Current metrics adopted in the clinical setting, such as the MIC, do not account for the time course of antimicrobial activity and are not sufficiently predictive of treatment efficacy [22,45 —47].

(A,F) Time courses for populations with initial densities that are 10X and 100x smaller than the base model.

(A) Time course .

(F) Time course .

A lower threshold was used for the initial data selection: A minimum sum of 3 TPM normalised by relative log expression (RLE) over the time course was used as a threshold to increase the number of time courses from the more conservative 10 TPM criteria used for protein coding genes.

DNaseI hypersensitivity data for MCF7 cells [37, 38] were determined for 200 bp windows centered at the midpoint of each protein-coding and non-coding MCF7 time course CAGE cluster.

Clusters associated with transcription factors were also in more accessible regions (p = 0.018), but, surprisingly, clusters assigned to known IEGs or nucleotide binding genes did not differ significantly from the reference set in either MCF7 time course (p > 0.08 by Wilcoxon rank sum test).

This pattern was less apparent in the MCF7-HRG cell line where the proportion of known IEGs found in an interval exceeded the overall average towards the end of the time course .

The transcriptional repressor NAB2 peaked relatively late in both MCF7 time courses .

Nucleotide binding genes found to peak within 240 min in both MCF7 time courses included the transcription factor RUNX1 and three IEGs: TRIB1, SIK1 and GEM.

Kinetic signatures serve as prototypical patterns reflecting changes in regulation, and are used here as a means to categorise time course responses for each transcript present.

CAGE clusters assigned to approximately 200 known IEGs showed significantly elevated expression at the start of the time course , hence the importance of including the p1 parameter in the kinetic signatures (see Fig 1B).

An example of fitting early peak and linear models to an EGR1 time course is presented in Fig 1C.

Time course of receptor number and IL-2 concentration at the cell surface, see Fig 3E and 3F.

Analysis of the time course (Fig 3E) shows that all cells upregulate IL-2R levels in response to the increased IL-2 concentration in the first hours after antigenic stimulation and IL-2 secretion.

Interestingly, the time courses of IL-2 concentrations at the surfaces of the cells show only small differences between IL-2Rhigh and IL-2R10W cells (Fig 3F): In the beginning, IL-2 equally rises near IL-2Rhigh and IL-2R10w cells (see Fig 3D), but as IL-2 depletion sets in, the cells that eventually become IL-2R10W cells receive slightly less IL-2.