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Males of many different mammal, bird and invertebrate species respond to their social and sexual environment. These responses have profound effects on their reproductive success. For example, males of many species that perceive rivals transfer more sperm to females during mating, to increase their share of paternity. However, the complete pathway from the detection of cues from rival males, to effects on the composition of the male ejaculate through to ultimate reproductive success is not known. Nor do we know the effects on ageing for males of responding to rivals. The discovery of the pathway between rival detection and paternity represents the next key stage in understanding the evolution of male mating success. In this proposal we aim to provide the first case study, using the fruitfly. The fruitfly offers a unique opportunity, its genome has been sequenced and there are many different genetic reagents available with which to manipulate a male's perception of the number of rivals present. We have also generated a substantial amount of relevant and novel background data. For example, males respond to the presence of rivals before mating, and subsequently mate for longer when they do meet a female. More importantly, during those longer matings they transfer more of key ejaculate components, which increase the overall number of offspring fathered. Males appear to detect rivals by smelling a particular male pheromone. Importance for pure research: The work tackles questions of fundamental importance: how do males respond to rivals and what are the fitness consequences of doing so. When ejaculates are limiting (e.g. when males that mate just a few times become exhausted), males partition their ejaculates among different matings and different females, according to how many rival males are present. However, despite the wealth of studies showing that males do this, key questions remain: (i) what are molecular mechanisms by which males signal and perceive rivals? and (ii) what are the overall consequences, particularly the impact on ageing, for males that respond to the presence of rivals. These are the questions we will answer. Importance for applied research: Of equal importance, our work will provide techniques to improve insect pest control. Insect pests are the source of the world's most serious agricultural (and health) problems. Research is focusing on methods whose basic principles lie in biological control. However, males produced for control often have poor mating success. We aim to provide methods to improve this (e.g. simple husbandry rules to increase exposure to rivals or pheromones) using the fruitfly, which is the only species in which the relevant background data and genetic reagents are available. We plan to apply our findings to pests in the future. Methodology: We will manipulate male numbers and length of exposure to rivals, and the smell pathways that our work has highlighted as important. We can test the amount of ejaculate proteins transferred to females during mating using a method developed by our project partner, Mariana Wolfner from Cornell University. We can test for sperm transfer by staining and counting the sperm transferred. To test for the effects of responding to rivals on male ageing, we will compare the lifespan and reproductive success of males that mate following exposure, or not, to rivals. Timeliness and originality: Our proposal will provide the first investigation of the complete pathway by which males respond to rivals. The work is timely given the recent elucidation of smell receptors, our recent discoveries of changes to ejaculate composition in the presence of rivals and the recent surge of developments in genetic insect pest control.

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.

