Erin Gombos

Mechanism of organization increase in complex systems

This article proposes a variational approach to describe the evolution of organization of complex systems from first principles, as increased efficiency of physical action. Most simply stated, physical action is the product of the energy and time necessary for motion. When complex systems are modeled as flow networks, this efficiency is defined as a decrease of action for one element to cross between two nodes, or endpoints of motion-a principle of least unit action. We find a connection with another principle, that of most total action, or a tendency for increase of the total action of a system. This increase provides more energy and time for minimization of the constraints to motion to decrease unit action, and therefore, to increase organization. Also, with the decrease of unit action in a system, its capacity for total amount of action increases. We present a model of positive feedback between action efficiency and the total amount of action in a complex system, based on a system of ordinary differential equations, which leads to an exponential growth with time of each and a power law relation between the two. We present an agreement of our model with data for core processing units of computers. This approach can help to describe, measure, manage, design, and predict future behavior of complex systems to achieve the highest rates of self-organization and robustness.

A hierarchy of affinities between cytokine receptors and the common gamma chain leads to pathway cross-talk

Limiting amounts of the common receptor subunit γc result in asymmetric cross-talk among cytokines. Hierarchical sharing of the γc subunit Cytokines that belong to the common gamma chain (γc) family, including interleukin-4 (IL-4), IL-7, and IL-21, not only bind to distinct receptor subunits but also rely on a shared γc subunit for signaling. Given the roles of these cytokines in immune cell survival, proliferation, and function, it is important to understand how their shared use of the γc receptor affects the responses of cells to multiple family members. Through computational modeling and experimental analysis of cytokine receptor signaling on naïve T cells, Gonnord et al. showed that whereas treatment with IL-7 reduced the responses of cells to subsequent treatment with IL-4 or IL-21, the reverse was not true. The amount of available γc subunit was limiting and bound more readily to the IL-7 receptor α subunit (IL-7Rα) than to IL-4Rα or IL-21Rα, thus sequestering the γc subunit. The γc subunit preassociated with the IL-7Rα in the absence of cytokine. These data suggest that there exists a hierarchy of responses of naïve T cells to cytokines, which has relevance for cells in inflammatory environments exposed to multiple cytokines. Cytokines belonging to the common gamma chain (γc) family depend on the shared γc receptor subunit for signaling. We report the existence of a fast, cytokine-induced pathway cross-talk acting at the receptor level, resulting from a limiting amount of γc on the surface of T cells. We found that this limited abundance of γc reduced interleukin-4 (IL-4) and IL-21 responses after IL-7 preexposure but not vice versa. Computational modeling combined with quantitative experimental assays indicated that the asymmetric cross-talk resulted from the ability of the “private” IL-7 receptor subunits (IL-7Rα) to bind to many of the γc molecules even before stimulation with cytokine. Upon exposure of T cells to IL-7, the high affinity of the IL-7Rα:IL-7 complex for γc further reduced the amount of free γc in a manner dependent on the concentration of IL-7. Measurements of bioluminescence resonance energy transfer (BRET) between IL-4Rα and γc were reduced when IL-7Rα was overexpressed. Furthermore, in a system expressing IL-7Rα, IL-4Rα, and γc, BRET between IL-4Rα and γc increased after IL-4 binding and decreased when cells were preexposed to IL-7, supporting the assumption that IL-7Rα and the IL-7Rα:IL-7 complex limit the accessibility of γc for other cytokine receptor complexes. We propose that in complex inflammatory environments, such asymmetric cross-talk establishes a hierarchy of cytokine responsiveness.