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Early diagnosis of cancer is important for improved survival and patient experience. Reaching a diagnosis needs correct and timely collection of information from consultations, tests and follow-up of results. However, diagnosis can be difficult as non-cancerous conditions are common and cancer is quite rare. The use of tests forms a very important part in diagnosis, but this may also increase the time to cancer diagnosis. It is likely that what and when tests are done and how results are communicated can vary for different patients with the same cancer. These differences may represent missed diagnostic opportunities in some cases. In this project, I will explore how patients with kidney and bladder cancer are diagnosed. Bladder and kidney cancer will be studied together as patients usually present with blood in the urine or other urinary symptoms, and similar tests are done to look for both types of cancer. Despite the increasing trends and gender differences in how quickly these cancers are diagnosed, there is little information on how they are diagnosed. Therefore, studying this and whether there are delays in the use of tests is important to understand how we can improve early diagnosis of these cancers.

The overall goal of the proposed Cofund is to strengthen the European Research Area (ERA) in maritime and marine technologies and Blue Growth. The realisation of a European research and innovation agenda needs a broad and systematic cooperation in all areas of waterborne transport, offshore activity, marine resources, maritime security, biotechnologies, desalination, offshore oil & gas, fisheries, aquaculture etc. covering all relevant maritime and marine sectors and regions for a sustainable development of the maritime sector. Research and innovation activities in these fields cannot be tackled either at national levels alone, or solely by a single sector. Coordinated actions are required for the maritime industry to strengthen Europe’s position in this important and complex economic field in a global market. The proposing consortium will organise and co-fund, together with the EU, a joint call for trans-national research projects on different thematic areas of Blue Growth. Furthermore, additional joint activities that go beyond this co-funded call are planned, in order to contribute to the national priorities as well as to the Strategic Research Agenda of JPI Oceans and WATERBORNE. With the cooperation of ERA-NET MARTEC and JPI Oceans, a broader variety of topics with a larger amount of funding will be available for the trans-national projects. Moreover, the focus of development in MarTERA is given to technologies (instead of sectors) due to their potentially large impact to a wide range of application fields. The proposal responds to the topic ERA-NET Cofund on marine technologies of the work programme 2016-2017 of the societal challenge 2 (Food security, sustainable agriculture and forestry, marine and maritime and inland water research and the bio-economy) under Horizon 2020. Thereby it also contributes to the overall EU objective of building the ERA through enhanced cooperation and coordination of national research programmes.

Understanding how the mammalian brain network acquires its ability during development to process information and interact with the environment is one of the fundamental challenges in modern biology. The brain originates from a sheet of neural progenitors during embryogenesis but rapidly develops into distinct functional areas such as primary sensory and the highly associative cortices. Although all cortical areas consist of the same main neuronal elements, excitatory and inhibitory cells, their functions are markedly distinct. Unlike others, primary sensory cortical regions receive direct inputs from the environment through the respective thalamic nuclei starting at an early stage in development and are therefore likely to be shaped by incoming activity from sensory modalities. Despite the plethora of data on the arealization of the cortex by early signaling centers and the critical period plasticity mechanisms which take place after the basic elements of the circuit have been laid out, very little is known about the important period in between and how individual elements bind together to construct a functional circuit. This proposal is aimed at bridging this gap in knowledge, by addressing the long-standing question of how genes and activity interact during development to establish the correct wiring of excitatory and inhibitory cells in cortical sensory areas. As the primary role of inhibitory cells is to shape the flow of information transfer in the brain, they are well positioned to contribute significantly to the distinct modes of information processing performed in different cortical areas. Considering that dysfunction of cortical inhibitory circuits has been proposed as a major contributor to the etiology of neuropsychiatric-neurodevelopmental disorders, it is my hope that this approach will not only provide insights into the making of the healthy brain, but also into clinically relevant pathologies.

