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81 Publications visible to you, out of a total of 81
Mapping connections in signaling networks with ambiguous modularity.

Abstract (Expand)

Modular Response Analysis (MRA) is a suite of methods that under certain assumptions permits the precise reconstruction of both the directions and strengths of connections between network modules from … network responses to perturbations. Standard MRA assumes that modules are insulated, thereby neglecting the existence of inter-modular protein complexes. Such complexes sequester proteins from different modules and propagate perturbations to the protein abundance of a downstream module retroactively to an upstream module. MRA-based network reconstruction detects retroactive, sequestration-induced connections when an enzyme from one module is substantially sequestered by its substrate that belongs to a different module. Moreover, inferred networks may surprisingly depend on the choice of protein abundances that are experimentally perturbed, and also some inferred connections might be false. Here, we extend MRA by introducing a combined computational and experimental approach, which allows for a computational restoration of modular insulation, unmistakable network reconstruction and discrimination between solely regulatory and sequestration-induced connections for a range of signaling pathways. Although not universal, our approach extends MRA methods to signaling networks with retroactive interactions between modules arising from enzyme sequestration effects.

Authors: D. Lill, O. S. Rukhlenko, A. J. Mc Elwee, E. Kashdan, J. Timmer, B. N. Kholodenko

Date Published: 1st Jun 2019

Publication Type: Not specified

MicroRNA-942 mediates hepatic stellate cell activation by regulating BAMBI expression in human liver fibrosis.

Abstract (Expand)

MicroRNA (miRNA)-mediated gene regulation contributes to liver pathophysiology, including hepatic stellate cell (HSC) activation and fibrosis progression. Here, we investigated the role of miR-942 in … human liver fibrosis. The expression of miR-942, HSC activation markers, transforming growth factor-beta pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI), as well as collagen deposition, were investigated in 100 liver specimens from patients with varying degree of hepatitis B virus (HBV)-related fibrosis. Human primary HSCs and the immortalized cell line (LX2 cells) were used for functional studies. We found that miR-942 expression was upregulated in activated HSCs and correlated inversely with BAMBI expression in liver fibrosis progression. Transforming growth factor beta (TGF-beta) and lipopolyssacharide (LPS), two major drivers of liver fibrosis and inflammation, induce miR-942 expression in HSCs via Smad2/3 respective NF-kappaB/p50 binding to the miR-942 promoter. Mechanistically, the induced miR-942 degrades BAMBI mRNA in HSCs, thereby sensitizing the cells for fibrogenic TGF-beta signaling and also partly mediates LPS-induced proinflammatory HSC fate. In conclusion, the TGF-beta and LPS-induced miR-942 mediates HSC activation through downregulation of BAMBI in human liver fibrosis. Our study provides new insights on the molecular mechanism of HSC activation and fibrosis.

Authors: L. Tao, D. Xue, D. Shen, W. Ma, J. Zhang, X. Wang, W. Zhang, L. Wu, K. Pan, Y. Yang, Z. C. Nwosu, S. Dooley, E. Seki, C. Liu

Date Published: 12th Aug 2018

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

Monitoring TGF-β1 effects on liver cells in vivo

Abstract

Not specified

Authors: Alaa Hammad, Seddik Hammad, Kerry Gould, Matthias P. Ebert, Steven Dooley, Anne Dropmann

Date Published: 2023

Publication Type: Journal

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