Multiplexing information flow through dynamic signalling systems

We consider how a signalling system can act as an information hub by multiplexing information arising from multiple signals. We formally define multiplexing, mathematically characterise which systems can multiplex and how well they can do it. While the results of this paper are theoretical, to motivate the idea of multiplexing, we provide experimental evidence that tentatively suggests that the NF-κB transcription factor can multiplex information about changes in multiple signals. We believe that our theoretical results may resolve the apparent paradox of how a system like NF-κB that regulates cell fate and inflammatory signalling in response to diverse stimuli can appear to have the low information carrying capacity suggested by recent studies on scalar signals. In carrying out our study, we introduce new methods for the analysis of large, nonlinear stochastic dynamic models, and develop computational algorithms that facilitate the calculation of fundamental constructs of information theory such as Kullback–Leibler divergences and sensitivity matrices, and link these methods to a new theory about multiplexing information. We show that many current models such as those of the NF-κB system cannot multiplex effectively and provide models that overcome this limitation using post-transcriptional modifications

Multi-species dementia studies : Contours, contributions and controversies

Developed via an online collaborative writing project involving members of the Multi-species Dementia International Research Network, this article seeks to refocus “the lens of the dementia debate” (Bartlett & O'Connor, 2007) by bringing dementia's complicated relations with the more-than-human world into sharper relief. Specifically, the article explores four thematic areas (contours) within contemporary dementia studies (Care & Caring; Illness Experience & Disease Pathology; Environment, Self & Sustainability; Power, Rights & Social Justice) where the application of multi-species theories and concepts has potential to foster innovation and lead to new ways of thinking and working. Whilst incorporating multi-species perspectives within dementia studies can create new ways of responding and new spaces of response-ability, the potential for conflict and controversy remains high. It is imperative, therefore, that the field of dementia studies not only becomes a site within which multi-species perspectives can flourish, but that dementia studies also becomes a vehicle through which multi-species concepts may be refined

Multi-species dementia studies:contours, contributions and controversies

Developed via an online collaborative writing project involving members of the Multi-species Dementia International Research Network, this article seeks to refocus “the lens of the dementia debate” (Bartlett & O'Connor, 2007) by bringing dementia's complicated relations with the more-than-human world into sharper relief. Specifically, the article explores four thematic areas (contours) within contemporary dementia studies (Care & Caring; Illness Experience & Disease Pathology; Environment, Self & Sustainability; Power, Rights & Social Justice) where the application of multi-species theories and concepts has potential to foster innovation and lead to new ways of thinking and working. Whilst incorporating multi-species perspectives within dementia studies can create new ways of responding and new spaces of response-ability, the potential for conflict and controversy remains high. It is imperative, therefore, that the field of dementia studies not only becomes a site within which multi-species perspectives can flourish, but that dementia studies also becomes a vehicle through which multi-species concepts may be refined

Multiplexing information flow through dynamic signalling systems

We consider how a signalling system can act as an information hub by multiplexing information arising from multiple signals. We formally define multiplexing, mathematically characterise which systems can multiplex and how well they can do it. While the results of this paper are theoretical, to motivate the idea of multiplexing, we provide experimental evidence that tentatively suggests that the NF-κB transcription factor can multiplex information about changes in multiple signals. We believe that our theoretical results may resolve the apparent paradox of how a system like NF-κB that regulates cell fate and inflammatory signalling in response to diverse stimuli can appear to have the low information carrying capacity suggested by recent studies on scalar signals. In carrying out our study, we introduce new methods for the analysis of large, nonlinear stochastic dynamic models, and develop computational algorithms that facilitate the calculation of fundamental constructs of information theory such as Kullback–Leibler divergences and sensitivity matrices, and link these methods to a new theory about multiplexing information. We show that many current models such as those of the NF-κB system cannot multiplex effectively and provide models that overcome this limitation using post-transcriptional modifications

Hyperglycemic conditions induce rapid cell dysfunction-promoting transcriptional alterations in human aortic endothelial cells

