Our gut is full of billions of bacteria; whilst some may be harmful, many of these live there without problem, and actually perform important roles in keeping us healthy. Some of these 'good' gut bacteria in fact appear to act to stop other bacteria that could cause harmful gut infections from growing within the gut. Whilst antibiotics help us overcome chest, urine and other infections, doctors now realise that an unintended effect of their use is that they may also destroy some of the gut's 'good' bacteria, meaning that we lose the benefit of their protective roles. One example of this occurs in Clostridium difficile infection (CDI). Clostridium difficile is a form of bacteria that can grow within the human gut and cause disease ranging from mild diarrhoea up to severe bowel inflammation and even death. CDI is responsible for many hospital admissions and deaths worldwide every year. Whilst this infection rarely happens in healthy people, it occurs much more frequently in people who have had recent antibiotics. Doctors believe that this is because antibiotics destroy the 'good' bacteria in the gut that protect against CDI, and therefore allows Clostridium difficile bacteria to grow within the gut and cause disease. However, exactly which beneficial bacteria they destroy - and how these bacteria protect us normally - is not properly understood. CDI is becoming more difficult to treat; the main reason for this is that the usual antibiotics used as treatment do not work as well as they used to. One unusual treatment that has been recently introduced is faecal microbiota transplantation (FMT), i.e. taking faeces from a healthy person (containing normal healthy gut bacteria), processing this in a laboratory to create a liquid suspension, and delivering this (via a tube up the nose and into the stomach, or via a colonoscopy) into the gut of people with CDI. Trials show that this appears to be a much more effective treatment for recurrent CDI than conventional antibiotic treatment. However, FMT is not without drawbacks; for instance, it may be unpleasant for a person with CDI to receive this, it can be difficult to administer, and there is a theoretical risk of transmitting infections from the donor to the recipient. Furthermore, exactly which 'good' bacteria in the transplant lead to treatment of CDI (and the means by which they do this) is still unknown. We intend to identify which 'good' bacteria are killed by antibiotics with CDI; in addition, we will find which bacteria replaced into the gut by FMT cause people to get better from the infection, and how they do this. Recent research shows that certain components of bile (a liquid made by our livers and secreted into our guts) help Clostridium difficile grow under the microscope, whilst other components prevent it growing. Based on this, we suspect that FMT may work by replacing the gut bacteria that produce enzymes that alter the composition of bile (called bile salt hydrolases (BSH)). We think that FMT restoring BSH-producing bacteria may result in an increase in bile components that stop C. difficile growing, and reduction in those that help the bacteria divide. To investigate this, we will take samples from healthy people and those with CDI (both pre- and post-FMT, both from people where FMT has worked and where it has not) to compare which bacteria and which bile components are present in the gut in these different situations, and to investigate how much BSH enzyme is present in all cases. We will then test adding bacteria that produce BSH to a simulated model of a gut suffering from CDI, to see if this is as effective as FMT, and also assess how these bacteria affect C difficile's survival. If our data support this hypothesis, we may in the future be able to move on from FMT and instead treat CDI (or people at risk of the condition) by giving a drink or pill specifically containing bacteria that produce BSH, or that just contain BSH alone.

