University of Bristol

UKRI Gateway to Research · FY 2024 · 2024-07

Freshwaters are losing biodiversity at a higher rate than any other planetary domain. A wide range of stressors are driving this trend, of which climate change and increasing nutrient delivery from food production and consumption are ubiquitous. Research to date on nutrient enrichment impacts on freshwater biota has been limited by the physical challenge of experimentation in a rapidly changing environment, and a narrow perception of bioavailable nutrient forms. It has focused on species-specific responses to inorganic nutrient forms, often in vitro or in lakes, rarely for flowing waters under ambient conditions, and usually for microbial or planktonic organisms, ignoring the responses of other biotic groups, community level responses to enrichment, and the combined impacts of the range of bioavailable organic compounds in freshwaters. Transformational research is needed to update current nutrient cycling theory for stream ecosystems, shifting from research explaining how part of the ecosystem responds to a limited range of stressors, to fundamental, holistic theory explaining how whole ecosystems respond to a broad palette of stressors. I will lead a multidisciplinary team to tackle this challenge, applying innovative techniques in molecular scale analysis, stable isotope probing and environmental genomics, under field and climatically-altered conditions. We will then use new data-driven modelling to understand relationships between taxonomic and functional shifts in response to dissolved organic matter (DOM) and inorganic nutrient exposure, revealing environment x gene interactions in biotic responses to nutrient and climate stressors. This will advance current theory and transform our understanding of the impacts of the full nutrient portfolio on freshwater ecosystems, revealing the specific role of DOM as this varies according to the composition of the DOM pool, species composition of the ecosystem, stream stoichoimetry and environmental character.

UKRI Gateway to Research · FY 2024 · 2024-07

The Nobel prize-winning technology of cryogenic Electron Microscopy (cryoEM) has transformed structural biology research, furthering our knowledge of biology, providing novel insights into the molecular mechanisms of health and disease, enabling drug design, and driving engineering biology efforts. Until recently, high-resolution cryoEM was limited to purified proteins and complexes, which necessitates removing the protein from its native environment. We therefore lose in situ information, which contains the functional data about the cellular context. Cryogenic electron tomography (cryoET) provides this information, but samples must be less than 200 nm thick for high-resolution imaging, whereas mammalian cells are >5000 nm thick, which completely precludes imaging. To produce thin samples, the optimal method is focussed ion beam (FIB) milling, performed at cryogenic temperatures (-180°C). Such a cryo-FIB removes material with nanometre precision, leaving behind a lamella - a thin slice - through the sample (e.g., cell, tissue, biopsy, etc). Cryo-FIB-SEMs contain integrated fluorescence modules that allow for targeted milling towards the fluorescent regions/molecules of interest, making the process more efficient and time-saving. CryoEM in the south-west of the UK is world-leading and highly collaborative, supported by the GW4 facility for high-resolution cryoEM. It is used extensively by the Universities of Bath, Bristol, Cardiff and Exeter (GW4) and beyond. Since 2017, the facility has enabled the determination of dozens of structures. However, research has so far largely focussed on single-particle analysis approaches. Driven by the aspiration and need of GW4 researchers to incorporate in situ structural biology using cryoET, the Universities of Bristol (the host institute) and Exeter have recently invested in equipment and personnel to expand the region's state-of-the-art cryoEM capabilities. In particular, the recent recruitment of Thom Sharp, a cryoET specialist, to Bristol was borne with that vision in mind. We seek to acquire the first cryo-FIB-SEM in the south-west of UK dedicated to strengthen in situ structural biology research in the region. Various types of integrated fluorescence cryo-FIB-SEMs are available; some are designed for the one single task of lamella preparation, which limits the application spectrum of such an (expensive) instrument. Here, we are applying for a microscope that, in addition to the targeted lamella preparation, will allow for "routine" cryo-SEM applications and uniquely incorporate elemental analysis capabilities (EDS) under cryo-conditions without compromising the cryo lamella preparation capabilities. Such an instrument would provide completely novel capabilities for GW4 but importantly will also replace an over 18-year old cryo-SEM and integrate the new capabilities (targeted lamella preparation and cryo-EDS) with existing ones ("routine" cryo-SEM) into 1 instrument to increase sustainability rather than running 2 individual instruments. The new instrument will support a very wide range of research projects, and herein we demonstrate the need for these new capabilities by 4 detailed case studies from GW4 researchers supplemented with the titles of an additional 18 planned projects, addressing fundamental biological understanding, advancing cell biology for an integrated understanding of health, engineering biology, and technology development, all key BBSRC strategic areas.

