In silico evolution of signaling networks using rule-based models: bistable response dynamics

One of the ultimate goals in biology is to understand the design principles of biological systems. Such principles, if they exist, can help us better understand complex, natural biological systems and guide the engineering of de novo ones. Towards deciphering design principles, in silico evolution of biological systems with proper abstraction is a promising approach. Here, we demonstrate the application of in silico evolution combined with rule-based modelling for exploring design principles of cellular signaling networks. This application is based on a computational platform, called BioJazz, which allows in silico evolution of signaling networks with unbounded complexity. We provide a detailed introduction to BioJazz architecture and implementation and describe how it can be used to evolve and/or design signaling networks with defined dynamics. For the latter, we evolve signaling networks with switch-like response dynamics and demonstrate how BioJazz can result in new biological insights on network structures that can endow bistable response dynamics. This example also demonstrated both the power of BioJazz in evolving and designing signaling networks and its limitations at the current stage of development.Comment: 24 pages, 7 figure

The incidence of unpleasant dreams after sub-anaesthetic ketamine

Ketamine is an N-methyl-D-aspartate (NMDA)receptor antagonist with psychotogenic effects and for whichthere are diverse reports of whether pleasant or unpleasantdreams result during anaesthesia, post-operatively or aftersub-anaesthetic use. The aim was to assess in healthy volunteers the incidence ofunpleasant dreams over the three nights after receiving asub-anaesthetic dose of ketamine, in comparison to placebo,and with retrospective home nightmare frequency as acovariate.Thirty healthy volunteers completed questionnairesabout retrospective home dream recall and were then giveneither ketamine or placebo. Ketamine resulted in significantly more meandream unpleasantness relative to placebo and caused athreefold increase in the odds ratio for the incidence of anunpleasant dream. The number of dreams reported over thethree nights did not differ between the groups. Theincidence of unpleasant dreams after ketamine use waspredicted by retrospectively assessed nightmare frequencyat home.Ketamine causes unpleasant dreams over thethree post-administration nights. This may be evidence of aresidual psychotogenic effect that is not found on standardself-report symptomatology measures or a result of disturbedsleep electrophysiology. The results have theoretical implications for the relationship between nightmares and schizotypy

Lung macrophage scavenger receptor SR-A6 (MARCO) is an adenovirus type-specific virus entry receptor

<div><p>Macrophages are a diverse group of phagocytic cells acting in host protection against stress, injury, and pathogens. Here, we show that the scavenger receptor SR-A6 is an entry receptor for human adenoviruses in murine alveolar macrophage-like MPI cells, and important for production of type I interferon. Scavenger receptors contribute to the clearance of endogenous proteins, lipoproteins and pathogens. Knockout of SR-A6 in MPI cells, anti-SR-A6 antibody or the soluble extracellular SR-A6 domain reduced adenovirus type-C5 (HAdV-C5) binding and transduction. Expression of murine SR-A6, and to a lower extent human SR-A6 boosted virion binding to human cells and transduction. Virion clustering by soluble SR-A6 and proximity localization with SR-A6 on MPI cells suggested direct adenovirus interaction with SR-A6. Deletion of the negatively charged hypervariable region 1 (HVR1) of hexon reduced HAdV-C5 binding and transduction, implying that the viral ligand for SR-A6 is hexon. SR-A6 facilitated macrophage entry of HAdV-B35 and HAdV-D26, two important vectors for transduction of hematopoietic cells and human vaccination. The study highlights the importance of scavenger receptors in innate immunity against human viruses.</p></div

Science-Driven Optimization of the LSST Observing Strategy

The Large Synoptic Survey Telescope is designed to provide an unprecedented optical imaging dataset that will support investigations of our Solar System, Galaxy and Universe, across half the sky and over ten years of repeated observation. However, exactly how the LSST observations will be taken (the observing strategy or "cadence") is not yet finalized. In this dynamically-evolving community white paper, we explore how the detailed performance of the anticipated science investigations is expected to depend on small changes to the LSST observing strategy. Using realistic simulations of the LSST schedule and observation properties, we design and compute diagnostic metrics and Figures of Merit that provide quantitative evaluations of different observing strategies, analyzing their impact on a wide range of proposed science projects. This is work in progress: we are using this white paper to communicate to each other the relative merits of the observing strategy choices that could be made, in an effort to maximize the scientific value of the survey. The investigation of some science cases leads to suggestions for new strategies that could be simulated and potentially adopted. Notably, we find motivation for exploring departures from a spatially uniform annual tiling of the sky: focusing instead on different parts of the survey area in different years in a "rolling cadence" is likely to have significant benefits for a number of time domain and moving object astronomy projects. The communal assembly of a suite of quantified and homogeneously coded metrics is the vital first step towards an automated, systematic, science-based assessment of any given cadence simulation, that will enable the scheduling of the LSST to be as well-informed as possible

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference