Understanding how the brain processes and transmits information is one the fundamental challenges for current basic and medical research. Recent evidence suggests two broad classes of processes can be distinguished that seem to support different functions and are characterized by distinct biological correlates: 1) a "feedforward" mode that transmits information based upon the characteristics of the incoming stimulus and 2) a "feedback" mode that is governed by the internal activity of the brain, such as expectations and predictions about events. This distinction may be fundamental for gaining novel insights into how the brain operates under normal circumstances and how changes in these two different modes may contribute to psychiatric disorders, such as schizophrenia (ScZ). Until now, distinguishing these different brain modes using non-invasive brain imaging, such as functional magnetic resonance imaging (fMRI) or Magnetoencephalography (MEG), has been challenging. However, novel evidence from basic anatomy and biology has suggested that distinct brain waves at different frequencies as well as particular brain layers may support these different brain modes. As a result, we will attempt for the first time to identify these brain modes through using state-of-the-art brain imaging and thus gain a new understanding of how the brain transmits information and how these processes might contribute to ScZ. In the first part of the project, we will present healthy volunteers sequences of sounds while they watch a movie. During this task, we measure their brain waves with a MEG-machine. In particular, we are interested in finding out whether changes in rhythms of neural activity, so-called "oscillations", may be influenced by the presence of sounds that deviate in duration. In particular, we aim to show that the flow of these oscillations between brain regions will change depending on whether a sound is different or not. The MEG-recordings will be accompanied by fMRI-measurements at 7 Tesla. In contrast to the majority of fMRI-research which is carried out with a field strength of 3 Tesla, we expect that fMRI-recordings at 7 Tesla reveal novel details about brain activity that cannot be observed with conventional fMRI-machines. In particular, based on our prior work in this area, we expect that we can observe brain activity in different layers which may be crucial for gaining new insights into how the brain uses different channels to communicate. Based on these new insights, we will then apply this framework to understand changes in brain activity in ScZ-patients and young people who are at high-risk for developing the disorder. ScZ is a common mental disorder which is associated with a range of complaints, including hallucinations and delusions. These symptoms of psychosis are accompanied by pronounced impairments in perception and cognition. A better understanding of cognitive deficits is particularly important because current treatments are unable to improve perception and memory functions which result in difficulties of patients' to organize their lives and maintain employment. We expect that our ability to distinguish different brain modes will allow us to identify the cause of patients' difficulties in perceiving the world and their problems in organizing their thoughts. Specifically, we will identify whether the problem for patients with ScZ is to register the information coming into the brain or whether their problems lies more in controlling their thoughts and perceptions through prior assumptions which are generated in higher brain areas. As a result, we expect that in addition to identifying the causes of ScZ, this approach may be relevant for novel therapies and early detection and diagnosis as it could inform whether therapies should focus on improving the ability to perceive auditory and visual information as opposed to focussing on the assumptions and thoughts about the world a patient may have.