UKRI Gateway to Research · FY 2024 · 2024-07

We request funds to purchase a UK-unique Atomic Force Microscopy (AFM) technology platform to enhance the bioscience research in multi-disciplinary research programmes across life, health, physical and environmental sciences. The platform provides holistic characterisation with direct correlation, for the first time in the UK, of AFM with high-resolution fluorescence optical microscopy, Raman spectral chemical analysis and nano-injection/manipulation over length scales from single biomolecules to tissue, all in biologically relevant environments. Specifically, we will procure a Raman-ready NanoWIzard V microscope with Leica DMi8 fluorescence microscope, Cellhesion head unit, Biomaterials Workstation, FluidFM and Tip Aligned Optics (TAO) coupled to a dedicated inVia Raman spectrometer, which will enable cutting-edge new bioscience for more than 20 research groups who lead over £35M of current funded projects. This will integrate capabilities for: Correlative AFM with fluorescence to study live engineered tissues with potential to develop new technologies for artificial musculoskeletal grafts; Total range of material stiffness characterisation in applications from unfolding sequences of individual synthetic biomolecules to cellulose-based spacers for future battery technologies and fundamental immune cell research; Hollow cantilever injection to insert materials in very localised (sub-micrometre) areas of samples, for example introducing bacteria to a localised position in dental treatment technologies and nucleic acid nanoplexes to targeted regions of plant cells and tissues; Correlative AFM and Raman spectroscopy enabling simultaneous detailed nanometre mapping with chemical composition analysis of samples such as in stem-cell scaffolds and artificially engineered protocell technologies; A Biomaterials workstation and environmental control cells ensure that experiments can be conducted in all necessary media, from ambient with controlled humidity for the investigation of aerosol droplets to harsh, extreme pH buffers. This unique combination of capabilities in a single AFM technology platform will establish a leading UK capability in AFM characterisation and enable multiple time-intensive AFM experiments to be conducted in tandem to reduce bottlenecks in a wide range of research projects across Biotechnology and Biological Sciences. The breadth of the science enabled will cover everything from the visualisation of peptide sheet growth, imaging communication networks across synthetic protocells, watching the in-situ formation of next-generation nanomaterials for spray-on crop protection, to the measurement of electrostatics in bee antennae and real-time imaging of immune cells adapting their own molecular composition.

UKRI Gateway to Research · FY 2024 · 2024-07

In many inherited genetic diseases, where no cure exists, the underlying mutation results in protein misfolding and subsequent mis-trafficking. However, some of these proteins retain partial function and restoring their folding and trafficking using small compounds may provide new therapeutic cures. An archetypal exemplar of this, which we have recently published on, is nephrotic syndrome. Steroid resistant nephrotic syndrome (SRNS) is a devastating disease resulting from breakdown of the kidney filtration barrier. It usually leads to end stage renal disease (ESRD) despite the use of prolonged and toxic immunosuppression, with associated lifelong costs of dialysis and transplantation. Mutations in the slit diaphragm protein podocin result in the commonest form of monogenic SRNS.  Podocin localizes to the podocyte slit diaphragm, at the cell surface, and is crucial for the filtration process. Most disease-causing mutations of podocin cause it to be trafficked incorrectly resulting in aberrant formation/function of the slit diaphragm complex. The R138Q mutation of podocin, one of the most common missense mutations in the podocin gene results in podocin being retained in the endoplasmic reticulum. We have used a podocyte cell line that we generated from a patient with the R138Q mutation in podocin, resulting in podocin misfolding and hence mis-trafficking, to identify compounds that could rescue this defect. Excitingly, we have shown that this mutation can be corrected by a tool compound, c407 which inhibits binding of the misfolded protein to a cellular chaperone, resulting in complete rescue of podocyte function in vitro, and complete correction of the disease in vivo in an analogous mouse model of the disease. Importantly c407 also rescues trafficking and function in cells and/or animals with mutations in cystic fibrosis (CFTR delta507) and alpha-1-antitrypsin disease. These results were discussed during partnering discussions with a number of potential licensees who all liked the biology, recognised the unmet need but did not consider the chemistry of c407 was progressable. Nevertheless, this led to a successful application to European Lead Factory, to support high throughput assay development based upon our unique and highly representative tools, and ran two screens to produce a qualified hit list of 49 compounds. The QHL was reviewed for biological activity, physiochemical properties, synthetic tractability, and ease of analogue generation by BioAscent and independently by Professor Varinder Aggarwal (University of Bristol), and 2 highly experienced commercial medicinal chemistry consultants, Dr John Dixon, (JD International Consulting Ltd) and Dr A.Mete, (Medsyndesign Ltd). This resulted in the hit list being reduced to 6 drug-like and synthetically tractable compounds with nanomolar potency. We now wish to reconfirm these with DPGF funding and carry out safety and ADME studies before embarking on formal hit to lead activity for a compound which cures this and potentially other protein mis-trafficking diseases.

