negative feedback circuit
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Author(s):  
Guangbao Zhang ◽  
Shuting Hu ◽  
Xiaoqiang Jia

Although many whole-cell biosensors (WCBs) for the detection of Cd2+ have been developed over the years, most lack sensitivity and specificity. In this paper, we developed a Cd2+ WCB with a negative feedback amplifier in P. putida KT2440. Based on the slope of the linear detection curve as a measure of sensitivity, WCB with negative feedback amplifier greatly increased the output signal of the reporter mCherry, resulting in 33% greater sensitivity than in an equivalent WCB without the negative feedback circuit. Moreover, WCB with negative feedback amplifier exhibited increased Cd2+ tolerance and a lower detection limit of 0.1 nM, a remarkable 400-fold improvement compared to the WCB without the negative feedback circuit, which is significantly below the World Health Organization standard of 27 nM (0.003 mg/L) for cadmium in drinking water. Due to the superior amplification of the output signal, WCB with negative feedback amplifier can provide a detectable signal in a much shorter time, and a fast response is highly preferable for real field applications. In addition, the WCB with negative feedback amplifier showed an unusually high specificity for Cd2+ compared to other metal ions, giving signals with other metals that were between 17.6 and 41.4 times weaker than with Cd2+. In summary, the negative feedback amplifier WCB designed in this work meets the requirements of Cd2+ detection with very high sensitivity and specificity, which also demonstrates that genetic negative feedback amplifiers are excellent tools for improving the performance of WCBs.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ying Tang ◽  
Adewunmi Adelaja ◽  
Felix X.-F. Ye ◽  
Eric Deeds ◽  
Roy Wollman ◽  
...  

AbstractCellular responses to environmental changes are encoded in the complex temporal patterns of signaling proteins. However, quantifying the accumulation of information over time to direct cellular decision-making remains an unsolved challenge. This is, in part, due to the combinatorial explosion of possible configurations that need to be evaluated for information in time-course measurements. Here, we develop a quantitative framework, based on inferred trajectory probabilities, to calculate the mutual information encoded in signaling dynamics while accounting for cell-cell variability. We use it to understand NFκB transcriptional dynamics in response to different immune threats, and reveal that some threats are distinguished faster than others. Our analyses also suggest specific temporal phases during which information distinguishing threats becomes available to immune response genes; one specific phase could be mapped to the functionality of the IκBα negative feedback circuit. The framework is generally applicable to single-cell time series measurements, and enables understanding how temporal regulatory codes transmit information over time.


2021 ◽  
Author(s):  
Jonathan B. Asfaha ◽  
Mihkel Örd ◽  
Mart Loog ◽  
David O. Morgan

AbstractOrdered phosphorylation of cyclin-dependent kinase (CDK) substrates leads to the sequential transcriptional activation and inhibition of hundreds of cell cycle-regulated genes. We find that Ndd1, an activator of genes required for mitotic progression, is both positively and negatively regulated by CDK activity. CDK activity initially stimulates Ndd1-dependent transcription as cells enter mitosis, but prolonged high CDK activity in a mitotic arrest inhibits transcription. The result is a time-delayed negative feedback circuit that generates a pulse of mitotic gene expression. Our results suggest that high CDK activity catalyzes the formation of multiple weak phosphodegrons on Ndd1, leading to its destabilization. Cyclin specificity and phosphorylation kinetics contribute to the timing of Ndd1 destruction. Failure to degrade Ndd1 in a mitotic arrest leads to elevated mitotic gene expression. We conclude that a combination of positive and negative Ndd1 regulation by CDKs governs the timing and magnitude of the mitotic transcriptional program.


Telecom IT ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 9-14
Author(s):  
Y. Nikitin ◽  
G. Tsygankov

A model of a pulse phase-locked loop multiplying ring in a MicroCap11 medium is considered. The analysis uses a nonlinear model of a voltage-controlled oscillator with a user-defined control characteristic. An RS-trigger is used as a pulse-phase detector, a pulse counter in the negative feedback circuit is implemented on JK-triggers. Transient processes in the ring, as well as the spectrum of the output oscillations in the steady (stationary) mode are considered.


2018 ◽  
Vol 32 (8) ◽  
pp. 4096-4106 ◽  
Author(s):  
Juan Li ◽  
Ao Guo ◽  
Qinying Wang ◽  
Yuanyuan Li ◽  
Jian Zhao ◽  
...  

2017 ◽  
Author(s):  
Winnie Y. Wen ◽  
Elena Ingerman ◽  
Maike M. K. Hansen ◽  
Brandon S. Razooky ◽  
Roy D. Dar ◽  
...  

ABSTRACTDiverse biological systems utilize gene-expression fluctuations (‘noise’) to drive lineage-commitment decisions1-5. However, once a commitment is made, noise becomes detrimental to reliable function6,7and the mechanisms enabling post-commitment noise suppression are unclear. We used time-lapse imaging and mathematical modeling, and found that, after a noise-driven event, human immunodeficiency virus (HIV) strongly attenuated expression noise through a non-transcriptional negative-feedback circuit. Feedback is established by serial generation of RNAs from post-transcriptional splicing, creating a precursor-product relationship where proteins generated from spliced mRNAs auto-deplete their own precursor un-spliced mRNAs. Strikingly, precursor auto-depletion overcomes the theoretical limits on conventional noise suppression—minimizing noise far better than transcriptional auto-repression—and dramatically stabilizes commitment to the active-replication state. This auto-depletion feedback motif may efficiently suppress noise in other systems ranging from detained introns to non-sense mediated decay.


2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Duchu Chen ◽  
Huiping Wang ◽  
Jude Juventus Aweya ◽  
Yanheng Chen ◽  
Meihua Chen ◽  
...  

In the past decade, much emphasis has been put on the transcriptional activation of HIV-1, which is proposed as a promised strategy for eradicating latent HIV-1 provirus. Two drugs, prostratin and hexamethylene bisacetamide (HMBA), have shown potent effects as inducers for releasing HIV-1 latency when used alone or in combination, although their cellular target(s) are currently not well understood, especially under drug combination. Here, we have shown that HMBA and prostratin synergistically release HIV-1 latency via different mechanisms. While prostratin strongly stimulates HMBA-induced HIV-1 transcription via improved P-TEFb activation, HMBA is capable of boosting NF-κB-dependent transcription initiation by suppressing prostratin-induced expression of the deubiquitinase A20, a negative feedback regulator in the NF-κB signaling pathway. In addition, HMBA was able to increase prostratin-induced phosphorylation and degradation of NF-κB inhibitor IκBα, thereby enhancing and prolonging prostratin-induced nuclear translocation of NF-κB, a prerequisite for stimulation of transcription initiation. Thus, by blocking the negative feedback circuit, HMBA functions as a signaling enhancer of the NF-κB signaling pathway.


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