It is now widely accepted that the "golden age" of antibiotics has passed, and that antimicrobial resistance (also known as "AMR") is on the rise. One extremely useful tool in the fight to understand AMR has been whole genome sequencing, in which the entire genetic "blueprint" of an organism can be elucidated. Using whole genome sequencing, researchers have found that mutations in certain genes are strongly associated with AMR. FusA1 is one such gene, and mutations in fusA1 are now recognized as being responsible for high level resistance to an important class of antibiotics called aminoglycosides. More worryingly, these mutations are particularly prevalent in an organism called Pseudomonas aeruginosa (hereafter, PA), which is ubiquitous in the built environment and is a major cause of potentially life threatening infections, especially in people who are less well able to fight such infections. The problem is that we currently have little idea about why mutations in fusA1 lead to AMR, and without this understanding, there is little we can do about this. FusA1 encodes a protein involved in making other proteins; a process called "translation". Here, mini-factories known as ribosomes "translate" the information coded in a molecule called messenger RNA (which itself, is copied from the DNA blueprint) to make all the proteins needed in the cell. The function of FusA1 is to help the ribosomes to "drop off" the RNA once they have made each new protein, or if they encounter a "stall signal". Ribosomal pausing at most stall sites is usually easily overcome if the FusA1 is functioning normally. However, based on our preliminary experiments, we suspect that the ability of mutant forms of FusA1 to facilitate this "ribosome recycling" reaction may be altered, thereby changing the dynamics of translation. For example, if dissociation of ribosomes from key "stall sites" or stop signals is even slightly impaired, ribosomes will start to queue-up at such sites, affecting the translation of the protein encoded on the messenger RNA. If that protein was itself associated (either directly or indirectly) with aminoglycoside resistance, this would provide a tangible link between the mutation in fusA1 and the AMR phenotype - a hypothesis that we are very keen on exploring using state-of-the-art approaches called RNA-seq, Ribo-seq and ChIP-seq. We also suspect that mutations in fusA1 might alter its ability to bind to other molecules in the cell, including other proteins or non-messenger RNA. Cutting-edge technological developments mean that we can now investigate these hypotheses directly using specialized "proteomic" approaches called TurboID and "OOPS", respectively. To increase the probability of success, these approaches will be carried out in collaboration with world leaders in their respective disciplines. By the end of this project, we will have a clear idea about how mutations in fusA1 lead to aminoglycoside resistance. This "mechanistic" understanding will be critical if we want to find better ways of combatting AMR, or of better predicting the AMR phenotype of a strain based on its whole genome sequence (an approach that, with ever-cheaper and faster sequencing, is likely to become widespread in the clinic in the near future). Excitingly, our preliminary data indicate that in principle, it is possible to reverse the AMR associated with fusA1 mutations, offering a line-of-sight - albeit, beyond the scope of the current proposal - towards resensitizing resistant PA to aminoglycoside antibiotics.

When confronted with the task of controlling a physical degree of freedom, observations and adjustments based on such observations are a most natural way to proceed. This is the basic idea behind the notion of feedback control, one of the standard paradigms of control engineering. If applied to systems subject to continuous noise, feedback control loops driven by continuous monitoring often allow one to cancel the effect of noise and to stabilise the system in a desirable configuration, up to a certain precision. Such powerful control routines are well established for macroscopic objects, obeying the laws of classical mechanics. However, it is becoming more and more desirable to extend the application of feedback control to microscopic degrees of freedom, governed by quantum mechanics. Due to the fundamentally probabilistic character of quantum mechanics, the observation of quantum objects typically results in a distribution of probabilistic outcomes, which manifests itself as additional noise (technically referred to as measurement back-action). This feature makes the theory of quantum feedback control, whereby quantum degrees of freedom are monitored and steered to desired states, rather more complex than its classical counterpart. Yet, the design and implementation of quantum feedback control schemes would be most timely and welcome, given the current struggle to achieve coherent manipulations for application in nano- and quantum technologies. The main obstacle standing in the way of exploitable quantum computation is still the problem of engineering multipartite microscopic systems where the interactions between the controlled subsystems are enhanced, while the unwanted interaction with their environment is suppressed. Feedback control schemes would offer an active way to suppress the effect of such environmental noise, with the possibility of stabilising the systems in quantum states useful as resources for quantum information processing. Recent advances in cooling, trapping and manifacturing techniques are bringing more and more degrees of freedom into the quantum regime. Among such degrees of freedom the family of cavity opto-mechanical systems, where resonating light is coupled to a micro- or nano-scopic mechanical oscillator, stand out for their interest in sensing, quantum information processing and as probes of the quantum to classical boundary (as they include massive oscillators of varying size). In particular, a new generation of such systems recently emerged where the mechanical oscillator is not clamped to a substrate but is instead a levitating bead, trapped by optical means. These set-ups are particularly promising because they are not influenced by the thermal fluctuations of a substratum. Still, because of their relatively low frequencies, which set much more stringent cooling requirements, they have not yet entered a fully quantum regime, where coherent, pure quantum states can be manipulated and observed. They would hence benefit greatly from the development of bespoke feedback control techniques. Our research project is aimed at the design and implementation of feedback schemes for the cooling and quantum control of opto-mechanical systems, and in particular for the levitated bead set-ups at University College London and at the University of Vienna (project partner). We intend to achieve ground state cooling as well as squeezed states (states where the uncertainty on position is below the uncertainty of the ground state, of relevance to quantum metrology), as well as non-classical superpositions (Schroedinger cats) of the levitated beads.

