In the UK there are one thousand new cancer cases each day and 450 cancer deaths. 45% of patients undergo surgery to remove tumours. Despite the approval of 97 new precision pharmaceutical treatments since 2011, only 8% of patients have cancer treatable by these precision medicines. These statistics highlight there is a real need to develop safe, broad-spectrum treatments for a substantial proportion of cancers. A feature of cancer is an ability to grow rapidly, continuously, and uncontrollably. Cancer commonly achieves this by putting our own cells' protein synthesis machinery into overdrive. The proteins in our cells are put together from parts by a complex called the ribosome. Cancer takes advantage of this by creating extra ribosome complexes, allowing for uncontrollable protein synthesis and cancer cell growth. It does this by increasing the productivity of the protein complex that controls ribosome building, the complex called RNA polymerase I (often just called Pol I). Many of the drugs that we already use to treat cancer turn off Pol I, so we know this is a good drug target. However, the drugs we already use are not specific, so they also hit many other important targets, giving us side effects. In this research we will make a compound that can only turn off Pol I, giving us a highly effective drug with far reduced side effects. Because Pol I is turned up in almost all cancers this drug will control almost all cancers, making a broad-spectrum cancer treatment. The Pol I complex, which is a collection of fourteenproteins, is normally very active in the cells responsible for development. As we age Pol I slows down, so in normal healthy cells Pol I has very low activity. This means that if we can make compounds that turn off Pol I in adults it will only affect cancer cells which have turned Pol I up, leaving our healthy cells alone. Some developmental disorders have DNA mutations that results in Pol I being turned off while we are developing. People with the developmental disorders show very low Pol I activity when it is needed most. This suggests that the mutations in the DNA of patients with developmental disorders hold the secret to how we can turn off Pol I in cancer. The knowledge we have learnt from one type of disease (developmental disorders) will allow us to selectively treat another disease (cancer). Over two years, this project aims to find molecules that control the interactions of the proteins in the Pol I complex. Protein-protein interactions control many diseases but are challenging for drugs to affect. Proteins are large molecules and drugs are small, like a Chihuahua trying to keep apart sumo-wrestlers. This project will use a new technique, developed in our research group, to make molecules that control the protein-protein interactions of Pol I. First, peptides, small protein like molecules that look and act like artificial sumo-wrestler arms, will be made by copying the natural protein structure. Using peptides as scaffolds, sections can be replaced with drug pieces to make a drug molecule. Work will focus on designing molecules for this purpose and developing them to be good precision medicine leads. These new molecules will break apart the Pol I complex, stopping cancer cells from growing uncontrollably and providing a broad-spectrum tools to investigate the control of protein synthesis in cancer. This project will build on previous research from our group that identifies drug-like compounds capable of controlling protein-protein interactions. We will investigate new methods to increase the speed and efficiency of this process so that chemical tools can be identified for any protein interaction of interest.

The global supply chain for semiconductor devices is founded on highly specialised and centralised manufacturing facilities. The result is an over-dependence on a handful of companies which may be in geopolitically unstable areas, a high cost for custom designs, and large barriers for innovation. A new decentralised manufacturing paradigm is needed using novel tools to enable low-cost point-of-use microelectronics manufacturing and rapid custom electronics manufacturing. Ideally, such a paradigm will allow the unimpeded heterogeneous integration of emerging quantum and semiconductor materials from the lab directly into real world electronic systems with enhanced performance and unique functionalities, facilitating innovation and industry uptake of novel materials. Manufacturing electronics is conventionally a top-down process where a semiconductor wafer is etched into transistor channels, and modified through the addition of dopants or dielectrics. There, the size and location of each device is defined deterministically. Nevertheless, many novel competing or complementary electronic materials, including quantum materials and novel semiconductor nanostructures, are grown bottom-up by nucleation or deposition processes that are inherently non-deterministic. While the performance of these materials can be extraordinary and enabling for applications in information and communication technologies and quantum technologies, positional accuracy is sacrificed, which is a challenge for traditional deterministic manufacturing methods. Efforts to deterministically define quantum and nanostructures are on-going, but yield remains low. An effectively perfect (100%) yield could be achieved if, instead of a top-down deterministic manufacturing approach, we used an adaptive approach that could select, address and connect the best performing randomly located elements (quantum structures, nanostructures, etc.) into functional systems. By combining computer vision-guided automated microscopy, dynamic circuit design, and advanced optical lithography into a desktop tool, our proposed technique will be used to rapidly manufacture custom electronic and photonic circuits. It will allow the unimpeded integration of new materials from the lab directly to real-world (opto)electronic, photonic and quantum device applications with enhanced performance and unique functionalities, enhancing innovation globally.

