The long-term science for this project is directed towards the preparation of new and effective therapeutics, and to dothis we need to ensure that our novel devices hit their biological targets and have proven efficacyin a particular disease application before we can commence a larger programme to guide theirdevelopment towards clinical practice. The European Science Foundation (ESF) Nanomedicine Forward Look describes the development ofnew multifunctional, spatially ordered, architecturally-varied systems for targeted drug delivery as apriority. Nanopharmaceuticals based on antibody-drug conjugates and polymer-biopolymerconjugates are a key component of enhanced efficacy medicines. While more complex, theseconjugates offer enhanced diversity, leading to drugs with much higher information content comparedto small molecule compounds. This allows for greater target specificity, improved functionality andthe opportunity to multi-task, for example to diagnose and treat in situ, or to act on more than onetherapeutic target or disease pathway simultaneously. The novel conjugate nanodevices we willprepare in this programme are thus uniquely able to address diseases which are inadequately treatednow. By exploiting new biological targets and interfaces, our materials will contribute a vital step inimproving patient, economic and society outcomes arising from disease.

The duplication of genes provides new genetic material that can be used for novel functions, allowing plants and animals to evolve biological innovations and adapt to environmental conditions. Whole genome duplication (WGD) is arguably the most dramatic mechanism for duplication, resulting in the production of a new copy of every gene in the nuclear genome. Around 430 million years ago, spiders and scorpions diverged from a common ancestor that had experienced a WGD. The retained duplicated genes from this WGD event (genes called ohnologs) can still be found in the genomes of the approximately 45,000 species of these animals alive today and may have contributed to their adaptation and diversification. Since then, some families of Synspermiata spiders have undergone at least two additional WGDs within a single lineage, reflecting a similar series of WGDs in vertebrates. This presents an opportunity to compare these events to determine whether there are general principals shaping the outcomes of WGDs and their contribution to animal diversification. In addition, Synspermiata represent a wide diversity of spiders that are understudied and poorly understood Therefore, the aims of this project are to identify spider ohnologs after multiple WGDs, explore whether and how they have contributed to the evolutionary success of these animals, and compare the outcomes of these events to repeated WGDs in vertebrates. We will first collect and carry out the first large scale detailed study of the morphology of Synspermiata spiders to better understand their evolution and phenotypic diversity. In parallel, we will identify the ohnologs that have been retained in spider groups after WGDs by comparing the repertoire and arrangement of the duplicated genes in these animals with relatives where there is no evidence of additional WGDs. As part of this aim, we will sequence the genomes of Synspermiata spiders that have undergone one (Pholcus phalangioides, Scytodes thoracica and Loxosceles reclusa), and two (Oonops pulcher, Segestria senoculata and Dysdera crocata) WGD, as well as the transcriptomes of Caponiidae species with two (Orthonops zebra) or three (Calponia harrisonfordi) WGDs. Since relatively little is known about these spiders this will provide new insights into the biology of these animals as well as their genome evolution. We will then compare the repertoires of genes retained after WGD between spiders and vertebrates to determine whether there are any similarities in the aftermath of these events. This information will help us to better understand the general consequences of WGD and the principles underlying their outcomes in terms of genes being preferentially retained or lost again. Identification of ohnologs will also allow us to ask if these genes have been subject to sub-, neofunctionalisation or specialisation during spider development and if their expression is associated with morphological diversification. Overall our project will provide new insights into the genomes of spiders and how WGDs in these animals have contributed to their morphological evolution. Our data will also allow comparisons to WGD events in other animals, including vertebrates, to better understand the general consequences of these events and their contribution to animal adaptation and diversification.

The duplication of genes provides new genetic material that can be used for novel functions, allowing plants and animals to evolve biological innovations and adapt to environmental conditions. Whole genome duplication (WGD) is arguably the most dramatic mechanism for duplication, resulting in the production of a new copy of every gene in the nuclear genome. Around 430 million years ago, spiders and scorpions diverged from a common ancestor that had experienced a WGD. The retained duplicated genes from this WGD event (genes called ohnologs) can still be found in the genomes of the approximately 45,000 species of these animals alive today and may have contributed to their adaptation and diversification. Since then, some families of Synspermiata spiders have undergone at least two additional WGDs within a single lineage, reflecting a similar series of WGDs in vertebrates. This presents an opportunity to compare these events to determine whether there are general principals shaping the outcomes of WGDs and their contribution to animal diversification. In addition, Synspermiata represent a wide diversity of spiders that are understudied and poorly understood Therefore, the aims of this project are to identify spider ohnologs after multiple WGDs, explore whether and how they have contributed to the evolutionary success of these animals, and compare the outcomes of these events to repeated WGDs in vertebrates. We will first collect and carry out the first large scale detailed study of the morphology of Synspermiata spiders to better understand their evolution and phenotypic diversity. In parallel, we will identify the ohnologs that have been retained in spider groups after WGDs by comparing the repertoire and arrangement of the duplicated genes in these animals with relatives where there is no evidence of additional WGDs. As part of this aim, we will sequence the genomes of Synspermiata spiders that have undergone one (Pholcus phalangioides, Scytodes thoracica and Loxosceles reclusa), and two (Oonops pulcher, Segestria senoculata and Dysdera crocata) WGD, as well as the transcriptomes of Caponiidae species with two (Orthonops zebra) or three (Calponia harrisonfordi) WGDs. Since relatively little is known about these spiders this will provide new insights into the biology of these animals as well as their genome evolution. We will then compare the repertoires of genes retained after WGD between spiders and vertebrates to determine whether there are any similarities in the aftermath of these events. This information will help us to better understand the general consequences of WGD and the principles underlying their outcomes in terms of genes being preferentially retained or lost again. Identification of ohnologs will also allow us to ask if these genes have been subject to sub-, neofunctionalisation or specialisation during spider development and if their expression is associated with morphological diversification. Overall our project will provide new insights into the genomes of spiders and how WGDs in these animals have contributed to their morphological evolution. Our data will also allow comparisons to WGD events in other animals, including vertebrates, to better understand the general consequences of these events and their contribution to animal adaptation and diversification.

