Instytut Podstawowych Problemów Techniki
Polskiej Akademii Nauk


B. Kell Douglas

Ostatnie publikacje
1.  Yunjiao W., Paszek P., Horton Caroline A., Kell Douglas B., White M., Broomhead David S., Muldoon M., Interactions among oscillatory pathways in NF-kappa B signaling, BMC SYSTEMS BIOLOGY, ISSN: 1752-0509, DOI: 10.1186/1752-0509-5-23, Vol.5, pp.23-1-11, 2011


Sustained stimulation with tumour necrosis factor alpha (TNF-alpha) induces substantial oscillations—observed at both the single cell and population levels—in the nuclear factor kappa B (NF-kappa B) system. Although the mechanism has not yet been elucidated fully, a core system has been identified consisting of a negative feedback loop involving NF-kappa B (RelA:p50 hetero-dimer) and its inhibitor I-kappa B-alpha. Many authors have suggested that this core oscillator should couple to other oscillatory pathways.

First we analyse single-cell data from experiments in which the NF-kappa B system is forced by short trains of strong pulses of TNF-alpha. Power spectra of the ratio of nuclear-to-cytoplasmic concentration of NF-kappa B suggest that the cells' responses are entrained by the pulsing frequency. Using a recent model of the NF-kappa B system due to Caroline Horton, we carried out extensive numerical simulations to analyze the response frequencies induced by trains of pulses of TNF-alpha stimulation having a wide range of frequencies and amplitudes. These studies suggest that for sufficiently weak stimulation, various nonlinear resonances should be observable. To explore further the possibility of probing alternative feedback mechanisms, we also coupled the model to sinusoidal signals with a wide range of strengths and frequencies. Our results show that, at least in simulation, frequencies other than those of the forcing and the main NF-kappa B oscillator can be excited via sub- and superharmonic resonance, producing quasiperiodic and even chaotic dynamics.

Our numerical results suggest that the entrainment phenomena observed in pulse-stimulated experiments is a consequence of the high intensity of the stimulation. Computational studies based on current models suggest that resonant interactions between periodic pulsatile forcing and the system's natural frequencies may become evident for sufficiently weak stimulation. Further simulations suggest that the nonlinearities of the NF-kappa B feedback oscillator mean that even sinusoidally modulated forcing can induce a rich variety of nonlinear interactions.

Afiliacje autorów:
Yunjiao W. - inna afiliacja
Paszek P. - IPPT PAN
Horton Caroline A. - inna afiliacja
Kell Douglas B. - inna afiliacja
White M. - inna afiliacja
Broomhead David S. - inna afiliacja
Muldoon M. - inna afiliacja
2.  Ashall L., Horton Caroline A., Nelson David E., Paszek P., Harper Claire V.V., Sillitoe K., Ryan S., Spiller David G., Unitt John F., Broomhead David S., Kell Douglas B., Rand David A.A., Sée V., White Michael R.R., Pulsatile Stimulation Determines Timing and Specificity of NF-κB-Dependent Transcription, Science, ISSN: 0036-8075, DOI: 10.1126/science.1164860, Vol.324, No.5924, pp.242-246, 2009

The nuclear factor κB (NF-κB) transcription factor regulates cellular stress responses and the immune response to infection. NF-κB activation results in oscillations in nuclear NF-κB abundance. To define the function of these oscillations, we treated cells with repeated short pulses of tumor necrosis factor–α at various intervals to mimic pulsatile inflammatory signals. At all pulse intervals that were analyzed, we observed synchronous cycles of NF-κB nuclear translocation. Lower frequency stimulations gave repeated full-amplitude translocations, whereas higher frequency pulses gave reduced translocation, indicating a failure to reset. Deterministic and stochastic mathematical models predicted how negative feedback loops regulate both the resetting of the system and cellular heterogeneity. Altering the stimulation intervals gave different patterns of NF-κB–dependent gene expression, which supports the idea that oscillation frequency has a functional role.

Afiliacje autorów:
Ashall L. - inna afiliacja
Horton Caroline A. - inna afiliacja
Nelson David E. - inna afiliacja
Paszek P. - inna afiliacja
Harper Claire V.V. - University of Manchester (GB)
Sillitoe K. - inna afiliacja
Ryan S. - inna afiliacja
Spiller David G. - inna afiliacja
Unitt John F. - inna afiliacja
Broomhead David S. - inna afiliacja
Kell Douglas B. - inna afiliacja
Rand David A.A. - University of Warwick (GB)
Sée V. - inna afiliacja
White Michael R.R. - University of Manchester (GB)

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