UKRI Gateway to Research · FY 2024 · 2024-06

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

UKRI Gateway to Research · FY 2024 · 2024-06

Australia

UKRI Gateway to Research · FY 2024 · 2024-06

The proposed project seeks to address the current deficiencies in antivenom treatment for snakebite envenoming (SBE) and alleviate the substantial burden of mortality and morbidity caused by this Neglected Tropical Disease. SBE affects economically and medically disadvantaged farming communities in Asia, sub-Saharan Africa, and Latin America, leading to up to 138,000 deaths and 400,000 disabilities annually. Currently, a major obstacle stems from the weak efficacy of existing antivenoms derived from hyperimmunized animals, requiring the usage of multiple vials and leading to increased adverse effects and treatment costs. Additionally, the wide variation in snake venoms at different taxonomic levels, especially with low-molecular mass toxins displaying limited immunogenicity, further complicates the issue with antivenom development. The proposed project is part of the larger ADDOvenom initiative but will have a specific focus on neutralizing the effects of neurotoxins responsible for descending neuromuscular paralysis after envenoming by Dendroaspis mambas. The project will select toxin candidates from mambas venoms and use them as a basis for designing consensus-toxins with cross-affinity towards different neurotoxins. These engineered consensus-toxins and original toxins will then be recombinantly produced to search for effective binders. To identify the specific agents with high affinity for the target toxins, the project will employ the advanced technique of Ribosome Display. This involves a diverse DNA library encoding ADDobodies, which are adenovirus-based protein scaffolds with the capacity to bind various molecules. Through in vitro evolution, these ADDobodies will be refined to effectively neutralize neurotoxins, offering a promising treatment for envenoming by the Dendroaspis mambas.

UKRI Gateway to Research · FY 2024 · 2024-06

Using "Smart Data" from sources like supermarket loyalty cards could be a big help for health and social science research. Smart Data are like logs of our actions when we use different services, such as shops. Research using shopping records has already taught us about health issues, from diets and food security; to detecting cancer early and understanding mental health in different groups of people. Shopping records can provide us with detailed information about how people behave, such as what types of food they buy, food budgeting, lifestyle choices, and health related habits such as smoking. But using this data for research comes with challenges, like making sure it's accurate and that people trust it's used ethically and securely. Our project aims to identify the best way to link Smart Data to data from participants in Longitudinal Population Studies (LPS). LPS are groups of people that researchers track over many years, often since their birth. Scientists conduct medical exams and ask questions about participants lives through surveys. These studies help us learn how various health and social issues unfold over time, and they also pinpoint factors like the environment that might influence these developments. By linking shopping records into LPS, we can improve the data and use it to answer new questions and provide new insights into how people behave and trends in the population. These linked data will also help other researchers to understand biases and data quality issues in the shopping data. Understanding of biases will make research more accurate and fairer by being more inclusive of different population groups. However, to be able to link the data, we need first to understand what participants from longitudinal studies think about these kinds of data being used for health and social science research. We will need to be careful about the practical, ethical, and other concerns when doing this across different LPS whose participants have different characteristics. For example, elderly participants may feel differently to younger participants, and views may differ in different parts of the UK. We also know that many people might not know much about this type of research, so in this project we will develop communication materials with public and participant contributors. To handle these issues, we want to work closely with the LPS participants, LPS leaders, data managers and broader LPS community. We're teaming up with the UK Longitudinal Linkage Collaboration (UK LLC), which brings together data from 24 UK LPS in a safe environment. This collaboration helps us create a consistent approach across multiple studies. We will work with public contributors from UK LLC to ask them how they feel about shopping data being used for health and social science studies, as well help us to design participant communication materials about linking shopping data, such as videos and infographics. We will further work with five partnering longitudinal studies - the 1970 British Cohort Study, Millennium Cohort Study, Generation Scotland, Twins UK, and Understanding Society - to engage their participants to help us to understand whether such data linkage is acceptable and possible in these studies and other studies too. This will mean all our thinking is properly informed by public and participant views. Over a year, our project aims to lay the groundwork for using loyalty card data in health and social science research. We want to explore how feasible and acceptable it is to use shopping data with different LPS, understand what worries people might have, create ethical guidelines for future studies, and figure out how to communicate with the public about it. We're also building a community of professionals and researchers interested in this type of research. This will provide the first step towards understanding how this kind of data can be used ethically and effectively across different studies.

