Climate change is predicted to negatively impact global agriculture, and if we are to prevent systemic crop failure, it is urgent to do all we can to better understand crop adaptability and the agriculture management interventions which may be required. While we often think of the impact of climate change for today and the future, prehistoric societies also experienced major variations in the climate. In this project we investigate these past changes using science-based archaeology to understand how ancient farming communities and their crops responded to climate variations. This information about agriculture in the past will help the scientific community better understand the risks we may face and possible responses which may be necessary to manage our agriculture systems. HIDDEN FRONTIERS focuses on past agriculture in the circum-Alpine region. The Alps--and specifically their world-famous prehistoric Alpine pile dwellings--provide the perfect opportunity to evaluate how crops responded to variation in climate. These sites provide three key resources to understand how climate impacts agriculture: - Preservation of plant remains and their DNA. The Alps possess some of Europe's most pristine ancient plant specimens, thanks to underwater preservation at many of the 111 UNESCO-listed pile dwelling sites. These sites, also referred to as the ancient Lake Villages, were settled by farmers between the fifth and first millennia BC, spanning the Neolithic, Bronze Age and Iron Age. The sites were built on wooden piles driven into marshy land, but over time the sites were abandoned and flooded by the lakes upon which they were constructed. Due to the underwater conditions, organic materials are exceptionally well preserved, allowing archaeologists to identify seeds and chaff to infer which crops were farmed in different periods. This project takes the next step, using state-of-the-art methods to recover ancient DNA directly from the remains of species like wheat and flax, and then analyse this DNA to understand a detailed history of crop movement, replacement and adaptation. - Dating. The excellent organic preservation of tree trunks at the pile dwelling sites enables high-resolution dating rarely afforded in prehistoric archaeology. Using "dendrochronology", researchers have carefully characterised patterns of tree ring growth, allowing for the sites to be dated on the scale of decades, which exceed the resolution normally provided by radiocarbon dating. These dates allow this project to link archaeological plant remains into a tight chronology informed by past climate data. - Paleoclimate reconstructions. The circum-Alpine lakes on which the pile dwelling sites were constructed have been carefully studied by climate researchers for decades. Using sediment cores from the lakes, researchers have been able to track local changes in the climate by measuring stable isotopes, identifying pollen types and observing different types of freshwater insects. These detailed reconstructions of past climates allow this project to fully appreciate the environmental conditions under which different crops were grown and evaluate the genetic impact when the climate changed. Through this remarkable combination of resources, HIDDEN FRONTIERS explores the interplay of climate and society to understand the story of Alpine Lake Villages and their food production systems. By analysing ancient DNA from the crops, the team identifies if local crop lineages went extinct during challenging climate phases. In addition, by looking at specific genes in these lineages, we come to understand how quickly crops can adapt and what genes are most responsible for new adaptations. These findings will be instrumental in predicting how our agricultural system may respond to climate change, thereby allowing our society to take the necessary steps to ensure our crops can feed many generations in the future.

Diabetes affects 8% of the world population. When poorly treated, blood sugar levels run dangerously high, which can lead to blindness, kidney failure, limb loss and death. In the UK the NHS spends over £10 billion every year on diabetes care, but we are no closer to a cure. In fact, the incidence of type 2 diabetes (which accounts for >90% cases) continues to rise unabated. Central to the development of diabetes is the failure of beta-cells, which are dispersed throughout the pancreas in the islets of Langerhans. The failing beta-cells are unable to secrete enough insulin to lower blood sugar levels. Crucially, a high prevailing blood sugar will itself further accelerate beta-cell failure in a vicious cycle. A deeper understanding of the molecules that control beta-cell function and survival is essential for the development of better targeted drugs that can prevent, slow down or even reverse beta cell demise and hence effectively treat diabetes. I have spent most of my career studying microRNAs (miRNAs), which are tiny molecules inside cells that have recently been discovered to regulate the genes that are required for a cell to function normally. There are more than 2000 different miRNAs in the human body and all cells, including the beta-cells, need miRNAs to work adequately. It has also been demonstrated that alteration of miRNAs can lead to diabetes. Nevertheless, very little is known about which miRNAs are important for beta-cell function, how they exert their influence and how their actions are controlled. I have now demonstrated that two miRNAs, miR-184 and miR-125b, are closely related to the activity of AMPK. AMPK is an enzyme that helps the beta-cell recognize what the prevailing blood sugar level is and it is vital to their survival and normal functioning. Furthermore, I have demonstrated that these miRNAs themselves go up and down in response to changes in the amount of the sugar. All of this points to AMPK and its related miRNAs as being important potential drug targets for diabetes. In fact, existing diabetes medications are already thought to work in part by modulating AMPK, but our understanding of the exact mechanisms and molecular interactions is patchy, which limits the development of even more effective treatments. In this project I will use state-of-the-art techniques to: 1. Fully elucidate the contribution of miR-184 and miR-125b (and their interactions with AMPK) towards beta-cell function and survival. 2. Show the real-life importance of this in animal models and donated human beta-cells - this is hugely important to ensure that this new knowledge can be potentially translated into highly effective new treatments for diabetes.

