As we get older our immune system tends to get weaker and it becomes increasingly difficult to shake off diseases. At the same time we tend to develop arthritis and other auto-immune diseases which are localised instances of uncontrolled inflammation. In this grant application our multidisciplinary team of scientists consisting of physiologists, biologists, mathematicians and computer scientists aim to look at a very important signalling system NF-kappaB. This system plays an important role in stress and the immune responses and determines the fate of cells in the body, which is essential for general health and wellbeing. We will use a combined experimental and mathematical approach to analyse integrated systems that control NF-kappaB signalling in normal cells and tissues. We found that NF-kappaB carries signal information in the timing of its movements between the nucleus and cytoplasm. The timing of these movements determines which genes are switched on. We now wish to understand how this key process of NFkappaB signalling is controlled through normal life. How is it controlled by the cell division cycle, and how is it controlled by the sleep-wake cycle of the 24 h circadian clock. Recently, we have found that the speed of the oscillations in the NF-kappaB signalling system are very temperature sensitive in the physiological and fever range between 35 and 40 degrees C. This also appears to markedly change the pattern of which genes are switched on or off. Our work so far has been in cell lines grown in the laboratory and we now wish to investigate NF-kappaB signalling in normal cells taken from transgenic mice that have fluorescently labelled NF-kappaB proteins. We will use these cells to determine the NF-kappaB response to temperature, a range of physiological stimuli including glucocorticoids (which are often used in inflammatory treatment), to screen small molecule drugs to find ones that modulate the response and to study the quantitative relationships with the cell cycle and the circadian clock. The data from these experiments and others published in the literature will be used to build integrated mathematical models that can predict important aspects of cell, tissue and animal physiology relevant to understanding the maintenance of a healthy organism and how this may change with age. Key aims will be to understand how the clock and cell cycle together affect the timing and level of NF-kappaB signalling and which target genes are switched on. One of the NF-kappaB family of proteins, p105 encoded by the NFkB1 gene, has been found to cause faster ageing in mice when this gene is missing (Mann and von Ziglnicki, personal communication). We wish to investigate whether changes in NF-kappaB dynamics are involved in this ageing condition. Therefore, we will make a BAC reporter for p105 with fluorescent fusions at either end of the protein. We are an ideal team to perform this work, because we have complementary interdisciplinary skills in cell imaging, image analysis, molecular cell biology, physiology, genomics, bioinformatics and mathematical modelling. A core part of the team has an excellent track record of working together to analyse the NF-kappaB signalling system. In addition, this new project brings in new team members with considerable expertise in animal physiology, circadian clocks and endocrinology.

Quantum technologies promise a transformation of measurement, communication and computation by using ideas originating from quantum physics. The UK was the birthplace of many of the seminal ideas and techniques in this area; the technologies are now ready to translate from the laboratory into industrial applications. Since international companies are already moving in this area, and technology transfer in the UK is being accelerated through a substantial national research and development programme, there is a critical need for highly-skilled researchers who can work with the new technologies at the level of whole systems to provide products that solve real-world problems. Our proposal is driven by the need to train this new generation of leaders. They will need to be equipped to function in the complex research and engineering landscape where quantum hardware (with the attendant challenges in cryptography, complexity and information theory, devices, materials, software and hardware engineering) meets real devices, real applications and real customers. We propose to train an additional cohort of leaders to meet these challenges within the highly interdisciplinary research environment provided by UCL, exploiting the existing training programmes of two highly successful EPSRC Centres for Doctoral Training, in Delivering Quantum Technologies and Integrated Photonic and Electronic Systems, along with the UCL Centre for Systems Engineering and their commercial and governmental laboratory partners. We will provide a new doctoral training route for outstanding engineers. In their first year the students will obtain a background in devices, information and computational sciences through three concentrated modules organized around current engineering challenges. They will complete a team project and a longer individual research project, preparing them for their choice of main research doctoral topic at the end of the year. They will then move into doctoral research either within UCL or in the wider national Quantum Technologies Programme. Cross-cohort training in communication skills, technology transfer, enterprise, teamwork and career planning will continue throughout the four years. Peer to peer learning will be continually facilitated not only by organized cross-cohort activities, but also by the day to day social interaction. Following their co-location at UCL during training we expect the Skills Hub cohort to form a national network to advance the application of quantum technologies. We will also provide opportunities for the best graduates to develop their ideas beyond the PhD stage and to accelerate new concepts towards applications, while at the same time offering continuing training to those already working in industries ripe for applying quantum technologies.

