Bacteria are tiny organisms that live in a wide range of environments on the earth, including humans and animals, where they have both a positive and negative impact on health. In this application, we propose a number of experiments that will help us to understand certain aspects of how dangerous bacteria are able to persist in the environment and cause disease in humans. We will specifically study the bacterium Legionella pneumophila, which is ubiquitous in aquatic systems (e.g. rivers, reservoirs, hot/cold water supplies, cooling towers) and highly prevalent in large buildings such as hospitals and hotels. L. pneumophila causes Legionnaires' disease (an often-fatal pneumonia), and Pontiac fever, (a milder flu-like disease) and rates of infection are increasing each year, both in the UK and globally. Within the environment L. pneumophila lives within biofilms where it clumps together with other bacteria and is covered in a defensive mesh. This protects it from external factors such as dehydration but also from attack by other organisms and antibacterial compounds. However, single celled organisms called amoebae can still graze on these bacteria and L. pneumophila has developed strategies to survive by going inside them and hiding away from attack. Once inside these hosts, L. pneumophila lives within a membrane-bound compartment (the Legionella containing vacuole; LCV), where it evades detection. Unfortunately, some types of human lung cells share similarities with amoebae and therefore Legionella causes disease when humans come into contact with contaminated water. L. pneumophila secrete many proteins outside of the bacterium that allow it to sense the outside world, interact with other organisms and also manipulate host amoebae and human cells so that they can survive inside them. For example, the 'type II secretion system' (T2SS) uses a syringe-like mechanism to export proteins that help form biofilms and enables L. pneumophila to become fully virulent. We have identified a unique class of these proteins that once exported are able to either bind to the surface of L. pneumophila, helping it stick to other bacteria in biofilms and recognize host cells; or, when inside a host, bind to the Legionella containing vacuole, helping it to become camouflaged so that it is not detected. Understanding the details of how these proteins function and why they localize to their specific membranes will be crucial to further our knowledge of L. pneumophila infection. Likewise, these studies may also reveal common pathways for infectious disease used by other bacteria, which may in turn help us design compounds which disarm L. pneumophila and other dangerous pathogens.

If one knew the positions of all the electrons in a material, there would be no need to find where the nuclei are . This is a very strong statement, and whilst it may not true in all possible cases, for many materials it is. Whilst there have been developments in our ability to determine the local structure of materials at atomic resolution in projection almost all of these have focused on locating the atom positions. The more difficult problem of determining the positions of the electrons is much less well developed but, if possible would provide a new dimension of information in materials research. If successful, the potential application of this type of data is very wide ranging and includes studies of catalysis; as new dielectric, ferroelectric and in some cases magnetic devices and in oxygen transport membranes and fuel-cells; it is also critical to the understanding at the atomic level of many corrosion problems. These studies will also provide a rich seam of experimental data against which theoretical models can be compared and calibrated at far higher precision than is currently possible. Our proposed research therefore poses a Grand Challenge , namely the experimental determination of local charge distribution in ceramic materials at the nanoscale with particular reference to studies of individual defects. To understand the effects of charge distribution on material properties we intend to develop methods for directly imaging charge . In particular we wish to examine the redistribution of charge at surfaces and defects which are often crucial to materials properties and device performance. To achieve this we will develop experimental methods for imaging charge using both Scanning Tunneling Microscopy (STM) and aberration corrected High Resolution Transmission Electron Microscopy (HRTEM). We will also compare results from these two techniques which provide complementary information. This project will span two internationally leading institutions, one in the UK and one in the USA each of which has access to unique instrumentation and computation for this purpose. Each part of the proposal will deliver new general methodologies and we will utilize these in pioneering experiments involving a range of technologically important materials. Funding for this project will support two post doctoral research fellows working at each of the collaborating institutions together with travel costs to enable members of both research teams to work in the collaborating laboratories.