Although there have been positive advances in the treatment of malaria, it remains a serious threat to global health, with 619,000 fatalities occurring worldwide (>90% in Africa) in 2021. These facts, combined with a threat of extended geographical malaria transmission due to climate change and increasing parasitic resistance towards available drugs , underline the importance in discovering new anti-malarial therapeutics with novel modes of action. In addition to drug resistance, significant drug attrition in the discovery phases of antimalarial drug development has occurred within the Medicines for Malaria Venture (MMV)'s portfolio over the last 5 years. (MMV is a not-for-profit public-private partnership, founded in 1999, with the mission to reduce the burden of malaria by the development of novel antimalarial drugs.) Malaria is a disease that is transmitted by the bite of the female Anopheles mosquito and is caused by a parasite belonging to Plasmodium genus. One of the challenges in drug treatment of this parasite is its complex life cycle which involves development in the mosquito, and two separate stages of development within the liver and red blood cells of the human host. Finding drug molecules that can target the parasite at all three development stages is the holy grail of antimalarial drug discovery since this will enable an highly effective antimalarial "triple-hit" to be exerted. Recently, two enzymes have been characterised known as Plasmepsins IX and X. These enzymes have been shown to be key to the parasite development in mosquito, blood and liver stages; inhibition of these proteins not only prevents the parasite invading human red blood cells but inhibition of plasmepsin X prevents the parasite from escaping the human red blood cell to continue the infection cycle. Recently, a breakthrough was made that showed a class of drug known as a protease inhibitor can inhibit these enzymes. This class of drug, which are chemically related to the HIV protease inhibitor drugs used for over two decades, have excellent parasite killing activity in test-tube experiments in the laboratory. More recently, one of these prototype drugs was shown to cure mice infected with Plasmodium species demonstrating the potential for development of an oral treatment of malaria infected human patients. Given the broad acting nature of these new parasite inhibitors, medicinal chemists have the opportunity to develop a novel drug with potential for malaria treatment, mosquito transmission blocking and for prevention (also known as chemoprophylaxis). A molecule with such properties would be highly valuable in the clinic. The aim of the research is to improve the prototype inhibitor by chemical modification of the scaffold to increase parasite killing activity as well as increasing drug stability within the human body. Ideally the drug treatment should be capable of curing malaria in a single or three daily doses treatment regimen. The project will use computational modelling, chemical synthesis and biological screening, as well as measurement and modelling of the metabolism of modified drugs to predict the drug exposures in humans. The aim is to obtain a molecule for preclinical profiling en route to a clinical trial in human inside 5 years. The programme is a multinational programme involving researchers in the UK (University of Liverpool, Imperial College, Liverpool School of Tropical Medicine), Italy (University of Milan) and Switzerland (MMV, University of Geneva).

