The search for materials that are lightweight and can withstand extreme service conditions has been a major driving force for material development in recent decades. Ceramic materials, while stable at high temperatures and in harsh environments, are limited in their structural applications due to their inherent brittleness and low damage tolerance compared to their metallic materials. An emerging class of materials referred to as micro-architectured materials offer a potential breakthrough to overcome this limitation. Our preliminary experimental results suggest that large-scale 3D micro-architectured materials, even when made from linear elastic brittle parent materials at scales that resemble bulk materials can exhibit extreme damage tolerance. Thus, in this project we propose to develop a deeper understanding of fracture and damage tolerance in a wide variety of micro-architectured materials made from (ceramic/ceramic-like) purely brittle parent materials. Our proposed research is based on two underlying hypotheses: (1) The discrete nature of the 3D micro-architectures either inherently gives rise to crack-bridging, introduces local anisotropy in the fracture toughness or both that leads to the observed extreme damage tolerance of micro-architectured materials made of inherently brittle parent materials. (2) The topological stochasticity in the 3D micro-architectures made of inherently brittle parent materials will result in diffused damage zones and enhanced crack-bridging, leading to further increase in damage tolerance. The specific objectives of our proposal are twofold. First, ascertain the crack growth and damage tolerance mechanisms of large-scale 3D periodic micro-architectures made of linear elastic brittle parent materials. Second, extend the mechanistic understanding of fracture in periodic micro-architectures to stochastic micro-architectures made of brittle ceramic parent materials. This will enable us to test our hypotheses and address several fundamental questions of technological relevance that are raised in this proposal. Our proposed education and outreach plans are also fully integrated with the research plan through a common focus on mechanics of micro-architectured materials. Classical fracture mechanics has been a highly successful theory for analyzing fracture of continuum materials. However, our preliminary results indicate that these concepts do not directly extend to discrete 3D micro-architectured materials, even those made of purely linear-elastic brittle parent materials. In particular, the discreteness of the microstructure renders standard measures of fracture properties and fracture testing protocols inadequate. This project will expand upon the traditional understanding of classical fracture mechanics and associated testing protocols by developing a comprehensive mechanistic understanding of damage tolerance and devising a novel methodology to characterize fracture response of a wide variety of 3D micro-architectured materials made from purely brittle materials. Furthermore, by gaining a deeper understanding of the correlation between micro-architecture and fracture response, we will create fracture mechanism and performance maps that can be used for selecting an optimum micro-architecture based on parameters such as size and density of the structure and loading conditions. The project's main impact lies in the development of a methodology that will enable the discovery, design, and development of lightweight, damage-tolerant micro-architectured materials for extreme loading conditions. These materials have potential uses not only in structural applications but also in relevant contemporary technologies such as energy, biomedical and micromechanical devices. This project will facilitate damage tolerance and structural integrity analysis for reliable use of micro-architectured materials in these highly sought-after technologies.

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.

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.

It is envisaged that he will work on new symmetries in quantum field theory. These symmetries are the large gauge transformations in electromagnetism and their generalisations to Yang-Mills theories and to BMS transformations in gravitational theories. They are also related to the soft theorems in these theories. Recent work has shown that they are more widely applicable than just symmetries at infinity and can be related to black hole hair and to cosmological horizons and quite possibly to the past null cone of any observer. They also can be extended to supersymmetric situations and to the conformal transformations. He will explore some of the avenues brought to light by recent research.