Fig. 4: Interdependency of consolidating signal transduction pathways, and oscillatory signaling processes and second messengers coordinating tissue function, in introducing complexity when setting optimization metrics, prescribed signaling targets, or scoring paradigms.

a Opposing and aligned roles of Akt and AMPK in cell processes. b Oscillatory inputs (e.g., [Ca²⁺] or [cAMP]; top) can be decoded on an amplitude-dependent (left) or frequency-dependent (right) basis based on receiver process kinetics being slow or fast, respectively, lending further mutability to the physiological manifestation of a set of interdependent and multi-step signaling pathways³⁷⁶. Reproduced with the express permission of the publisher and authors. c Simulated interactions between calcium and cAMP levels in a model of mutual enzymatic activation, based on active phospholipase Cβ (PLCβ) concentration and a set adenylate cyclase concentration of 0.17 µM²⁴⁸; demonstrating interdependency of second messenger kinetics on their ultimate manifestation as an output response. Reproduced under a CC-BY license with express permission of the authors. d Sample visualization of an iterative High Dimensional, Differential Evolutionary (HD-DE) algorithm with successive generations outperforming each other on a normalized objective metric, with biological variability represented by temporary differences in performance between independent iterative runs that ultimately converge at highly-performing solution scores; this algorithm was used to optimize hematopoietic stem cell expansion medium efficacy³⁸⁸. Reproduced under a CC-BY license with express permission of the authors.