The way in which bacteria divide in order to grow is a highly-coordinated process and requires a complex choreography of many proteins, working inside and outside the cell membrane. Many of these proteins have a functional relationship with the synthesis and coordination of the external cell shape determining polymer called peptidoglycan (PG). This polymer provides a structural scaffold for many cellular processes as well as mechanical strength and protection, which requires modification during the process of cell division. A critical point occurs during cell division when the "old" cell wall PG must be degraded to allow separation of newly synthesized cells and this function is provided by a variety of PG hydrolases associated with the cell division FtsE-FtsX protein complex. At Warwick we have recently contributed to a new understanding of how this process occurs in rod shaped, gram negative bacteria. However, the situation in respiratory infection associated, ovoid-shaped gram positive bacterial pathogens, including Streptococcus pneumoniae is unclear at present. Notably there is a direct interaction and functionally essential interaction between FtsEX and a single specific PG hydrolase called PcsB making it an attractive extracellular target to prevent pneumococcal disease. In this proposal we directly address questions concerning a particular essential enzyme and the complex it makes with cell division proteins in Streptococcus pneumoniae. The cell division proteins FtsE and FtsX form a complex together that spans the bacterial membrane and anchors an extracellular enzyme called PcsB that is required for cell division. The binding and hydrolysis of ATP inside the cell by FtsE is transmitted through its membrane anchor partner protein FtsX and results in a major conformational shape change in PcsB outside the cell which controls its ability to cut the peptidoglycan layer and allow cell division. Building on new structural data and models, genetic constructs, biochemical data, assays and international collaboration, the goal of this proposal is to understand the role of PcsB in complex with FtsEX and elucidate the molecular events linking cell division with PG degradative enzymes required for growth and division in S. pneumoniae. Drugs or vaccines that interfere with this process could prevent division and could provide routes to new treatments for pneumococcal and related infectious disease. The research proposed in this grant proposal forms part of an international effort with colleagues in the US and Singapore to combat this problem. The scientific principles that we will reveal may also have application in other, related bacterial species. Our work leading to this application, provides computer simulations, microbiological tools, techniques and biochemical approaches that can now be applied to the key biological questions of how are these proteins controlled, how do they function and how we might interfere with this this process to provide future antimicrobial strategies for human or animal health.

The overarching goal of our research programme is to address aspects of the broad science challenge: "What are the basic constituents of matter and how do they interact?". In particular, by performing experiments primarily with electron and photon beams, we study questions such as "How do quarks and gluons form hadrons?", and by studying these basic, strongly-interacting building blocks we are able to tackle the question "What is the nature of nuclear matter?"

Quantum computation promises to solve certain problems that are fundamentally out of reach without it. But taking advantage of quantum capability requires a radical change in approach to computation. Quantum computation operates on fundamentally different principles than classical computation. By far the most prevalent model of quantum computation uses quantum circuits. Programming in this low-level and rigid model needs specialist knowledge. Most current quantum programming languages they describe how to construct a circuit, rather than what the circuit should actually do. Universal properties can extract conceptual essence without superfluous mathematical details. A quantum programming language based on them can be used by programmers who understand the concepts but not necessarily the mathematics behind quantum computation. Such a language frees the programmer to express algorithms at a higher level of abstraction. Universal quantum programming is also better at preventing and fixing programming errors. Universal quantum programming has three main advantages. First, programmers can build programs out of smaller components, which can be individually constructed and tested. This is essential for scalability: increasing the size and complexity of programs is only possible if programmers can control this complexity. Second, there are mathematical semantics that abstract from merely implementational details. Programmers can only invent truly new quantum algorithms if the language allows a sufficiently high-level view of computation. Third, the programmer can express their thoughts freely at a natural level of abstraction. This project has two main contributions towards universal quantum programming. First, as a short-term test case, we focus on dynamic quantum measurement. Every step in a quantum circuit is reversible, and only at the end is classical data extracted by an irreversible measurement. There are many advantages to performing measurements dynamically, partway along the quantum circuit, but this breaks many verification tools for quantum programs. Existing languages can express dynamic measurement at a low level of abstraction, but ideally the programmer need not specify when measurements happen and can leave this burden to the compiler. Supporting dynamic measurement through universal properties lets the programmer write bigger and better quantum programs. Second, the project will consider robustness in the face of error-prone quantum hardware. Dynamic quantum programs need to deal with noisy measurements. Relatedly, quantum computation can in theory be more energy-efficient than classical computation, but there is currently a lack of in-depth analysis of the in-principle energy use of quantum computation. This project will quantify the effect of dynamic measurement on the robustness of quantum programs, letting the programmer trade off robustness and energy use against quantum measurements. This project provides Dynamic and Universal Quantum programming, which is more flexible, more scalable, and more verifiable.

