The switch of DNA states filtering the extrinsic noise in the system of frequency modulation.

There is a special node, which the large noise of the upstream element may not always lead to a broad distribution of downstream elements. This node is DNA, with upstream element TF and downstream elements mRNA and proteins. By applying the stochastic simulation algorithm (SSA) on gene circuits inspired by the fim operon in Escherichia coli, we found that cells exchanged the distribution of the upstream transcription factor (TF) for the transitional frequency of DNA. Then cells do an inverse transform, which exchanges the transitional frequency of DNA for the distribution of downstream products. Due to this special feature, DNA in the system of frequency modulation is able to reset the noise. By probability generating function, we know the ranges of parameter values that grant such an interesting phenomenon.

The common misuse of noise decomposition as applied to genetic systems.

The noise-decomposition technique is applied in several fields, including genetic systems, optical images, recording, and navigation. In genetic systems, noise decomposition is usually achieved by using two reporters [Elowitz M.B., Levine A.J., Siggia E.D., Swain P·S., 2002. Stochastic gene expression in a single cell. Science 297, 1183-6.]. A reporter is a protein with fluorescence, an RNA hybridized with a fluorescent probe, or any other detectable intracellular component. If a reporter is constructed in addition to the original reporter, the system's stochasticity may change. Such phenomena became severe for genes in plasmids with a high copy number. By SSA (stochastic simulation algorithm), we observed an approximately 50% increment in the coefficient of variation while introducing additional reporters. Besides, if two reporters respond to the upstream element at a different time, the trunk noise (or extrinsic noise) cannot be accurately determined. This is because the "calculative trunk noise" changes along with the delay, though the real trunk noise does not. For RNA reporters, a 5-min transcriptional delay caused a calculative trunk noise that was 90% less than the real trunk noise. Fortunately, this problem is negligible when the degradation rate constant is low, and it is usually true in the case of the protein reporters. One can check the lifespan of the reporter before applying the noise-decomposition technique.

A Practicable Method of Tuning the Noise Intensity at Protein Level.

The expression of genes is inevitably subject to intracellular noise. Noise, for some regulatory networks, is constructive but detrimental to many others. The intensity of the noise is a determinant factor and the method of tuning it is of great value. In this study, we illustrated that the transcriptional delay in an incoherent feedforward loop (FFL) grants the target protein modulation the intensity of noise. Remarkably, for a wide range, the coefficient of variation (COV) of the target protein appeared to be about linear to the time span of the transcriptional delay. Without a noise-buffering method, the COV of the target protein is 0.455. While applying incoherent FFL, the COV reduced to 0.236. Then, it changed from 0.236 to 0.630 as the transcriptional delay raised from 0 to 1000 seconds. If we further increased the delay out of the linear range, the COV finally reached 0.779. In addition, we incorporated the distribution of the transcriptional delay in the delay stochastic simulation algorithm. This distribution is based on the experimental observation in the literature. The outcome suggested that the distributed delay slightly improved the ability of tuning noise. In conclusion, we demonstrated a noise-tuning method that altered only the intensity of noise without changing the deterministic steady-state behaviors. It is ready to be applied to various systems in the field of synthetic biology.

Exposure to One Antibiotic Leads to Acquisition of Resistance to Another Antibiotic via Quorum Sensing Mechanisms.

The vancomycin-resistant Enterococci (VRE) have progressively become a severe medical problem. Although clinics have started to reduce vancomycin prescription, vancomycin resistance has not been contained. We found that the transfer of vancomycin resistance in Enterococcus faecalis increased more than 30-fold upon treatment by streptomycin. Notably, treatment with an antibiotic caused the bacteria to become resistant to another. The response was even stronger in the well-studied plasmid pCF10 and the number of transconjugants increased about 100,000-fold. We tested four different antibiotics, and all of them induced conjugal response. Through a mathematical model based on gene regulation, we found a plausible explanation. Via quorum sensing, the change of the cell density triggers the conjugation. Moreover, we searched for generality and found a similar strategy in Bacillus subtilis. The outcome of the present study suggests that even common antibiotics must not be overused.