Abstract Hyperglycemia is a major risk factor in the development of diabetic complications and promotes vascular complications through dysregulation of endothelial cell function. Various mechanisms have been proposed for endothelial cell dysregulation but the early transcriptomic alterations of endothelial cells under hyperglycemic conditions are not well documented. Here we use deep time-series RNA-seq profiling of human aortic endothelial cells (HAECs) following exposure to normal (NG) and high glucose (HG) conditions over a time course from baseline to 24 h to identify the early and transient transcriptomic changes, alteration of molecular networks, and their temporal dynamics. The analysis revealed that the most significant pathway activation/inhibition events take place in the 1- to 4-h transition and identified distinct clusters of genes that underlie a cascade of coordinated transcriptional events unique to HG conditions. Temporal co-expression and causal network analysis implicate the activation of type 2 diabetes (T2D) and growth factor signalling pathways including STAT3 and NF-κB. These results document HAEC transcriptional changes induced by hyperglycemic conditions and provide basic insight into the rapid molecular alterations that promote endothelial cell dysfunction

Population robustness arising from cellular heterogeneity

Heterogeneity between individual cells is a common feature of dynamic cellular processes, including signaling, transcription, and cell fate; yet the overall tissue level physiological phenotype needs to be carefully controlled to avoid fluctuations. Here we show that in the NF-kappa B signaling system, the precise timing of a dual-delayed negative feedback motif [involving stochastic transcription of inhibitor kappa B (I kappa B)-alpha and -epsilon] is optimized to induce heterogeneous timing of NF-kappa B oscillations between individual cells. We suggest that this dual-delayed negative feedback motif enables NF-kappa B signaling to generate robust single cell oscillations by reducing sensitivity to key parameter perturbations. Simultaneously, enhanced cell heterogeneity may represent a mechanism that controls the overall coordination and stability of cell population responses by decreasing temporal fluctuations of paracrine signaling. It has often been thought that dynamic biological systems may have evolved to maximize robustness through cell-to-cell coordination and homogeneity. Our analyses suggest in contrast, that this cellular variation might be advantageous and subject to evolutionary selection. Alternative types of therapy could perhaps be designed to modulate this cellular heterogeneity

Dynamic analysis of stochastic transcription cycles

In individual mammalian cells the expression of some genes such as prolactin is highly variable over time and has been suggested to occur in stochastic pulses. To investigate the origins of this behavior and to understand its functional relevance, we quantitatively analyzed this variability using new mathematical tools that allowed us to reconstruct dynamic transcription rates of different reporter genes controlled by identical promoters in the same living cell. Quantitative microscopic analysis of two reporter genes, firefly luciferase and destabilized EGFP, was used to analyze the dynamics of prolactin promoter-directed gene expression in living individual clonal and primary pituitary cells over periods of up to 25 h. We quantified the time-dependence and cyclicity of the transcription pulses and estimated the length and variation of active and inactive transcription phases. We showed an average cycle period of approximately 11 h and demonstrated that while the measured time distribution of active phases agreed with commonly accepted models of transcription, the inactive phases were differently distributed and showed strong memory, with a refractory period of transcriptional inactivation close to 3 h. Cycles in transcription occurred at two distinct prolactin-promoter controlled reporter genes in the same individual clonal or primary cells. However, the timing of the cycles was independent and out-of-phase. For the first time, we have analyzed transcription dynamics from two equivalent loci in real-time in single cells. In unstimulated conditions, cells showed independent transcription dynamics at each locus. A key result from these analyses was the evidence for a minimum refractory period in the inactive-phase of transcription. The response to acute signals and the result of manipulation of histone acetylation was consistent with the hypothesis that this refractory period corresponded to a phase of chromatin remodeling which significantly increased the cyclicity. Stochastically timed bursts of transcription in an apparently random subset of cells in a tissue may thus produce an overall coordinated but heterogeneous phenotype capable of acute responses to stimuli