Sensitivity analysis of circadian entrainment in the space of phase response curves

Sensitivity analysis is a classical and fundamental tool to evaluate the role of a given parameter in a given system characteristic. Because the phase response curve is a fundamental input--output characteristic of oscillators, we developed a sensitivity analysis for oscillator models in the space of phase response curves. The proposed tool can be applied to high-dimensional oscillator models without facing the curse of dimensionality obstacle associated with numerical exploration of the parameter space. Application of this tool to a state-of-the-art model of circadian rhythms suggests that it can be useful and instrumental to biological investigations.Comment: 22 pages, 8 figures. Correction of a mistake in Definition 2.1. arXiv admin note: text overlap with arXiv:1206.414

Adolescents’ responses to the promotion and flavouring of e-cigarettes

Objectives The purpose of the study is to examine adolescents’ awareness of e-cigarette marketing and investigate the impact of e-cigarette flavour descriptors on perceptions of product harm and user image. Methods Data come from the 2014 Youth Tobacco Policy Survey, a cross-sectional in-home survey conducted with 11–16 year olds across the UK (n = 1205). Adolescents’ awareness of e-cigarette promotion, brands, and flavours was assessed. Perceptions of product harm, and likely user of four examples of e-cigarette flavours was also examined. Results Some participants had tried e-cigarettes (12 %) but regular use was low (2 %) and confined to adolescents who had also smoked tobacco. Most were aware of at least one promotional channel (82 %) and that e-cigarettes came in different flavours (69 %). Brand awareness was low. E-cigarettes were perceived as harmful (M = 3.54, SD = 1.19) but this was moderated by product flavours. Fruit and sweet flavours were perceived as more likely to be tried by young never smokers than adult smokers trying to quit (p < 0.001). Conclusions There is a need to monitor the impact of future market and regulatory change on youth uptake and perceptions of e-cigarettes

Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites

Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter μ, the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, μ was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery

Global parameter search reveals design principles of the mammalian circadian clock

Background: Virtually all living organisms have evolved a circadian (~24 hour) clock that controls physiological and behavioural processes with exquisite precision throughout the day/night cycle. The suprachiasmatic nucleus (SCN), which generates these ~24 h rhythms in mammals, consists of several thousand neurons. Each neuron contains a gene-regulatory network generating molecular oscillations, and the individual neuron oscillations are synchronised by intercellular coupling, presumably via neurotransmitters. Although this basic mechanism is currently accepted and has been recapitulated in mathematical models, several fundamental questions about the design principles of the SCN remain little understood. For example, a remarkable property of the SCN is that the phase of the SCN rhythm resets rapidly after a 'jet lag' type experiment, i.e. when the light/ dark (LD) cycle is abruptly advanced or delayed by several hours. Results: Here, we describe an extensive parameter optimization of a previously constructed simplified model of the SCN in order to further understand its design principles. By examining the top 50 solutions from the parameter optimization, we show that the neurotransmitters' role in generating the molecular circadian rhythms is extremely important. In addition, we show that when a neurotransmitter drives the rhythm of a system of coupled damped oscillators, it exhibits very robust synchronization and is much more easily entrained to light/dark cycles. We were also able to recreate in our simulations the fast rhythm resetting seen after a 'jet lag' type experiment. Conclusion: Our work shows that a careful exploration of parameter space for even an extremely simplified model of the mammalian clock can reveal unexpected behaviours and non-trivial predictions. Our results suggest that the neurotransmitter feedback loop plays a crucial role in the robustness and phase resetting properties of the mammalian clock, even at the single neuron level

Sonification and Music as Support to the Communication of Alcohol-Related Health Risks to Young People : Study design and results

Excessive consumption of alcohol has been recognised as a significant risk factor impacting the health of young people. Effective communication of such risk is considered to be one key step to improve behaviour. We evaluated an innovative multimedia intervention that utilised audio (sonification—using sound to display data—and music) and interactivity to support the visual communication of alcohol health risk data. A 3-arm pilot experiment was undertaken. The trial measures included health knowledge, alcohol risk perception and user experience of the intervention. Ninety-six subjects participated in the experiment. At 1 month follow-up, alcohol knowledge and alcohol risk perception improved significantly in the whole sample. However, there was no difference between the intervention groups that experienced (1) visual presentation with interactivity (VI-Exp group) and, (2) visual presentation with audio (sonification and music) and interactivity (VAI-Exp group), when compared to the control group which experienced a (3) visual only presentation (V-Cont group). Participants reported enjoying the presentations and found them educational. The majority of participants indicated that the audio, music and sonification helped to convey the information well, and, although a larger sample size is needed to fully establish the effectiveness of the different interventions, this study provides a useful model for future similar studies

