Instytut Podstawowych Problemów Techniki
Polskiej Akademii Nauk


Wang Yunjiao

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.  Turner D., Paszek P., Woodcock D. J., Nelson David E., Horton Caroline A., Yunjiao W., Spiller David G., Rand D. A., White M., Harper C. V., Physiological levels of TNFalpha stimulation induce stochastic dynamics of NF-kappaB responses in single living cells, Journal of Cell Science, ISSN: 0021-9533, DOI: 10.1242/jcs.069641, Vol.123, No.16, pp.2834-2843, 2010

Nuclear factor kappa B (NF-kappaB) signalling is activated by cellular stress and inflammation and regulates cytokine expression. We applied single-cell imaging to investigate dynamic responses to different doses of tumour necrosis factor alpha (TNFalpha). Lower doses activated fewer cells and those responding showed an increasingly variable delay in the initial NF-kappaB nuclear translocation and associated IkappaBalpha degradation. Robust 100 minute nuclear:cytoplasmic NF-kappaB oscillations were observed over a wide range of TNFalpha concentrations. The result is supported by computational analyses, which identified a limit cycle in the system with a stable 100 minute period over a range of stimuli, and indicated no co-operativity in the pathway activation. These results suggest that a stochastic threshold controls functional all-or-nothing responses in individual cells. Deterministic and stochastic models simulated the experimentally observed activation threshold and gave rise to new predictions about the structure of the system and open the way for better mechanistic understanding of physiological TNFalpha activation of inflammatory responses in cells and tissues.

Słowa kluczowe:

Afiliacje autorów:
Turner D. - inna afiliacja
Paszek P. - IPPT PAN
Woodcock D. J. - University of Warwick (GB)
Nelson David E. - inna afiliacja
Horton Caroline A. - inna afiliacja
Yunjiao W. - inna afiliacja
Spiller David G. - inna afiliacja
Rand D. A. - University of Warwick (GB)
White M. - inna afiliacja
Harper C. V. - University of Manchester (GB)

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