It is well established that long-term exposure to aircraft and wind turbine noise is responsible for many physiological and psychological effects. According to the recent studies, noise not only creates a nuisance by affecting amenity, quality of life, productivity, and learning, but it also increases the risk of hospital admissions and mortality due to strokes, coronary heart disease, and cardiovascular disease. The World Health Organization estimated in 2011 that up to 1.6 million healthy life years are lost annually in the western European countries because of exposure to high levels of noise. The noise is also acknowledged by governments as a limit to both airline fleet growth, acceptability of Urban Air Mobility, operation and expansion of wind turbines, with direct consequences to the UK economy. With regards to aerodynamic noise, aerofoil noise is perhaps one of the most important sources of noise in many applications. While aerofoils are designed to achieve maximum aerodynamic performance by operating at high angles of attack, they become inevitably more susceptible to flow separation and stall due to changing inflow conditions (gusts, wind shear, wake interaction). Separation and stall can lead to a drastic reduction in aerodynamic performance and significantly increased aerodynamic noise. In applications involving rotating blades, the near-stall operation of blades, when subjected to highly dynamic inflows, gives rise to an even more complex phenomenon, known as dynamic stall. While the very recent research into the aerodynamics of dynamic stall has shown the complexity of the problem, the understanding of dynamic stall noise generation has remained stagnant due to long-standing challenges in experimental, numerical and analytical methods. This collaborative project, which includes contributions from strong industrial and academic advisory boards, aims to develop new understanding of dynamic stall flow and noise and develop techniques to control dynamic stall noise. The team will make use of the state-of-the-art experimental rigs, dedicated to aeroacoustics of dynamic stall and GPU-accelerated high-fidelity CFD tools to generate unprecedented amount of flow and noise data for pitching aerofoils over a wide range of operating conditions (flow velocity, pitching frequency/amplitude, etc.). The data will then be used to identify flow mechanisms that contribute to the different aerofoil noise sources at high angles of attack, including aerofoil unsteady loading and flow quadrupole sources, and detailed categorisation of dynamic stall regimes. A set of new frequency- and time-domain analytical tools will also be developed for the prediction of dynamic stall noise at different dynamic stall regimes, informed by high-fidelity experimental and numerical datasets. This project will bring about a step change in our understanding of noise from pitching aerofoils over a wide range of operations and pave the way to more accurate noise predictions and development of potential noise mitigation strategies.
Our Universe contains billions of galaxies like our own Milky Way, each harbouring a supermassive black-hole at its centre. The biggest galaxies today weigh more than a trillion times the mass of our Sun with supermassive black-holes weighing the equivalent of a billion Suns. But how did these galaxies and black-holes get so big? The Universe is almost 14 billion years old but the major growth spurt of galaxies took place more than ten billion years ago. Theory predicts that this epoch in our Universe's history was characterized by violent collisions of small galaxies. These collisions compressed the gas in galaxies to form stars, the new stars provided fuel for the supermassive black-holes to feed on and the massive galaxies of today were assembled with enormous black-holes at their centres. Despite this well-accepted picture of galaxy formation we still have not observed many of these processes happening, particularly during the very active period of growth in our Universe's history more than 10 billion years ago. We want to catch the most massive galaxies and supermassive black-holes as they are growing but these systems are very rare; looking for them is comparable to looking for a needle in a haystack! Not only do we need sophisticated telescopes that can scan the entire sky searching for these monster galaxies, they also need to be sensitive enough to detect light that has traveled billions of years from when the galaxies were first forming, to reach us today. This has only recently become possible and new digital cameras have been mounted on some of the largest telescopes in the world to provide sensitive images covering most of the sky. I am working on data from several of these new digital imaging surveys. My research involves scanning the digital images to locate the most enormous galaxies in our Universe as they are undergoing a major growth spurt. I have already identified the first of these ultra-massive growing galaxies in the distant Universe. Through high-resolution imaging of these newly discovered galaxies, we will be able to observe the various physical processes going on within them and how the supermassive black-hole is affecting these processes. Within our new digital images of the sky lurk even rarer systems such as the first galaxies and supermassive black-holes in our Universe dating back to when the Universe was only 500 million years old. We are now able to watch these galaxies as they begin to feed their supermassive black-hole for the first time on their journey to growing to the monster black-holes of today. Observing this first feeding phase is critical for building up an understanding of how supermassive black-holes grow. Most digital imaging surveys detect starlight from galaxies in the visible portion of the electromagnetic spectrum. However, dust in galaxies can absorb visible light, which is then re-radiated at the longer infrared wavelengths. Infrared data therefore allows the most unbiased view of star formation in galaxies. Utilising new surveys that trace light at infrared wavelengths, my research will measure the number of stars being formed in distant galaxies with actively feeding supermassive black holes. The aim is to determine if the supermassive black-hole directly impacts the rate at which a galaxy is forming stars, therefore controlling how massive its host galaxy will eventually become. Taken together my research aims to build up a coherent observational picture of the formation of massive galaxies and supermassive black-holes by directly observing them as they are being assembled in the early Universe. This will be done by bringing together new data from some of the largest astronomical surveys across the electromagnetic spectrum, that are currently underway.
