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Whole body exposure changes in atmospheric pressure are common. For example, passengers on commercial air flights are exposed to a hypobaric pressure of approximately 170 mm Hg for the duration of the flight. Similarly activities such as deep sea diving and hyperbaric medicine, both of which are becoming more popular, can expose the body pressures of up to 6,000 mm Hg. Physiological changes in blood circulation and respiration under hyper and hypo baric pressures have been well documented, but the effects on xenobiotic entry into the body have not been systematically investigated. Whole body exposure to barometric pressure changes would be expected to have very different effects to local pressure changes induced by methods such as suction because the latter generates a pressure differential which could draw molecules across the barrier and has less profound effects on whole body physiology. The comparative effects of these two means of inducing barometric pressure changes to externally facing barriers such as the skin are at present unknown. The aim of this project is to determine the effects of whole body and local barometric pressure changes on membrane physiology and transmembrane chemical penetration. In oder to achieve this aim the project will: - Design and build a series of specialised cells that will allow the assessment of membrane physiology and penetration under both equilibrated and differential hyper and hypo baric conditions in vitro - Determine the effects of locally induced barometric changes upon membrane physiology and permeability using a complimentry range of transport models and analytical techniques - Mathematically model the process of barrier penetration using the in vitro data and design a series of in vivo tests. - Test whole body exposure changes to acute hyperbaric and hypobarric conditions, compare and contrast this data to the in vitro data and adapt the in silico model describing permeation It is anticipated that the data generated from this work can be used to assess both the toxicological exposure risk and potential to improve the delivery of therapeutic agents when applying barometric stress to biological membranes. Work Plan A systems biology approach to the design will be taken. The employment of a hierarchal series of membranes will allow mathematical modelling and descrition of barrier transport in multiple tissue types. Part 1 - 'In vitro assessment of barometric pressure changes on transport'. A specially designed jacket that can independently seal the donor and receiver compartment of a Franz cell will be designed and tested. A series of both porous and non porous synthetic membranes will be employed to investigate the influence of pressure on permeate diffusion and partition. Part 2 - 'Mathematical modelling'. The data sets generated in Part 1 will be fitted to the ideal behaviour expected from non-porous or porous membrane transport processes. A mathematical model to describing transmembrane transport in the absence of barrier changes under different barometric pressures will be developed and this will inform the study design for Part 3. Part 3 - 'Skin physiology and barrier changes'. The cells designed in Part 1 will be used to assess transmembrane penetration through full thickness skin. Pre and post pressure exposure transepidermal water loss, skin lipid packing, water permeability, coenocyte size and skin anatomy will be characterised using analytical techniques and structural changes correlated to barrier properties. The findings will be used to adapt and test the mathematical model generated in Part 2. Part 4 - 'In vivo assessment'. Whole animal protocols developed in previous work (Staff PhD student, 2010) but adapted to specalised hyper and hypobarric chambers will assess animal physiology, skin barrier properties and skin permeability under differential pressure condi

Aerosol science, the study of airborne particles from the nanometre to the millimetre scale, has been increasingly in the public consciousness in recent years, particularly due to the role played by aerosols in the transmission of COVID-19. Vaccines and medications for treating lung and systemic diseases can be delivered by aerosol inhalation, and aerosols are widely used in agricultural and consumer products. Aerosols are a key mediator of poor air quality and respiratory and cardiac health outcomes. Improving human health depends on insights from aerosol science on emission sources and transport, supported by standardised metrology. Similar challenges exist for understanding climate, with aerosol radiative forcing remaining uncertain. Furthermore, aerosol routes to the engineering and manufacture of new materials can provide greener, more sustainable alternatives to conventional approaches and offer routes to new high-performance materials that can sequester carbon dioxide. The physical science underpinning the diverse areas in which aerosols play a role is rarely taught at undergraduate level and the training of postgraduate research students (PGRs) has been fragmentary. This is a consequence of the challenges of fostering the intellectual agility demanded of a multidisciplinary subject in the context of any single academic discipline. To begin to address these challenges, we established the EPSRC Centre for Doctoral Training in Aerosol Science in 2019 (CDT2019). CDT2019 has trained 92 PGRs with 40% undertaking industry co-funded research projects, leveraged £7.9M from partners and universities based on an EPSRC investment of £6.9M, and broadened access to our unique training environment to over 400 partner employees and aligned students. CDT2019 revealed strong industrial and governmental demand for researchers in aerosol science. Our vision for CDT2024 is to deliver a CDT that 'meets user needs' and expands the reach and impact of our training and research in the cross-cutting