Despite the recent developments in breast cancer treatments, the high variability of cancer cells and their related drug resistance still pose a huge obstacle to improving clinical outcomes. It is now well-known that cancer cells must reprogram their cellular metabolism (chemical processes that occur within the cell to maintain life) to support rapid proliferation and promote acquired drug resistance. However, the underlying mechanisms regulating such biological changes are neither fully understood nor sufficiently treated. Only recently, with the advent of single cell analysis (a novel technique that allows the analysis of individual cancer cells), it has been possible to analyse changes at the cellular level that have helped in identifying four main breast cancer subtypes (i.e., Luminal A, Luminal B, TNB, and HER2 positive) and developing different treatment routes. However, patient survival remains low - especially for the most aggressive breast cancer subtypes - since cellular changes cannot be easily connected to an alteration in the metabolic state that promotes drug resistance. Moreover, the lack of specific tools to analyse a vast quantity of single cell metabolic profiles makes single-cell analysis at the metabolic level still impractical. This proposal aims at initiating an international collaboration between Teesside University (UK) and Cornell University (US) to characterise the metabolic profile of 32 different breast cancer cell types (i.e., cell lines) from the four main breast cancer subtypes to identify metabolic dysregulations and allow informed treatment decisions. Advanced computation techniques (i.e., artificial intelligence) will be applied to identify the metabolic reactions and changes responsible for cancer progression in each cancer subtype. The final objective of the proposed collaboration will be to elucidate the main differences among breast cancer subtypes at the metabolic level to inform the development of targeted drugs and support clinical decisions. First, mathematical techniques will be applied to develop metabolic models (through a set of mathematical equations) of 32 different breast cancer cell lines. These 32 models will mathematically describe the metabolic reactions taking place inside the different cancer cells. This will be achieved by integrating the expertise in metabolic modelling of the PI (Dr Occhipinti) with the knowledge of single cell analysis of the International Partner (Dr Betel). Second, advanced computational techniques will be applied to identify the key features affecting the proliferation of each of the 32 cancer cell types. Such features will include a set of biological elements (i.e., information related to cancer metabolism) specific to each cell type, which can be used to predict cell-specific drug resistance or inform clinical decisions. Finally, the selected key features (e.g. the metabolic reactions that are contributing the most to the growth of each cancer cell type) will be validated through computational and lab experiments and shared with breast cancer clinicians and experts through regular meetings and discussions that will be arranged during the project. Specifically, the academic team will coordinate a wide range of activities, including regular meetings with breast cancer experts from the NHS, designed to provide feedback on the developed computational model through knowledge and skills exchange while promoting connectivity across different sectors both in the medical and computational areas. The proposed project brings together academics from two centres of excellence in the healthcare sector (i.e., Weill Cornell Medicine at Cornell University and the National Horizon Centre at Teesside University), who have a strong track record in working with cell analysis, metabolic modelling, and artificial intelligence to better understand the metabolic mechanisms of cancer development and improve cancer outcomes.

Even very simple creatures need to co-ordinate their activities. For example, the sea anemone has a simple net of connected neurons with which it can control the movements within its body wall. As organisms increase in complexity, there are ever more examples where coordinated control of bodily processes is required. We often know a lot about how individual components in these systems might function. However, we have a serious lack of knowledge about how groups of gene products are controlled in the highly precise and flexible way they often are. This is systems biology and is recognized as an increasingly important way in which to understand the complex world around us. Our focus is on a group of vitally important semen proteins transferred along with sperm - the 'transferome'. It has been realized for many decades seminal fluid proteins are far more than a simple sperm buffer. In fact they can cause profoundly important effects on female behaviour and physiology. These effects have been best studied in the fruitfly, which we use as the model system here. However, similar effects are also seen across a huge variety of animal taxa. It has been reported recently that the transfer of seminal fluid proteins by human males causes changes in the expression of immune genes in the female cervix. This is thought to prepare the womb for implantation as well as protecting against sexually transmitted infections. In the fruitfly there are about 130 semen proteins making up the transferome. They are made mostly in the male accessory glands (the fly equivalent of the human male prostate) the ejaculatory ducts and a few in the testes. They result in a huge variety of vitally important effects: they cause females to lay more eggs, to eat more (and of different types of foods), to be less sexually receptive to males, to switch on immune genes, to retain more sperm in storage, to show altered patterns of water balance and to sleep less! We also know from our own work that males can respond in a highly sophisticated and individually flexible manner to their social and sexual environment. When males are exposed to rivals they mate for longer when they meet a female and transfer more transferome components during those longer matings. This results in a higher number of offspring. Furthermore, there is recent evidence to show that the composition of the transferome can change in response to social context. Despite the importance of the transferome to both males and females and its high degree of flexibility, we know next to nothing about how it is controlled. However, we have gathered strong background data and have excellent experimental tools in the fruitfly to tackle this omission, giving us a unique and unparalleled opportunity to investigate for the first time the control of this complex and important system. We hypothesise that an effective way to regulate 130 individual components of the transferome is to manage them in 'sets' controlled by the same activator / inactivator. This facilitates the quick and co-ordinated release of groups of substances as soon as they are required, rather than trying to make them all individually from scratch. We predict that this level of control is achieved in practice by transcription factors that turn on the expression of genes and by different types of small RNAs that then bind to, repress and 'manage' gene sets. Our investigations provide strong evidence that is consistent with these predictions. What we propose here are important tests of these ideas by experimentally altering directly these different types of gene regulation and testing the effects on the control and function of the transferome. This will elucidate how it is that the transferome can be regulated with robustness, precision and flexibility.