The magnitude and colour of noise in genetic negative feedback systems.
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ABSTRACT:
SUBMITTER: Voliotis M
PROVIDER: S-EPMC3424552 | biostudies-literature | 2012 Aug
REPOSITORIES: biostudies-literature
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Project description:Negative feedback loops have been invoked as a way to control and decrease transcriptional noise. Here, we have built three circuits to test the effect of negative feedback loops on transcriptional noise of an autoregulated gene encoding a transcription factor (TF) and a downstream gene (DG), regulated by this TF. Experimental analysis shows that self-repression decreases noise compared to expression from a non-regulated promoter. Interestingly enough, we find that noise minimization by negative feedback loop is optimal within a range of repression strength. Repression values outside this range result in noise increase producing a U-shaped behaviour. This behaviour is the result of external noise probably arising from plasmid fluctuations as shown by simulation of the network. Regarding the target gene of a self-repressed TF (sTF), we find a strong decrease of noise when repression by the sTF is strong and a higher degree of noise anti-correlation between sTF and its target. Simulations of the circuits indicate that the main source of noise in these circuits could come from plasmid variation and therefore that negative feedback loops play an important role in suppressing both external and internal noise. An important observation is that DG expression without negative feedback exhibits bimodality at intermediate TF repression values. This bimodal behaviour seems to be the result of external noise as it can only be found in those simulations that include plasmid variation.
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Project description:It is well known that noise is inevitable in gene regulatory networks due to the low-copy numbers of molecules and local environmental fluctuations. The prediction of noise effects is a key issue in ensuring reliable transmission of information. Interlinked positive and negative feedback loops are essential signal transduction motifs in biological networks. Positive feedback loops are generally believed to induce a switch-like behavior, whereas negative feedback loops are thought to suppress noise effects. Here, by using the signal sensitivity (susceptibility) and noise amplification to quantify noise propagation, we analyze an abstract model of the Myc/E2F/MiR-17-92 network that is composed of a coupling between the E2F/Myc positive feedback loop and the E2F/Myc/miR-17-92 negative feedback loop. The role of the feedback loop on noise effects is found to depend on the dynamic properties of the system. When the system is in monostability or bistability with high protein concentrations, noise is consistently suppressed. However, the negative feedback loop reduces this suppression ability (or improves the noise propagation) and enhances signal sensitivity. In the case of excitability, bistability, or monostability, noise is enhanced at low protein concentrations. The negative feedback loop reduces this noise enhancement as well as the signal sensitivity. In all cases, the positive feedback loop acts contrary to the negative feedback loop. We also found that increasing the time scale of the protein module or decreasing the noise autocorrelation time can enhance noise suppression; however, the systems sensitivity remains unchanged. Taken together, our results suggest that the negative/positive feedback mechanisms in coupled feedback loop dynamically buffer noise effects rather than only suppressing or amplifying the noise.
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Project description:PhoP and PhoQ comprise a two-component system in the bacterium Salmonella enterica. PhoQ is the sensor kinase/phosphatase that modifies the phosphorylation state of the regulator PhoP in response to stimuli. The amount of phosphorylated PhoP surges after activation, then declines to reach a steady-state level. We now recapitulate this surge in vitro by incubating PhoP and PhoQ with ATP and ADP. Mathematical modeling identified PhoQ's affinity for ADP as the key parameter dictating phosphorylated PhoP levels, as ADP promotes PhoQ's phosphatase activity toward phosphorylated PhoP. The lid covering the nucleotide-binding pocket of PhoQ governs the kinase to phosphatase switch because a lid mutation that decreased ADP binding compromised PhoQ's phosphatase activity in vitro and resulted in sustained expression of PhoP-dependent mRNAs in vivo. This feedback mechanism may curtail futile ATP consumption because ADP not only stimulates PhoQ's phosphatase activity but also inhibits ATP binding necessary for the kinase reaction.
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Project description:BackgroundOutcome feedback which indicates behavioral consequences are crucial for reinforcement learning and environmental adaptation. Nevertheless, outcome information in daily life is often totally or partially ambiguous. Studying how people interpret this kind of information would provide important knowledge about the human evaluative system.MethodsThis study concentrates on the neural processing of partially ambiguous feedback, that is, either its valence or magnitude is unknown to participants. To address this topic, we sequentially presented valence and magnitude information; electroencephalography (EEG) response to each kind of presentation was recorded and analyzed. The event-related potential components feedback-related negativity (FRN) and P3 were used as indices of neural activity.ResultsConsistent with previous literature, the FRN elicited by ambiguous valence was not significantly different from that elicited by negative valence. On the other hand, the FRN elicited by ambiguous magnitude was larger than both the large and small magnitude, indicating the motivation to seek unambiguous magnitude information. The P3 elicited by ambiguous valence and ambiguous magnitude was not significantly different from that elicited by negative valence and small magnitude, respectively, indicating the emotional significance of feedback ambiguity. Finally, the aforementioned effects also manifested in the stage of information integration.ConclusionThese findings indicate both similarities and discrepancies between the processing of valence ambiguity and that of magnitude ambiguity, which may help understand the mechanisms of ambiguous information processing.
