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University of Southampton

Country: United Kingdom

University of Southampton

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3,592 Projects, page 1 of 719
  • Funder: UKRI Project Code: 2441588

    Proteolysis targeting chimeras (PROTACs) are hetero-bifunctional molecules where one fragment interacts with the protein of interest (POI) and the other binds to a component of an ubiquitin ligase. This results in the poly-ubiquitination of the POI, which then undergoes irreversible proteasomal degradation, in a catalytic manner. This strategy to reduce cellular protein levels has generated huge interest and excitement in biology, and at present, there is significant research aimed at developing PROTACs to target proteins and signalling pathways previously thought undruggable using classical protein-protein interaction inhibitors. This project aims to develop/characterise new classes of cell permeable PROTACs, as novel probes to interrogate important signalling pathways and their key protein effectors. Examples include the Wnt/Beta-catenin signalling pathway and chromatin remodelling complexes, which play multiple pivotal functions in human physiology. These critical roles are underscored by the observation that their dysregulation leads to multiple cancer types. First, the candidate will focus on the development of PROTAC probes targeting key POIs at regulatory nodes. This will involve the molecular design, chemical synthesis and in vitro biophysical characterisation (NMR, ITC, MS) of the PROTACs. A second objective will focus on elucidating the cellular mode of action of the new PROTACs. Their selectivity and ability to deplete the POIs will be quantified by WB and live imaging using GFP constructs; and their downstream effects determined by monitoring mRNA levels of downstream genes known to respond to POI inhibition across a panel of cancer cell lines. This project builds on i)recent proof-of-concept results in the Baud and Linclau laboratories showing that it is possible to enhance PROTAC properties (e.g. solubility/lipophilicity) and selectivity through synthetic alteration, circumventing an important historical bottleneck in the field; and ii)expertise in cancer cell biology and signalling in the Giamas laboratory (e.g. identification/deciphering of new genes/proteins implicated in important biological processes).

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  • Funder: UKRI Project Code: 2124085

    Systematic investigation of reading has played a vital role over the past decades in informing educators, and has included programs of research to understand reading development in children as well as research to understand the mental processes that are active during skilled reading (for a review, see Rayner, 2009). In the current research project, we will adopt a novel approach in the study of reading by examining eye movements that are made not within the traditionally well-studied populations of skilled adults or of struggling readers (e.g. dyslexic readers,...), but of skilled adults that are exceptionally good readers (i.e. fast while maintaining high levels of comprehension). A great amount of knowledge has been acquired about the cognitive processes active during reading by registering the eye movements that are being made whilst processing the text. Research indicates that besides the currently fixated word, readers do routinely pick up information from the upcoming word as well, a word that will typically be located in an area of the visual field called the parafovea (for a review, see Schotter, Angele, & Rayner, 2012). Parafoveal processing is considered a hallmark of skilled reading (Rayner, 2009). Indeed, research has shown that developing readers or readers with reading difficulties have reduced parafoveal processing compared to skilled, adult readers. However, very little is known about the parafoveal processing of exceptionally good readers. These readers will be selected by means of very high scores on standardised reading comprehension tests.

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  • Funder: UKRI Project Code: AH/E504043/1
    Funder Contribution: 28,298 GBP

    This monograph roots the inter-relationship of gender, class and national identity within the multi-national context of the British state. A rich body of both primary and secondary literature is deployed both to place England within the British context, and to examine the class-based nature of the domestic ideal. Linda Colley's Britons: Forging the Nation 1707-1837 {1992} posited an over-arching British identity superimposed on to older identities, both regional and national, by the start of the Victorian period. The introduction to the monograph addresses issues around national identities, including attitudes towards 'British-ness'. Even where the union with England was largely accepted, education was seen as integral to preserving national distinctiveness, and tensions over English presumptions (or perceived indifference) were evident in both Scotland and Wales. In Ireland, the British state sought to intervene in education as early as the 1830s, though it failed to overcome denominational rivalries over control of education, which was present throughout the UK. The Catholic Church opted to keep its schools outside of the {different) structures established by the 1870 Elementary Education Act {for England and Wales) and the Education {Scotland) Act of 1872, while in Ireland it eventually withdrew its support from the National board of Education, set up in 1831. Thus, the role of religion in the schooling of girls is a major theme in this research. This research also emphasises the importance of specific contexts and cultures for shaping definitions of gender. Both the ideology of women's place and what was taught to girls in schools are examined through a comparative national framework, and also within regional and local contexts. Focusing on the interaction of gender and nationality with social class in education allows the identification of variations, alterations and contestations in nineteenth-century concepts of women's role. Organisation of the research is chronological as well as thematic, to show both continuity and change. One chapter provides an overview of female education throughout the UK to the mid-nineteenth century, setting the context for another chapter concerning midcentury debates about the condition of education in general and female education in particular. Close attention is paid to discourses on gender assumptions and concerns about the perceived gaps between the ideal and reality, reflected in parliamentary debates and enquiries into education, and the reporting of these in pamphlets, journals and newspapers. Two further chapters consider separately working-class and middle-class girls' schooling from the 1870s, while a third will focus on the schoolmistresses and female members of school boards.

