p53 convergently activates Dux/DUX4 in embryonic stem cells and in facioscapulohumeral muscular dystrophy cell models

p53 activates Dux in mouse embryos and embryonic stem cells, as well as DUX4 in human facioscapulohumeral muscular dystrophy cell models.In mammalian embryos, proper zygotic genome activation (ZGA) underlies totipotent development. Double homeobox (DUX)-family factors participate in ZGA, and mouse Dux is required for forming cultured two-cell (2C)-like cells. Remarkably, in mouse embryonic stem cells, Dux is activated by the tumor suppressor p53, and Dux expression promotes differentiation into expanded-fate cell types. Long-read sequencing and assembly of the mouse Dux locus reveals its complex chromatin regulation including putative positive and negative feedback loops. We show that the p53-DUX/DUX4 regulatory axis is conserved in humans. Furthermore, we demonstrate that cells derived from patients with facioscapulohumeral muscular dystrophy (FSHD) activate human DUX4 during p53 signaling via a p53-binding site in a primate-specific subtelomeric long terminal repeat (LTR)10C element. In summary, our work shows that p53 activation convergently evolved to couple p53 to Dux/DUX4 activation in embryonic stem cells, embryos and cells from patients with FSHD, potentially uniting the developmental and disease regulation of DUX-family factors and identifying evidence-based therapeutic opportunities for FSHD.Molecular Technology and Informatics for Personalised Medicine and HealthFunctional Genomics of Muscle, Nerve and Brain Disorder

The INtegrated CAtchment model of phosphorus dynamics (INCA-P): description and demonstration of new model structure and equations

INCA-P is a dynamic, catchment-scale phosphorus model which has been widely applied during the last decade. Since its original release in 2002, the model structure and equations have been significantly altered during several development phases. Here, we provide the first full model description since 2002 and then test the latest version of the model (v1.4.4) in a small rural catchment in northeast Scotland. The particulate phosphorus simulation was much improved compared to previous model versions, whilst the latest sorption equations allowed us to explore the potential time lags between reductions in terrestrial inputs and improvements in surface water quality, an issue of key policy relevance. The model is particularly suitable for use as a research tool, but should only be used to inform policy and land management in data-rich areas, where parameters and processes can be well-constrained. More long-term data is needed to parameterise dynamic models and test their predictions

TRY plant trait database – enhanced coverage and open access

Plant traits—the morphological, anatomical, physiological, biochemical and phenological characteristics of plants—determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits—almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Steady state and dynamic modelling of nitrogen in the River Kennet: impacts of land use change since the 1930s

Steady state and dynamic models have been developed and applied to the River Kennet system. Annual nitrogen exports from the land surface to the river have been estimated based on land use from the 1930s and the 1990s. Long term modelled trends indicate that there has been a large increase in nitrogen transport into the river system driven by increased fertiliser application associated with increased cereal production, increased population and increased livestock levels. The dynamic model INCA Integrated Nitrogen in Catchments. has been applied to simulate the day-to-day transport of N from the terrestrial ecosystem to the riverine environment. This process-based model generates spatial and temporal data and reproduces the observed instream concentrations. Applying the model to current land use and 1930s land use indicates that there has been a major shift in the short term dynamics since the 1930s, with increased river and groundwater concentrations caused by both non-point source pollution from agriculture and point source discharges.

Moderate structural realism about space-time

This paper sets out a moderate version of metaphysical structural realism that stands in contrast to both the epistemic structural realism of Worrall and the – radical – ontic structural realism of French and Ladyman. According to moderate structural realism, objects and relations (structure) are on the same ontological footing, with the objects being characterized only by the relations in which they stand. We show how this position fares well as regards philosophical arguments, avoiding the objections against the other two versions of structural realism. In particular, we set out how this position can be applied to space-time, providing for a convincing understanding of space-time points in the standard tensor formulation of general relativity as well as in the fibre bundle formulation

Modelling phosphorus dynamics in multi-branch river systems: A study of the Black River, Lake Simcoe, Ontario, Canada

High rates of nutrient loading from agricultural and urban development have resulted in surface water eutrophication and groundwater contamination in regions of Ontario. In Lake Simcoe (Ontario, Canada), anthropogenic nutrient contributions have contributed to increased algal growth, low hypolimnetic oxygen concentrations, and impaired fish reproduction. An ambitious programme has been initiated to reduce phosphorus loads to the lake, aiming to achieve at least a 40% reduction in phosphorus loads by 2045. Achievement of this target necessitates effective remediation strategies, which will rely upon an improved understanding of controls on nutrient export from tributaries of Lake Simcoe as well as improved understanding of the importance of phosphorus cycling within the lake. In this paper, we describe a new model structure for the integrated dynamic and process-based model INCA-P, which allows fully-distributed applications, suited to branched river networks. We demonstrate application of this model to the Black River, a tributary of Lake Simcoe, and use INCA-P to simulate the fluxes of P entering the lake system, apportion phosphorus among different sources in the catchment, and explore future scenarios of land-use change and nutrient management to identify high priority sites for implementation of watershed best management practi

Standardisation of a European measurement method for organic carbon and elemental carbon in ambient air: Results of the field trial campaign and the determination of a measurement uncertainty and working range

The European Committee for Standardisation (CEN) Technical Committee 264 'Air Quality' has recently produced a standard method for the measurements of organic carbon and elemental carbon in PM2.5 within its working group 35 in response to the requirements of European Directive 2008/50/EC. It is expected that this method will be used in future by all Member States making measurements of the carbonaceous content of PM2.5. This paper details the results of a laboratory and field measurement campaign and the statistical analysis performed to validate the standard method, assess its uncertainty and define its working range to provide clarity and confidence in the underpinning science for future users of the method. The statistical analysis showed that the expanded combined uncertainty for transmittance protocol measurements of OC, EC and TC is expected to be below 25%, at the 95% level of confidence, above filter loadings of 2 μg cm-2. An estimation of the detection limit of the method for total carbon was 2 μg cm-2. As a result of the laboratory and field measurement campaign the EUSAAR2 transmittance measurement protocol was chosen as the basis of the standard method EN 16909:2017. © 2017 The Royal Society of Chemistry. Chemicals/CAS: carbon, 7440-44-

Action in context and context in action: Modelling complexity in multimedia systems development

Whereas multimedia systems development (MSD) is inherently complex, and increasingly so, little is known about how multimedia designers manage or cope with this complexity. In particular, little is known about complexity beyond technical and process levels, and how such complexity impacts design activity. In this paper we construct a model of MSD based on the formulation of the broader concept of context complexity. This concept, which subsumes but also transcends technical and process complexity, is used to explain design strategies and their consequences. We identify four design contexts that explain, and are also explained by, complexity. These contexts map out the 'landscape for action' over which design activity takes place. They shape the design environment and the responses taken to it. We use a grounded theory approach to study what designers actually do (as opposed to theorising what they should do). We argue that a better understanding of context determined and context determining strategies better informs interventions aimed at improving MSD design practice. Our main conclusion is that interventions should be directed to those situations where there is a mismatch between the level of complexity in the design context and the level of complexity in the design strategy taken in response to that context. We call these situations 'breakdown' contexts and examine their causes and consequences in greater detail. Our claimed contribution is to broaden the concept of design breakdowns through a specific understanding of the role and impact of (context) complexity in MSD