Homologous recombination plays a crucial role to repair DNA strand breaks that may occur spontaneously upon replication fork collapse, during the course of radio- or chemotherapy or in a programmed manner during meiosis. Understanding the molecular mechanisms of re-combinational repair is thus very important not only from a basic research viewpoint, but it is also highly relevant for human health. Here, we will define the function of nucleases in homol-ogous recombination. First, we will study the initial steps in this pathway. We could show previously that the S. cerevisiae Sae2 protein promotes the endonuclease activity of the Mre11-Rad50-Xrs2 (MRX) complex near protein blocked DNA ends. This initiates nucleolytic resection of DNA breaks and activates homologous recombination. Our biochemical setup will be instrumental to define how is the activity of Sae2 regulated by phosphorylation on a mech-anistic level and how physiological protein blocks direct the Mre11 endonuclease. We will ex-tend the study to the human system, and attempt to apply the gained knowledge to improve the efficiency of genome editing by activating recombination in conjunction with the CRISPR-Cas9 nuclease system. Second, we will study how homologous recombination promotes gen-eration of genetic diversity during sexual reproduction. DNA strand breaks are introduced in-tentionally during the prophase of the first meiotic division. They are then processed by the recombination machinery into Holliday junction intermediates. These joint molecules are preferentially converted into crossovers in meiosis, resulting in exchange of genetic infor-mation between the maternal and paternal DNA molecules. This is dependent on the Mlh1-Mlh3 nuclease through a yet unknown mechanism. We will study how Mlh1-Mlh3 in complex with other proteins guarantee crossover outcome to promote diversity of the progeny.

The discovery of novel sustainable catalytic reactions is a major current goal. Based on recent discoveries in our group, we plan to develop unprecedented sustainable catalytic reactions with special emphasis on reactions catalyzed by complexes of earth-abundant metals. We have recently discovered an intriguing reaction, namely the oxidation of organic compounds using water, with no added oxidant, evolving H2. This simple, selective reaction, offers now a novel, conceptually new, environmentally benign approach in the field of oxidation of organic compounds, which we will explore. We recently discovered a new mode of activation of multiple bonds by metal-ligand cooperation, including activation of CO2 and nitrile triple bonds, in which reversible C-C bond formation with the ligand is involved. Based on that, activation of nitriles has resulted in unprecedented C-C bond formation involving addition of simple aliphatic nitriles to various α,β-unsaturated carbonyl compounds. This mode of multiple bond activation may open a new approach to catalysis, “template catalysis”, which we plan to explore. In addition, the highly desirable, catalytic activation of the kinetically very stable, potent greenhouse gas N2O for the (so far elusive), efficient oxygen transfer to organic compounds, will be pursued. The use of CO2 in organic synthesis is an important timely topic. Based on its activation by metal ligand cooperation, new catalytic reactions of CO2 will be pursued, including unprecedented carbonylation of non-activated C-H bonds. Most reactions catalysed by metal complexes involve noble metals. Development of sustainable catalysis based on complexes of earth-abundant metals is of great interest. In all topics described above, catalysis by complexes of such metals will be emphasized. Moreover, based on recent results in our group, we plan to develop an unprecedented family of complexes of earth-abundant metals, and pursue novel sustainable catalysis, based on it.

Nanomedicine is the application of nanotechnology to medicine and healthcare. The field takes advantage of the physical, chemical and biological properties of materials at the nanometer scale to be used for a better understanding of the biological mechanisms of diseases at the molecular level, leading to new targets for earlier and more precise diagnostics and therapeutics. Nanomedicine, rated among the six most promising Key Enabling Technologies, is one of the most important emerging areas of health research expected to contribute to one of the strategic challenges that Europe has to face in the future: Provide effective and affordable health care and assure the wellbeing of an increasingly aged population. EuroNanoMed III (ENM III) builds on the foundations of ENM I & II, which launched 7 successful joint calls for proposals since 2009, funded 51 transnational research projects involving 269 partners from 25 countries/regions, and allocated € 45,5 million to research projects from ENM funding agencies. ENM III consortium, reinforced with 12 new partners from Europe, Canada and Taiwan, is committed to fostering the competiveness of European nanomedicine actors taking into account recent changes in the landscape and new stakeholders and challenges, as identified in the SRIA in nanomedicine. The first joint call for proposals will be co-funded by ENM III partners and the EC. After the co-funded call, three additional joint transnational calls will be organized and strategic activities will be accomplished in collaboration with key initiatives in the field. ENM III actions focus on translatability of project results to clinical and industry needs.