UKRI Gateway to Research · FY 2024 · 2024-06

The UK composites industry faces an imperative to prioritise sustainability. The urgent need to reduce impact on the environment and ensure the availability of resources for future generations is critical to securing a prosperous and resilient future. Composite materials are crucial for delivering a Net-Zero future but pose several unique technical challenges. Sustainable Composites Engineering defines a holistic means of achieving environmental neutrality for composite products through production, service, and reuse. It incorporates the pursuit of more sustainable composite materials, with a mission of creating inherently sustainable composite solutions, able to perform in diverse environments, and made using new scientific advances, and new energy efficient, waste-free manufacturing procedures. Our proposed CDT in Innovation for Sustainable Composites Engineering will address the challenges by developing a workforce equipped with the skills to become leaders in the future sustainable economy and support UK industry competitiveness. Our CDT is jointly created by the Bristol Composites Institute, the University of Nottingham and the National Composites Centre (NCC). In addition to the EPSRC funding our CDT is also supported by industry and we have received 27 letters of support from companies in the UK Composites sector: Aerospace (Airbus, Rolls-Royce, Dowty, Leonardo, GKN), Defence (QinetiQ, AWE, BAE Systems), Automotive (Gordan Murray, JLR), Wind Energy (Vestas, EDF-Renewables), Marine (Tods), Rail (Network Rail), Oil and Gas (Magma Global), Hydrogen (Luxfer) alongside material suppliers (Hexcel, Solvay, iCOMAT, SHD), and specialist design and manufacturing companies (Pentaxia, Actuation Lab, LMAT, Molydyn), as well as RTOs (NPL, NCC). The total industrial commitment to our CDT is >£10M, with>£4M from NCC. From this it is clear that our CDT fits the Focus Area of Meeting a User Need. The CDT will provide a science-based framework for innovative, curiosity driven research and skills development to facilitate composites as the underpinning technology for a sustainable future. Critically, the CDT will offer an agile doctoral educational environment focused on advanced competencies and skills, tailored to industrial and commercial needs, providing academic excellence and encourage innovation. The ambitious goal of spanning Technology Readiness Levels (TRL 1-4) will be achieved by having a mix of university-based PhDs and industrially-based EngDs . Fundamental industrial sponsored research will be carried out by PhD students based at the Universities. The EngD students will spend 75% of their time in industry conducting a research project that is defined industry. Students will complete their doctoral studies in four years, the doctoral research will run concurrently with the taught component, so students are immersed in the research environment from the outset. The bespoke training programme demands the critical mass of a cohort. A specific role on our Management Board focuses on maximising cohort benefits to students. The cohort continuity across years will be ensured by a peer-to-peer mentoring programme, with all new students assigned a student mentor to support their studies, thereby creating an inclusive environment to provide students with a sense of place and ownership. Methods for developing and maintaining a cohort across multiple sites will be supported by our previous experience with the IDCs strategy and by: -A first year based in Bristol with students co-located to encourage interaction. -In-person workshops in year 2 credit bearing units and professional activities. -Peer-to-peer individual mentoring, as well as in DBT and credit-bearing workshops. -Annual welcome cohort integration event. -Annual conference and student-led networking. -Internal themed research seminars and group meetings -Student-led training and outreach activities.