Multiple myeloma is the second most common form of blood cancer and is a cancer of plasma cells, a type of white blood cell, which normally help to fight infections through the production of antibodies. Patients with multiple myeloma develop complications including low blood counts (anaemia), kidney damage, and bone damage including fractures which can cause significant symptoms. Multiple myeloma progresses from asymptomatic precursor conditions, but most patients are diagnosed at the active, symptomatic stage. There are treatments for multiple myeloma, but it remains almost always incurable, and most patients will die because of their myeloma. In multiple myeloma there are changes in the genes of the cancerous cells which can give rise to different behaviours and outcomes with treatment. These genetic changes can include gains or losses of whole or parts of chromosomes (copy number abnormalities), movement of genes between chromosomes (translocations), and changes in the sequence of genes (mutations). We know that some of these genetic changes are linked with worse outcomes despite treatment (termed high-risk genetics). Chromosome 13 is often lost in multiple myeloma and is one of the most common genetic changes, seen in about half of patients at diagnosis. The presence of chromosome 13 loss is associated with progression from the asymptomatic precursor conditions into symptomatic disease. Whether chromosome 13 loss itself is linked with worse outcomes in multiple myeloma is not entirely clear but it is seen more commonly with other high-risk genetic features and due to this, overall patients who have this abnormality have inferior outcomes despite current treatments. However, the impact of these changes on the myeloma cells remains largely unknown and we need a better understanding as it could make an ideal candidate for targeted treatments. This project has two linked aims: 1. To characterise the effect of chromosome 13 loss in myeloma genetically I will perform gene sequencing in samples from patients with newly diagnosed multiple myeloma enrolled into a clinical trial, including those with and without loss of chromosome 13 to assess the impact of this abnormality on other chromosomes and genes as well as on RNA (the intermediate step between DNA and proteins within the cell). With this information, I aim to improve understanding of: 1.What happens to other genes and why this might happen 2.Why some genetic events are seen more commonly with one another 3.How chromosome 13 loss may impact on proteins (which are the drivers of behaviour) in myeloma cells 2. To characterise the effect of chromosome 13 loss in myeloma functionally In myeloma cells which grow in the laboratory (myeloma cell lines), which have the normal two copies of the chromosome, I will use a recently described gene editing technique to create cells which have lost one of these copies mimicking what we see in some patient samples with myeloma. This will enable these cells to be grown and compared with those cells with the normal two copies in functional experiments. The advantage of this approach is that this will be the only significant difference between these cells and therefore the specific effects of this abnormality can be studied. These functional studies will aim to understand the impact on: 1.How these cells grow 2.How these cells respond to current myeloma treatments 3.How this change specifically impacts proteins in myeloma cells 4.Whether any of these changes can be targeted with new treatments The overall aim therefore is to improve the outcomes of patients with multiple myeloma who have loss of chromosome 13 through improving understanding of this genetic event on their cancer and how we may be able to treat this in a targeted manner.

This is a follow on proposal to the ongoing project "From Lima to Canton and Beyond: An AI-aided heritage materials research platform for studying globalisation through art", which set out to investigate the large group of ethnographic and selected scientific watercolours (e.g. maps and botanical drawings), made for export to Europe or North America by local artists in north-western Latin America and Asia from 1780 to 1850. Inspired by the Enlightenment, these works were the result of the European colonial powers such as Britain and Spain, collecting information from around the world via local officials in their colonies, but are now widely dispersed in public collections in the UK and US. The aim was to solidify our understanding of the large corpus (several thousands) of ethnographic works, on the one hand, and maps and botanical drawings on the other, by linking scientific analysis of artist materials such as pigments and paper to parallel research in art history, social and economic history, biography, and artistic analysis (connoisseurship) - establishing datasets combining analytic physical description with documentation of places of manufacture, names and locations of collectors, provenance (collection histories) of objects, and groupings of works by attributions to different artistic hands. Among the secondary objectives is to understand the global cultural and economic connections from Latin America to Asia and Europe. In the current project we visited a diverse range of cultural organisations from university libraries and museums, national libraries and archives, national museums, learned societies. The follow on project is informed by the feedback we received in discussion with the various partners of the project, advisors, consultants and others including those on European and UK research infrastructure projects (IPERION HS, E-RIHS, DigiLab, RICHeS, TANC) or those in receipt of infrastructure investment (AHRC Capco) of the needs as follows: 1) Active dissemination of a well-tested heritage material analysis workflow to the heritage science community to improve efficiency through the AI-assisted tools that ensure thorough but efficient analysis 2) Addition of a digital tool to streamline the workflow from data collection to interpretation and public engagement 3) Addition of Filipino collection that potentially fills the gap between Peruvian watercolours and their Chinese copies on pith from Canton to enhance our understanding of early 19th century global circulation of ethnographic watercolours - studying new collections naturally leads to engagement with new cultural organisations 4) Including the American and Dutch activities during this period using either new data or data collected from past AHRC projects 5) Inclusion of detailed analysis of the paper substrate in addition to spectral analysis of the paper through interaction with paper conservators 6) Dissemination to curators and the general public of the artist materials from different cultures, geographic locations and for different consumers studied in this project, which covers Peru, Colombia, China, Japan, Southeast Asia, the Indian subcontinent, Iran and selected European and American artists who visited these locations and co-created with local artists. Such engagement will showcase the benefits of interdisciplinary research and how scientific analysis of materials brings a different perspective to historical research.