FGF and EDA pathways control initiation and branching of distinct subsets of developing nasal glands

Hypertrophy, hyperplasia and altered mucus secretion from the respiratory submucosal glands (SMG) are characteristics of airway diseases such as cystic fibrosis, asthma and chronic bronchitis. More commonly, hyper-secretion of the nasal SMGs contributes to allergic rhinitis and upper airway infection. Considering the role of these glands in disease states, there is a significant dearth in understanding the molecular signals that regulate SMG development and patterning. Due to the imperative role of FGF signalling during the development of other branched structures, we investigated the role of Fgf10 during initiation and branching morphogenesis of murine nasal SMGs. Fgf10 is expressed in the mesenchyme around developing SMGs while expression of its receptor Fgfr2 is seen within glandular epithelial cells. In the Fgf10 null embryo, Steno's gland and the maxillary sinus gland were completely absent while other neighbouring nasal glands showed normal duct elongation but defective branching. Interestingly, the medial nasal glands were present in Fgf10 homozygotes but missing in Fgfr2b mutants, with expression of Fgf7 specifically expressed around these developing glands, indicating that Fgf7 might compensate for loss of Fgf10 in this group of glands. Intriguingly the lateral nasal glands were only mildly affected by loss of FGF signalling, while these glands were missing in Eda mutant mice, where the Steno's and maxillary sinus gland developed as normal. This analysis reveals that regulation of nasal gland development is complex with different subsets of glands being regulated by different signalling pathways. This analysis helps shed light on the nasal gland defects observed in patients with hypohidrotic ectodermal dysplasia (HED) (defect EDA pathway) and LADD syndrome (defect FGFR2b pathway). (C) 2016 Elsevier Inc. All rights reserved.Peer reviewe

Interfacial Self-Assembly to Spatially Organize Graphene Oxide Into Hierarchical and Bioactive Structures

Multicomponent self-assembly holds great promise for the generation of complex and functional biomaterials with hierarchical microstructure. Here, we describe the use of supramolecular co-assembly between an elastin-like recombinamer (ELR5) and a peptide amphiphile (PA) to organise graphene oxide (GO) flakes into bioactive structures across multiple scales. The process takes advantage of a reaction – diffusion mechanism to enable the incorporation and spatial organization of GO within multiple ELR5/PA layers. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and ImageJ software were used to demonstrate the hierarchical organisation of GO flakes within the ELR5/PA layers and the distribution profiles of GO throughout the ELR5/PA membranes. Furthermore,atomic force microscopy (AFM) revealed improved Young’s moduli of the ELR5/PA/GOmembranes compared to the ELR5/PA membranes. Lastly, we investigated biocompatibility of the ELR5/PA/GO membrane via various cell culture methods

Beef production from feedstuffs conserved using new technologies to reduce negative environmental impacts

