Logical-continuous modelling of post-translationally regulated bistability of curli fiber expression in Escherichia coli

Bacteria have developed a repertoire of signalling mechanisms that enable adaptive responses to fluctuating environmental conditions. The formation of biofilm, for example, allows persisting in times of external stresses, e.g. induced by antibiotics or a lack of nutrients. Adhesive curli fibers, the major extracellular matrix components in Escherichia coli biofilms, exhibit heterogeneous expression in isogenic cells exposed to identical external conditions. The dynamical mechanisms underlying this heterogeneity remain poorly understood. In this work, we elucidate the potential role of post- translational bistability as a source for this heterogeneity. We introduce a structured modelling workflow combining logical network topology analysis with time-continuous deterministic and stochastic modelling. The aim is to evaluate the topological structure of the underlying signalling network and to identify and analyse model parameterisations that satisfy observations from a set of genetic knockout experiments. Our work supports the hypothesis that the phenotypic heterogeneity of curli expression in biofilm cells is induced by bistable regulation at the post-translational level. Stochastic modelling suggests diverse noise-induced switching behaviours between the stable states, depending on the expression levels of the c-di-GMP-producing (diguanylate cyclases, DGCs) and -degrading (phosphodiesterases, PDEs) enzymes and reveals the quantitative difference in stable c-di-GMP levels between distinct phenotypes. The most dominant type of behaviour is characterised by a fast switching from curli-off to curli-on with a slow switching in the reverse direction and the second most dominant type is a long-term differentiation into curli-on or curli-off cells. This behaviour may implicate an intrinsic feature of the system allowing for a fast adaptive response (curli-on) versus a slow transition to the curli-off state, in line with experimental observations. The combination of logical and continuous modelling enables a thorough analysis of different determinants of bistable regulation, i.e. network topology and biochemical kinetics, and allows for an incorporation of experimental data from heterogeneous sources. Our approach yields a mechanistic explanation for the phenotypic heterogeneity of curli fiber expression. Furthermore, the presented work provides a detailed insight into the interactions between the multiple DGC- and PDE-type enzymes and the role of c-di-GMP in dynamical regulation of cellular decisions

A screening platform for glioma growth and invasion using bioluminescence imaging: Laboratory investigation

10.3171/2008.8.JNS08644Journal of Neurosurgery1112238-246JONS

Plumbing systems of shallow level intrusive complexes

We have come a long way from simple straw and balloon models of magma plumbing systems to a more detailed picture of shallow level intrusive complexes. In this chapter, the sub-volcanic plumbing system is considered in terms of how we can define the types and styles of magma networks from the deep to the shallow subsurface. We look at the plumbing system from large igneous provinces, through rifted systems to polygenetic volcanoes, with a view to characterising some of the key conceptual models. There is a focus on how ancient magmatic centres can help us better understand magmatic plumbing. New innovative ways to consider and quantify magma plumbing are also highlighted including 3D seismic, and using the crystal cargo to help fingerprint key magma plumbing events. Conclusions are drawn to our understanding of the 3D plumbing system and how these recent advances can be helpful when exploring the other chapters of this contribution