We know that many signals and functions in the body follow a set pattern that repeats everyday (called circadian rhythms). We also know that the timing of this pattern can have an effect on how well our bodies work - for example, shift workers who are active and eat at night when most people are asleep tend to have more health problems such as diabetes and heart disease. Research using mice shows that these repeating patterns depend on the timing of daily events, like sleep, eating and activity. It is important to study humans as well because mice differ from us both in their behaviour and their metabolism - for example, mice are naturally most active at night and at times when food is limited they become even more active, with the chemistry in mouse muscle responding differently to human muscle. Muscles are some of the most important body parts for metabolism and health as they use most of the sugar and fat that we eat and have the capacity to dramatically increase our metabolism by moving around (contracting) - and an active lifestyle help us stay healthy. To prepare for this project, we did a pilot study where we took small pieces of muscle from the thighs of human volunteers every few hours for an entire day and night. We discovered repeating patterns in human muscle, with genetic signals linked to sugar, fat and protein metabolism going up and down every 24 hours. We did this once with people eating in the normal way during the daytime and fasting while asleep at night but also did other studies where we fed people through a tube during sleep - by feeding continuously we removed the acute responses to mealtimes and so could see the underlying rhythms in metabolism, and how they were affected by nutrient availability. Now that we have seen these patterns in genetic signals, our proven method of collecting human muscle samples for 24 hours whilst feeding continuously (even at night) can be used to study whether those signals actually change how our muscles use carbohydrate and protein over time. We will also be able to find out whether these rhythms in metabolism depend of whether and when the muscle contracts (by asking people to move around at different times of day). To study cause and effect we will use an experiment where volunteers are randomly divided into three groups: one group will rest for 24 hours, one group will be more active in the morning and the final group will be more active in the evening. We will then be able to see the pattern of metabolism in human muscle for the first time and can compare the muscle samples between the groups to learn about how rhythms in chemical processes are affected by muscle contraction. As an extra follow-up question, the volunteers will also then continue with their prescribed pattern of rest and activity for two weeks as part of their normal lives, just so we can explore how their muscles and health change in that time. Our prediction is that there will be clear 24-h rhythms in muscle metabolism, with more carbohydrate and protein taken into muscle to be used or stored earlier in the day. We also think that muscle contractions in the morning will be especially important in driving these rhythmic differences in metabolism over the course of a day. This research will provide the first information about changes in how our muscles use carbohydrate and protein over time and in relation to our activity patterns. This will improve understanding of how and why daily patterns as sleep, activity, diet and medications can be used to improve human health.

Summary:The smooth operation and growth of modern economies is increasingly dependant on memory and data storage. Consequently, technological advancement in this area is of great significance for all of us. A variety of possible future memory technologies are now being driven forward. Amongst these are systems based on ferroelectric capacitors (FeRAM), where the ferroelectric material has the important property that it can be electrically polarised into two possible states. If one state can be read as a '0' then the other state will be a '1' in the conventional binary code that is still used for storing data. FeRAM is comparable to or potentially better than all other computer memory technologies in performance, and in addition has the very strong advantage of being 'non-volatile' - in other words when you switch off the power to your computer, the data that you forgot to save will not be lost.However, FeRAM is a still-maturing technology. Despite 2002 being seen as a coming of age , it will need further development if it is to take over from the mainstream established Si-based systems. It is against this technological backdrop that the applicants seek to embark upon a highly adventurous programme, unlike any that are currently being reported in the global community. We propose a study focusing on two issues: the fabrication of nano-scale (below 100x10^(-9) m) capacitors through self assembly techniques (the capacitors form themselves and are therefore very cheap to make), and the investigation of the functional properties of the resulting nanoscale ferroelectric architectures (the properties of such small ferroelectric units are not well known).Self-assembly of capacitor structures:A novel and attractive way to create both high cell-density and ease in production is to capitalise on self-assembly of nanometre-scale capacitor structures. One of the members of the research team has pioneered work in this field examining the self-assembly of top electrode material on a continuous film of ferroelectric, but other approaches have been to create islands of ferroelectric material on a continuous lower layer. The field is, however, only in its infancy. We propose to take forward the self-assembly of capacitor structures by using a technique developed by our research group in which functionally active materials are deposited onto Si wafers coated in a thin film of porous aluminium oxide (where the pore size is in the nanometre scale range). Key advantages of this technique are that the resulting capacitor structures will be electrically isolated from each other, and their architectures will strongly mirror those used in FeRAM devices currently in production.Evaluation of size-effects in nanometre-scale capacitors: Ferroelectricity is a collective phenomenon - it is only stable if a region of ferroelectric is electrically polarised in the same direction. Hence when the ferroelectric units are made to be small, size-effects on functional behaviour are fully expected. Although considerable exploratory work has been done in the area of size-effects on the functional properties of ferroelectrics, there is still a great deal that is unknown about ferroelectric behaviour at radically reduced dimensions. Reduction of capacitor cell size into the nanometre regime is largely a journey into the unknown. Capacitor cells in ferroelectric computer memory of 0.26 square microns should be realised by 2007, and in the longer term this will reduce to 0.0075 square microns by 2017. Our proposed research project will allow us to create capacitors of the size envisioned in 2017 now, allowing evaluation of the underlying physics of size effects that will influence devices and technology in general far into the future.