UKRI Gateway to Research · FY 2024 · 2024-06

Few problems in fundamental physics are as clearly motivated or as important as discovering the nature of the elusive dark matter that accounts for most of the mass of the universe. Direct detection experiments located deep underground are searching for the rare interactions of these well-motivated, relic particles in very sensitive detectors. Liquid xenon (LXe) technology has led these searches for over a decade. Recently, the top international collaborations in the field have come together in the XLZD consortium to build the definitive experiment: one able to discover or rule out electroweak-scale particle dark matter in the accessible parameter space remaining above the very challenging neutrino background. Exciting opportunities exist also in neutrino physics, including establishing the existence of neutrinoless double-beta decay; this is another paradigm-shifting discovery which may be accessible to such an experiment, which could explain the matter-antimatter asymmetry in the universe. This proposed 'rare event observatory' will deploy a LXe detector with up to 80 tonnes of 'active' mass in an ultra-low-background experiment to address these and other questions, at least two of which could entail Nobel-Prize worthy discoveries. This Pre-Construction project prepares the UK contribution to the XLZD experiment and builds the case to bring this ambitious international experiment to the UK. STFC is developing a major new underground laboratory at the Boulby mine, and XLZD would be the centrepiece of the new state-of-the-art facility. A future construction project must be carefully prepared, and this development work is delivered through this Pre-Construction project. The proposed UK contribution to XLZD includes major experimental hardware systems, especially those most naturally suited to the host nation; these will be designed and prepared in this phase. In addition, we will deliver with key industrial partners bold programmes for clean manufacture underground, for engineering and skills development, and for environmental sustainability. These programmes relate to challenges that must be addressed, but which we deliberately develop into opportunities: to provide return to UK industry and wider economic impact, to develop capabilities that support future STFC and UKRI projects, and to be a pathfinder in how Big Science moves towards Net Zero.

UKRI Gateway to Research · FY 2024 · 2024-06

The aim of this Centre for Doctoral Training (CDT) is to equip students with essential interdisciplinary skills needed by industry and to deliver cutting edge research in the area of superconductivity. The unique properties of superconducting materials mean that they can deliver revolutionary technologies which will help to decarbonize our energy production and improve healthcare. Superconductors are also an essential component in many quantum devices such as those used for quantum computing. The promise of limitless carbon free power promised by magnetically confined plasma nuclear fusion reactors can only be realised using superconducting magnets. Other major applications under development, which also will contribute to reducing carbon emissions include superconducting cables for electrical power transmission, light and powerful motors and generators for electric and hybrid power aircraft, superconducting magnetically levitating trains and high efficiency generators for wind-power generators. Development, manufacture, and deployment of these technologies needs people with the skills our CDT will deliver. Superconductors are also an essential component in magnetic resonance imaging (MRI) machines used for medical diagnosis and this forms the majority of the current £7 billion per annum market in superconductors that is projected to double by 2030. Development of improved superconducting materials will transform MRI both in terms of reducing cost and thereby availability and enabling higher magnetic field strengths that increase resolution and enhanced diagnostic capabilities. We will capitalize on the UK's established leadership in superconductivity through the development of a CDT with cohort-based training that will engender teamwork and an interdisciplinary approach in close collaboration with industry and international research facility partners. This is crucial to drive the development of these groundbreaking superconducting technologies and to empower our graduates with the combination of technical and personal skills sought after by industry. The CDT brings together graduate superconductivity training in the Universities of Bristol, Oxford and Cambridge across their Physics, Material Science, Engineering and Chemistry departments. The CDT is created in partnership with 26 industrial companies, international research institutions and other educational institutions. Our training programme includes lecture-based learning, extensive practical training in relevant techniques and experimental methods as well as real-world experience at implementing the knowledge gained within projects based at one of our partners. The CDT will form a nucleus for the UK superconductivity community offering training and networking opportunities to those outside of the CDT.