What is the link between blood clotting and liver disease? Liver disease is common and is now the largest cause of death in adults aged 30 to 59 years of age. Two serious complications of liver disease are bleeding and blood clots (thrombosis). Bleeding affects up to 1 in 10 adults with liver disease per year and blood clots up to 1 in 20 adults with liver disease per year. Most bleeding is due to pressure changes in the blood vessels in the abdomen leading to swelling of veins around the oesophagus (called varices). What is known about blood clotting in liver disease? The liver produces many of the substances involved in blood clotting, and patients with liver disease often have marked abnormalities in blood clotting measured with routinely available tests. This is because routinely available tests only measure the effect of proteins which increase blood clotting (pro-coagulants). In liver disease, the proteins which reduce blood clotting (anti-coagulants) are also reduced and overall, clotting is thought to be 'rebalanced'. Specialist tests (thrombin generation and thromboelastography) which are able to measure either the effect of the body's anti-coagulants or blood cells demonstrate that clotting is actually normal or increased in most patients with liver disease. Why are blood tests to measure blood clotting in liver disease important? Current routine tests are poor at predicting bleeding and clotting complications in patients with liver disease. Because the blood clotting tests in patients with liver disease look abnormal, treatments like transfusion of plasma (blood clotting proteins), platelets (small cells important for blood clotting) or fibrinogen (the final protein needed for blood clot formation) may be given to try and improve the blood test results, even though this might not reduce the risk of bleeding. In patients who are bleeding, the treatment approach is based on studies in different patient groups such as trauma where plasma transfusion has been shown to improve outcomes. In liver disease, studies show treatment with plasma can worsen bleeding from varices by increasing the pressure in the veins. Patients with liver disease are also at increased risk of thrombosis; most patients in hospital are given medications to reduce the risk of thrombosis ('blood thinners' or anticoagulants) but due to the changes seen on routine laboratory tests, doctors sometimes worry these medications might increase the risk of bleeding. Balancing the risks of bleeding and thrombosis and deciding which blood test results should be treated can be very difficult. This is particularly important in seriously ill patients as they are at higher risk of bleeding and thrombosis, and often need multiple procedures. What will I do? I will look at specialist blood tests (thrombin generation, thromboelastography, neutrophil extracellular traps) in patients with liver disease admitted to intensive care to see whether these tests could be used routinely to guide the need for transfusion and predict the risk of bleeding or thrombosis. I will also look at whether these tests remain the same over time and how transfusion changes the results. Why is this research important? As current tests are not helpful, many patients get transfusions when they probably don't need to. This is wasteful, costly and puts patients at risk of side effects. This is important both for patients with liver disease and bleeding (4000/year) and those having procedures/operations. Better tests will reassure doctors when transfusion is not needed and will improve management of bleeding complications and prevention of thrombosis in hospital.

Antibiotics revolutionized modern medicine, but these 'wonder' drugs are under threat due to the rapid emergence of antimicrobial resistant bacterial strains that no longer respond to standard antibiotic treatment. This endangers current standard procedures, such as major surgery, cancer therapy and organ transplantation. Monitoring these resistant strains is key to combating them. In this proposal, we will produce a biosensor for the detection of bacteria, particularly those with antimicrobial resistance. In a simple and low-cost manner, we can rapidly identify the source of bacterial infection to enable clinicians to develop a personalized treatment plan that will benefit patients' care. In addition, we will expand this to an array format for the simultaneous detection of bacteria and antibiotics, which can serve to screen (food) samples for antibiotic residues and will provide valuable insight into how bacteria develop AMR properties. We will use a technique called molecular imprinting for producing the sensor platform. These Molecularly Imprinted Polymers (MIPs) are often referred to as "plastic" antibodies. These materials have a porous structure, with high affinity binding sites for their target molecule. Their advantages over "natural" antibodies include low-cost, straightforward preparation, robustness, and ability to work in extreme environments (pH, adverse temperatures and organic solvents). Prior work in the PI's group has shown that binding of targets to imprinted polymers can alter the conduction of heat through the polymer essentially blocking heat-flow. This can lead to a temperature differential which can be measured by a thermal sensor (thermocouple device). This change in heat-flow is dependent on target concentration. This method, patented as the Heat-Transfer Method (HTM), has only been studied with MIP microstructures. In this proposal, we will take a novel electrochemical approach to develop MIP nanolayers that will increase the sensitivity of the developed sensor platform. This project consists of the following steps: (a) Use of electrochemical methods to prepare MIP sensors. We will prepare nanometre thick bacterial imprinted layers functionalised onto electrodes from five different monomers, which have been identified from literature databases to bind bacteria. Using HTM it will be determined which monomer has the highest potential to bind a particular bacterial strain allowing us to optimise the MIP. A series of medically relevant targets (including Staphylococcus aureus strains, some of which exhibit antimicrobial resistance) will be measured and the sensor performance will be optimised in terms of time, selectivity and affinity. (b) Thermal measurements of bacterial in buffered solutions We will perform thermal measurements with the MIP sensors (library of six bacteria) to evaluate the bacterial loads in buffered solutions. These measurements will be validated against current gold-standard techniques (ELISA, genotyping) to determine the accuracy and precision of the developed thermal sensing strategy. (c) Thermal measurements of "complex" samples Clinical or food samples are complex matrices - we will evaluate if we can selectively detect certain bacterial strains in the presence of an excess of other (harmless) bacteria. Finally, we will explore if we can transform this sensor into an array format for the simultaneous detection of bacteria and antibiotics, by integrating MIPs specific for antibiotic compounds. This proposal will build the research portfolio of the PI, establish her independence, and lay the foundation of a multidisciplinary and exciting research programme. A project partner at Maastricht will provide advice on thermal measurements and serve for knowledge exchange visits. The developed sensor platform has commercial potential due to its low-cost and simplicity and the PI will explore its this during the project timeline.

