Complex dynamical networks consisting of many components that interact and produce each other are difficult to understand, especially, when new components may appear. In this paper we outline a theory to deal with such systems. The theory consists of two parts. The first part introduces the concept of a chemical organization as a closed and mass-maintaining set of components. This concept allows to map a complex (reaction) network to the set of organizations, providing a new view on the system's structure. The second part connects dynamics with the set of organizations, which allows to map a movement of the system in state space to a movement in the set of organizations.Our world is changing, qualitatively and quantitatively. The characteristics of its dynamics can be as simple as in the case of a friction-less swinging pendulum, or as complex as the dynamical process that results in the creative apparition of novel ideas or entities. We might characterize the nature of a dynamical process according to its level of novelty production. For example, the friction-less swinging pendulum implies a process where the novelty is only quantitative. Whereas the process of biological evolution is highly creative and generates qualitative novelties, which then spread in a quantitative way.Fontana and Buss [1] called processes and systems that display the production of novelty, constructive (dynamical) processes and constructive (dynamical) systems, respectively. Constructive systems can be found on all levels of scientific abstraction: in nuclear physics, where the collision of atoms or subatomic particles leads to the creation of new particles; in molecular chemistry, where molecules can react to form new molecules; or in social systems, where communication can lead to new communication [2]. As a result of a combinatorial explosion, it is easy to create something that is new, e.g., a molecule or a poem that is unique in the whole known universe. Nevertheless, it should be noted that novelty is relative. Whether something is considered to be new or not, depends on what is already there. Thence it follows that whether a system 1 Both authors contributed equally.

All data and a Java implementation that plugs into the Systems Biology Workbench is available from http://www.minet.uni-jena.de/csb/prj/ot/tools.

Influenza A virus is recognized today as one of the most challenging viruses that threatens both human and animal health worldwide. Understanding the control mechanisms of influenza infection and dynamics is crucial and could result in effective future treatment strategies. Many kinetic models based on differential equations have been developed in recent decades to capture viral dynamics within a host. These models differ in their complexity in terms of number of species elements and number of reactions. Here, we present a new approach to understanding the overall structure of twelve influenza A virus infection models and their relationship to each other. To this end, we apply chemical organization theory to obtain a hierarchical decomposition of the models into chemical organizations. The decomposition is based on the model structure (reaction rules) but is independent of kinetic details such as rate constants. We found different types of model structures ranging from two to eight organizations. Furthermore, the model’s organizations imply a partial order among models entailing a hierarchy of model, revealing a high model diversity with respect to their long-term behavior. Our methods and results can be helpful in model development and model integration, also beyond the influenza area.

BackgroundSuburothelial myofibroblasts (sMF) are located underneath the urothelium in close proximity to afferent nerves. They express purinergic receptors and show calcium transients in response to ATP. Therefore they are supposed to be involved in afferent signaling of the bladder fullness. Since ATP concentration is likely to be very low during the initial filling phase, we hypothesized that sMF Ca2+ activity is affected even at very low ATP concentrations. We investigated ATP induced modulation of spontaneous activity, intracellular calcium response and purinergic signaling in cultured sMF.Methodology/Principal FindingsMyofibroblast cultures, established from cystectomies, were challenged by exogenous ATP in presence or absence of purinergic antagonist. Fura-2 calcium imaging was used to monitor ATP (10−16 to 10−4 mol/l) induced alterations of calcium activity. Purinergic receptors (P2X1, P2X2, P2X3) were analysed by confocal immunofluorescence. We found spontaneous calcium activity in 55.18%±1.65 of the sMF (N = 48 experiments). ATP significantly increased calcium activity even at 10−16 mol/l. The calcium transients were partially attenuated by subtype selective antagonist (TNP-ATP, 1 µM; A-317491, 1 µM), and were mimicked by the P2X1, P2X3 selective agonist α,β-methylene ATP. The expression of purinergic receptor subtypes in sMF was confirmed by immunofluorescence.Conclusions/SignificanceOur experiments demonstrate for the first time that ATP can modulate spontaneous activity and induce intracellular Ca2+ response in cultured sMF at very low concentrations, most likely involving P2X receptors. These findings support the notion that sMF are able to register bladder fullness very sensitively, which predestines them for the modulation of the afferent bladder signaling in normal and pathological conditions.

M2, P2X1, P2X2 and H1 were significantly upregulated in BPS/IC patients, and H2 was occasionally highly overexpressed. There was no significant correlation between receptor protein and gene expression, implying posttranslational mechanisms being responsible for the altered receptor expressions. On the basis of individual receptor profiles, upregulated receptors could be targeted by monotherapy or combination therapy with already approved receptor inhibitors, thereby promoting tailored therapy for patients suffering from BPS/IC-like symptoms.