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Wolkenhauer O.,University of Rostock | Wolkenhauer O.,Stellenbosch Institute for Advanced Study STIAS | Shibata D.K.,University of Southern California | Mesarovic M.D.,Case Western Reserve University
BMC Systems Biology | Year: 2011

Background: Multilevelness is a defining characteristic of complex systems. For example, in the intestinal tissue the epithelial lining is organized into crypts that are maintained by a niche of stem cells. The behavior of the system 'as a whole' is considered to emerge from the functioning and interactions of its parts. What we are seeking here is a conceptual framework to demonstrate how the fate of intestinal crypts is an emergent property that inherently arises from the complex yet robust underlying biology of stem cells.Results: We establish a conceptual framework in which to formalize cross-level principles in the context of tissue organization. To this end we provide a definition for stemness, which is the propensity of a cell lineage to contribute to a tissue fate. We do not consider stemness a property of a cell but link it to the process in which a cell lineage contributes towards tissue (mal)function. We furthermore show that the only logically feasible relationship between the stemness of cell lineages and the emergent fate of their tissue, which satisfies the given criteria, is one of dominance from a particular lineage.Conclusions: The dominance theorem, conceived and proven in this paper, provides support for the concepts of niche succession and monoclonal conversion in intestinal crypts as bottom-up relations, while crypt fission is postulated to be a top-down principle. © 2011 Wolkenhauer et al; licensee BioMed Central Ltd. Source

Kossow C.,University of Rostock | Jose D.,University of Rostock | Jose D.,Max Delbruck Center for Molecular Medicine | Jaster R.,University of Rostock | And 3 more authors.
IET Systems Biology | Year: 2012

Interferon-γ (IFNγ)-mediated signal transduction via upregulation of signal transducer and activator of transcription (STAT) 1 leads to the expression of the mucin (MUC) 4 gene in pancreatic cancer cells. Upregulation of STAT1 may also implicate STAT1 tyrosine- or serine-phosphorylation. Experimental data indicate that reaction steps involved in IFNγ-induced serine-phosphorylation of STAT1 vary between cell types in contrast to conserved IFNγ-induced tyrosine-phosphorylation of STAT1. The above observations raise the following two questions: (i) How does IFNγ stimulation regulates serine-phosphorylation of STAT1 in the pancreatic cancer cell line CD18/HPAF? (ii) Which type of STAT1 acts as a transcription factor of MUC4? Our objective is to address these two questions by data-driven mathematical modelling. Simulation results of the parameterised ordinary differential equation models show that serine-phosphorylation of unphosphorylated STAT1 occurs in the cytoplasm. In contrast, serine-phosphorylation of tyrosine-phosphorylated STAT1 can take place in the cytoplasm or in the nucleus. In addition, our results propose that unphosphorylated or serine-phosphorylated STAT1 can act as transcription factors of MUC4, either alone by progressive binding to different sites in the promoter or both together. © 2012 The Institution of Engineering and Technology. Source

Lao A.,University of Rostock | Schmidt V.,Max Delbruck Center for Molecular Medicine | Schmitz Y.,University of Rostock | Willnow T.E.,Max Delbruck Center for Molecular Medicine | And 2 more authors.
BMC Systems Biology | Year: 2012

Background: Proteolytic breakdown of the amyloid precursor protein (APP) by secretases is a complex cellular process that results in formation of neurotoxic Aβ peptides, causative of neurodegeneration in Alzheimer's disease (AD). Processing involves monomeric and dimeric forms of APP that traffic through distinct cellular compartments where the various secretases reside. Amyloidogenic processing is also influenced by modifiers such as sorting receptor-related protein (SORLA), an inhibitor of APP breakdown and major AD risk factor.Results: In this study, we developed a multi-compartment model to simulate the complexity of APP processing in neurons and to accurately describe the effects of SORLA on these processes. Based on dose-response data, our study concludes that SORLA specifically impairs processing of APP dimers, the preferred secretase substrate. In addition, SORLA alters the dynamic behavior of β-secretase, the enzyme responsible for the initial step in the amyloidogenic processing cascade.Conclusions: Our multi-compartment model represents a major conceptual advance over single-compartment models previously used to simulate APP processing; and it identified APP dimers and β-secretase as the two distinct targets of the inhibitory action of SORLA in Alzheimer's disease. © 2012 Lao et al.; licensee BioMed Central Ltd. Source

Govaerts J.,Catholic University of Louvain | Govaerts J.,University Abomey Calavi | Govaerts J.,Stellenbosch Institute for Advanced Study STIAS | Zonetti S.,Catholic University of Louvain
Classical and Quantum Gravity | Year: 2011

A two-dimensional matter-coupled model of quantum gravity is studied in the Dirac approach to constrained dynamics in the presence of a cosmological constant. It is shown that after partial fixing to the conformal gauge, the requirement of a quantum realization of the conformal algebra for physical quantum states of the fields naturally constrains the cosmological constant to take values in a well-determined and mostly discrete spectrum. Furthermore, the contribution of the quantum fluctuations of the single dynamical degree of freedom in the gravitational sector, namely the conformal mode, to the cosmological constant is negative, in contrast to the positive contributions of the quantum fluctuations of the matter fields, possibly opening an avenue towards addressing the cosmological constant problem in a more general context. © 2011 IOP Publishing Ltd. Source

Zonetti S.,Catholic University of Louvain | Govaerts J.,Catholic University of Louvain | Govaerts J.,University Abomey Calavi | Govaerts J.,Stellenbosch Institute for Advanced Study STIAS
Journal of Physics A: Mathematical and Theoretical | Year: 2012

We present an interesting reformulation of a collection of dilaton gravity models in two spacetime dimensions into a field theory of two decoupled Liouville fields in flat space, in the presence of a Maxwell gauge field. An effective action is also obtained, encoding the dynamics of the dilaton field and the single gravitational degree of freedom in a decoupled regime. This effective action represents an interesting starting point for future work, including the canonical quantization of these classes of nontrivial models of gravity-coupled matter systems. © 2012 IOP Publishing Ltd. Source

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