Analysis of DDR1 function at epithelial cell contacts

Discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase (RTK) family, and binds to collagen in the extracellular matrix (ECM). It therefore plays an important role in relaying information from outside the cell to intracellular components. Accordingly, DDR1 contributes to many cellular processes including migration and differentiation amongst others. In malignant states, cell-matrix interactions are often deregulated, resulting in the pro-invasive phenotype characteristic of tumours. Increased DDR1 expression is a negative prognostic marker for many cancers, however the molecular mechanisms are not fully understood. Interestingly, novel ligand-independent roles of DDR1 have recently emerged that potentially implicate the receptor at epithelial cell contacts. In this thesis, I show that during new keratinocyte contact formation, DDR1 is recruited after E-cadherin. In contrast to previous literature, DDR1 does not form a complex with E-cadherin, and distinct separate clusters of DDR1 and E-cadherin are observed at mature cell contacts. DDR1 depletion decreases the junctional E-cadherin and actin levels during cell contact formation. This phenotype is independent of actin recruitment to clustered E-cadherin receptors. Actin thin bundles are also visibly disrupted during contact formation with DDR1 depletion, which is further linked to a reduction in Rho-ROCK signalling and actomyosin contractility. Not only are the levels of phosphorylated myosin light chain and myosin phosphatase reduced, but ROCK1 levels are also reduced by DDR1 knockdown, suggesting that DDR1 has a regulatory role upstream of ROCK1. Preliminary experiments demonstrate potential binding between DDR1 and some members of the catenin protein family, however the significance of these interactions requires further investigation. Data collected from keratinocytes and a series of lung cancer cell lines, suggest that E-cadherin-mediated cell contacts inhibit collagen-mediated DDR1 activation, possibly by preventing DDR1 ligand accessibility. Overall, my results suggest that DDR1 stabilizes epithelial cell contacts through regulation of actomyosin contractility.Open Acces

Dynamic distributed monitoring of masonry railway bridges

Novel sensing technologies – for instance, fibre-optic Fibre Bragg Grating (FBG) sensors – offer engineers new means to study the dynamic distributed behaviour of complex structures, such as masonry arch bridges. These bridges, which are common features of many European transport networks, are often ageing structures, with complex histories of damage and repair work. Furthermore, their material properties and non-visible geometry may be challenging, if not impossible, to ascertain, creating uncertainty in the reliability of computational analyses. Particularly in light of the financial and environmental costs of their replacement, and the contributions that many of these bridges make to our shared architectural and industrial heritage, it is increasingly urgent to improve our understanding of the structural behaviour of masonry arch bridges under their real working loads. As these bridges undergo many cycles of loading, which may directly drive their deterioration, their response in working conditions is often more important than an understanding of their collapse behaviour, which can be studied using established methods such as limit state analysis. In this thesis, Structural Health Monitoring is used to gain new insights into the behaviour of masonry arch bridges and viaducts. Part 1 includes an initial study in which the outputs of simplified finite element models are compared against previously gathered FBG monitoring data, describing the response of a damaged masonry viaduct under applied train loading. It is found that the impact of damage on the viaduct response is primarily local, while common ‘single-point’ measurements, such as the crown vertical displacements, can be well matched by the simplified models. Furthermore, relative contributions from each of the main structural components of the viaduct, towards its overall SLS performance, are quantified. The remainder of the thesis is concerned with the monitoring of a case study structure: a recently repaired, skewed, masonry arch railway bridge. FBGs are used to monitor the dynamic behaviour of this bridge in detail – in particular, the in-plane strain response and the movements across cracks, including both opening and shearing movements across a key separation crack between the arch barrel and a spandrel wall. The sensitivity of these responses to a range of external variables – namely train speed, ambient temperature, time of day, and date – is presented. Trains travelling between approximately 80 and 90 mph are observed to induce a local strain response that is up to 15% higher than that of slower trains, although this effect is only present close to the arch crown, where loads are most concentrated at the extrados. The trend with time-of-day follows anticipated passenger behaviour. Trains at peak commute times result in higher magnitude and lower statistical spread in the bridge response; hence, comparing trains recorded at these times allows for variable passenger loading to be normalised. The in-plane flow of force throughout the skewed arch is also measured and visualised, using a novel ‘FBG strain rosette’ implementation that monitors the arch principal strains. These force flow distributions, experimentally mapped in detail for the first time for a skewed masonry arch, are highly consistent across many train events, suggesting a common response to different types of train loading. Separately, videogrammetry is used to measure the out-of-plane, vertical displacements of the arch. The distribution of these movements is used to fit a simplified beam model of the transverse bending component of the arch response. This structural monitoring is part of a broader, collaborative study, trialling a large range of different monitoring technologies at the case study bridge. A practical evaluation of these various technologies is presented in this thesis; despite the larger initial costs for an FBG system, the many measurement locations and high quality of data afforded by this technology meant that it compared favourably with more established approaches. In another collaboration, existing laser scan analysis methods for masonry arch bridges have been extended to skewed arches, and employed to study the historic, distributed deformation of this bridge. It is shown that the current deformed geometry could have been caused by small support movements at the obtuse corners of the arch abutments, which are consistent with past hypotheses in the literature regarding the behaviour of skewed masonry arch bridges. Much of this thesis is concerned with the analysis and interpretation of data collected through on-site monitoring of the case study bridge, carried out over a six-month period. Since this time, the FBG system at the bridge has been adapted for autonomous, remote sensing. The necessary improvements to the system are presented, covering both the equipment installed at the bridge and the accompanying data processing strategies, which now allow for automated data categorisation, analysis, and visualisation. Following this, the long-term data gathered to date is analysed. These data reveal further trends – in particular, linking the bridge response to ambient temperature. Lower temperatures lead to a larger magnitude response – potentially due to thermal contraction of the masonry causing existing cracks throughout the bridge to open, and thus increasing the potential for movements to occur under applied loads.I would like to acknowledge additional funding from Network Rail, and in kind support from AECOM, which supported the field monitoring components of my PhD research

