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

Learning how to model ecosystem trade-offs at the farm scale

Paper from: International Environmental Modelling and Software Society (iEMSs) 2010 International Congress on Environmental Modelling and Software Modelling for Environment’s Sake, Fifth Biennial Meeting, Ottawa, Canada David A. Swayne, Wanhong Yang, A. A. Voinov, A. Rizzoli, T. Filatova (Eds.) http://www.iemss.org/iemss2010/index.php?n=Main.ProceedingsThe full conference proceedings are available from: http://www.iemss.org/iemss2010/The ecosystem service framework provides a forum for scientists from a range of disciplines to communicate and work together alongside other key stakeholders. However to be effective, place-based comparison of the tradeoffs of ecosystem services need further development. These place-based comparisons are vital in agricultural systems due to the increasing global demand for food production, coupled with the realization that this should be achieved with minimal negative impact on the environment. The farm is the logical unit of management in agricultural systems and hence there is a need for ecosystem tradeoff assessments at the farm scale. We have carried out a literature review of thetradeoffs in the delivery of ecosystem services from intensively managed temperate grassland systems. Building on this work, we are now setting up a farm scale experiment to examine the tradeoffs, identified from the refereed literature, as requiring further investigation due to either limited or conflicting evidence. To facilitate an improved understanding of these tradeoffs we need to learn how to model them, based on previous and current modelling frameworks and coupled with improved knowledge of international best practice. Fundamentally, this requires a dialogue between modellers and field scientist

Novel sampling method for assessing human-pathogen interactions in the natural environment using boot socks and citizen scientists, with application to Campylobacter seasonality

This paper introduces a novel method for sampling pathogens in natural environments. It uses fabric boot socks worn over walkers' shoes to allow the collection of composite samples over large areas. Wide-area sampling is better suited to studies focusing on human exposure to pathogens (e.g., recreational walking). This sampling method is implemented using a citizen science approach: groups of three walkers wearing boot socks undertook one of six routes, 40 times over 16 months in the North West (NW) and East Anglian (EA) regions of England. To validate this methodology, we report the successful implementation of this citizen science approach, the observation that Campylobacter bacteria were detected on 47% of boot socks, and the observation that multiple boot socks from individual walks produced consistent results. The findings indicate higher Campylobacter levels in the livestock-dominated NW than in EA (55.8% versus 38.6%). Seasonal differences in the presence of Campylobacter bacteria were found between the regions, with indications of winter peaks in both regions but a spring peak in the NW. The presence of Campylobacter bacteria on boot socks was negatively associated with ambient temperature (P = 0.011) and positively associated with precipitation (P < 0.001), results consistent with our understanding of Campylobacter survival and the probability of material adhering to boot socks. Campylobacter jejuni was the predominant species found; Campylobacter coli was largely restricted to the livestock-dominated NW. Source attribution analysis indicated that the potential source of C. jejuni was predominantly sheep in the NW and wild birds in EA but did not differ between peak and nonpeak periods of human incidence

Horizontal DNA transfer mechanisms of bacteria as weapons of intragenomic conflict

Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs that reduce the concentration of extracellular DNA through secretion of DNases. Simulations predicted that either mechanism of limiting transformation would benefit individual MGEs, but also that this tactic's effectiveness was limited by competition with other MGEs coinfecting the same cell. A further observed behaviour we hypothesised to reduce elimination by transformation was MGE activation when cells become competent. Our model predicted that this response was effective at counteracting transformation independently of competing MGEs. Therefore, this framework is able to explain both common properties of MGEs, and the seemingly paradoxical bacterial behaviours of transformation and cell-cell killing within clonally related populations, as the consequences of intragenomic conflict between self-replicating chromosomes and parasitic MGEs. The antagonistic nature of the different mechanisms of HDT over short timescales means their contribution to bacterial evolution is likely to be substantially greater than previously appreciated

An Updated Review of Interventions that Include Promotion of Physical Activity for Adult Men