Antibiotics revolutionized modern medicine, but these 'wonder' drugs are under threat due to the rapid emergence of antimicrobial resistant bacterial strains that no longer respond to standard antibiotic treatment. This endangers current standard procedures, such as major surgery, cancer therapy and organ transplantation. Monitoring these resistant strains is key to combating them. In this proposal, we will produce a biosensor for the detection of bacteria, particularly those with antimicrobial resistance. In a simple and low-cost manner, we can rapidly identify the source of bacterial infection to enable clinicians to develop a personalized treatment plan that will benefit patients' care. In addition, we will expand this to an array format for the simultaneous detection of bacteria and antibiotics, which can serve to screen (food) samples for antibiotic residues and will provide valuable insight into how bacteria develop AMR properties. We will use a technique called molecular imprinting for producing the sensor platform. These Molecularly Imprinted Polymers (MIPs) are often referred to as "plastic" antibodies. These materials have a porous structure, with high affinity binding sites for their target molecule. Their advantages over "natural" antibodies include low-cost, straightforward preparation, robustness, and ability to work in extreme environments (pH, adverse temperatures and organic solvents). Prior work in the PI's group has shown that binding of targets to imprinted polymers can alter the conduction of heat through the polymer essentially blocking heat-flow. This can lead to a temperature differential which can be measured by a thermal sensor (thermocouple device). This change in heat-flow is dependent on target concentration. This method, patented as the Heat-Transfer Method (HTM), has only been studied with MIP microstructures. In this proposal, we will take a novel electrochemical approach to develop MIP nanolayers that will increase the sensitivity of the developed sensor platform. This project consists of the following steps: (a) Use of electrochemical methods to prepare MIP sensors. We will prepare nanometre thick bacterial imprinted layers functionalised onto electrodes from five different monomers, which have been identified from literature databases to bind bacteria. Using HTM it will be determined which monomer has the highest potential to bind a particular bacterial strain allowing us to optimise the MIP. A series of medically relevant targets (including Staphylococcus aureus strains, some of which exhibit antimicrobial resistance) will be measured and the sensor performance will be optimised in terms of time, selectivity and affinity. (b) Thermal measurements of bacterial in buffered solutions We will perform thermal measurements with the MIP sensors (library of six bacteria) to evaluate the bacterial loads in buffered solutions. These measurements will be validated against current gold-standard techniques (ELISA, genotyping) to determine the accuracy and precision of the developed thermal sensing strategy. (c) Thermal measurements of "complex" samples Clinical or food samples are complex matrices - we will evaluate if we can selectively detect certain bacterial strains in the presence of an excess of other (harmless) bacteria. Finally, we will explore if we can transform this sensor into an array format for the simultaneous detection of bacteria and antibiotics, by integrating MIPs specific for antibiotic compounds. This proposal will build the research portfolio of the PI, establish her independence, and lay the foundation of a multidisciplinary and exciting research programme. A project partner at Maastricht will provide advice on thermal measurements and serve for knowledge exchange visits. The developed sensor platform has commercial potential due to its low-cost and simplicity and the PI will explore its this during the project timeline.

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.