Our ability to communicate successfully with others can be strongly affected by the presence of noise and other voices in the environment, and children and older adults are more greatly affected than young adults in these situations. Even greater disruption is experienced for populations with hearing or language impairments, or even healthy adults who are non-native speakers. Some of the disruption is due to physical masking by interfering sounds (energetic masking EM) but if the disrupting sound can be understood, this also causes further difficulty (informational masking IM). Previous work suggests that informational masking causes relatively more disruption for children and older adults than for young adults but these findings are based on laboratory tests that are far from realistic communication. Although the impact of adverse conditions on speech communication has been the object of studies in different age groups, no study to date has taken a full lifespan view, looking at the relative impact of IM and EM on participants aged from 8 to 85 using a common experimental design. Also, many studies have focused on the impact of EM and IM on speech perception using recorded sentences or words; this ignores the fact that speakers make dynamic adaptations in speech communication to counter the effects of masking. We evaluate the impact of adverse conditions in an interactive task using measures reflecting speech communication efficiency (e.g., task transaction time, rate of dysfluencies). Finally, there is little evidence to date as to whether laboratory-based evaluations reflect the level of difficulty experienced in everyday life. The proposed project will, for the first time, relate evaluations of speech communication difficulties in adverse listening conditions as measured in the laboratory with real-life ratings of difficulty collected in real time over a two week period. It will also test whether primarily informational masking causes greater interference for some age groups (e.g. children, older adults), and if the underlying reasons for the interference differ between children and adults. In Study 1, 120 individuals aged 8 to 85 yrs will be tested in pairs while they carry out a problem-solving task in conditions varying in the degree of informational and energetic masking present. A secondary task will be added to make the task more cognitively demanding, thus reflecting real-life multitasking situations. Baseline measures of hearing, speech perception and cognitive function and a standardised questionnaire of auditory disability (SSQ) will also be collected. In Study 2, the same participants will be asked to report perceived communication difficulty and their listening environment on 6-7 occasions per day during a 2-week period using a smartphone-based app. Data from this study will be related to measures of communication effectiveness and SSQ data collected in Study 1. Finally, in Study 3, spontaneous speech will be collected for a group of 4-7 year olds using the same interactive task to complement measures from our previous corpora (and data for Study 1) and gain a full lifespan set of acoustic descriptors for conversational speech in good listening conditions. This project will lead to a better understanding of how the impact of adverse listening conditions changes across the lifespan, of the relative effects of IM and EM in different age groups, evaluated in realistic communicative conditions, and of the true ecological validity of laboratory-based evaluations. It will also provide normative data for a set of acoustic-phonetic measures across a 4-85 year age range. This benchmark will be of use for practitioners such as speech and language therapists and audiologists who work on aspects of communication with individuals of all ages. Importantly, this research will also contribute to our basic understanding of speech perception and production development across the lifespan.

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.

Research is proposed on the synthesis, characterisation and application of new classes of multimetallic coordination complexes derived from porphyrazines, which are peripherally fused to 2-trans- or 4 salen residues, or functionalised with 4 or 8 Collins ligands [NHCOC(Me2)OH] or oxamido groups (NHCOCO2H). These polydentate ligands will be converted into the derived trimetallic and pentametallic complexes. The metallic entities within the porphyrazine cavity and peripherally bound will be systematically varied with particular focus on paramagnetic and/or redox-active metallic complexes. Selected multi-manganese complexes will be assayed as potential optical and dual optical-MRI agents for application in medicine. In addition, the same complexes should be models for related technetium complexes of potential as dual optical-PET agents. Secondly, a new chromatography-free large-scale synthesis of seco-porphyrazines will be developed, which relies on a polymer-capture-release strategy. This new approach will greatly facilitate the application of these macrocycles as both biomedical-imaging agents and in photodynamic therapy. New potential applications of porphyrazines will be examined with focus on anti-E-selectin-conjugated macrocycles for the detection and treatment (photoangioplasty) of lesions associated with major diseases such as atherosclerosis, rheumatoid arthritis and Crohn's disease. The synthesis, characterisation and application of novel high dipole moment porphyrazines will be undertaken including hexaamino-porphyrazine-tropyllium systems.