Light induced processes are fundamental in Nature. Indeed, the Sun is the earth's energy source and it's light is captured and converted in a multitude of different molecular processes, on intrinsic ultrafast time scale. Whilst the 20th century was the scientific era in which the structure of matter drove much scientific discovery and technology in the 21st century we are now poised to see the emergence of structural dynamics as a driving force in science and technology. The desire to create "molecular movies" of molecular function and light induced processes has driven rapid technological advances in the area of ultrafast crystallography. A picture says more than a thousand words. Indeed, the most direct observation of a molecular motion is a time resolved measurement in 'real-space' of the atomic coordinates. The spatial resolution is achieved by crystallography with Angstrom wavelength radiation, while the time resolution is achieved with the generation of intense femtosecond pulses for both the excitation and the X-ray probe. Recent developments in laser technology allow the construction of a laboratory based instrument that is capable of femtosecond time resolved X-ray crystallography primarily using the powder diffraction method. The instrumentation will enable a large range of science applications, including experiments photopharmacology, solar cell research, energy storage, optoelectronics, pyroelectrics, nuclear coherence research, nanophotonics and plasmonics, colloids and biomolecular structure. A compelling example will be the demonstration of a photoisomerisation reaction of a dye-based photoswitching molecule which is used for photopharmacology and energy storage. The ultrafast measurements will determine the excited state reconfiguration and non-adiabatic dynamics of cis/trans photoisomerisation of the organic molecule. The impact is demonstrated by usage of the indigoid moiety in photopharmacology targets such that light regulates the substrate binding in biomolecular target molecules. Additionally, studies of the structural dynamics following illumination of solar energy materials are vital to understand and optimise functions In particular, with the rapid developments in the solar cell technology, novel materials and continuous improvements in the efficiency will require ultrafast structural measurements of the materials and even working devices.

High-intensity laser interactions with matter produce extreme environments with very high temperatures and densities such that the electrons within the atoms of the material no longer remain bound to the atomic nuclei and the material becomes a plasma. These interactions can create conditions for studying astrophysical phenomena, including supernova shocks and solar flares, as well as supporting very high electric fields that can be used to accelerate charged particles over distances 100s to 1000s times shorter than the limits of radio-frequency accelerator technology. These compact accelerators have been shown to generate ion beams with highly desirable properties for key applications in materials testing, radiobiology, and inertial fusion energy. So far, full exploration and exploitation of these interactions has been hampered by the difficulty in reproducing their complex behaviour in numerical and computational models and by the limited data available which is caused by the low repetition rate of the high-energy pulsed laser (typically <<0.002 Hz - a shot every 10 mins) used to create the plasma and drive particle acceleration. This is particularly the case in the study of fragile ultra-thin opaque targets where the absorption of energy from the laser causes the target to heat and expand leading to the target becoming transparent as the density falls. When this occurs the laser can propagate through the target and the transfer of laser energy to the plasma is no-longer localised at the target surface. This interaction is of significant interest as it is here that the highest energy laser-accelerated protons have been recorded. A new generation of multi-Hz high-energy laser-technology is facilitating orders of magnitude increase in data acquisition rate. In order to exploit these new lasers, it is also necessary to test target technology that can provide fresh ultra-thin foils with high positional stability at multi-Hz repetition rate. In addition, despite the enormous increase in data acquisition-rate the dependence of the interaction dynamics on a large number of variables (e.g. laser energy, laser spatial and temporal energy distribution, target density profile) means that `grid-scanning' each parameter is not an efficient method to map their interdependence. By incorporating machine learning tools the high data rate enabled by the lasers and target can be used to intelligently sample the parameter space to model the interaction and quantify the stability of these novel accelerators. The proposed collaboration will address this challenge by coupling a liquid sheet target, developed at the US SLAC National Accelerator Laboratory (SLAC), with a new computer-guided approach to laser-plasma experiments, pioneered by researchers at Queen's University Belfast (QUB). The development of this novel experimental platform will enable deeper understanding of the key energy transfer pathways between laser and plasma and their dependence on experimental variables. The research will directly impact on plasma modelling, advanced accelerator research, plasma astrophysics, inertial confinement fusion, materials testing and FLASH radiobiology. The research outputs will feed into EPSRC 2022-2025 strategic priorities on the physical and mathematical sciences powerhouse, frontiers in engineering and artificial intelligence up-skilling through the research themes: AI and Data Science for Engineering, Health and Government by exploiting AI for experimental science; Energy through inertial confinement fusion; Plasma and lasers by developing crucial technology to facilitate deeper understanding and broader exploitation of novel radiation sources; and research infrastructure by enhancing the capabilities of high-intensity laser facilities.

