFLD model. In conclusion, our integrative analysis facilitates the understanding of the regulatory mechanism of these perturbed TFs and their associated biological processes.

Authors: H. Yang, M. Arif, M. Yuan, X. Li, K. Shong, H. Turkez, J. Nielsen, M. Uhlen, J. Boren, C. Zhang, A. Mardinoglu

Date Published: 19th Nov 2021

Publication Type: Journal

Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders.

Abstract (Expand)

BACKGROUND: Defects in genes involved in mitochondrial fatty-acid oxidation (mFAO) reduce the ability of patients to cope with metabolic challenges. mFAO enzymes accept multiple substrates of different … chain length, leading to molecular competition among the substrates. Here, we combined computational modeling with quantitative mouse and patient data to investigate whether substrate competition affects pathway robustness in mFAO disorders. RESULTS: First, we used comprehensive biochemical analyses of wild-type mice and mice deficient for medium-chain acyl-CoA dehydrogenase (MCAD) to parameterize a detailed computational model of mFAO. Model simulations predicted that MCAD deficiency would have no effect on the pathway flux at low concentrations of the mFAO substrate palmitoyl-CoA. However, high concentrations of palmitoyl-CoA would induce a decline in flux and an accumulation of intermediate metabolites. We proved computationally that the predicted overload behavior was due to substrate competition in the pathway. Second, to study the clinical relevance of this mechanism, we used patients' metabolite profiles and generated a humanized version of the computational model. While molecular competition did not affect the plasma metabolite profiles during MCAD deficiency, it was a key factor in explaining the characteristic acylcarnitine profiles of multiple acyl-CoA dehydrogenase deficient patients. The patient-specific computational models allowed us to predict the severity of the disease phenotype, providing a proof of principle for the systems medicine approach. CONCLUSION: We conclude that substrate competition is at the basis of the physiology seen in patients with mFAO disorders, a finding that may explain why these patients run a risk of a life-threatening metabolic catastrophe.

Authors: K. van Eunen, C. M. Volker-Touw, A. Gerding, A. Bleeker, J. C. Wolters, W. J. van Rijt, A. M. Martines, K. E. Niezen-Koning, R. M. Heiner, H. Permentier, A. K. Groen, D. J. Reijngoud, T. G. Derks, B. M. Bakker

Date Published: 7th Dec 2016

Publication Type: Journal

A Predictive 3D Multi-Scale Model of Biliary Fluid Dynamics in the Liver Lobule.

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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