Imagine a world where every fleeting thought and trivial detail were permanently etched into your long-term memory. Your cognitive faculties would quickly become overwhelmed with irrelevant information, hindering your ability to focus on what truly matters. Memory triage is the brain's solution to this dilemma. When we sleep, it selects and strengthens the memories that are most relevant, significant, or emotionally charged while allowing less crucial information to fade away. In our age of information overload and digital distractions, our memory systems are constantly under pressure. As we absorb vast amounts of data daily, our brains must efficiently prioritise what to remember and what to discard. Failure in this process can lead to cognitive overload, reduced productivity, and heightened stress. Additionally, as we age, the quality and duration of our sleep tend to decline. This in turn can affect memory consolidation, a sleep-dependent process, leading to memory problems and cognitive decline. Understanding the mechanisms behind memory triage, and its relationship with sleep, can inform interventions to alleviate these age-related memory issues, enhancing the quality of life for older individuals. In this proposal we will examine neural replay, the spontaneous reactivation of memory traces by the hippocampus, which we hypothesize to be the mechanism central to the memory prioritisation process. We will test our model, where replay activity in the awake state tags important memories that should be prioritised later during sleep, which then increases the amount of replay for this memory during sleep, which speeds up the consolidation process. We will use a combination of optogenetics, electrophysiology, pharmacology, and behaviour to interrogate the relationship between awake and sleep replay, within the context of memory prioritisation.

OCT-OVA is an innovative, multi-lab, multi-disciplinary project that straddles both basic and translational science. It aims to investigate how a single neurotransmitter receptor, and highly promising target for vector control, is necessary for viable egg production in female mosquitoes. In the process, OCT-OVA will provide both big data and transgenic resources for the community and give evolutionary insight into what might be a distinct system for the neuromodulation of fertility in a facultative blood-feeder. Mosquitoes require protein-rich blood in order to lay eggs, and it is this blood-feeding behaviour which leads to the spread of debilitating diseases such as malaria. Once they have acquired a bloodmeal, the process of ovulation begins, followed by fertilisation. We have found that mutation of the gene encoding Octbeta2R leads to a complete disruption of fertilisation. Octbeta2R is a G Protein- Coupled Receptor (GPCR) that is bound by octopamine - a neuroactive molecule that in invertebrates, acts as the functional homologue of adrenergic transmitters. GPCRs are highly "druggable". Molecules that block Octbeta2R could thus act as mosquito contraceptives, preventing them from laying fertile eggs and controlling populations. However, the cause of this phenotype is unclear. Which cells are responsible for the defect and what do they do? I would like to use state-of-the-art methods to molecularly profile the female mosquito reproductive system. I will then identify clusters of cells that express Octbeta2R, and using transgenic drivers and responders, explore which cell types are responsible for the fertility defect. This project will bridge the gap between genes, circuits and fertility, and reveal how molecular cell state influences organismal reproductive state. Understanding Octbeta2R-dependent mosquito sterility will galvanise the development of much needed mosquito control tools, in line with EU strategies for epidemic management and preparedness.

Tuberculosis (TB) remains one of the leading infectious causes of death. At present, the World Health Organization (WHO) recommends treating drug susceptible pulmonary TB (pTB) with a two-month course of Rifampicin, Isoniazid, Pyrazinamide and Ethambutol (RHZE), followed by a four-month course of Rifampicin and Isoniazid (RH). Some patients are unable to adhere to this protracted treatment and discontinue treatment prematurely. This often results in TB recurrence and development of drug resistance. TB requires protracted treatment because Mycobacterium tuberculosis (Mtb), the causative agents for TB, exists as a heterogenous population of bacilli, a fraction of which are tolerant to anti-TB agents. New TB treatment regimens that are more effective against drug-tolerant Mtb would therefore help improve outcomes of TB treatment. While more than 800,000 people are successfully cured of TB every year, all-cause mortality rates are 6 times higher in TB survivors than in the general population. This is in-part because up to half of pTB survivors sustain severe lung damage and develop post-tuberculosis lung disease (PTLD) . At present, there are no interventions for preventing or managing PTLD. PTLD is largely caused by host responses to Mtb. Anti-Mtb host responses also promote Mtb drug tolerance. Host-directed therapies could therefore help alleviate both PTLD and Mtb drug tolerance. More than a hundred host molecular pathways, and even more genes, have been implicated in the evolution of PTLD and Mtb drug tolerance. It remains unclear which of these genes, or combinations of genes, should be targeted to reduce Mtb drug tolerance and/or PTLD. While single-gene-knockout experiments can be performed relatively easily, it is difficult to simultaneously knockout multiple genes to identify the ideal combination of genes to target to reduce Mtb drug tolerance or PTLD, given the myriad possibilities. Further, as most of the genes and pathways have been identified from animal models and in-vitro experiments, their relevance in natural human Mtb infections remains unclear. We, therefore, propose to leverage 1) single-cell transcriptomics of lung airway cells from pTB patients, 2) functional assessment of lung injury, and 3) sputum microbiologic assessment to identify the host cell types and molecular pathways associated with Mtb drug tolerance and PTLD. We will then leverage computational biology and machine learning to perform in-silico knock-up and knock-down experiments to hasten identification of single or combination host-directed therapeutics for reversing host transcriptomic perturbations associated with Mtb drug tolerance and PTLD. Finally, we will test the predicted compounds in an ex-vivo Mtb-human alveolar macrophage infection model.

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.

Here we propose to investigate the synthesis and characterization of novel classes of metal-based nano-structuredparticles and composites with well-defined geometry and connectivity. The materials are obtained by a modular bottom-upapproach of metal-containing nanoparticles (NPs) with core-shell architecture as well as nanocomposites from metal NPsand block copolymers (BCs) as structure-directed agents. The aim of the proposed program is to understand theunderlying fundamental chemical, thermodynamic and kinetic formation principles enabling general and relativelyinexpensive wet-chemistry methodologies for the efficient creation of multiscale functional metal materials with noveloptical property profiles that may revolutionize the field of nanophotonics/plasmonics/ metamaterials, enabled by nmscalecontrol over the underlying structure over large dimensions. The proposed research includes synthesis of allnecessary organic/polymer and inorganic components, characterization of assembly structures using various scattering,optical and electron microscopy techniques, as well as thorough investigations of their optical properties includingsimulation and modeling efforts, and work towards major novel optics in the form of sub-wavelength imaging, highlysensitive hot-spot arrays over macroscopic dimensions for sensing, and sub-wavelength waveguiding. While the mainfocus of our proposed work lies on non-magnetic materials and the assessment of linear optical properties of thefabricated compounds, a crucial point is that we are aiming at synthesis approaches that can be generalized over a widerclass of materials systems. A final thrust of the program addresses a particularly topical exploitation area, where we willintegrate specific plasmonic structures into hybrid solar cells and characterize and optimize plasmon enhancedphotogeneration of charges and subsequent solar cell efficiency. If successful this will lead to a new generation, or classof photovolatics, namely plasmonic solar cells.