The marked disparity in life expectancy between men and women suggests men are a vulnerable group requiring targeted health promotion programs. As such, there is an increasing need for health promotion strategies that effectively engage men with their health and/or illness management. Programs that promote physical activity could significantly improve the health of men. Although George et al. (Sports Med 42(3):281, 30) reviewed physical activity programs involving adult males published between 1990 and 2010, developments in men’s health have prompted the emergence of new sex- and gender-specific approaches targeting men. The purpose of this review was to: (1) extend and update the review undertaken by George et al. (Sports Med 42(3):281, 30) concerning the effectiveness of physical activity programs in males, and (2) evaluate the integration of gender-specific influences in the content, design, and delivery of men’s health promotion programs. A search of MEDLINE, CINAHL, ScienceDirect, Web of Science, PsycINFO, the Cochrane Library, and the SPORTDiscus databases for articles published between January 2010 and August 2014 was conducted. In total, 35 studies, involving evaluations of 31 programs, were identified. Findings revealed that a variety of techniques and modes of delivery could effectively promote physical activity among men. Though the majority of programs were offered exclusively to men, 12 programs explicitly integrated gender-related influences in male-specific programs in ways that recognized men’s interests and preferences. Innovations in male-only programs that focus on masculine ideals and gender influences to engage men in increasing their physical activity hold potential for informing strategies to promote other areas of men’s health

Local spatial regression models : a comparative analysis on soil contamination

Spatial data analysis focuses on both attribute and locational information. Local analyses deal with differences across space whereas global analyses deal with similarities across space. This paper addresses an experimental comparative study to analyse the spatial data by some weighted local regression models. Five local regression models have been developed and their estimation capacities have been evaluated. The experimental studies showed that integration of objective function based fuzzy clustering to geostatistics provides some accurate and general models structures. In particular, the estimation performance of the model established by combining the extended fuzzy clustering algorithm and standard regional dependence function is higher than that of the other regression models. Finally, it could be suggested that the hybrid regression models developed by combining soft computing and geostatistics could be used in spatial data analysis

MFG-E8 Regulates the Immunogenic Potential of Dendritic Cells Primed with Necrotic Cell-Mediated Inflammatory Signals

Dendritic cells (DC) manipulate tissue homeostasis by recognizing dying cells and controlling immune functions. However, the precise mechanisms by which DC recognize different types of dying cells and devise distinct immunologic consequences remain largely obscure. Herein, we demonstrate that Milk-fat globule-EGF VIII (MFG-E8) is a critical mediator controlling DC immunogenicity in inflammatory microenvironments. MFG-E8 restrains DC-mediated uptake and recognition of necrotic cells. The MFG-E8-mediated suppression of necrotic cell uptake by DC resulted in the decreased proinflammatory cytokines production and activated signal components such as STAT3 and A20, which are critical to maintain tolerogenic properties of DC. Furthermore, the DC-derived MFG-E8 negatively regulates the cross-priming and effector functions of antigen-specific T cells upon recognition of necrotic cells. MFG-E8 deficiency enhances an ability of necrotic cell-primed DC to stimulate antitumor immune responses against established tumors. Our findings define what we believe to a novel mechanism whereby MFG-E8 regulates the immunogenicity of DC by modulating the modes of recognition of dying cells. Manipulating MFG-E8 levels in DC may serve as a useful strategy for controlling inflammatory microenvironments caused by various pathological conditions including cancer and autoimmunity

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Regulation of Epithelial Cell Morphology and Functions Approaching To More In Vivo-Like by Modifying Polyethylene Glycol on Polysulfone Membranes

Cytocompatibility is critically important in design of biomaterials for application in tissue engineering. However, the currently well-accepted “cytocompatible" biomaterials are those which promote cells to sustain good attachment/spreading. The cells on such materials usually lack the self-assembled cell morphology and high cell functions as in vivo. In our view, biomaterials that can promote the ability of cells to self-assemble and demonstrate cell-specific functions would be cytocompatible. This paper examined the interaction of polyethylene glycol (PEG) modified polysulfone (PSf) membranes with four epithelial cell types (primary liver cells, a liver tumor cell line, and two renal tubular cell lines). Our results show that PSf membranes modified with proper PEG promoted the aggregation of both liver and renal cells, but the liver cells more easily formed aggregates than the renal tubular cells. The culture on PEG-modified PSf membranes also enhanced cell-specific functions. In particular, the cells cultured on F127 membranes with the proper PEG content mimicked the in vivo ultrastructure of liver cells or renal tubules cells and displayed the highest cell functions. Gene expression data for adhesion proteins suggest that the PEG modification impaired cell-membrane interactions and increased cell-cell interactions, thus facilitating cell self-assembly. In conclusion, PEG-modified membrane could be a cytocompatible material which regulates the morphology and functions of epithelial cells in mimicking cell performance in vivo