Quantum mechanics is one of our most powerful theories of nature and describes our world on the microscopic scale with incredible accuracy. Our knowledge of quantum mechanics has enabled humanity to develop powerful technologies such as the laser, electronic silicon chips in computers and smartphones, and has given us great insight into the fundamental workings of the universe. This fellowship aims to deepen our understanding and control of quantum mechanics by conducting experiments with lasers and high frequency mechanical vibrations. Dr Vanner and the members of his team will use lasers to prepare a mechanical oscillator in a quantum superposition of moving up and down 'at the same time'. This type of motion is then a realization of the infamous 'Schrodinger's cat' thought experiment. Empirically studying the dynamics of this state will enable us to shed much needed light on the fundamental mechanisms at the divide between the quantum and classical worlds. Moreover, the techniques developed, and the new knowledge gained within this project, will be utilized to develop powerful new quantum-physics-enhanced technologies for the information processing applications of the future.

Nanostructures such as carbon nanotubes and ZnO nano-particles are already being used in commercialproducts such as tyres and sunscreens. However, despite progress in understanding the mechanical andoptical properties of nano-materials we are still at the dawn of the fields of nano-optoelectronics andnano-photonics. Advances in understanding the fundamental materials science of these nano-materials todaywill therefore have a major impact on a wide range of commercial products over the next 30 years. One of thedifficulties with developing nano-optoelectronic components is the complexity of measuring their electricalproperties. Traditionally, new materials and devices have been tested via electrical transport measurements.Unfortunately, it is extremely difficult to make electrical contacts on a 30nm diameter nano-wire or anano-particle. Indeed even if the contacts are made it is then difficult to separate the properties of thenano-material from those of the contact. Additionally, such measurements are plagued by reproducibilityproblems. Thus there is a pressing need for techniques that can quickly and reliably extract the electricalproperties of nano-structured materials. The availability of such techniques would greatly accelerate thedevelopment of new materials and allow devices based on these materials to be brought to the market sooner.We propose to solve these problems by applying the technique of optical pump terahertz probe spectroscopy(OPTPS) to semiconductor nano-wires, and by developing refined models to extract the most importantdevice-specific electrical properties from the measured data. The knowledge we gain will help us develop newoptoelectronic devices based on semiconductor nano-wires.

Conditions experienced during early life can have large impacts on individual fitness. An important source of these early life effects is variation in pre- and postnatal maternal care - hence 'maternal effects', defined as the influence of a mother's phenotype on the phenotype of her offspring over and above the direct effect of genes inherited from her. Variation in maternal effects can be large, at least as large as that due to influences of the environment or of an individual's own genes. However, there are strikingly few investigations of these effects in natural as opposed to laboratory or farm populations and so their importance and evolutionary consequences have not been fully assessed; if these maternal effects are genetic in origin, they could be a major source of constraint in evolution. In this study we will investigate the causes and consequences of maternal effects in the individually-monitored red deer of the Isle of Rum, Scotland. This is a particularly appropriate study population as males play no part in parental care, whilst females produce many calves over long lifetimes. Maternal effects on offspring traits are known to be large in this population; combined with complete pedigree information, high density genotyping data and life history data, this system is an excellent candidate for characterising the magnitude, direction and genomic location of maternal genetic effects on offspring phenotype. Our aims are first, to estimate the variation in a range of traits such as birth weight and juvenile survival that is explained by different kinds of maternal effects: permanent environment effects such as those due to a mother's own rearing conditions and those due to additive genetic variation between mothers (i.e. genetic variation that can respond to directional selection). Second, we will determine the extent to which these maternal effects vary (interact) with the sex of the calf, the reproductive status of the mother, environmental conditions during pregnancy and the mother's age. Generally we expect maternal effects variance to increase as the investment required gets greater (sons more costly than daughters) or the conditions get tougher, but the reverse is also possible. Third, we will use new phenotypes obtained during the project for early milk quality, parasite load and antibody production, estimated non-invasively from faecal and neonatal blood samples, to investigate the extent to which we can explain the maternal effects documented earlier. Fourth, we will use genomic information to investigate the genomic location of maternal genetic effects, first by considering each chromosome in turn (chromosome partitioning), then by considering smaller regions of each chromosome (regional heritability, genome-wide association). The final and ultimate aim of our proposal is to address a major puzzle in evolutionary research. In most cases where it has been measured, natural selection favours larger body size, and most body size traits are heritable, and yet species do not change body size over time. One hypothesis explaining this stasis is that there are constraints arising from the genetics of and selection on mothers. Thus, a mother's genes may affect offspring body size independently of the offspring's genes (maternal additive genetic effect) and there may be a negative genetic correlation between the maternal genetic effect and the offspring's own genetic effect on a trait. Whether this genetic correlation acts as an evolutionary constraint depends critically on the strength and direction of selection on both the offspring trait and maternal performance for this trait. We intend to measure all the parameters required to test the prediction of evolutionary constraint for the first time in a free-living population.