Network Models of Phage-Bacteria Coevolution

Bacteria and their bacteriophages are the most abundant, widespread and diverse groups of biological entities on the planet. In an attempt to understand how the interactions between bacteria, virulent phages and temperate phages might affect the diversity of these groups, we developed a novel stochastic network model for examining the co-evolution of these ecologies. In our approach, nodes represent whole species or strains of bacteria or phages, rather than individuals, with "speciation" and extinction modelled by duplication and removal of nodes. Phage-bacteria links represent host-parasite relationships and temperate-virulent phage links denote prophage-encoded resistance. The effect of horizontal transfer of genetic information between strains was also included in the dynamical rules. The observed networks evolved in a highly dynamic fashion but the ecosystems were prone to collapse (one or more entire groups going extinct). Diversity could be stably maintained in the model only if the probability of speciation was independent of the diversity. Such an effect could be achieved in real ecosystems if the speciation rate is primarily set by the availability of ecological niches.Comment: 8 pages, 6 figure

Cooperative stabilization of the SIR complex provides robust epigenetic memory in a model of SIR silencing in Saccharomyces cerevisiae

How alternative chromatin-based regulatory states can be made stable and heritable in order to provide robust epigenetic memory is poorly understood. Here, we develop a stochastic model of the silencing system in Saccharomyces cerevisiae that incorporates cooperative binding of the repressive SIR complex and anti-silencing histone modifications, in addition to positive feedback in Sir2 recruitment. The model was able to reproduce key features of SIR regulation of an HM locus, including heritable bistability, dependence on the silencer elements, and sensitivity to SIR dosage. We found that antisilencing methylation of H3K79 by Dot1 was not needed to generate these features, but acted to reduce spreading of SIR binding, consistent with its proposed role in containment of silencing. In contrast, cooperative inter-nucleosome interactions mediated by the SIR complex were critical for concentrating SIR binding around the silencers in the absence of barriers, and for providing bistability in SIR binding. SIR-SIR interactions magnify the cooperativity in the Sir2-histone deacetylation positive feedback reaction and complete a double-negative feedback circuit involving antisilencing modifications. Thus, our modelling underscores the potential importance of cooperative interactions between nucleosome-bound complexes both in the SIR system and in other chromatin-based complexes in epigenetic regulation.Kim Sneppen and Ian B Dod

Nonadherence to treatment protocol in published randomised controlled trials: a review.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.This review aimed to ascertain the extent to which nonadherence to treatment protocol is reported and addressed in a cohort of published analyses of randomised controlled trials (RCTs). One hundred publications of RCTs, randomly selected from those published in BMJ, New England Journal of Medicine, the Journal of the American Medical Association and The Lancet during 2008, were reviewed to determine the extent and nature of reported nonadherence to treatment protocol, and whether statistical methods were used to examine the effect of such nonadherence on both benefit and harms analyses. We also assessed the quality of trial reporting of treatment protocol nonadherence and the quality of reporting of the statistical analysis methods used to investigate such nonadherence. Nonadherence to treatment protocol was reported in 98 of the 100 trials, but reporting on such nonadherence was often vague or incomplete. Forty-two publications did not state how many participants started their randomised treatment. Reporting of treatment initiation and completeness was judged to be inadequate in 64% of trials with short-term interventions and 89% of trials with long-term interventions. More than half (51) of the 98 trials with treatment protocol nonadherence implemented some statistical method to address this issue, most commonly based on per protocol analysis (46) but often labelled as intention to treat (ITT) or modified ITT (23 analyses in 22 trials). The composition of analysis sets for their benefit outcomes were not explained in 57% of trials, and 62% of trials that presented harms analyses did not define harms analysis populations. The majority of defined harms analysis populations (18 out of 26 trials, 69%) were based on actual treatment received, while the majority of trials with undefined harms analysis populations (31 out of 43 trials, 72%) appeared to analyse harms using the ITT approach. Adherence to randomised intervention is poorly considered in the reporting and analysis of published RCTs. The majority of trials are subject to various forms of nonadherence to treatment protocol, and though trialists deal with this nonadherence using a variety of statistical methods and analysis populations, they rarely consider the potential for bias introduced. There is a need for increased awareness of more appropriate causal methods to adjust for departures from treatment protocol, as well as guidance on the appropriate analysis population to use for harms outcomes in the presence of such nonadherence

A framework for the design, conduct and interpretation of randomised controlled trials in the presence of treatment changes.

BACKGROUND: When a randomised trial is subject to deviations from randomised treatment, analysis according to intention-to-treat does not estimate two important quantities: relative treatment efficacy and effectiveness in a setting different from that in the trial. Even in trials of a predominantly pragmatic nature, there may be numerous reasons to consider the extent, and impact on analysis, of such deviations from protocol. Simple methods such as per-protocol or as-treated analyses, which exclude or censor patients on the basis of their adherence, usually introduce selection and confounding biases. However, there exist appropriate causal estimation methods which seek to overcome these inherent biases, but these methods remain relatively unfamiliar and are rarely implemented in trials. METHODS: This paper demonstrates when it may be of interest to look beyond intention-to-treat analysis for answers to alternative causal research questions through illustrative case studies. We seek to guide trialists on how to handle treatment changes in the design, conduct and planning the analysis of a trial; these changes may be planned or unplanned, and may or may not be permitted in the protocol. We highlight issues that must be considered at the trial planning stage relating to: the definition of nonadherence and the causal research question of interest, trial design, data collection, monitoring, statistical analysis and sample size. RESULTS AND CONCLUSIONS: During trial planning, trialists should define their causal research questions of interest, anticipate the likely extent of treatment changes and use these to inform trial design, including the extent of data collection and data monitoring. A series of concise recommendations is presented to guide trialists when considering undertaking causal analyses

