Positive and Negative Feedback Loops

Once a mechanistic model of a pathway has been constructed, different methods of sensitivity analysis can be applied [15]. Sensitivity analysis is a means of showing the impact of each parameter in the model on output. It can also indicate where in the pathway the greatest effect of drug intervention would be expected, which could be beneficial to the drug discovery process. 

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P. Smolen, D. A. Baxter, and J. H. Byrne, Modeling circadian oscillations with interlocking positive and negative feedback loops. J. Neurosci. 21, 6644-6656 (2001). 

The autonomous functions exhibit circadian rhythms which are under the control of a neuronal pacemaker, located in the suprachiasmatic nuclei (SCN) of the hypothalamus. The circadian pacemaker arises from complex dynamics of gene expression and is synchronized to the external light. In the case of mental disorders, the regular rhythms of autonomous functions are obviously disturbed which led to the formulation of the desynchronization hypotheses [8, 9], This does not necessarily contradict the transmitter hypothesis . Transmitter imbalance, of course, also interferes with the inherent system dynamics and can change the endogenous rhythmicity, eventually with the result of desynchronization. A first computational approach which simulates the rhythmicity of the HPA axis and its alterations with scaling of transmitter mediated positive and negative feedback loops is briefly summarized in the second Results section. 

The feedback mechanisms are mediated via mineralocorticoid and glucocorticoid receptors (MR, GR), which means overlapping of nonlinear positive and negative feedback loops with nonlinear dependencies on cortisol (Michaelis-Menten kinetics, sigmoidal activation curves of corticoid receptors). 

Fig. 7.11 The main common features of the different modeling approaches for computer simulations of mental disorders, hormone release and neural discharges. Despite significant differences in details and several additional components in the specific models, the principle dynamics originate from a combination of positive and negative feedback loops. The necessary ingredients are ...

In two recent papers Naito et al. [129, 130] discuss a slightly modified model that differs in some details of the chemical reaction steps, but apparently not in the origin of the positive and negative feedback loops. One important conclusion from their studies is that the electrode potential can be eliminated adiabatically. As far as the differences in the mechanistic steps of the two models are concerned, without further studies it does not seem possible to decide which one describes the system better. 

Harris SF, Fevine AJ. The p53 pathway positive and negative feedback loops. Oncogene 2005 24 2899-2908. 

The inflammatory reaction is a complex series of iterating cascades with positive and negative feedback loops that provide a vast range of responses. Messengers and effectors of the inflammatory process have been identified in a wealth of studies. Probably the best series, where detailed and up-to-date information can be found on these topics is the Progress in Inflammation Research series published by Birkhauser (Basel). Of particular interest for the readers are the following books Free Radicals and Inflammation (Winyard et al.) [1] and Nitric Oxide and Inflammation (Salvemini et al.) [2]. 

Rubin, C., et al. 2003. Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops. Curr. Biol. 13 297-307. 

These five principles give rise to several positive and negative feedback loops that determine population density. In addition, there is a natural variability that is often considered to be random, although the causes may be deterministic but just presently unknown. 

System behavior in system dynamics is modeled by using feedback (causal) loops, stock and flows (levels and rates), and the nonlinearities created by interactions between system components. In this view of the world, behavior over time (the dynamics of the system) can be explained by the interaction of positive and negative feedback loops [185]. The models are constructed from three basic building blocks ... 

Tsai, T.Y.-C., Choi, Y.S., Ma, W., Pomerening, ).R., Tang, C., and Ferrell, ).E ). (2008) Robust, tunable biological oscillations from interlinked positive and negative feedback loops. Science, 321, 126-129. 

Genetic circuits must integrate specific components or network motifs that make them robust to fluctuations in the kinetics of biochemical reactions. Gene expression tends to be noisy because of the stochastic nature of the constituent biochemical reactions (Elowitz et al., 2002 McAdams and Arkin, 1997). In addition, fluctuations in environmental conditions, such as temperature and nutrient levels, affect cellular metabolism and consequently the operation of genetic circuits. Circuits that achieve reproducible, reliable behavior must do so despite components whose behavior fluctuates considerably. Mitigating the effects of gene expression noise will probably require a solution that incorporates positive and negative feedback loops. 

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