End of project reportMost (ca. 86%) Irish farms make some silage. Besides directly providing feed for livestock, the provision of grass silage within integrated grassland systems makes an important positive contribution to effective grazing management and improved forage utilisation by grazing animals, and to effective feed budgeting by farmers. It can also contribute to maintaining the content of desirable species in pastures, and to livestock not succumbing to parasites at sensitive times of the year. Furthermore, the optimal recycling of nutrients collected from housed livestock can often be best achieved by spreading the manures on the land used for producing the conserved feed. On most Irish farms, grass silage will remain the main conserved forage for feeding to livestock during winter for the foreseeable future. However, on some farms high yields of whole-crop (i.e. grain + straw) cereals such as wheat, barley and triticale, and of forage maize, will be an alternative option provided that losses during harvesting, storage and feedout are minimised and that input costs are restrained. These alternative forages have the potential to reliably support high levels of animal performance while avoiding the production of effluent. Their production and use however will need to advantageously integrate into ruminant production systems. A range of technologies can be employed for crop production and conservation, and for beef production, and the optimal options need to be identified. Beef cattle being finished indoors are offered concentrate feedstuffs at rates that range from modest inputs through to ad libitum access. Such concentrates frequently contain high levels of cereals such as barley or wheat. These cereals are generally between 14% to 18% moisture content and tend to be rolled shortly before being included in coarse rations or are more finely processed prior to pelleting. Farmers thinking of using ‘high-moisture grain’ techniques for preserving and processing cereal grains destined for feeding to beef cattle need to know how the yield, conservation efficiency and feeding value of such grains compares with grains conserved using more conventional techniques. European Union policy strongly encourages a sustainable and multifunctional agriculture. Therefore, in addition to providing European consumers with quality food produced within approved systems, agriculture must also contribute positively to the conservation of natural resources and the upkeep of the rural landscape. Plastics are widely used in agriculture and their post-use fate on farms must not harm the environment - they must be managed to support the enduring sustainability of farming systems. There is an absence of information on the efficacy of some new options for covering and sealing silage with plastic sheeting and tyres, and an absence of an inventory of the use, re-use and post-use fate of plastic film on farms. Irish cattle farmers operate a large number of beef production systems, half of which use dairy bred calves. In the current, continuously changing production and market conditions, new beef systems must be considered. A computer package is required that will allow the rapid, repeatable simulation and assessment of alternate beef production systems using appropriate, standardised procedures. There is thus a need to construct, evaluate and utilise computer models of components of beef production systems and to develop mathematical relationships to link system components into a network that would support their integration into an optimal system model. This will provide a framework to integrate physical and financial on-farm conditions with models for estimating feed supply and animal growth patterns. Cash flow and profit/loss results will be developed. This will help identify optimal systems, indicate the cause of failure of imperfect systems and identify areas where applied research data are currently lacking, or more basic research is required

Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor

Tamoxifen has been used for many years to target estrogen receptor signalling in breast cancer cells. Tamoxifen is also an agonist of the G protein-coupled estrogen receptor (GPER), a GPCR ubiquitously expressed in tissues that mediates the acute response to estrogens. Here we report that tamoxifen promotes mechanical quiescence in hepatic stellate cells (HSCs), stromal fibroblast-like cells whose activation triggers and perpetuates liver fibrosis in hepatocellular carcinomas. This mechanical deactivation is mediated by the GPER/RhoA/myosin axis and induces YAP deactivation. We report that tamoxifen decreases the levels of hypoxia-inducible factor-1 alpha (HIF-1α) and the synthesis of extracellular matrix proteins through a mechanical mechanism that involves actomyosin-dependent contractility and mechanosensing of tissue stiffness. Our results implicate GPER-mediated estrogen signalling in the mechanosensory-driven activation of HSCs and put forward estrogenic signalling as an option for mechanical reprogramming of myofibroblast-like cells in the tumour microenvironment. Tamoxifen, with half a century of safe clinical use, might lead this strategy of drug repositioning.Peer reviewe

Syndecan-4 tunes cell mechanics by activating the kindlin-integrin-RhoA pathway

A mechanism of cell response to localized tension shows that syndecan-4 synergizes with EGFR to elicit a mechanosignalling cascade that leads to adaptive cell stiffening through PI3K/kindlin-2 mediated integrin activation. Extensive research over the past decades has identified integrins to be the primary transmembrane receptors that enable cells to respond to external mechanical cues. We reveal here a mechanism whereby syndecan-4 tunes cell mechanics in response to localized tension via a coordinated mechanochemical signalling response that involves activation of two other receptors: epidermal growth factor receptor and beta 1 integrin. Tension on syndecan-4 induces cell-wide activation of the kindlin-2/beta 1 integrin/RhoA axis in a PI3K-dependent manner. Furthermore, syndecan-4-mediated tension at the cell-extracellular matrix interface is required for yes-associated protein activation. Extracellular tension on syndecan-4 triggers a conformational change in the cytoplasmic domain, the variable region of which is indispensable for the mechanical adaptation to force, facilitating the assembly of a syndecan-4/alpha-actinin/F-actin molecular scaffold at the bead adhesion. This mechanotransduction pathway for syndecan-4 should have immediate implications for the broader field of mechanobiology.Peer reviewe