The behaviour of natural systems at ultra-low temperatures and at very small length scales is governed by quantum mechanics. Natural phenomena of super massive objects at astronomical length scales is governed by general relativity. Both regimes of physical laws come together in relativistic quantum mechanics which helps us understand the formation of elementary particles and fundamental forces in the Universe. This theory is widely known as the standard model, abbreviated SM, of particle physics. It has been highly successful in proving experimental observations made in large accelerators and colliders. Our programme proposes a model laboratory system to probe a variety of phenomena related to the standard model, while offering a surprising added benefit. The second lightest element, helium, is liquid at the lowest temperature due to the quantum wave-particle duality of helium atoms. At millikelvin temperatures, it undergoes a transition to a phase in which it flows without friction or viscosity, a manifestation of a quantum phenomenon on a macroscopic scale. This "superfluid" of the lighter isotope(helium-3) is is an unconventional superfluid exhibiting various complex phenomena related to fundamental symmetries and serves as a model system. The complex symmetry of the early universe corresponds to the rich symmetry structure of superfluid helium-3 which thus serves as a laboratory cosmological analogue. The equations that govern what happens at the boundaries of confining surfaces of superfluid helium-3 are mathematically similar to equations of motion of particles that are currently not included in this standard model. We propose to investigate the nature and behaviour of such superfluid surface states. This could reveal clues on any extensions of the standard model, often referred to as SM+. We plan to design a device to study superfluid surface states, in collaboration with the University of Alberta, Edmonton, Canada. The helium-3 group at the University of Alberta is the biggest expert enterprise in superfluid helium-3 in Canada and a global leader in this field. The aim is to collaborate and develop the specifications of a programme that will most sensitively probe this SM+ physics. We envisage this device to be a hybrid superconducting superfluid device that could also, fascinatingly, serve as an analogue of a superconducting quantum circuit. These circuits form the building elements of quantum computers. An enormous research effort is ongoing in academia and industry to develop insights into errors in quantum computers and methods to mitigate them. Our proposal will contribute to this endeavour and potentially advance the design of a novel superfluid platform for quantum computing. We will develop this facet of the programme with special expert groups at Northwestern University, USA. Northwestern is involved in a nationwide USA network advancing Quantum Information Science. They will provide key input to our quantum computing direction. The Quantum Fluids group at Northwestern is deeply entrenched in superfluid helium-3 expertise. They will work with us providing insight into the workings of the superfluid in this device. Our proposal synergises theory and experiment, bringing together world-leading expertise to materialise our multi-faceted vision. The proposed programme is motivated by the accessibility to test cosmological ideas through the ability to perform controlled experiments on superfluid helium. We twin this with an impact on quantum technology through designing experiments, in parallel, to reveal insights into the working of quantum computers.

STFC: Samuel D. Walton: 2062533 Near-Earth space holds two major surprises that scientists are yet to understand, one of which is the Van Allen Radiation Belts. As an astrophysical object, the Earth's magnetosphere would seem to be a rather small and insignificant item bathed by the wind that emanates from the Sun. However, this space contains an exotic zoo of high energy particles and electromagnetic waves that pose a significant hazard to space exploration. In the solar wind, the Earth's magnetic field is altered such that its bar magnet field becomes a bullet-shaped cavity that shields the Earth from the harmful output from the Sun. Only in specific circumstances can the solar wind penetrate this shield, and it is under these circumstances that the Earth's space environment becomes the most interesting and dynamic. The Earth's Radiation Belts were discovered by James Van Allen some 50 years ago quite by chance. These belts are doughnut-shaped regions of high-energy particle radiation trapped by Earth's magnetic field. These electrons are energised to significant fractions of the speed of light but as yet, scientists can offer no definitive explanation for how they are accelerated to such high energies. Since the discovery of the radiation belts, scientists have linked the acceleration and resultant loss of these electrons to the impact of large geomagnetic storms caused by explosive output from the Sun (such as Coronal Mass Ejections) on near-Earth space. However, no conclusive evidence has been put forward which can adequately explain this link. Understanding how these electrons are accelerated to very high energies (and then lost) is of critical importance to the exploitation of near-Earth space for human and technological gain. Most communication and military satellites must orbit through this harsh radiation environment. In fact, several satellite failures have been attributed to component failure during geomagnetic storms. It is essential, therefore, to monitor this "space weather" in order to protect the multi-billion pound space industry. This placement will be taken by Samuel Walton under the guidance of Professor Ian Mann, and will focus on the energetic electron dynamics in the Van Allen Radiation Belts from a long-lasting NASA spacecraft mission and, coupled with another NASA mission, be able to understand the dynamics of the radiation belts from the relative safety of low-earth orbit using novel techniques developed at the University of Alberta. The proposed project is therefore the natural culmination of methods and ideas developed separately in the UK and Canada, to advance our understanding of Van Allen radiation belt dynamics, improving current models and ultimately improving our ability to predict the behaviour.