UKRI Gateway to Research · FY 2024 · 2024-06

The major obstacle to a cure for HIV-1 infection is the presence of viral reservoirs formed by latently infected CD4 T cells, in which the virus is transcriptionally silent and thus hidden from the host immune response and shielded from current antiretroviral therapies. To overcome this barrier, it is essential to find a cellular signature of latent HIV-1 infection allowing the detection and the selective targeting of latently infected cells. However, the identification of specific markers of latency has proven so far difficult and few in vitro studies have translated into clinical trials. One potential reason is the difficulty to recapitulate with standard 2D in vitro cultures the complex tissue environment in which the viral reservoir is mainly seeded in vivo, the lymph node. In addition, the direct study of lymph nodes is hampered by the need of an invasive procedure for their isolation. This project is aimed at leveraging my expertise in working with 3D immune cell cultures to study latency markers of infection in a tonsil-derived organoid system that closely recapitulates the lymph node environment while conserving the tunability and practicality of standard in vitro systems. With this tool, I will focus the research of latency markers on cellular metabolic imbalances induced by HIV-1 infection. This line of study is pursued by my host lab and has already been proven promising, having led to the reduction of the viral reservoir in a macaque model and in a phase IIa clinical trial. I plan to obtain a comprehensive picture of the metabolic landscape of latently infected CD4 T cells in a lymphoid organoid, which will guide the identification of selective markers of latency. The organoid system will then be employed to test therapeutic candidates, which will be identified by in silico screenings, for their ability to kill latently infected cells in their native environments: the lymph node organoids and finally in lymphoid tissues of people living with HIV.

UKRI Gateway to Research · FY 2024 · 2024-06

UKRI has announced investment in new infrastructure projects. The funding will provide world-class facilities and equipment to help maintain the UK's position as a science superpower in line with the ambitions set out in the government's Science and Technology Framework. The funding includes £23 million (including contingency funds and indexation) for individual wind tunnels, an experimental database and upgrades to existing facilities across the UK's National Wind Tunnel Facility network to transform UK research capability in fluid dynamics. The aim is for NWTF+ to deliver a network of world-leading wind tunnels. It will address societal and industrial grand challenges including: - the generation of net zero technologies - advances in emissions reduction - future technologies for transport, energy, and healthcare At Bristol, the UKRI funding will be used to invest into three new state-of-the-art facilities: (1) A multi-purpose boundary layer wind tunnel facility, (2) a new pressure-neutral acoustic wind tunnel, and (3) a novel highly instrumented propeller testbed. The new facilities are expected to enable a wide range of academic and industrial research for the next 20-30 years and turn Bristol into a research hub for research in environmental aerodynamics, pollution, aeroacoustics, propulsion, etc. The new facilities will also place Bristol and the UK at the forefront of research in these areas and enable the UK partners to join major international collaborations. The new facilities will also play a major role in the training of the next generations of highly-skilled researchers and engineers in some strategically important fields of research.

UKRI Gateway to Research · FY 2024 · 2024-06

An ideal single-photon source will produce a single-photon triggered by the push of a button. Remarkable progress has been made in recent years to the point where photons from such sources can be delivered to an end user with a probability exceeding 50%. The downside to current state of the art single-photon source technology is the high barrier to entry: sources are triggered by pulsed laser systems, operate at cryogenic temperatures, and frequently require employment of specialist staff all of which exacerbates costs. The result is that for many applications, potential users opt for simpler and more cost-effective probabilistic sources, where the single photon probability is capped at <10%. COMPHORT tackles this challenge by developing a user-friendly "plug & play" device that will feature single-photon generation probabilities exceeding 80% without requiring bulky laser systems or cryogenics. To achieve this, we take advantage of the exceptional optical properties of single photons generated by quantum emitters in hexagonal boron nitride, when operated under ambient conditions (20 degC). We will then enhance this by directly integrating emitters into bespoke open optical cavities, which will be packaged into a robust assembly to provide reliable operation. Further, a pump LED will be monolithically integrated into our open cavity design to trigger single-photon emission, providing the end user with a simplified electrically driven device. Both the quantum emitters and optical cavity can be engineered to suit a range of quantum applications (from communications to metrology or imaging). To showcase the suitability of our technology for real-world applications, we will implement free-space quantum communication protocols at the laboratory-scale and in a metropolitan free-space link in Berlin city. This quantum application is crucial to interconnect networks where optical fibers are not available (such as disaster zones, or field hospitals) and/or a changing geo-localisation between nodes is required (autonomous car, aeroplanes, drones, etc). The project will develop in close collaboration with the SME partners Nanoplus GmbH and QLocked, bridging the connection between our technology outcomes and the quantum photonics market. The outputs of COMPHORT are aimed at providing Europe with a valuable sovereign technology in an increasingly competitive quantum-enabled world economy