Interviews With HMA Directors: Dr. Jane Cocking

The Journal of Conventional Weapons Destruction is introducing a section dedicated to sharing the insights and experiences of those working in the field. This issue features HMA directors. Future issues will feature interviews with photojournalists, survivors, and veterans of the HMA community

The prospect of N2-fixing crops galore!

The impact of carbon on our climate has been of major concern for a number of years. However, we are now learning to be equally concerned about the next element in the periodic table, nitrogen, and the consequences of using synthetic nitrogen fertilizers in agriculture that pollute our planet and its atmosphere

Some theoretical and practical possibilities of plant genetic manipulation using protoplasts

Protoplasts capable of division and plant regeneration are now available for a large number of vegetable, oil and forage crops. However, routine hybrid production is not possible due to methodological limitations in selection and culture of hybrid cells. Recent improvement in techniques are the use of a double mutant as a universal hybridizer and the use of fluorescence activated cell sorter to recover hybrid cells. Interest is also centered on limited gene transfer by protoplast fusion. We propose a model of generating triploid plants by somatic cell fusion to transfer limited genomic information from an alien plant to a crop plant. Somatic hybridization has some novel features but, in practice and conception, it is an extension of the methods of sexual hybridization. By contrast, genetic transformation is a radically different approach to plant genetic manipulation. The success of this approach will depend upon how readily genotype can be related to phenotype in a tangible way so as to ascertain what biochemical and developmental activity is controlled or modulated by a DNA sequence

Recognising and understanding collective resilience in crowds of survivors

No description supplie

Interpretation of the Dynamic Response of a Masonry Arch Rail Viaduct Using Finite-Element Modeling

Linear-elastic finite-element analysis is sometimes used to assess masonry arch bridges under service loads, despite the limitations of this method. Specifically, linear-elastic analysis can be sensitive to material properties, geometry, and support settlements, while also allowing the development of tensile stresses that may be unrealistic for masonry structures. However, even though linear-elastic methods remain appealing for their simplicity, it is rare to evaluate their output against experimental data. In this paper, detailed strain and displacement monitoring data for a masonry arch viaduct are used to evaluate a series of independently developed linear-elastic simulations of this structure. Although uncertainties in input parameters mean the magnitude of modeling results cannot be presumed accurate, the simulated response pattern was found to agree reasonably well with monitoring data in regions of low damage. However, more damaged regions produced a markedly different local response. Comparisons between the simulations revealed useful conclusions regarding common modeling assumptions, namely the importance of modeling backing material, spandrels, and foundation stiffness, to capture their influence on the arch response.This work forms part of a PhD, which is funded through an EPSRC Doctoral Training Partnership (grant reference number EP/M506485/1). Data collection was made possible by the Cambridge Centre for Smart Infrastructure and Construction, through additional EPSRC funding (grant reference number EP/L010917/1)

The importance of modelling assumptions when analysing the dynamic response of a masonry railway viaduct

© 2018 The International Masonry Society (IMS). The masonry viaduct at Marsh Lane is an important part of the railway network near Leeds, UK, dating from the 1860s. However, deterioration has resulted in notable deflections under train loads, which have concerned asset managers. Coupled with uncertainty regarding the true structural behaviour under serviceability conditions, this has led to detailed monitoring of the viaduct. This paper summarises the main conclusions of the monitoring installation before focusing on the evaluation of computational modelling of the viaduct, through comparison of modelling and monitoring results. In the monitoring scheme, fibre-optic cables containing Fibre-Bragg Gratings allowed measurement of dynamic in-plane barrel strains while digital image correlation captured displacements using commercial video cameras. The results illuminated a complicated three-dimensional dynamic response under train loading and highlighted the importance of interaction between adjacent spans. Separately, rail loading of the viaduct was simulated with a series of finite element models, each with increasing levels of complexity, to establish the relative stiffness contributions of various structural components. These models were then compared to detailed measurements from the real viaduct so that their validity could be evaluated. This approach revealed the impact of some common modelling assumptions and permitted assessment of nonlinear contributions to structural behaviour