EPSRC theme of Physical and Mathematical Sciences, specifically in areas where aerosol science is key. The Centre brings together an academic team from the Universities of Bristol (the hub), Bath, Birmingham, Cambridge, Hertfordshire, Manchester, Surrey and Imperial College London spanning science, engineering, medical, and health faculties. We will assemble a multidisciplinary team of supervisors with expertise in chemistry, physics, chemical and mechanical engineering, life and medical sciences, and environmental sciences, providing the broad perspective necessary to equip PGRs to address the challenges in aerosol science that fall at the boundaries between these disciplines. To meet user needs, we will devise and adopt an innovative Open CDT model. We will build on our collaboration of institutions and 80 industrial, public and third sector partners, working with affiliated academics and learned societies to widen global access to our training and catalyse transformative research, establishing the CDT as the leading global centre for excellence in aerosol science. Broadly, we will: (1) Train over 90 PGRs in the physical science of aerosols equipping 5 cohorts of graduates with the professional agility to tackle the technical challenges our partners are addressing; (2) Provide opportunities for Continuing Professional Development for partner employees, including a PhD by work-based, part-time study; (3) Deliver research for end-users through partner-funded PhDs with collaborating academics, accelerating knowledge exchange through PGR placements in partner workplaces; (4) Support the growth of an international network of partners working in aerosol science through focus meetings, conferences and training. Partners and academics will work together to deliver training to our cohorts, including in the areas of responsible innovation, entrepreneurship, policy, regulation, environmental sustainability and equality, diversity and inclusion.

An aerosol consists of solid particles or liquid droplets dispersed in a gas phase with sizes spanning from clusters of molecules (nanometres) to rain droplets (millimetres). Aerosol science is a term used to describe our understanding of the collective underlying physical science governing the properties and transformation of aerosols in a broad range of contexts, extending from drug delivery to the lungs to disease transmission, combustion and energy generation, materials processing, environmental science, and the delivery of agricultural and consumer products. Despite the commonality in the physical science core to all of these sectors, doctoral training in aerosol science has been focussed in specific contexts such as inhalation, the environment and materials. Representatives from these diverse sectors have reported that over 90% of their organisations experience difficulty in recruiting to research and technical roles requiring core expertise in aerosol science. Many of these will act as CDT partners and have co-created this bid. We will establish a CDT in Aerosol Science that, for the first time on a global stage, will provide foundational and comprehensive training for doctoral scientists in the core physical science. Not only will this bring coherence to training in aerosol science in the UK, but it will catalyse new collaborations between researchers in different disciplines. Inverting the existing training paradigm will ensure that practitioners of the future have the technical agility and confidence to move between different application contexts, leading to exciting and innovative approaches to address the technological, societal and health challenges in aerosol science. We will assemble a multidisciplinary team of supervisors from the Universities of Bristol, Bath, Cambridge, Hertfordshire, Imperial, Leeds and Manchester, with expertise spanning chemistry, physics, biological sciences, chemical and mechanical engineering, life and medical sciences, pharmacy and pharmacology, and earth and environmental sciences. Such breadth is crucial to provide the broad perspective on aerosol science central to developing researchers able to address the challenges that fall at the boundaries between these disciplines. We will engage with partners from across the industrial, governmental and public sectors, and with the Aerosol Society of the UK and Ireland, to deliver a legacy of training packages and an online training portal for future practitioners. With partners, we have defined the key research competencies in aerosol science necessary for their employees. Partners will provide support through skills-training placements, co-sponsored studentships, and contribution to taught elements. 5 cohorts of 16 doctoral students will follow a period of intensive training in the core concepts of aerosol science with training placements in complementary application areas and with partners. In subsequent years we will continue to build the activity of the cohort through summer schools, workshops and conferences hosted by the Aerosol Society, virtual training and enhanced training activities, and student-led initiatives. The students will acquire a perspective of aerosol science that stretches beyond the artificial boundaries of traditional disciplines, seeing the commonalities in core physical science. A cohort-based approach will provide a national focal point for training, acting as a catalyst to assemble a multi-disciplinary team with the breadth of research activity to provide opportunities for students to undertake research in complementary areas of aerosol science, and a mechanism for delivering the broad academic ingredients necessary for core training in aerosol science. A network of highly-skilled doctoral practitioners in aerosol science will result, capable of addressing the biggest problems and ethical dilemmas of our age, such as healthy ageing, sustainable and safe consumer products, and climate geoengineering.