Around 45% of cancer patients are diagnosed at a late stage, and only 50% experience 10 years of life post diagnosis - with earlier diagnosis ~90% would survive. Therefore, delivering early diagnosis is a key priority for many organisations (CRUK, NHS, WHO etc). Current leading diagnostic technologies on the market like Grail (~$8bn company) for early detection of 50 cancer types have test costs between $1 and 7k per patient. There is an international requirement for cost effective testing for many international markets (47% of the global population do not have access to diagnostics) and repeated monitoring. Metaguidex (MGX) has clinical validation for a novel early multi-cancer detection diagnostic assay using surface proteins on nano-scale extracellular vesicles (EVs) released into the blood from multiple cancer cells (breast, colon and lung). High specificity of antibodies to these proteins in the assay is needed for maximum sensitivity, but there is batch-to-batch variation during the expensive antibody manufacture and MGX have found deterioration of antibody quality over time, which has severe implications on assay effectiveness. Molecularly Imprinted Polymers (MIPs), small plastic antibody mimics with exceptional selectivity that exhibit nM/pM level affinities, offers an industrially competitive alternative to antibodies. Molecular imprinting is a leading artificial molecular recognition technology which creates robust, reproducible, scaleable, cost-effective antibody mimics that counter several downsides observed in biological recognition. This project therefore aims to create and test the binding of these MIP mimics to the cancer EVs to be tested in clinical blood samples. This starts with the creation of MIPs to generic surface proteins on EVs and MGX IP-protected cancer specific proteins. At the Central Laser Facility (Octopus, STFC, Rutherford Appleton Lab, Harwell) these mimics will be tested for surface binding for positive control cancer EVs alongside current antibodies at using surface plasmon resonance (Biacore), then further measured for colocalization, sensitivity and specificity on the high-resolution microscopy (STED/dSTORM) on positive and negative cell line EVs and characterised clinical samples. With the understanding from this MGX can test these MIPs against current antibodies on a larger clinical scale using in-house platforms. This has a huge potential for MGX to drive forward the IP on current cancer monitoring assays; saving loss of time on the constant testing of antibody batches and quantity control retesting required, but importantly, allow MGX to commercialise an international competitive multi-cancer diagnostic and monitoring assay in a $1.903bn market* where whole genomic testing would be overkill. More widely MGX is looking in the long run to expand beyond cancer to many other diseases where blood EVs play a role or quality control monitoring of the manufactured EVs and AAV therapeutics currently require expensive platforms to assess quality. It will also have impact on the molecular imprinting field where application is key to driving the use of these polymers forward. * calculated on UK, seven EU countries with >10,000 breast cancer cases per year and North America could yield $100 initial test prices followed by bespoke three-year monitoring programmes)

LightOx, an SME based in Newcastle upon Tyne, are developing LXD191, a novel light-activated therapy targeted as a preventative treatment to eliminate early-stage/precancerous lesions that arise in the mouth before they can develop into challenging cancerous tumours. LXD191 is a molecule that, when activated by light from an LED device, elicits the generation of radical oxygen species (ROS) that are highly toxic towards precancerous cells and tissues. This kind of behaviour is common in molecules known as photosensitisers, typically utilised for a type of light-activated treatment known as photodynamic therapy (PDT). However, LightOx believe LXD191 operates through a novel mechanism that is distinct from common photosensitisers and has not been reported in the literature before. Learning more about the unique activity of LXD191 will help LightOx progress this new molecule into clinical trials and to develop innovative light-activated products for other challenging diseases. To help them understand this fascinating new drug molecule, LightOx have formed an exciting partnership with leaders in spectroscopy and photochemistry at University College London (UCL) and the Science and Technology Facilities Council's Central Laser Facility (CLF) to develop a project that aims to fully understand the unique behaviour of LXD191, and to help LightOx bring this innovative therapy to clinical utility. The project