The term "dementia" is used to describe a syndrome that results, initially, in cognitive function impairment and in many cases, a descending staircase of psychological dysfunction, leading eventually to death. It is a major socio-economic challenge with care costs approaching 1% of global GDP. Several conditions that lead to serious loss of cognitive ability are grouped under this syndrome, including Alzheimer's disease (AD), Vascular Dementia (VaD), Frontotemporal Dementia, etc. A high publicity announcement was made in 2012, by the Prime Minister, emphasising the high priority that should be given to dementia-related research and that funding will more than double in the immediate future, to partially remedy the fact that the overwhelming impact of the syndrome has been over-looked (Guardian, 26/3/12). On Dec 2013, the G8 Summit hosted in London brought together G8 ministers, researchers, pharmaceutical companies, and charities to develop co-ordinated global action on dementia. Dementia has marked adverse effects on the quality of life of tens of millions of people (both patients and carers) and exerts tremendous pressure on healthcare systems, especially when clear trends towards an ageing population, changing environmental influences and contemporary lifestyle choices are considered. Ca. 35M people suffer from dementia worldwide, a figure to quadruple by 2050. Europe and North America share a disproportionally high burden: the effects of ageing are particularly stark for these regions, exacerbating the healthcare provision implications. The Clinical Relevance: Vascular Cognitive Impairment (VCI). VCI defines alterations in cognition attributable to cerebrovascular causes, ranging from subtle or fixed deficits to full-blown dementia. VCI is a wide and accepted term referring to the "syndrome with evidence of clinical stroke or subclinical vascular brain injury and cognitive impairment affecting at least one cognitive domain", with resulting VaD being its most severe form. VaD is responsible for at least 20% of dementias, second only to AD, with a prevalence doubling every 5. 3 years. Several trials examined cholinesterase inhibitors for the treatment of vascular dementia, but the benefits are very modest, except in the individuals with a combination of AD and VaD. Vascular changes result in white matter (WM) damage (leukoaraiosis), which profoundly affect the fidelity of the information transfer underlying brain function and cognitive health8. Cerebral Magnetic Resonance Imaging (MRI) of Diffusion and Perfusion. MRI is a medical imaging technique affording non-invasive investigation of anatomy and tissue function, which is particularly suited to studying cognitive disorders due to its sensitivity and reliability. Our main interest is to characterise vascular and non-vascular tissues using quantitative diffusion and perfusion MR. Our overall aim is to characterise and quantify early differential alterations in brain blood transport and subsequent microstructural tissue damage using one-stop-shop perfusion/diffusion MR GSI incorporating novel MR signal models and optimal MR sequence design based on new human brain histomorphometric data in health and disease.