Challenges in Estimating Insecticide Selection Pressures from Mosquito Field Data

Insecticide resistance has the potential to compromise the enormous effort put into the control of dengue and malaria vector populations. It is therefore important to quantify the amount of selection acting on resistance alleles, their contributions to fitness in heterozygotes (dominance) and their initial frequencies, as a means to predict the rate of spread of resistance in natural populations. We investigate practical problems of obtaining such estimates, with particular emphasis on Mexican populations of the dengue vector Aedes aegypti. Selection and dominance coefficients can be estimated by fitting genetic models to field data using maximum likelihood (ML) methodology. This methodology, although widely used, makes many assumptions so we investigated how well such models perform when data are sparse or when spatial and temporal heterogeneity occur. As expected, ML methodologies reliably estimated selection and dominance coefficients under idealised conditions but it was difficult to recover the true values when datasets were sparse during the time that resistance alleles increased in frequency, or when spatial and temporal heterogeneity occurred. We analysed published data on pyrethroid resistance in Mexico that consists of the frequency of a Ile1,016 mutation. The estimates for selection coefficient and initial allele frequency on the field dataset were in the expected range, dominance coefficient points to incomplete dominance as observed in the laboratory, although these estimates are accompanied by strong caveats about possible impact of spatial and temporal heterogeneity in selection

Structural Perturbations to Population Skeletons: Transient Dynamics, Coexistence of Attractors and the Rarity of Chaos

Simple models of insect populations with non-overlapping generations have been instrumental in understanding the mechanisms behind population cycles, including wild (chaotic) fluctuations. The presence of deterministic chaos in natural populations, however, has never been unequivocally accepted. Recently, it has been proposed that the application of chaos control theory can be useful in unravelling the complexity observed in real population data. This approach is based on structural perturbations to simple population models (population skeletons). The mechanism behind such perturbations to control chaotic dynamics thus far is model dependent and constant (in size and direction) through time. In addition, the outcome of such structurally perturbed models is [almost] always equilibrium type, which fails to commensurate with the patterns observed in population data.We present a proportional feedback mechanism that is independent of model formulation and capable of perturbing population skeletons in an evolutionary way, as opposed to requiring constant feedbacks. We observe the same repertoire of patterns, from equilibrium states to non-chaotic aperiodic oscillations to chaotic behaviour, across different population models, in agreement with observations in real population data. Model outputs also indicate the existence of multiple attractors in some parameter regimes and this coexistence is found to depend on initial population densities or the duration of transient dynamics. Our results suggest that such a feedback mechanism may enable a better understanding of the regulatory processes in natural populations

The Chemical Information Ontology: Provenance and Disambiguation for Chemical Data on the Biological Semantic Web

Cheminformatics is the application of informatics techniques to solve chemical problems in silico. There are many areas in biology where cheminformatics plays an important role in computational research, including metabolism, proteomics, and systems biology. One critical aspect in the application of cheminformatics in these fields is the accurate exchange of data, which is increasingly accomplished through the use of ontologies. Ontologies are formal representations of objects and their properties using a logic-based ontology language. Many such ontologies are currently being developed to represent objects across all the domains of science. Ontologies enable the definition, classification, and support for querying objects in a particular domain, enabling intelligent computer applications to be built which support the work of scientists both within the domain of interest and across interrelated neighbouring domains. Modern chemical research relies on computational techniques to filter and organise data to maximise research productivity. The objects which are manipulated in these algorithms and procedures, as well as the algorithms and procedures themselves, enjoy a kind of virtual life within computers. We will call these information entities. Here, we describe our work in developing an ontology of chemical information entities, with a primary focus on data-driven research and the integration of calculated properties (descriptors) of chemical entities within a semantic web context. Our ontology distinguishes algorithmic, or procedural information from declarative, or factual information, and renders of particular importance the annotation of provenance to calculated data. The Chemical Information Ontology is being developed as an open collaborative project. More details, together with a downloadable OWL file, are available at http://code.google.com/p/semanticchemistry/ (license: CC-BY-SA)