team, comprising Dr. David Chisholm of LightOx, Prof. Helen Fielding of UCL, and Dr. Igor Sazanovich, Dr. Partha Malakar and Dr. Sneha Banerjee of the CLF are aiming to utilise the world-leading facilities at UCL and the CLF to investigate LXD191 using two cutting-edge techniques: time-resolved infrared spectroscopy (TRIR) and transient absorption spectroscopy (TA). Both techniques examine the changes that occur to LXD191 at the precise moment it is activated by light and how the molecule utilises energy from the light. TRIR measures changes in precise vibrations that occur within the bonds of LXD191's chemical structure, while TA measures the energy that this structure absorbs. These data can help build a computational model to describe how LXD191 interacts with light that the team can use to understand how this molecule destroys precancerous and cancerous cells. There are around ~8800 cases of oral cancer diagnosed in the UK each year, with most presenting at an advanced stage with poor prognosis. The incidence has been increasing for decades, particularly in those over the age of 50, and mortality rates are not improving. Around 50% of patients die within 5-years of diagnosis, whilst a reliance on invasive surgery (used in 95% of cases) means that survivors are left with severe life-long impacts affecting swallowing, eating and speech. Prevention strategies are urgently needed to address this increasing burden of disease. LXD191 promises to be the first preventative treatment for early-stage/precancerous lesions that progress to oral cancer and this project is aimed at characterising the novel activity of LXD191 to help accelerate its development towards clinical trials, and advance the understanding of light-activated chemical processes.

Impairment of the skin's structural integrity initially results in acute wounds which can become chronic or form scars such as atrophic, keloid or hypertrophic scars if timely wound closure is not achieved. The global incidence of chronic wounds (CWs) exceeds 1%, with a rising prevalence attributed to an aging demographic. Excessive scarring significantly affects the patient's quality of life, both physically and psychologically. Each year, in the developed world alone, 100 million patients develop scars resulting from 55 million elective operations and 25 million operations after trauma. The incidence rates of hypertrophic scarring range from 40 to 70% after surgery, with up to 91% following burn injury, depending on the depth of the wound. Phytoceutical have developed 20 nm in diameter nano-micellar formulations of retinol and retinaldehyde formulations with improved stability (UK and EU Patent protection is in place, further patents pending). For instance, in the nano-micellar retinol product, the retinol is wrapped within tiny ball-like "particles" made of substances that are soluble in water, which helps to protect the retinol from oxidation and also helps to deliver it more effectively into the skin. Retinol is an unstable but important molecule, a critical regulator of skin/tissue regeneration that helps healthy wound closure. While scar formation is affected by many factors, speedy wound closure is essential in restoring the skin to its original anatomical integrity without abnormal scarring. Our research has demonstrated the potential of 0.3% retinol nano-micellar formulation speeding up wound closure, this findings were, however, obtained from limited in vitro skin wound model. Moreover, preliminary studies of the formulations against skin cells showed cellular toxicity at lower concentrations of retinol, yielding inconclusive results. The primary technical challenge is to define the safe retinoid dosages for optimum cellular function, specifically in promoting collagen generation and subsequent wound closure. Tracking the biochemical cellular changes at nanoscale after formulation dosing is integral to overcoming this hurdle. Furthermore, there is a need for additional data to establish key performance metrics for Phytoceutical retinol formulations for collagen generation. This will not only validate the wound closure results from the previous limited number of skin wound samples but also aid in optimising and refining the formulation.Understanding how the dose levels affect collagen production enables optimised formulations to improve structural collagen matrix formation, minimising scar formation. The purpose of this study is: (1) to define the safe limit of the micellar retinol formulations developed by the Company using CryoSIM at Diamond; (2) measure the key performance metrics of retinol formulations for collagen generation by using the Light Sheet microscopy at STFC. Clinicians and clinics canvassed have requested this as a major need.