By exploiting three important new advances in ice sheet modelling, and major new Antarctic-wide datasets, we aim to predict how far and how fast the observed ocean-driven thinning of floating ice shelves will propagate into the interior of the Antarctic ice sheet, and assess the consequences for global sea level over decadal-to-century timescales. Whereas previous studies have used simplified models, idealised forcing, or limited domains, we will use a comprehensively initialised model of ice flow throughout Antarctica, including all mechanical processes that propagate thinning into the interior, to produce a highly-realistic simulation that can predict the response of the grounded ice sheet to the ice-shelf thinning observed by satellite. We will validate the simulations against further satellite observations, before using them with scenarios of ice-shelf melt, guided by ocean models, to produce a probabilistic forecast of the future sea-level contribution from Antarctica to 2100.

This proposal is based on a fundamentally important and previously unexpected change to our understanding of the marine inorganic carbon cycle. It follows our recent revelation that calcium carbonates excreted by fish make a significant contribution but our current estimates vary over more than a 10-fold range (3 to 45 % of global marine carbonate). BACKGROUND: As humans burn more fossil fuels, atmospheric concentrations of the 'greenhouse gas' carbon dioxide (CO2) rise contributing to climate change. Atmospheric CO2 is in balance with CO2 dissolved in the oceans, in something referred to as the marine-atmospheric carbon cycle. Whatever happens to CO2 in the oceans, will ultimately have an effect on CO2 in the atmosphere, and hence can influence global climate. When CO2 dissolves in seawater, it forms bicarbonate ions. An important part of the marine-atmospheric carbon cycle is the reaction of this bicarbonate with seawater calcium to produce a solid precipitate of white calcium carbonate (the mineral found in limestone). These precipitates are very dense, and sink to the ocean bottom in a continuous 'rain' of white crystals. The rate at which they form and sink (or re-dissolve) is important in the marine carbon cycle. The majority of calcium carbonate is generated by marine life that promotes this reaction to make a hard protective 'shell'. The most famous organisms involved in this 'biogenic' calcification are corals. However, those thought to produce the most are actually microscopic phytoplankton called coccolithophores that live in the open ocean. Dense skeletons of these and other microscopic organisms are normally considered to be the only important source of marine carbonates. Scientists collect samples in deep ocean traps, to measure this carbonate 'rainfall' for use in computer models of the carbon cycle. We have recently discovered that marine fish also produce substantial amounts of precipitated calcium carbonate, but for a very different purpose. They produce it in their intestines, by drinking large volumes of seawater and actively promoting the reaction of seawater calcium with bicarbonate ions that are produced by their own metabolism. Fish then excrete the precipitated calcium carbonate into the surrounding seawater, where it probably mixes with all the better known (planktonic) sources. In fact, some tropical fish will excrete calcium carbonate equivalent to its own dry body weight every year! We have conservatively estimated that the contribution of fish may be up to 45% of the total global carbonate production. This novel discovery suggests that fish also contribute to the marine carbon cycle, but scientists who model this cycle have never previously taken this into account. Indeed, the unusual chemistry of fish carbonates (which are more soluble than carbonate from more traditional sources), may explain a phenomenon that has puzzled oceanographers for decades - the rapid dissolution of 'apparently insoluble' carbonates in the upper layers of the ocean. Our research is a multi-disciplinary project that for the first time aims to precisely model how much calcium carbonate is produced by marine fish under different environmental conditions and determine its fate within in our oceans. This will also help with predictions about how carbonate excretion by marine fish will be affected by future environmental changes, such as temperature and CO2. We predict that fish will become even more important in this regard in the future, whereas marine plankton will become less important. Thus a precise understanding of this fish contribution to the global marine carbon cycle is both a novel and environmentally important topic.