University of Birmingham

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 www.rcuk.ac.uk/StudentshipTerminology. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

Sectors like automotive and aerospace have taken a series of hits from the impacts of Covid-19 (supply chain disruption, cancelled orders, chip shortages, labour shortages etc). These have come on top of the impacts of Brexit on manufacturing supply chains for example through extra costs in terms of complying with customs and rules of origin, in stockpiling goods, in shifting suppliers and so on. And the war in Ukraine has added to industry stress by increasing energy prices and disrupting the supply of some components yet further (such as for the wiring harnesses used in cars or the neon gas used to regulate the lasers etching chips). Such impacts on manufacturing have had a profound regional impact (at the time of writing London's GDP is 1% higher than it was pre-Covid. The West Midlands' GDP is 10% lower). That makes 'levelling up' even tougher. In better understanding these potential impacts, the Fellowship will look at a number of linked issues and their policy implications. 1 What are the ongoing impacts of Brexit, Covid-19 and the war in Ukraine on manufacturing? For example, a key point we found in earlier research is that small firms simply really struggle with post-Brexit customs and Rules of Origin paperwork and in some cases have either stopped bothering exporting or stockpile at hubs in say the Netherlands, adding to costs; 2 What opportunities exist around 'reshoring' manufacturing and what barriers could prevent this, in the context of Brexit, Covid-19 and the war in Ukraine? Could this help bring back some manufacturing jobs to UK regions?; 3 Given that the EU is likely to bring in a 'carbon border adjustment tax' how could this impact on UK and EU manufacturing and how firms might respond?; 4 Manufacturing is undergoing a 'twin transition' in terms of the need to reach Net Zero and embrace a mix of 'Industry 4.0' technologies like AI and automation. What could a 'just transition' look like specifically in the auto industry given the ongoing shift to electric vehicles (EVs)? Here the Brexit dimension is especially relevant given the Trade & Cooperation Agreement's requirements for batteries in EVs to be made in the UK or EU after 2026 for electric cars exported between the two to avoid tariffs. Is the UK doing enough to build an electric vehicle supply chain? 5 What does this mean for government policy across these four areas and related areas (eg skills needs, regional level industrial policy) especially as the government, And given that the government has largely scrapped its industrial strategy, (how) can the UK 'grow back better'?.

The transmembrane metalloproteinase ADAM10 is a ubiquitously expressed 'molecular scissor' that cleaves the extracellular regions from its substrates, which include Notch, amyloid precursor protein and cadherins. ADAM10 can be regarded as a 'master regulator' of embryonic development. ADAM10 also impacts on human health via its role in diseases such as Alzheimer's, cancer, Staphylococcus aureus infection and inflammatory diseases including heart attack, stroke and asthma. As such, therapeutic targeting of ADAM10 has huge potential. However, realising this potential is currently impossible due to the toxicity that would result from targeting ADAM10 on every cell in the body. Our recent research demonstrates how we can solve this problem. We and others have recently identified six tetraspanin proteins, which we termed TspanC8s, which promote ADAM10 cleavage of specific substrates. Therefore future therapeutic targetting of specific TspanC8/ADAM10 complexes may be applicable to certain diseases, whilst minimising the toxic side effects of global ADAM10 targetting. The aim of this project is to determine how one of the TspanC8s, Tspan15, specifically promotes ADAM10 cleavage of the N-cadherin adhesion molecule. N-cadherin acts as 'molecular velcro' and is essential for maintaining tissue architecture in the beating heart, and regulates neuronal synapse formation and cancer cell metastasis. We hypothesise that Tspan15 promotes cleavage of N-cadherin by regulating ADAM10 subcellular localisation and/or causing it to adopt a specific conformation. To address this hypothesis, we will use cell line models that include our new Tspan15- and ADAM10-knockout CRISPR/Cas9 cells. The main objectives are as follows: 1) To discover how Tspan15 localises ADAM10 to N-cadherin. We will use advanced fluorescent microscopy to determine the extent of Tspan15/ADAM10 localisation to N-cadherin, in comparison to other TspanC8/ADAM10 complexes. We will identify the intracellular trafficking proteins that promote Tspan15 localisation using proteomics and co-immunoprecipitation. We will demonstrate their importance by assessing ADAM10 cleavage of N-cadherin in their absence following knockdown, and in the presence of Tspan15 mutants that cannot bind to the trafficking proteins. 2) To determine whether Tspan15 induces a distinct ADAM10 conformation. We will investigate ADAM10 conformation in complex with Tspan15 by flow cytometry using a panel of conformational ADAM10 monoclonal antibodies, and compare with the other five TspanC8/ADAM10 complexes. We will obtain structural information on the Tspan15/ADAM10 complex, again compared to the other TspanC8/ADAM10 complexes, using a novel membrane protein encapsulation method that we have developed for the purification of membrane proteins in their native state. Encapsulated TspanC8/ADAM10 structures will be determined by analytical ultracentrifugation, small-angle X-ray scattering, negative stain transmission electron microscopy and cryo-electron microscopy. 3) To investigate the functional effects of Tspan15 monoclonal antibodies. We will determine how each of our 12 new Tspan15 monoclonal antibodies affects ADAM10 cleavage of N-cadherin using western blotting and an N-cadherin-dependent functional assay for cell migration. The findings from this work will help us to understand how other TspanC8s regulate ADAM10 cleavage of other substrates, and allow us to assess for the first time how TspanC8 antibodies might act in a therapeutic setting.

