Data-based stochastic modeling reveals sources of activity bursts in single-cell TGF-ß signaling.

Cells sense their surrounding by employing intracellular signaling pathways that transmit hormonal signals from the cell membrane to the nucleus. TGF-ß/SMAD signaling encodes various cell fates, controls tissue homeostasis and is deregulated in diseases such as cancer. The pathway shows strong heterogeneity at the single-cell level, but quantitative insights into mechanisms underlying fluctuations at various time scales are still missing, partly due to inefficiency in the calibration of stochastic models that mechanistically describe signaling processes. In this work we analyze single-cell TGF-ß/SMAD signaling and show that it exhibits temporal stochastic bursts which are dose-dependent and whose number and magnitude correlate with cell migration. We propose a stochastic modeling approach to mechanistically describe these pathway fluctuations with high computational efficiency. Employing high-order numerical integration and fitting to burst statistics we enable efficient quantitative parameter estimation and discriminate models that assume noise in different reactions at the receptor level. This modeling approach suggests that stochasticity in the internalization of TGF-ß receptors into endosomes plays a key role in the observed temporal bursting. Further, the model predicts the single-cell dynamics of TGF-ß/SMAD signaling in untested conditions, e.g., successfully reflects memory effects of signaling noise and cellular sensitivity towards repeated stimulation. Taken together, our computational framework based on burst analysis, noise modeling and path computation scheme is a suitable tool for the data-based modeling of complex signaling pathways, capable of identifying the source of temporal noise.

A Multiscale Approach to the Migration of Cancer Stem Cells: Mathematical Modelling and Simulations.

We propose a multiscale model for the invasion of the extracellular matrix by two types of cancer cells, the differentiated cancer cells and the cancer stem cells. We investigate the epithelial mesenchymal-like transition between them being driven primarily by the epidermal growth factors. We moreover take into account the transdifferentiation program of the cancer stem cells towards the cancer-associated fibroblast cells as well as the fibroblast-driven remodelling of the extracellular matrix. The proposed haptotaxis model combines the macroscopic phenomenon of the invasion of the extracellular matrix by both types of cancer cells with the microscopic dynamics of the epidermal growth factors. We analyse our model in a component-wise manner and compare our findings with the literature. We investigate pathological situations regarding the epidermal growth factors and accordingly propose "mathematical-treatment" scenarios to control the aggressiveness of the tumour.

Open IoT Ecosystem for Enhanced Interoperability in Smart Cities-Example of Métropole De Lyon.

The Internet of Things (IoT) has promised a future where everything gets connected. Unfortunately, building a single global ecosystem of Things that communicate with each other seamlessly is virtually impossible today. The reason is that the IoT is essentially a collection of isolated "Intranets of Things", also referred to as "vertical silos", which cannot easily and efficiently interact with each other. Smart cities are perhaps the most striking examples of this problem since they comprise a wide range of stakeholders and service providers who must work together, including urban planners, financial organisations, public and private service providers, telecommunication providers, industries, citizens, and so forth. Within this context, the contribution of this paper is threefold: (i) discuss business and technological implications as well as challenges of creating successful open innovation ecosystems, (ii) present the technological building blocks underlying an IoT ecosystem developed in the framework of the EU Horizon 2020 programme, (iii) present a smart city pilot (Heat Wave Mitigation in Métropole de Lyon) for which the proposed ecosystem significantly contributes to improving interoperability between a number of system components, and reducing regulatory barriers for joint service co-creation practices.