Major breakthroughs in information technologies over the past 50 years have relied heavily on knowledge of electronic processes, utilisation of magnetic states (such as giant magnetoresistance read heads for hard drives) and usage of lasers (e.g., CDs and fibre optics). Today, information technologies are ubiquitous, allowing us to solve more and more complex computational problems than ever. Nowadays, a key concern is to improve the efficiency of digital devices, coupled with miniaturisation and increased processing speed, as the increase in computational power and data density comes at high costs with respect to energy consumption. This is made worse by the fact that - rather than being used in an effective way - a sizeable fraction of electricity used to drive modern chips gets dissipated as heat, which can have negative effects on device performance and data retention. However, heat itself is not bad, and particularly interesting phenomena potentially useful for future computational devices, occur in situations where the temperature distribution is not uniform, e.g., if one side of a device is hot while its opposite side is cold. In combination with magnetic materials, such heat differentials can be used to (i) generate electricity, (ii) move spin structures that encode information bits, or (iii) enhance unconventional computing schemes by their intrinsic stochasticity. To date, our experimental understanding of these effects, and their effective integration into devices is hampered by the fact that contemporary methods to create heat differentials lack the flexibility to be suitable for miniaturised technological applications, as they are slow and have large spatial extension, can be prone to damage, and - most importantly - are not reconfigurable. Taking inspiration from the field of photonics and functional magnetic materials, here I will implement a hybrid approach for novel magneto-thermoplasmonic devices: The main objective of the Fellowship is to develop a novel experimental platform enabling fast, precise, and reconfigurable optical control of nano- to microscale temperature distributions by light for key magnetic and spintronic applications. Specific aims are to (i) create fast and optically reconfigurable spin current generators, (ii) experimentally quantify the thermally driven motion of spin textures to further our understanding of fundamental phenomena, and (iii) use light as a flexible and high-bandwidth input for unconventional nanomagnetic computation schemes. The research outputs generated with the Fellowship will tackle fundamental questions regarding non-equilibrium behaviour of magnetic materials, and the newly developed magneto-thermoplasmonic platform will generate impact on the areas of spintronics, optically reconfigurable metamaterials, and energy.