Daily irrigation attenuates xylem abscisic acid concentration and increases leaf water potential of Pelargonium×hortorum compared with infrequent irrigation

The physiological response of plants to different irrigation frequencies may affect plant growth and water use efficiency (WUE; defined as shoot biomass/cumulative irrigation). Glasshouse-grown, containerized Pelargonium × hortorum BullsEye plants were irrigated either daily at 100% of plant evapotranspiration (ET) (well-watered; WW), or at 50% ET applied either daily [frequent deficit irrigation (FDI)] or cumulatively every 4 days [infrequent deficit irrigation (IDI)], for 24 days. Both FDI and IDI applied the same irrigation volume. Xylem sap was collected from the leaves, and stomatal conductance (gs) and leaf water potential (Ψleaf) measured every 2 days. As soil moisture decreased, gs decreased similarly under both FDI and IDI throughout the experiment. Ψleaf was maintained under IDI and increased under FDI. Leaf xylem abscisic acid (ABA) concentrations ([X-ABA]leaf) increased as soil moisture decreased under both IDI and FDI, and was strongly correlated with decreased gs, but [X-ABA]leaf was attenuated under FDI throughout the experiment (at the same level of soil moisture as IDI plants). These physiological changes corresponded with differences in plant production. Both FDI and IDI decreased growth compared with WW plants, and by the end of the experiment, FDI plants also had a greater shoot fresh weight (18%) than IDI plants. Although both IDI and FDI had higher WUE than WW plants during the first 10 days of the experiment (when biomass did not differ between treatments), the deficit irrigation treatments had lower WUE than WW plants in the latter stages when growth was limited. Thus, ABA-induced stomatal closure may not always translate to increased WUE (at the whole plant level) if vegetative growth shows a similar sensitivity to soil drying, and growers must adapt their irrigation scheduling according to crop requirements

Ultrasensitive gene regulation by positive feedback loops in nucleosome modification

Eukaryotic transcription involves the synergistic interaction of many different proteins. However, the question remains how eukaryotic promoters achieve ultrasensitive or threshold responses to changes in the concentration or activity of a single transcription factor (TF). We show theoretically that by recruiting a histone-modifying enzyme, a TF binding non-cooperatively to a single site can change the balance between opposing positive feedback loops in histone modification to produce a large change in gene expression in response to a small change in concentration of the TF. This mechanism can also generate bistable promoter responses, allowing a gene to be on in some cells and off in others, despite the cells being in identical conditions. In addition, the system provides a simple means by which the activities of many TFs could be integrated at a promoter

Rootstock – scion signalling: factors that mediate scion performance and graft compatibility (abstract)

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Sensitivity of Gramineacous Leaf Growth to Abscisic Acid: Its Potential Importance to Leaf Growth of Plants in Drying Soil.

Recent reports have indicated that leaf growth of plants in drying soil can be regulated by chemical signals originating from the roots. A potential signal is the plant hormone abscisic acid, ABA. This thesis aimed to identity sources of variation in the sensitivity of cereal leaf growth to ABA using a detached shoot leaf elongation assay. Preliminary experiments showed that altering the nutrient composition or pH of the feeding solution had no effect on sensitivity. Assay variability resulted in considerable uncertainty over whether observed genotypic differences in sensitivity were real, or reproducible. Increasing the air temperature around the detached shoots greatly increased the sensitivity of leaf growth to ABA. Increased concentrations of ABA in the elongation zone ( [EZ-ABA] ) of detached shoots seemed to account for this increased sensitivity. When detached shoots were fed sap from droughted plants, sap ABA concentration could not explain the growth inhibitory activity. Measurement of [EZ-ABA] accounted for this "unexplained" growth inhibition. When intact plants were subjected to a slowly developing drought, growth was reduced by 35 % without any increases in [EZ-ABA]. Measurement of leaf water relations and xylem sap pH similarly failed to account for the growth inhibition. The diurnal growth pattern of droughted plants suggested an interaction of water relations with chemical signals. Use of a coleoptile growth assay showed that individual application of mild osmotic stresses or ABA did not inhibit growth. However, osmotic stress and ABA applied together significantly reduced growth. This interaction may be an important mechanism in explaining leaf growth inhibition of droughted plants. It also accounts for the relative (compared to droughted plants) insensitivity of leaf elongation to ABA in the leaf elongation assay

Efficiency of a nature-like bypass channel for restoring longitudinal connectivity for a river-resident population of brown trout

Man-made, physical barriers have disrupted longitudinal connectivity for migratory fish in many river systems throughout the world for centuries. These barriers are considered to be a key reason for the decline of many fish species in river systems. To date, most research to ease movement of anadromous salmonids past such barriers to help dwindling populations has focused on the use of technical fishways. More recently emphasis has been placed on nature-like fishways to enable a wider range of fish species to bypass these barriers, but few studies have examined their efficacy. In this study, Passive Integrated Transponder (PIT) telemetry was used to assess the upstream-directed movements of 111 river-resident brown trout (length, 151–510-mm) into and through a 150-m long, nature-like bypass on the River Aire, England. Attraction (51%), entrance (86%), passage (78%) and exit (97%) efficiencies were high, and trout of a wide range of sizes entered and exited (197–510 mm) the pass across a wide range of flows (entrance = 3.55–67.44 m 3 s −1 and exit = 3.89–35.5 m 3 s −1 ). There was evidence that two trout inhabited the pass during the day, entering at sunrise and exiting at sunset. This information is important to improve understanding of fish pass performance, thus informing future best practice guidance of fish passage designs