Theme: Bioscience for Health P-Rex guanine-nucleotide exchange factors (GEFs) activate the small GTPase Rac upon stimulation of various cell surface receptors, including G-protein coupled receptors (GPCRs). Through their ability to activate Rac, they control gene expression, cell growth, cell survival and motility, among other responses, and thus regulate important physiological processes such as innate immunity, glucose homeostasis, thermogenicity, pigmentation and synaptic plasticity. We have data suggesting a new role of P-Rex in GPCR trafficking. Ligand binding to GPCRs not only induces signalling (within seconds) but also the internalisation of the receptor by clathrinmediated endocytosis (within minutes) to switch off signalling. P-Rex deficiency promotes GPCR internalisation, whereas overexpression, inversely, blocks the first step of endocytosis - receptor phosphorylation - independently of catalytic Rac-GEF activity (unpublished). We hypothesise that increased GPCR cell surface levels caused by P-Rex expression may result in constitutive cell signalling and responses, and that such upregulated GPCRs may be targetable. This project aims to uncover the molecular mechanism and function of GPCR trafficking control by P-Rex Rac-GEFs and explore its potential for controlling P-Rex signalling. Mechanism (18 months): We will quantify the effects of P-Rex1 and P-Rex2 on receptor internalisation in HEK293 cells which express the GPCR for sphingosine 1-phosphate (S1PRGFP), by using image analysis and cell fractionation. We will test the interactions of P-Rex or catalytically-inactive P-Rex* with S1PR-GFP, heterotrimeric G proteins and the GPCR-kinase Grk2 by co-IPs, assess which domains are required using P-Rex mutants, and test if interactions are direct using recombinant proteins. If we can pinpoint P-Rex residues required for GPCR trafficking control, we will generate traffic-deficientmutants. We will measure if P-Rex alters GPCR ligand binding capacity, use antagonists to determine if GPCR activity is required, and test if PRex regulates Grk2 activity. To determine receptor specificity, we will measure the trafficking effects of P-Rex on different receptor classes. Function (18 months): We will elucidate if increased GPCR surface levels in P-Rex expressing cells result in prolonged signalling and responses in 3 cell types: P-Rex or P-Rex* expressing HEK293 S1PR-GFP cells, PC12 S1PR-GFP cells with knock-down of endogenous P-Rex1, and primary murine P-Rex null or P-Rex1* neutrophils. PC12 cells and neutrophils express high levels of endogenous P-Rex1 and generate responses known to be P-Rex1 dependent, thus allowing us to determine physiological importance. They also express endogenous GPCRs (e.g. C5R1) tractable by sensitive antibodies. We will measure Ca2+ fluxes and cAMP levels, using P-Rex1* to determine Rac dependence, and test activities of pathway components, e.g. PKA, PI3K, Akt, ERK, Rac1 and RhoG. We will assay cell adhesion, morphology, migration, cell cycle progression, survival and proliferation, using various techniques including imaging and flow cytometry. Targeting potential (6 months, including +3 at Vernalis): During the internship at Vernalis, we will develop assays for screening libraries of fragments and other small-molecule compounds to modulate the P-Rex dependent cell surface levels of GPCRs. Active compounds will be assessed as chemical probes for use as a complementary approach to genetic manipulation.
The aim of this postdoctoral mobility project is to demonstrate the potential of a microchannel flow cell in a total analytical system (microTAS), point of care life sciences application. The goal is to integrate a novel multiplexed-immunoassay into a micro channel flow cell, for the simultaneous measurement of multiple biomarkers and other antigenic analytes that play a key role in the diagnosis of disease state. The proposed scheme for multiplexed immunoassay in a microTAS flow cell includes metal ion labelling of the antibody in a sandwich or competitive immunoassay format, together with electrochemical capture and anodic stripping analysis. A key issue is the design of the microchannel flow cell that can be tailored with different lengths, widths, heights and flow rates to control concentration of reactants at different points in the channel. The success of the assay is the tailoring of the channel to the binding kinetics of the antigen-antibody reaction and capture efficiency of the labelled antigen/biomarker.The main focus of the project will be on quantifying relationships of the concentrations of biomarkers /metal-labelled biomarker and the striping charge of captured metal on the microband sensing electrodes within the designed channel flow cells. Initially the performance of the designed cells will be evaluated with a single biomarker, and the experimental conditions for single immunoassay established. Afterwards, the experimental evaluation of the proposed methodology will be extended for simultaneous determination of multiple biomarkers with different metal labels in the designed channel flow cell.
Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.