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  • Funder: UKRI Project Code: EP/R010609/1
    Funder Contribution: 310,055 GBP

    The determination of chemical structure is vital in understanding the efficacy of medicines and materials and consequently underlies innovation. The equilibrium positions of atomic nuclei can be routinely determined by the technique of X-ray diffraction. However, this provides only part of the information required by a chemist. In order to develop new medicines and materials it is necessary to understand bonding character and reactivity; these are determined by the energies and spatial distributions of electrons, the so-called "electronic structure". In order to investigate electronic structure, including the changes it undergoes during a chemical reaction, new probes are required. Whereas photoelectron spectroscopy (the emission of electrons caused by the interaction of molecules with UV light) has long been known to be sensitive to electronic structure, far more intimate details can be obtained by the measurement and analysis of the angles through which the photoelectrons are emitted. The information content of these angular measurements dramatically improves if measurements can be made relative to bonds in individual molecules. This is challenging because free molecules rotate, and measurements are therefore averaged over all the possible molecular orientations. Furthermore, a full characterization requires measurements to be made over a wide energy range. The combination of these requirements has severely limited the scope of most experiments to date. The recent parallel developments of (a) techniques to align molecules in space, and (b) technologies that have enabled the development of a new generation of high energy light sources, is set to revolutionize capabilities, bringing the exciting prospect of observing how electronic structure evolves in time. Here, we propose a series of novel experiments that will combine and exploit these ideas and technologies to develop sensitive probes of evolving electronic structure, and protocols for their implementation and interpretation, facilitating uptake by other groups. The proposed work is timely because of the recent technological developments and the research team is well-placed to advance the state-of-the-art through their expertise in the measurement and interpretation of photoelectron angular distributions and in light source development.

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  • Funder: UKRI Project Code: MR/T019638/1
    Funder Contribution: 893,071 GBP

    Multifunctional ferroic materials are materials that simultaneously exhibit more than one ferroic property including ferromagnetism, ferroelectricity, ferroelasticity or ferrotoroidicity. Ferroic materials that exhibit more than one property are of great interest because the different properties may work together in different ways and lead to exciting new potential applications, if we could understand this better. For example, the coupling between magnetic and ferroelectric ordering can be utilised to develop low power magnetoelectronic devices (such as non-volatile magnetic computer memory) where the spin polarised transport of electrons can be used to flip magnetic memory bits. As a result there is a vibrant effort to understand the underlying mechanisms at work in bulk and thin film materials. Many of the multiferroic materials that I am interested in have a certain structure called a perovskite crystal structure. Before multiferroic perovskite materials can find significant utility in a device setting, a clear understanding of the materials behaviour at the nanoscale is needed. Often the role of crystal defects and other topological structures remains unclear as (to date) no reliable means exists to image in three-dimensions and observe such effects in real-time. Moreover, if the crystal isn't grown carefully, it can easily grow in a different structure that doesn't display the properties that we want to investigate. To better understand these materials I will use a technique called Bragg coherent X-ray diffractive imaging (BCXDI) without lenses. This is a form of x-ray microscopy that can permit high resolution imaging where the use of conventional optics is not feasible. The ability that BCXDI has to directly image time varying structural properties of materials in three-dimensions at the surface and in the bulk can greatly increase our understanding of how novel phases emerge and influence the material properties. The application of BCXDI to the study of multifunctional materials will enable a wide range of next generation technologies that otherwise are inaccessible due to an incomplete understanding of their properties. A prominent example prototypical system is bismuth ferrite which exhibits a large reversible crystal deformation (up to 0.5%) in response to optical excitation. It remains unclear exactly how optically generated electron-hole pairs in bismuth ferrite can cause a large lattice deformation which appears to propagate faster than the speed of sound in the material. Moreover the exact role of electron-hole pairs and the propagation vector of the distortion remains unclear. Utilising time-resolved BCXDI will enable direct visualisation of the lattice distortion in three-dimensions from which the atomic displacements can be inferred and contrasted with model predictions. This project will focus on imaging time-varying structural phenomena in a wide range of ordered multifunctional matrials by employing a novel deterministic form of BCXDI to obtain three-dimensional images. The application of deterministic BCXDI to the study of dynamic structural phenomena will provide a novel and robust means to directly image in three-dimensions non-equilibrium dynamics of the material undergoing a symmetry breaking structural transformation. Knowledge of the atomic displacements from equilibrium is obtained with sub-angstrom sensitivity and will greatly aid our understanding of the kinetics of dynamic phenomena that are central to the development of next generation materials and devices. This research proposal will be carried out in collaboration with Prof. Steve Collins, Diamond Light Source, Oxfordshire and Prof. Hans Fangohr, European Xray Free Electron Laser (E-XFEL) Facility in Hamburg.

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