The term "dementia" is used to describe a syndrome that results, initially, in cognitive function impairment and in many cases, a descending staircase of psychological dysfunction, leading eventually to death. It is a major socio-economic challenge with care costs approaching 1% of global GDP. Several conditions that lead to serious loss of cognitive ability are grouped under this syndrome, including Alzheimer's disease (AD), Vascular Dementia (VaD), Frontotemporal Dementia, etc. A high publicity announcement was made in 2012, by the Prime Minister, emphasising the high priority that should be given to dementia-related research and that funding will more than double in the immediate future, to partially remedy the fact that the overwhelming impact of the syndrome has been over-looked (Guardian, 26/3/12). On Dec 2013, the G8 Summit hosted in London brought together G8 ministers, researchers, pharmaceutical companies, and charities to develop co-ordinated global action on dementia. Dementia has marked adverse effects on the quality of life of tens of millions of people (both patients and carers) and exerts tremendous pressure on healthcare systems, especially when clear trends towards an ageing population, changing environmental influences and contemporary lifestyle choices are considered. Ca. 35M people suffer from dementia worldwide, a figure to quadruple by 2050. Europe and North America share a disproportionally high burden: the effects of ageing are particularly stark for these regions, exacerbating the healthcare provision implications. The Clinical Relevance: Vascular Cognitive Impairment (VCI). VCI defines alterations in cognition attributable to cerebrovascular causes, ranging from subtle or fixed deficits to full-blown dementia. VCI is a wide and accepted term referring to the "syndrome with evidence of clinical stroke or subclinical vascular brain injury and cognitive impairment affecting at least one cognitive domain", with resulting VaD being its most severe form. VaD is responsible for at least 20% of dementias, second only to AD, with a prevalence doubling every 5. 3 years. Several trials examined cholinesterase inhibitors for the treatment of vascular dementia, but the benefits are very modest, except in the individuals with a combination of AD and VaD. Vascular changes result in white matter (WM) damage (leukoaraiosis), which profoundly affect the fidelity of the information transfer underlying brain function and cognitive health8. Cerebral Magnetic Resonance Imaging (MRI) of Diffusion and Perfusion. MRI is a medical imaging technique affording non-invasive investigation of anatomy and tissue function, which is particularly suited to studying cognitive disorders due to its sensitivity and reliability. Our main interest is to characterise vascular and non-vascular tissues using quantitative diffusion and perfusion MR. Our overall aim is to characterise and quantify early differential alterations in brain blood transport and subsequent microstructural tissue damage using one-stop-shop perfusion/diffusion MR GSI incorporating novel MR signal models and optimal MR sequence design based on new human brain histomorphometric data in health and disease.

Dramatic progress has been made in the past few years in the field of photonic technologies, to complement those in electronic technologies which have enabled the vast advances in information processing capability. A plethora of new screen and projection display technologies have been developed, bringing higher resolution, lower power operation and enabling new ways of machine interaction. Advances in biophotonics have led to a large range of low cost products for personal healthcare. Advances in low cost communication technologies to rates now in excess of 10 Gb/s have caused transceiver unit price cost reductions from >$10,000 to less than $100 in a few years, and, in the last two years, large volume use of parallel photonics in computing has come about. Advances in polymers have made possible the formation of not just links but complete optical subsystems fully integrated within circuit boards, so that users can expect to commoditise bespoke photonics technology themselves without having to resort to specialist companies. These advances have set the scene for a major change in commercialisation activity where photonics and electronics will converge in a wide range of systems. Importantly, photonics will become a fundamental underpinning technology for a much greater range of users outside its conventional arena, who will in turn require those skilled in photonics to have a much greater degree of interdisciplinary training. In short, there is a need to educate and train researchers who have skills balanced across the fields of electronic and photonic hardware and software. The applicants are unaware of such capability currently.This Doctoral Training Centre (DTC) proposal therefore seeks to meet this important need, building upon the uniqueness of the Cambridge and UCL research activities that are already focussing on new types of displays based on polymer and holographic projection technology, the application of photonic communications to computing, personal information systems and indeed consumer products (via board-to-board, chip to chip and later on-chip interconnects), the increased use of photonics in industrial processing and manufacture, techniques for the low-cost roll-out of optical fibre to replace the copper network, the substitution of many conventional lighting products with photonic light sources and extensive application of photonics in medical diagnostics and personalised medicine. Many of these activities will increasingly rely on more advanced systems integration, and so the proposed DTC includes experts in computer systems and software. By drawing these complementary activities together, it is proposed to develop an advanced training programme to equip the next generation of very high calibre doctoral students with the required expertise, commercial and business skills and thus provide innovation opportunities for new systems in the future. It should be stressed that the DTC will provide a wide range of methods for learning for students, well beyond that conventionally available, so that they can gain the required skills. In addition to lectures and seminars, for example, there will be bespoke experimental coursework activities, reading clubs, roadmapping activities, secondments to collaborators and business planning courses.Photonics is likely to become much more embedded in other key sectors of the economy, so that the beneficiaries of the DTC are expected to include industries involved in printing, consumer electronics, computing, defence, energy, engineering, security, medicine and indeed systems companies providing information systems for example for financial, retail and medical industries. Such industries will be at the heart of the digital economy, energy, healthcare and nanotechnology fields. As a result, a key feature of the DTC will be a developed awareness in its cohorts of the breadth of opportunity available and a confidence that they can make impact therein.