Instytut Podstawowych Problemów Techniki
Polskiej Akademii Nauk


James Boyd

Ostatnie publikacje
1.  Bagnall J., Boddington C., England H., Brignall R., Downton P., Alsoufi Z., Boyd J., Rowe W., Bennett A., Walker C., Adamson A., Patel Nisha M. X., O’Cualain R., Schmidt L., Spiller David G., Jackson Dean A., Müller W., Muldoon M., White Michael R. H.R., Paszek P., Quantitative analysis of competitive cytokine signaling predicts tissue thresholds for the propagation of macrophage activation, Science Signaling, ISSN: 1945-0877, DOI: 10.1126/scisignal.aaf3998, Vol.11, No.540, pp.1-15, 2018

Toll-like receptor (TLR) signaling regulates macrophage activation and effector cytokine propagation in the constrained environment of a tissue. In macrophage populations, TLR4 stimulates the dose-dependent transcription of nuclear factor κB (NF-κB) target genes. However, using single-RNA counting, we found that individual cells exhibited a wide range (three orders of magnitude) of expression of the gene encoding the proinflammatory cytokine tumor necrosis factor–α (TNF-α). The TLR4-induced TNFA transcriptional response correlated with the extent of NF-κB signaling in the cells and their size. We compared the rates of TNF-α production and uptake in macrophages and mouse embryonic fibroblasts and generated a mathematical model to explore the heterogeneity in the response of macrophages to TLR4 stimulation and the propagation of the TNF-α signal in the tissue. The model predicts that the local propagation of the TLR4-dependent TNF-α response and cellular NF-κB signaling are limited to small distances of a few cell diameters between neighboring tissue-resident macrophages. In our predictive model, TNF-α propagation was constrained by competitive uptake of TNF-α from the environment, rather than by heterogeneous production of the cytokine. We propose that the highly constrained architecture of tissues enables effective localized propagation of inflammatory cues while avoiding out-of-context responses at longer distances.

Afiliacje autorów:
Bagnall J. - inna afiliacja
Boddington C. - inna afiliacja
England H. - inna afiliacja
Brignall R. - inna afiliacja
Downton P. - inna afiliacja
Alsoufi Z. - inna afiliacja
Boyd J. - inna afiliacja
Rowe W. - inna afiliacja
Bennett A. - inna afiliacja
Walker C. - inna afiliacja
Adamson A. - inna afiliacja
Patel Nisha M. X. - inna afiliacja
O’Cualain R. - inna afiliacja
Schmidt L. - inna afiliacja
Spiller David G. - inna afiliacja
Jackson Dean A. - inna afiliacja
Müller W. - inna afiliacja
Muldoon M. - inna afiliacja
White Michael R. H.R. - University of Manchester (GB)
Paszek P. - inna afiliacja
2.  Phillips N., Manning C., Pettini T., Veronica B., Elli M., Peter S., Boyd J., Bagnall J., Paszek P., Spiller David G., White M., Goodfellow M., Tobias G., Magnus R., Nancy P., Stochasticity in the miR-9/Hes1 oscillatory network can account for clonal heterogeneity in the timing of differentiation, eLife, ISSN: 2050-084X, DOI: 10.7554/eLife.16118, Vol.5, pp.e16118-1-33, 2016

Recent studies suggest that cells make stochastic choices with respect to differentiation or division. However, the molecular mechanism underlying such stochasticity is unknown. We previously proposed that the timing of vertebrate neuronal differentiation is regulated by molecular oscillations of a transcriptional repressor, HES1, tuned by a post-transcriptional repressor, miR-9. Here, we computationally model the effects of intrinsic noise on the Hes1/miR-9 oscillator as a consequence of low molecular numbers of interacting species, determined experimentally. We report that increased stochasticity spreads the timing of differentiation in a population, such that initially equivalent cells differentiate over a period of time. Surprisingly, inherent stochasticity also increases the robustness of the progenitor state and lessens the impact of unequal, random distribution of molecules at cell division on the temporal spread of differentiation at the population level. This advantageous use of biological noise contrasts with the view that noise needs to be counteracted.

Afiliacje autorów:
Phillips N. - inna afiliacja
Manning C. - inna afiliacja
Pettini T. - inna afiliacja
Veronica B. - inna afiliacja
Elli M. - inna afiliacja
Peter S. - inna afiliacja
Boyd J. - inna afiliacja
Bagnall J. - inna afiliacja
Paszek P. - IPPT PAN
Spiller David G. - inna afiliacja
White M. - inna afiliacja
Goodfellow M. - inna afiliacja
Tobias G. - inna afiliacja
Magnus R. - inna afiliacja
Nancy P. - inna afiliacja
3.  Ankers John M., Awais R., Jones Nicholas A., Boyd J., Ryan S., Adamson Antony D., Harper Claire V.V., Bridge L., Spiller David G., Jackson Dean A., Paszek P., Sée V., White Michael R.R., Dynamic NF-κB and E2F interactions control the priority and timing of inflammatory signalling and cell proliferation, eLife, ISSN: 2050-084X, DOI: 10.7554/eLife.10473, Vol.5, pp.e10473-1-35, 2016

Dynamic cellular systems reprogram gene expression to ensure appropriate cellular fate responses to specific extracellular cues. Here we demonstrate that the dynamics of Nuclear Factor kappa B (NF-κB) signalling and the cell cycle are prioritised differently depending on the timing of an inflammatory signal. Using iterative experimental and computational analyses, we show physical and functional interactions between NF-κB and the E2 Factor 1 (E2F-1) and E2 Factor 4 (E2F-4) cell cycle regulators. These interactions modulate the NF-κB response. In S-phase, the NF-κB response was delayed or repressed, while cell cycle progression was unimpeded. By contrast, activation of NF-κB at the G1/S boundary resulted in a longer cell cycle and more synchronous initial NF-κB responses between cells. These data identify new mechanisms by which the cellular response to stress is differentially controlled at different stages of the cell cycle.

Afiliacje autorów:
Ankers John M. - inna afiliacja
Awais R. - inna afiliacja
Jones Nicholas A. - Massachusetts Institute of Technology (US)
Boyd J. - inna afiliacja
Ryan S. - inna afiliacja
Adamson Antony D. - inna afiliacja
Harper Claire V.V. - University of Manchester (GB)
Bridge L. - inna afiliacja
Spiller David G. - inna afiliacja
Jackson Dean A. - inna afiliacja
Paszek P. - inna afiliacja
Sée V. - inna afiliacja
White Michael R.R. - University of Manchester (GB)

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