Cancer is a major health concern, with one in three adults developing the disease over their lifetime. However, on a cellular level, the probability of a cell developing into a tumour is very low. Cells prevent the development of tumours through a combination of mechanisms, which operate over different scales. Within a single cell, proteins and genes form signalling pathways which reliably interpret and respond to both the cell state and the cell environment, including specific signals passed from other cells. At the same time, within a tissue, the movements and locations of cells can add a further layer of control, by limiting the communication between cells and mixing populations of cells. I will build mathematical representations (a “model”) of the early stages of tumour formation in cancer which bridges these two phenomena. By running simulations using this model, I will learn more about how the signalling and physical components combine to control cell growth and death in the oesophageal epithelium. I will further mutate and wound my model, to explore how these events can cause a breakdown of the controlling mechanisms and lead to tumour growth.

Over the last 200 years human activity has increased CO2 in the atmosphere by around 40%, roughly 25% of which has been absorbed by the oceans. This has increased oceanic acidity by around 30%. Many studies have shown negative effects of lowered pH on biological functions in a wide range of marine animals and algae. There is widespread concern from scientists, policymakers and conservationists over the effects this change is having, and will increasingly have, on marine life and on the stability of marine ecosystems. This is especially so for species with high requirements for CaCO3 to make skeletons (Royal Society 2005, IPCC 2007). There is thus a need to understand better how marine species can cope with lowered pH, how those currently living in environments of different pH are adapted to those conditions, and how these groups have coped with varying pH in the past both since industrialisation and in deeper geological time. The best way to address questions of this type is to study a marine group that is heavily calcified, has widespread distributions in sites of different pH and has a long and well represented fossil record. In this respect living articulated brachiopods are, if not the best candidate group, then certainly one of the best. They inhabit all of the world's oceans from the poles to the tropics, and from the deep sea to the intertidal. They are possibly the most calcium carbonate dependent on Earth. Over 90% of their dry mass (in some species over 97%) is accounted for by calcareous skeleton. They also have one of the best fossil records in terms of representation and abundance over long geological periods of any marine animal group. There are excellent museum collections for this group, including repeat samples of the same species over the last 150 years and extensive collections at the family level for several major geological periods from single sites. They are, therefore ideal for investigating questions associated with changing environmental pH. We will use up to date SEM and ion probe techniques to quantify articulated brachiopod skeletal characteristics (shell thickness, primary & secondary layer thickness, crystal morphology, major & minor elemental composition) to address questions in four main areas. Firstly we will investigate the effects of varying pH in current environments by sampling populations of key species living in sites of different pH. Terebratulina retusa is distributed from the Mediterranean to Svalbard, with populations living in sealochs and harbours where pH is lower than offshore. Calloria inconspicua inhabits a similar range of sites around New Zealand. We will sample populations living in different pH conditions and analyse their shells. We will also monitor pH in the areas sampled for at least a year. This will allow us to identify skeletal responses to being raised in reduced pH in the natural environment. Secondly we will quantify changes in skeletons that have occurred since the industrial revolution, when CO2 levels have been consistently rising. Both our key species have good museum collections from given localities covering the last 50 years, and T. retusa collections date back to 1870 in the BM Nat Hist. Collections of the Antarctic L. uva also date back to the 1960's. We plan to exploit these collections to identify skeletal changes over the recent past as oceanic CO2 has risen. Thirdly we will analyse shell characteristics in Articulated brachiopods from different geological periods when CO2 levels in the environment were markedly different from today. This will allow evolutionary scale responses to be addressed. Finally we will hold our key species in culture systems with altered pH conditions and assess changes in skeletal composition and structure. These approaches should provide a very good understanding of how marine species have and can respond to acidification over as wide a range of time and spatial scales as possible.

This grant award is for the purchase of eInfrastructure (CPU, storage and networking) as part of the IRIS consortium. IRIS supports STFC Science Projects, including the National Facilities and Science Programmes. Refer to the Business Case for eInfrastructure for the exploitation of the UK National Facilities and STFC Frontier Science programme.

With the growing concerns over the use of antibiotics and the urgent need for novel therapeutics, this project aims to design and synthesise new inhibitors targeting bacterial membrane proteins. ATP-binding cassette transporters (ABC) are ubiquitous membrane proteins involved in cell viability and drug resistance. MsbA is an ABC transporter native to pathogenic bacteria including E. coli, Salmonella spp., P. aeruginosa, V. cholerae and K. pneumoniae where it has a primary role in the transport of Lipid A in the first stage of lipopolysaccharide biosynthesis of the outer membrane of these pathogens. The synthesis of the outer membrane is vital for the viability of these bacteria and makes this class of bacteria particularly challenging to target with therapeutics. MsbA has been extensively studied biochemically and structurally. It is an essential lipid transporter in many Gram-negative pathogens and is also well recognised as a model ABC multidrug transporter in drug resistance studies. This project will apply a rational design approach to manufacture synthetic peptide inhibitors. Peptides are a newly emerging class of therapeutics that have not yet been developed for bacterial ABC transporters. The design of peptides using the primary sequence of transmembrane domain alpha-helices has the potential to allow for insertion of peptide across the phospholipid bilayer and specific disruption of both the lipid and drug transport activities of MsbA. Despite having promising medicinal applications, peptide therapeutics are limited by poor stability, membrane permeability and oral bioavailability. The benefits, such as high efficacy, selectivity, low toxicity, and low production costs compared to other biotherapeutics, have encouraged investigations into new methods to overcome the intrinsic limitations of peptides. Peptide stapling is a technique that can constrain peptide sequences into their biologically-active conformations through a chemical brace. This project will aim to develop and identify peptide staples that utilise natural amino acid chemistry and can be further modified for specific cell tagging or tagging to specific uptake pathways to improve peptide accumulation in Gram-negative bacteria. ABC transporters play a large role in multidrug resistance as well as being essential for cell viability. Drugs are often effluxed by native, fast-acting export systems with broad substrate specificity, which therefore significantly contribute to bacterial multidrug resistance. Through identification and characterisation of these peptide inhibitors this project aims to better understand the transport of cytotoxic molecules out of bacteria in the hope of designing a systematic protocol for development of new antibiotics and modulators against multidrug resistant pathogens.

Project problem: Automated fault-detection and repair of expressways can improve their lifespan. Automating the repair process requires robotic devices that are capable of localizing and reaching the damaged location, perform manipulation of deformable materials and perform controlled interaction with the uneven road surfaces. Autonomous robot maintenance and repair processes will also be investigated in simulation at first, then proceed to real world demonstrations as the main outcome of this project. Project summary: The proof-of-concept will be first developed in simulation and later tested in an in-vitro setup. The student will develop simulated robotic platforms that can autonomously reach target locations on static uneven surfaces and perform object manipulation tasks. The student will develop algorithms for precisely localizing and reaching the damaged location once the region of interest is identified. Finally, the project involves development and testing of closed-loop control strategies for shaping deformable functional materials and patching damaged surface areas.