Between the fourth and the sixth centuries exile was a legal sanction frequently used by Roman emperors and the rulers of the post-Roman successor states against dissident Christian clerics. This project seeks to test the hypothesis that such exile proved to be not only a form of punishment, but also, and more importantly, a form of cultural encounter. Clerics in exile spread their ideas at places where they had previously been unknown. They also absorbed influences from their new environment and, in the case of recall from exile, transferred ideas and experiences elsewhere. This process, the project contends, had a profound impact on the development of Christianity and its foundational texts in this period, which are still noticeable today. For example, the Nicene creed, which most of modern Christian denominations subscribe to, may not have had the same impact without the banishment of its original supporters during the fourth century. In order to prove its hypothesis, the project adopts an interdisciplinary approach with an innovative methodology. It is a collaboration between Dr Julia Hillner (Sheffield, PI), a legal historian, and two international co-investigators, Prof Jörg Ulrich (Halle), a theologian, and Associate Prof Jakob Engberg (Aarhus), a cultural historian. While both the development of Christian theology and ritual in this period and the legal development of the Roman penalty of exile have been extensively studied, the two have not been brought together before. The project seeks to rectify this gap in scholarship by re-invigorating traditional legal and theological studies that have typically concentrated on normative sources through the application of a digital approach that will help to set these sources in context. To this end, the project includes the construction of a relational database that collects all available information on individual clerical exiles. The data will be derived from printed and online source editions and we anticipate a dataset comprising records for approximately 1,000 individuals. This will allow the project team to trace and visualise the personal and geographical networks clerical exiles developed and maintained from their place of banishment and after return from exile. The quantitative information will provide the basis for a thorough qualitative re-assessment of selected legal, theological and hagiographical texts of the period (also available in edited form), which will be investigated in the light of the networks of their authors and audiences. This part of the project will seek to establish the influence of exile experiences on the formation of Christian law, Christian doctrine and Christian cult in late antiquity. In short, the project involves a long-term study of exile that focuses on social networks of individual clerics and interprets institutional texts and structures not according to a top-down model of change, but as a result of relations among individuals, facilitated by exile, within a decentralised framework, in which every element of the network contributed to shape institutional developments. The results of the project will be disseminated via a book co-authored by the PI, the Co-Is and the research associate of the project, and via a doctoral dissertation. The project will also maintain a project blog and website, which will ensure access to the database for a larger academic audience, and, embedded in educational material, for a broader non-academic audience, and will hold a final international conference. The project will also develop a network of local museums and heritage organisations at places of late antique banishment with a view to develop closer collaboration for future funding applications. The project will commence in May 2014 and is scheduled to run for 36 months.

Although the main functions of the human nose are often reduced to delivering air to the lungs and the perception of smell, increasing evidence reveals a complex nose-microbiome interplay related to health and disease. Age and gender are suggested to have the most impact on nose physiology. The nasal cavity predominantly consists of a respiratory barrier that protects from the entry of external substances (e.g. viruses, pollutants) and commensal nasal bacteria that suppress colonization by pathogens. A smaller surface area above the respiratory epithelium is covered by olfactory epithelium including olfactory neurons that are chemosensors and are activated after binding of odorants (e.g. cinnamon) to olfactory receptors (ORs). The complexity of the nasal host-microbiome interactions is even more emphasized considering that olfactory neurons can sense metabolites, small molecules produced by the bacteria. Up to now, mechanisms of the microbiome-nose to brain axis are not well understood, mainly due to a lack of suitable human in vitro models. The commercially available nasal in vitro cell line RPMI2650 is commonly used on 2D Transwell inserts for studying barrier integrity. Although this is a highly valuable tool for high throughput screening, its translation to humans is limited: RPMI2650 cells derive from a different area of the nasal epithelium with much tighter barrier characteristics. The mechanism of smell is often studied in engineered cell lines overexpressing one receptor protein or in animals that express 1,000 - 2,000 olfactory receptors. Up to now, it is not known how humans can perceive 1 trillion odors with only 400 ORs. We are aiming to build an urgently needed, advanced 3D in vitro model of the human nose-brain axis for exploiting the full potential of the healthy human nose. Since this human nose platform will improve predictions on barrier integrity and neuron activity, this will be a next-generation non-animal technology development. We expect that our platform will reduce the number of mice used for studying the nose-brain axis, which is still the gold standard. Our collaborator Dr Rishi Sharma (ENT surgeon, Addenbrooke's Hospital) will provide freshly obtained human microbiome and tissue biopsies (respiratory & olfactory) from sinonasal surgery from patients of different ages and gender. The bioelectronic platform will connect the recently developed e-Transmembrane device for measuring the electrical resistance of barrier models and microelectrode arrays allowing to record the spontaneous firing of neurons. Nasal organoids will be cultured on PEDOT:PSS electroactive scaffolds integrated into the e-Transmembrane device. The scaffold consists of biomimetic polymers, with a tissue-like structure. The devices promote the hosting of complex 3D models compared to rigid 2D counterparts such as the Transwell. In addition, this scaffold compartmentalizes the device into a top and bottom chamber, allowing the study of the uptake of drugs and metabolites into the respiratory and olfactory epithelium. Transferring the flow-through from the bottom chamber onto the whole olfactory tissue fixed on microelectrode arrays allows for the recording of the spontaneous firing of neurons. By identifying the complete set of bacteria and metabolites (metabolome) as well as RNA transcripts (transcriptome), correlation analysis will reveal the structure-activity relationship between the electrical signal and the microbes. CNBio (an organ-on-chip company) and Symrise AG (producer of flavors and fragrances) have already declared their interest in our model.