Abstract: The number of mathematical models for biological pathways is rapidly growing. In particular, Boolean modelling proved to be suited to describe large cellular signalling networks. Systems biology is at the threshold to holistic understanding of comprehensive networks. In order to reach this goal, connection and integration of existing models of parts of cellular networks into more comprehensive network models is necessary. We discuss model combination approaches for Boolean models. Boolean modelling is qualitative rather than quantitative and does not require detailed kinetic information. We show that these models are useful precursors for large-scale quantitative models and that they are comparatively easy to combine. We propose modelling standards for Boolean models as a prerequisite for smooth model integration. Using these standards, we demonstrate the coupling of two logical models on two different examples concerning cellular interactions in the liver. In the first example, we show the integration of two Boolean models of two cell types in order to describe their interaction. In the second example, we demonstrate the combination of two models describing different parts of the network of a single cell type. Combination of partial models into comprehensive network models will take systems biology to the next level of understanding. The combination of logical models facilitated by modelling standards is a valuable example for the next step towards this goal.
Abstract: BACKGROUND: The decision pro- or contra apoptosis is complex, involves a number of different inputs, and is central for the homeostasis of an individual cell as well as for the maintenance and regeneration of the complete organism. RESULTS: This study centers on Fas ligand (FasL)-mediated apoptosis, and a complex and internally strongly linked network is assembled around the central FasL-mediated apoptosis cascade. Different bioinformatical techniques are employed and different crosstalk possibilities including the integrin pathway are considered. This network is translated into a Boolean network (74 nodes, 108 edges). System stability is dynamically sampled and investigated using the software SQUAD. Testing a number of alternative crosstalk possibilities and networks we find that there are four stable system states, two states comprising cell survival and two states describing apoptosis by the intrinsic and the extrinsic pathways, respectively. The model is validated by comparing it to experimental data from kinetics of cytochrome c release and caspase activation in wildtype and Bid knockout cells grown on different substrates. Pathophysiological modifications such as input from cytomegalovirus proteins M36 and M45 again produces output behavior that well agrees with experimental data. CONCLUSION: A network model for apoptosis and crosstalk in hepatocytes shows four different system states and reproduces a number of different conditions around apoptosis including effects of different growth substrates and viral infections. It produces semi-quantitative predictions on the activity of individual nodes, agreeing with experimental data. The model (SBML format) and all data are available for further predictions and development.
Abstract: It was shown that compensatory base changes (CBCs) in internal transcribed spacer 2 (ITS2) sequence-structure alignments can be used for distinguishing species. Using the ITS2 Database in combination with 4SALE â a tool for synchronous RNA sequence and secondary structure alignment and editing â in this study we present an in-depth CBC analysis for placozoan ITS2 sequences and their respective secondary structures. This analysis indicates at least two distinct species in Trichoplax (Placozoa) supporting a recently suggested hypothesis, that Placozoa is âno longer a phylum of oneâ.
Abstract: Given two organisms, how can one distinguish whether they belong to the same species or not? This might be straightforward for two divergent organisms, but can be extremely difficult and laborious for closely related ones. A molecular marker giving a clear distinction would therefore be of immense benefit. The internal transcribed spacer 2 (ITS2) has been widely used for low-level phylogenetic analyses. Case studies revealed that a compensatory base change (CBC) in the helix II or helix III ITS2 secondary structure between two organisms correlated with sexual incompatibility. We analyzed more than 1300 closely related species to test whether this correlation is generally applicable. In 93%, where a CBC was found between organisms classified within the same genus, they belong to different species. Thus, a CBC in an ITS2 sequence-structure alignment is a sufficient condition to distinguish even closely related species.
Abstract: Cytomegaloviruses efficiently block apoptosis of host cells by using viral proteins. We investigate this here in simulations using squad. We compare and show four different viral proteins (pM36, pm38.5, pm41.1, pM45) and their effects on the cellular network. pM36 blocks the cascade directly, inhibiting the extrinsic pathway whereas pm38.5 and pm41.1 prevent the cell from apoptosis by influencing the intrinsic pathway. M45 inhibits the induction of caspase-independent cell death (programmed necrosis, necroptosis) and also blocks NFĸB mediated antiapoptotic signaling.
After sequence- and domainanalysis all components and interactions of the network were collected and included. A model was established using Celldesigner. In the lack of detailed dynamical data, a boolean model was constructed and SQUAD used to interpolate between system states. The SQUAD simulation allows to compare the system effects and efficiencies of these different ways to block apoptosis. Furthermore, quantitative strengths of the different protein blocks can be compared amongst each other and with experimental data. Moreover, we can now ask and investigate, whether this quadruple block of apoptosis really is complete or whether there are alternative paths which still allow apoptosis. In this way, our assay system allows to identify new independent pathways of apoptosis.
Abstract: In the C1 project we combine different approaches to model as well as measure
apoptotic and antiapoptotic signalling in liver cells. Here we show data from
our analysis regarding cross-talks between different pathways. One focus is the
crosstalk modulating the apoptotic response in liver cells. In particular, in
vitro growth of primary hepatocytes on collagen or Matrigel circumvents the
mitochondrial pathway, which is usually needed for amplifying FasL-induced
apoptotic signalling in vivo or in hepatocytes in suspension. We show first data
from a genome-wide pathway analysis to elucidate modulating input on this growth
condition dependent response. Regarding profliferation, we investigate the
effect of the tumor suppressor protein DiRas3 (also known as Noey2/ARHI) on the
Ras/RAF/MEK/ERK pathway using dynamic modelling based on ordinary differential
equations (ODEs).