Antibiotics are life-saving treatments for bacterial infections, but there may be (collateral damage) with overuse upon the gut microbiome (i.e. the billions of microorganisms within the gut). Specifically, any associated loss of (beneficial) commensal gut bacteria results in loss of their ability to protect against disease-causing (pathogenic) bacteria causing gut infections, e.g. Clostridioides difficile infection (CDI). Similarly, recurrent antimicrobials (select out) gut bacteria with antimicrobial resistance (AMR), increasing vulnerability to the presence of intestinal multidrug resistant organisms (MDROs). Currently, we have limited therapeutic strategies to minimise this problem; however, one approach to restore the antibiotic-damaged microbiome is faecal microbiota transplant (FMT; stool microbiome transfer from healthy screened donor into a patient). FMT is an established treatment for CDI, and shows promise in patients colonised with (carriers of) intestinal MDROs. However, we do not fully understand how antibiotics produce these (side effects), and have limited knowledge about mechanisms of action of FMT, although the more donor microbiome engrafting (taking hold) within the recipient, the more likely success. Better understanding of how antibiotics and FMT impact the gut microbiome to respectively increase vulnerability to/ protect against (antibiotic-associated infections) - including factors influencing FMT's engraftment - could be exploited to develop more effective (microbiome therapeutics). One mediator of FMT's effectiveness are metabolites (small chemical molecules). My research demonstrates that patients with an antibiotic-damaged gut microbiome have alterations in various lipid (fat-related) gut metabolites related to the microbiome compared to healthy people, and these are restored (to normal) by FMT. This includes a post-FMT reduction in certain lipids containing sulfate groups, including a group called sulfatides. Further research demonstrates that FMT restores 'beneficial' bacteria possessing (sulfatase) enzymes (which remove the sulfate group from gut lipids, as well as molecules on our own (host cells called glycans); FMT also restores bacterial enzymes that chemically alter glycans. This is interesting, as sulfatides and sulfated glycans - but not desulfated versions - are associated with gut colonisation of disease-associated bacteria or common MDROs (such as C. difficile, E. coli and K. pneumoniae), and binding of their toxins (poisons), enabling them to attack the gut. I hypothesise that antibiotics causes loss of beneficial gut bacteria (containing sulfatases and glycan-altering enzymes) which protect against gut colonisation with pathogenic bacteria and their toxins; successful FMT reverses this and restores engraftment with these beneficial bacteria instead.

NERC : Rory Burford : NE/R011524/1 Simple description of research: We are investigating the source of dissolved organic matter (or DOM) - a class of nutrients known to fertilise aquatic ecosystems - in two glacial rivers in Canada (one in the Rockies and one in the Arctic). DOM is a very diverse group of different molecules, and some of these molecules are better food for bacteria (heterotrophs) than others. In our experiments, we will look at the molecular composition of DOM in water samples and we will measure how much of this DOM is able to be consumed by bacteria (its bioavailability). By comparing different water samples, we should be able to work out which groups of molecules (that tend to appear together) are most important to downstream ecosystems. We will also measure certain isotopes (rare forms of chemical elements) in our samples. When chemicals undergo certain transformations (e.g. inside of cells), chemicals containing these rare isotopes may be more or less likely to be transformed than chemicals containing common isotopes. This means, for instance, that if we start with a group of chemicals where 1% are rare isotopes, and half of them are transformed into new chemicals, then the proportion of rare isotopes in these new chemicals may be more or less than the original 1%. We can therefore use isotopic ratios to understand which processes a particular group of molecules has been through in order to reach that form. In this case, we can use isotopes of carbon and nitrogen to understand where the bioavailable dissolved organic matter is coming from. We will then use a form of radiocarbon dating to measure the age of carbon dioxide that is respired (given out) when bacteria consume DOM in our samples. This will tell us how old the bioavailable DOM molecules were before they were consumed by bacteria. This information is again useful to know when trying to work out the source of bioavailable DOM. For instance, if the DOM comes from tiny particles in the air released by burning fossil fuels (coal, oil and gas), then we would expect it to be very old (because fossil fuels are formed from prehistoric plants). In addition, there is a biological component to our plans. We will analyse a particular kind of genetic material (16S ribosomal RNA) in our natural samples and our incubation experiments. This rRNA is present in all living cells and is very conserved (i.e. it's very similar in closely related species) because of its importance. By analysing all of the rRNA in a natural sample, we can get an idea of the entire community of aquatic microbes. If some samples contain DOM that favours one group of cells over another, then we should be able to see this in the 16S rRNA composition of the water. This allows us to link water chemistry - the quantity and quality of DOM - with tangible biological impacts. Lastly, we will compare the results with those from different regions (e.g. the Himalaya and the Andes) to see whether or not the same key groups of molecules are found across the world; if not, this indicates that the main source of bioavailable DOM varies between different regions.