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Project description:Natural selection for specific functions places limits upon the amino acid substitutions a protein can accept. Mechanisms that expand the range of tolerable amino acid substitutions include chaperones that can rescue destabilized proteins and additional stability-enhancing substitutions. Here, we present an alternative mechanism that is simple and uses a frequently encountered network motif. Computational and experimental evidence shows that the self-correcting, negative-feedback gene regulation motif increases repressor expression in response to deleterious mutations and thereby precisely restores repression of a target gene. Furthermore, this ability to rescue repressor function is observable across the Eubacteria kingdom through the greater accumulation of amino acid substitutions in negative-feedback transcription factors compared to genes they control. We propose that negative feedback represents a self-contained genetic canalization mechanism that preserves phenotype while permitting access to a wider range of functional genotypes.
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Project description:BACKGROUND:This article presents the details and findings of a practical implementation of a preliminary model for use in hearing conservation programmes (HCPs) in the mining sector in South Africa. OBJECTIVES:The implementation is based on a previously published model, called feedback-based noise monitoring model (FBNMM), and represents its implementation as a tool of predicting occupational noise-induced hearing loss (ONIHL), as well as monitoring and managing HCPs in the mining sector within the South African context. METHOD:The article, utilising real miners' data, demonstrates this basic static feedback model with its practical applications such as estimating, monitoring and providing quantitative information to aid miners, mining administrators and policymakers in decision-making around HCPs, as recommended in the previous 2019 publication by Moroe et al. This study was conducted in a South African platinum mine. Evidence on the model's sensitivity and practicability in early identification, intervention and management of ONIHL in the workplace is presented. RESULTS:Findings show how the use of the model within an HCP viewed as a complex intervention can allow for early prediction of ONIHL, consequently affording more accurate early intervention as part of preventive audiology within the health and safety goals of mines. CONCLUSION:The feedback-based model should be a useful tool for successful implementation and monitoring of HCPs within South African mines.
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Project description:Feedback oscillators, consisting of an amplifier whose output is partially fed back to its input, provide stable references for standardization and synchronization. Notably, the laser is such an oscillator whose performance can be limited by quantum fluctuations. The resulting frequency instability, quantified by the Schawlow-Townes formula, sets a limit to laser linewidth. Here, we show that the Schawlow-Townes formula applies universally to feedback oscillators beyond lasers. This is because it arises from quantum noise added by the amplifier and out-coupler in the feedback loop. Tracing the precise origin of quantum noise in an oscillator informs techniques to systematically evade it: we show how squeezing and entanglement can enable sub-Schawlow-Townes linewidth feedback oscillators. Our analysis clarifies the quantum limits to the stability of feedback oscillators in general, derives a standard quantum limit (SQL) for all such devices, and quantifies the efficacy of quantum strategies in realizing sub-SQL oscillators.
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Project description:BackgroundFeedback regulation plays crucial roles in the robust control and maintenance of many cellular systems. Negative feedbacks are found to underline both stable and unstable, often oscillatory, behaviours. We explore the dynamical characteristics of systems with single as well as coupled negative feedback loops using a combined approach of analytical and numerical techniques. Particularly, we emphasise how the loop's characterising factors (strength and cooperativity levels) affect system dynamics and how individual loops interact in the coupled-loop systems.ResultsWe develop an analytical bifurcation analysis based on the stability and the Routh-Hurwitz theorem for a common negative feedback system and a variety of its variants. We demonstrate that different combinations of the feedback strengths of individual loops give rise to different dynamical behaviours. Moreover, incorporating more negative feedback loops always tend to enhance system stability. We show that two mechanisms, in addition to the lengthening of pathway, can lower the Hill coefficient to a biologically plausible level required for sustained oscillations. These include loops coupling and end-product utilisation. We find that the degradation rates solely affect the threshold Hill coefficient for sustained oscillation, while the synthesis rates have more significant roles in determining the threshold feedback strength. Unbalancing the degradation rates between the system species is found as a way to improve stability.ConclusionThe analytical methods and insights presented in this study demonstrate that reallocation of the feedback loop may or may not make the system more stable; the specific effect is determined by the degradation rates of the newly inhibited molecular species. As the loop moves closer to the end of the pathway, the minimum Hill coefficient for oscillation is reduced. Furthermore, under general (unequal) values of the degradation rates, system extension becomes more stable only when the added species degrades slower than it is being produced; otherwise the system is more prone to oscillation. The coupling of loops significantly increases the richness of dynamical bifurcation characteristics. The likelihood of having oscillatory behaviour is directly determined by the loops' strength: stronger loops always result in smaller oscillatory regions.
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