Cirsium species show disparity in patterns of genetic variation at their range-edge, despite similar patterns of reproduction and isolation

Genetic variation was assessed across the UK geographical range of Cirsium acaule and Cirsium heterophyllum. A decline in genetic diversity and increase in population divergence approaching the range edge of these species was predicted based on parallel declines in population density and seed production reported seperately. Patterns were compared with UK populations of the widespread Cirsium arvense.Populations were sampled along a latitudinal transect in the UK and genetic variation assessed using microsatellite markers. Cirsium acaule shows strong isolation by distance, a significant decline in diversity and an increase in divergence among range-edge populations. Geographical structure is also evident in C. arvense, whereas no such patterns are seen in C.heterophyllum. There is a major disparity between patterns of genetic variation in C. acaule and C. heterophyllum despite very similar patterns in seed production and population isolation in these species. This suggests it may be misleading to make assumptions about the geographical structure of genetic variation within species based solely on the present-day reproduction and distribution of populations

Retrieval study of cool, directly imaged exoplanet 51 Eri b

Retrieval methods are a powerful analysis technique for modelling exoplanetary atmospheres by estimating the bulk physical and chemical properties that combine in a forward model to best-fit an observed spectrum, and they are increasingly being applied to observations of directly-imaged exoplanets. We have adapted TauREx3, the Bayesian retrieval suite, for the analysis of near-infrared spectrophotometry from directly-imaged gas giant exoplanets and brown dwarfs. We demonstrate TauREx3's applicability to sub-stellar atmospheres by presenting results for brown dwarf benchmark GJ 570D which are consistent with previous retrieval studies, whilst also exhibiting systematic biases associated with the presence of alkali lines. We also present results for the cool exoplanet 51 Eri b, the first application of a free chemistry retrieval analysis to this object, using spectroscopic observations from GPI and SPHERE. While our retrieval analysis is able to explain spectroscopic and photometric observations without employing cloud extinction, we conclude this may be a result of employing a flexible temperature-pressure profile which is able to mimic the presence of clouds. We present Bayesian evidence for an ammonia detection with a 2.7$\sigma$ confidence, the first indication of ammonia in an exoplanetary atmosphere. This is consistent with this molecule being present in brown dwarfs of a similar spectral type. We demonstrate the chemical similarities between 51 Eri b and GJ 570D in relation to their retrieved molecular abundances. Finally, we show that overall retrieval conclusions for 51 Eri b can vary when employing different spectral data and modelling components, such as temperature-pressure and cloud structures

Beef production from feedstuffs conserved using new technologies to reduce negative environmental impacts

End of Project ReportThe three separate components with parallel objectives to this programme were to: 1. Develop technologies for conserving and optimally feeding alternative/complimentary feedstuffs to grass silage. 2. Quantify the use and re-use of plastic sheeting or film used to seal ensiled feedstuffs or mulch maize, and evaluate some new options. 3. Develop computer programs that will facilitate investigating prototype models of forage-based beef production systems

Peptide-Protein Coassemblies into Hierarchical and Bioactive Tubular Membranes

Multicomponent self-assembly offers opportunities for the design of complex and functional biomaterials with tunable properties. Here, we demonstrate how minor modifications in the molecular structures of peptide amphiphiles (PAs) and elastin-like recombinamers (ELs) can be used to generate coassembling tubular membranes with distinct structures, properties, and bioactivity. First, by introducing minor modifications in the charge density of PA molecules (PAK2, PAK3, PAK4), different diffusion-reaction processes can be triggered, resulting in distinct membrane microstructures. Second, by combining different types of these PAs prior to their coassembly with ELs, further modifications can be achieved, tuning the structures and properties of the tubular membranes. Finally, by introducing the cell adhesive peptide RGDS in either the PA or EL molecules, it is possible to harness the different diffusion-reaction processes to generate tubular membranes with distinct bioactivities. The study demonstrates the possibility to trigger and achieve minor but crucial differences in coassembling processes and tune material structure and bioactivity. The study demonstrates the possibility to use minor, yet crucial, differences in coassembling processes to tune material structure and bioactivity