Osteoporosis is a disease of the bone which affects 3M people in the UK, is associated with 300,000 fractures per year, and costs the NHS £1.9B/yr (figures provided by the National Osteoporosis Society, 2015). Current medical practice is to diagnose osteoporosis and provide pharmacological treatment only after a fragility fracture has occurred. This project seeks to revolutionise treatment through a drug-free, proactive management, through use of precision nanovibrational stimulation applied via bone conduction (similar to bone conduction headphones). Nanovibrational stimulation has recently been shown to produce osteoblasts (bone building cells) in the lab from mesenchymal stem cells (MSCs - adult stem cells found in the bone and elsewhere in the human body). This was the first time that osteogenesis (promotion of bone) has been observed in MSCs without the requirement for drugs and/or complex engineered scaffolds. Since osteoporosis has been linked to insufficient osteogenesis in MSCs, nanovibrational stimulation could provide a breakthrough route to decrease the onset, or perhaps even reverse the effects, of osteoporosis. In order to evaluate this in a timely manner, this project will study disuse-related osteoporosis (due to spinal injury) since this provides a time-accelerated model for testing interventions. The academic team will work alongside the clinicians within the Scottish Centre for Innovation in Spinal Cord Injury (SCISCI) in the Queen Elizabeth National Spinal Injuries Unit and conduct the first trials in nanovibrational stimulation for proactive treatment of osteoporosis.

Remaking Society will be: 1) Working with local partners in demonstrating and assessing participatory cultural activities in four contrasting contexts of deprivation - Bradford, Glasgow, Fraserburgh and Newcastle. 2) Using these four pilots to generate new forms of evidence about the lived experience of poverty and exclusion. 3) Creating opportunities for marginalised and less visible sections of society to communicate with wider audiences, including policy-makers. In this project, the concept of community is not restricted to communitarian accounts of 'a group of people in a given place', or as a site of consensus and constructed oneness based on social categories such as race, class, gender or location. Ours is a dynamic model in which community formation is seen as a continual re-negotiation of co-existence and interdependence, not confined by place, as illustrated by the thirty years of pioneering work by Southall Black Sisters. Questions about how communities conduct these negotiations become particularly important now, at a time of economic crisis, when resources are scarce and stress levels among vulnerable individuals are high. The study will make critical connections between our understanding of community performance and participatory process across academic fields - including conflict resolution, cultural geography, public health, social psychology and sociology. It will allow a re-examination of inter-disciplinary concepts of community through arts and media practices. Belonging to a community is critical to a sense of wellbeing for individuals and families, particularly significant for those who live on the breadline. The second element of Remaking Society is the generation of narrative evidence on the cultural dimensions of poverty and social exclusion. It will add a unique inter-disciplinary arts and humanities perspective to the ESRC's national study, Poverty and Social Exclusion in the UK (www.poverty.ac.uk). Running until 2013, it is the UK's largest ever research project on the impact of poverty.

Defects in the gene, sphingosine-1-phosphate lyase, SGPL1, are associated with a rare disease affecting multiple organs. Children affected with disease can have problems with their endocrine organs (including the adrenal glands, testes, and thyroid gland), kidneys and skin. They can have delay in their development and develop progressive neurological disease. They have a reduction in SGPL1, a key enzyme of an important lipid system, the sphingolipids, which are present throughout the body. Smaller sphingolipids have important roles in signalling whereas the larger sphingolipids have a structural role in the body's cells. Deficiency of SGPL1 results in a block in the system, likely to cause certain sphingolipids to accumulate. Whilst rare, SGPL1 deficiency is extremely debilitating and can significantly affect life expectancy. We will conduct a range of patient studies and cell experiments to try to gain a better understanding of the disease mechanism. We will investigate disease progression in patients identified with SGPL1 deficiency. These individuals will be identified through genetic screening of patients with adrenal and kidney disorders. For the first time we will also be studying the effects of having a genetic defect in SGPL1 in children with delay in their development in an allied study. We need to understand in what way the sphingolipid system is disturbed by deficiency of SGPL1. We will be investigating this by measurement of the sphingolipids in patient blood samples and in our adrenal cell model of disease. Our group primarily investigates adrenal insufficiency, where inherited genetic defects result in the adrenal glands failing to produce cortisol, an essential steroid in maintaining the body's appropriate response during times of physical and emotional stress. In our established adrenal cell model of SGPL1 deficiency we will test the effects of manipulating the sphingolipid system, in restoring the ability to produce cortisol. Work in our group is underway to try to identify the disease mechanism in the adrenals at the cellular level. Our work to date indicates that SGPL1 deficiency affects mitochondria, regarded as the powerhouse of cells, reducing their normal ability to provide cells with energy. In this study we will look at the knock-on effects on another component of the cell, lysosomes, which are normally responsible for clearing defective mitochondria. In circumstances where there are increased mitochondrial abnormalities the lysosomes can become overwhelmed with deleterious effects. This may explain the overlap that patients with SGPL1 deficiency have with other disorders involving the sphingolipid system, which are known to specifically affect lysosome function. Disease mechanisms identified in our adrenal studies may inform how SGPL1 deficiency affects other organs. We are establishing a consortium of experts with wide-ranging research interests to develop studies to investigate the disease mechanism in the other organ systems involved and identify new therapeutic targets. Study of how the disease progresses will guide clinical screening to allow early treatment and inform genetic counselling for the families. It is crucial to our patients that we are able to discern the specific sphingolipid abnormalities and disease mechanism in order to identify where treatments need to be targeted. The study may be relevant to a wider population furthering our understanding of endocrine, kidney and neurological disease. It will provide better understanding of how the sphingolipid system affects cellular components (such as lysosomes and mitochondria) and how this can contribute towards disease. Furthermore, as strategies to alter SGPL1 activity are being explored in therapies for several conditions, understanding the impact of SGPL1 deficiency in human disease will provide important insights into the potential effects of manipulating this lipid system.