UKRI Gateway to Research · FY 2024 · 2024-06

Four decades after its identification, the human immunodeficiency virus (HIV) continues to infect almost 40 million people worldwide, causing hundreds of thousands of deaths each year. Infection by HIV mainly targets white blood cells and, if left untreated, can lead to a severe, potentially fatal, acquired immunodeficiency syndrome (AIDS). Antiviral drugs have been developed and have drastically improved the life expectancy and quality of people living with HIV. However, these drugs require lifelong administration, and do not lead to a cure. Importantly, HIV persists in a dormant (latent) form in a subset of white blood cells (called CD4 T-lymphocytes) for the entire lifespan of infected individuals. This latency allows the virus to elude antiviral drugs and the immune system. Several studies have been conducted with the aim to identify features of persistently infected cells that could allow us to specifically target these cells for elimination and, thus, potentially cure the infection. Although multiple features have been proposed, few have the specificity required for safe therapeutic application, and most of the studies have failed to decrease the frequency of persistently infected cells. No current treatment to target persistently HIV-infected cells is approved. One of the therapeutic approaches undergoing clinical testing is based on our research showing that persistently infected cells have specific alterations in energy metabolism. Our studies, as well as those of other groups, however, focussed on whole cells. In reality, most cellular energy production is located within highly specialised subcellular compartments. To allow us to identify functional, structural, and/or spatial features of metabolic regulation that distinguish cells harbouring the virus from those that do not, the proposed project will produce an in-depth characterization (identikit) of persistently HIV-infected cells. We will approach this work both using CD4 T-lymphocytes infected with HIV in vitro and using CD4 T-lymphocytes isolated from the blood of individuals living with HIV. We will first separate cells infected in vitro based on the presence and stage of infection, and then individually study the main cellular sites of energy production and storage (i.e., nucleus/cytoplasm and mitochondria). The data obtained will comprehensively capture the content of proteins and metabolites, as well as the genetic regulation underpinning their production. These data will be computationally combined and complemented by experimental assessments of the functionality of each major cellular metabolic step in order to identify distinguishing features of persistently infected cells that can be explored for their potential to serve as therapeutic targets. We will then use computer models to predict effective drug candidates and put these predictions in practice by testing drugs in the laboratory for their target affinity and ability to selectively eliminate persistently infected cells. Overall, this study will aim to provide a unified profile of metabolic determinants of HIV persistence and furnish pre-clinical evidence for novel therapeutic strategies to eliminate infected cells resistant to currently available antiviral drugs. Ultimately, this work could lead to a therapeutic approach to remove the virus from its cellular hideout in infected individuals.

UKRI Gateway to Research · FY 2024 · 2024-06

Staphylococcus aureus is a major human pathogen that causes a broad range of infections resulting in significant morbidity and mortality globally. Due to the constant threat of antimicrobial resistance, the WHO has placed S aureus on the list of priority pathogens for which the development of antibiotics and novel immunotherapeutics is urgently required. All successful pathogens have evolved mechanisms to resist host immunity which are intimately aligned with their pathogenicity. Importantly, the primary host response to S aureus occurs via complement. Complement is an elegant evolutionarily conserved system, playing essential roles in early defences by working in concert with immune cells to survey, label and destroy microbial intruders and coordinate inflammation. To tackle S aureus infection we have designed this project with two major goals: 1) Construct novel anti-infective immunotherapeutic fusion proteins which will bind to the surface of S aureus and disrupt essential virulence mechanisms while simultaneously activate the complement system, facilitating enhanced complement fixation and subsequent clearance by immune cells. 2) Develop a machine learning framework to predict the severity of S aureus infection. By combining genotype and virulence phenotype generated in this proposal, this aim will first identify and functionally confirm virulence signatures associated with immune evasion. Secondly, this data together with previously obtained clinical patient data, will be incorporated into mathematical and statistical models designed to predict determinants associated with poor infection outcome. Combined, these goals will address central issues regarding the treatment and disease management of multi-drug resistant S aureus infections.

Other NSERC · FY 2024

Multiplicative number theory, Liouville function, Riemann Hypothesis, Short intervals, Omega results