The SIGMA - 'Study of Industrial Gravity Measurement Applications' project is a collaboration between RSK and the University of Birmingham (UoB) to carry out a feasibility study identifying the potential of Quantum Technology (QT) gravity sensors in geophysical surveys for environmental and engineering applications such as locating buried objects and finding voids. These QT sensors currently do not exist, but are the focus of many research activities in UK universities such as the GG-TOP project at the UoB developing a gravity gradient sensors with many more sensor developments planned as part of the UoB led QT Hub, if funded. For the QT sensors to achieve an accelerated commercialization, it is vital to ensure that they meet user needs. Therefore, this project will assess the current geophysical sensing technologies, establish their limitations and also operational parameters. This will allow provide a quantitative assessment matrix against which the QT sensors can be judged. It will further provide those developing the QT sensors with a specification of capability to strive for. In a second step, this project will assess environmental and instrument noise and incorporate these into a forward model. This will provide information on the necessary sensitivity and tolerable noise levels for the QT sensors. Ultimately, it will be necessary to develop inversion models, which relate the measured signals to buried features in the ground. It is not within the scope of this project to seek to create new inversion tools, however it is possible to use the output from the forward models to evaluate the capability of existing inversion tools available in the commercial market, and to prescribe the additional requirements of a

Worldwide 1 in 8 people are malnourished whilst it is predicted that a third of all food produced annually is wasted. Reducing this waste is crucial in order to improve food security. Food spoilage is a significant contributer toward food waste, with food spoilage due to fungal contamination occurring at pre harvest, storage, processing and packaging stages of food production. Germination of fungal spores in food products is responsible for spoilage and will be the main process this project focuses on. This project will aim to characterise the morphological changes that occur in fungal spores of the Zygomycete class as they germinate. Specifically studying how a variety of germination ques, nutrient sources and other environmental factors effect germination should allow a better understanding of the processes that are triggered throughout germinantion. Gene expression in germinating spores will also be studied to determine genes essential for this process. Alongside this, compounds extracted from plants, lichen and fungi will be tested for activity against germination. The pathways affected by inhibitory compounds will be studied and used to form a better understanding of the mechanisms controlling germination. The roles of identified genes will be confirmed by the production of mutant strains. Once intracellular pathways essential to germination are known, possible mechanisms that can be targeted in order to decrease food spoilage by Zygomycete can be proposed. This will be a multidisciplinary project using applied microbiology, developmental biology, genomics and modelling to i) characterise the regulatory network governing spore germination; ii) identify novel fungicidal and fungistatic compounds iii) understand the mechanisms of action of established and novel compounds inhibiting fungal spore germination.