Speech Sound Disorders (SSDs) are the most common communication impairment in childhood; 16.5% of eight year olds have SSDs ranging from problems with only one of two speech sounds to speech that even family members struggle to understand. SSDs can occur in isolation or be part of disability such as Down syndrome, autism or cleft palate. In 2015, the James Lind Alliance identified improving communication skills and investigating the direction of interventions as the top two research priorities for children with disabilities. Our programme of research aims to fulfil this need by developing technology which will aid the assessment, diagnosis and treatment of SSDs. Currently in Speech and Language Therapy, technological support is sparse. Through our previous work in the Ultrax project we showed that by using ultrasound to image the tongue in real-time, children can rapidly learn to produce speech sounds which have previously seemed impossible for them. Through this project, we developed technology that enhances the ultrasound image of the tongue, making it clearer and easier to interpret. Ultrax2020 aims to take this work forward, by further developing the ultrasound tongue tracker into a tool for diagnosing specific types of SSDs and evaluating how easy it is to use ultrasound in NHS clinics. The ultimate goal of our research is that Ultrax2020 will be used by Speech and Language Therapists (SLTs) to assess and diagnose SSDs automatically, leading to quicker, more targeted intervention. Normally speech assessment involves listening to the child and writing down what they say. This approach can miss important subtleties in the way children speak. For example, a child may try to say "key" and it may be heard as "tea". This leads the SLT to believe the child cannot tell the difference between t and k and select a therapy designed to tackle this. However, ultrasound allows us to view and measure the tongue, revealing that in many cases children are producing imperceptible errors. In the above example, an ultrasound scanner placed under the chin shows that the child produces both t and k simultaneously. Identification of these errors means that the SLT must choose a different therapy approach. However, ultrasound analysis is a time consuming task which can only be carried out by a speech scientist with specialist training. It is a key output of Ultrax2020 to develop a method for analysing ultrasound automatically, therefore creating a speech assessment tool which is both more objective and quicker to use. Building on the work of the Ultrax project, where we developed a method of tracking ultrasound images of the tongue, Ultrax2020 aims to develop a method of classifying tongue shapes to form the basis of an automatic assessment and a way of measuring progress objectively. We are fortunate to already have a large database of ultrasound images of tongue movements from adults and primary school children, including those with speech disorders, on which to base the model of tongue shape classification and to test its performance. At the same time, we will evaluate the technology we develop as part of Ultrax2020 by partnering with NHS SLTs to collect a very large database of ultrasound from children with a wide variety of SSDs. In three different NHS clinics, SLTs will record ultrasound from over 100 children before and after ultrasound-based speech therapy. This data will be sent to a university speech scientist for analysis and feedback to clinicians recommending intervention approaches. Towards the end of the project, we will be able to compare this gold-standard hand-labelled analysis with the automatic classification developed during the project. At the conclusion of our research project we will have developed and validated a new ultrasound assessment and therapy tool (Ultrax2020) for Speech and Language Therapists to use in the diagnosis and treatment of SSDs.

Osteoporosis and osteoarthritis affect millions of patients around the world and are eventually characterised by a reduction of bone strength that results in increased rates of fractures. Life expectancy continues to rise but patient specific treatment solutions to optimally manage those patients are sill not available. Such solutions could consist of tailored medication strategies and, at a later stage, tailored implant solutions which require a thorough understanding of the mechancial competence of structural tissue. While the mechanical behaviour of bone is currently well characterised at the upper level of tissue organisation, the underlying nonlinear mechanical properties of mineralised collagen fibre assemblies, however, remain obscured by structural features such as cellular porosity, lamellar organisation, cement lines, cracks and other interfaces. Starting from preliminary pilot experiments, this proposal aims at performing simultaneous uniaxial micropillar strength tests and structural measurements using small-angle X-ray scattering and wide-angle X-ray diffraction on micron-sized volumes of the extra-cellular matrix (ECM) and, thus, on mineralised collagen fibre assemblies only. This project will result in a versatile and powerful experimental framework that will be used to understand the structure-mechanics relation of ECM with an unprecedented spatial resolution of the mechanical experiment. The results of this project will inform the engineering of patient-specific material solutions in silico through all relevant length scales starting from the ECM level. This, in turn, will foster the development and realisation of production technologies for manufacturing patient-specific "implants on demand" which could be offered as a service or embedded in a hospital. The novel experimental techniques may be useful for testing and developing functional thin films such as implant coatings, investigating the impact of pathological changes on the ECM, or even to reduce, refine, and replace animal experiments.