This proposal aims to address a simple question: what is the fundamental unit of computation in the brain? Answering this question is crucial not only for understanding how the brain works, but also if we are to build accurate models of brain function, which require abstraction based on identification of the essential elements for carrying out computations relevant to behaviour. In this proposal, we will build on recent work demonstrating that dendrites are highly electrically excitable to test the possibility that single dendritic branches may act as individual computational units during behaviour, challenging the classical view that the neuron is the fundamental unit of computation. We will address this question using a combination of electrophysiolgical, anatomical, imaging, molecular, and modeling approaches to probe dendritic integration in pyramidal cells and Purkinje cells in mouse cortex and cerebellum. We will first define the computational rules for integration of synaptic input in single and multiple dendrites by examining the somatic and dendritic responses to different spatiotemporal patterns of excitatory and inhibitory inputs in brain slices. Next, we will determine how these rules are engaged by patterns of sensory stimulation in vivo, by using various strategies to map the spatiotemporal patterns of synaptic inputs onto single dendrites. To understand how physiological patterns of activity in the circuit engage these dendritic computations, we will use anatomical approaches to map the wiring diagram of synaptic inputs to individual dendrites. Finally, we will perturb the dendritic computational rules by manipulating dendritic function using molecular and optogenetic tools, in order to provide causal links between specific dendritic computations and sensory processing relevant to behaviour. These experiments will provide us with deeper insights into how single neurons act as computing devices.

The CAROLINE Fellowship Programme proposed by the Irish Research Council (IRC) will provide a unique opportunity for researchers to further develop their skills, competencies and experience through inter-sectoral collaboration with NGOs and International Organisations (IO). Proposals will be invited from all disciplines that speak to the overarching theme of global sustainable development as set out under the United Nations 2030 Agenda for shared economic prosperity, social development, and environmental protection. CAROLINE will fund 50 experienced researchers across two modes; International Fellowships (three-year) and Irish Fellowships (two-year). The IRC, a national agency, funds excellent research across all disciplines. Unique aspects of CAROLINE include the European and global resonance of the overarching research theme, the inclusion of NGO and IO partners with the host research performing organisations, flexibility in secondments, comprehensive approaches to equal opportunities and gender aspects, and dedicated core training and career support activities. Research outcomes and activities of the CAROLINE Fellows will benefit Europe, given the significance of the theme to Europe 2020, e.g. in employment, climate change and energy, education, and poverty reduction. CAROLINE will deliver experienced researchers with enhanced skills in inter-sectoral and interdisciplinary research and better access to a wider set of future career opportunities. The IRC has built an impressive array of support for this proposal from stakeholders in Ireland, Europe and internationally, including research performing-organisations, NGOs, IOs and other partners.

Over 100 types of distinct modifications are catalyzed on RNA molecules post-transcriptionally. In an analogous manner to well-studied chemical modifications on proteins or DNA, modifications on RNA - and particularly on mRNA - harbor the exciting potential of regulating the complex and interlinked life cycle of these molecules. The most abundant modification in mammalian and yeast mRNA is N6-methyladenosine (m6A). We have pioneered approaches for mapping m6A in a transcriptome wide manner, and we and others have identified factors involved in encoding and decoding m6A. While experimental disruption of these factors is associated with severe phenotypes, the role of m6A remains enigmatic. No single methylated site has been shown to causally underlie any physiological or molecular function. This proposal aims to establish a framework for systematically deciphering the molecular function of a modification and its underlying mechanisms and to uncover the physiological role of the modification in regulation of a cellular response. We will apply this framework to m6A in the context of meiosis in budding yeast, as m6A dynamically accumulates on meiotic mRNAs and as the methyltransferase catalyzing m6A is essential for meiosis. We will (1) aim to elucidate the physiological targets of methylation governing entry into meiosis (2) seek to elucidate the function of m6A at the molecular level, and understand its impact on the various steps of the mRNA life cycle, (3) seek to understand the mechanisms underlying its effects. These aims will provide a comprehensive framework for understanding how the epitranscriptome, an emerging post-transcriptional layer of regulation, fine-tunes gene regulation and impacts cellular decision making in a dynamic response, and will set the stage towards dissecting the roles of m6A and of an expanding set of mRNA modifications in more complex and disease related systems.

Software-intensive systems pervade modern society and industry. These systems often play critical roles from an economic, safety or security standpoint, thus making their dependability indispensible. Software Verification and Validation (V&V) is core to ensuring software dependability. The most prevalent V&V technique is testing, that is the automated, systematic, and controlled execution of a system to detect faults or to show compliance with requirements. Increasingly, we are faced with systems that are untestable, meaning that traditional testing methods are highly expensive, time-consuming or infeasible to apply due to factors such as the systems’ continuous interactions with the environment and the deep intertwining of software with hardware. TUNE will enable testing of untestable systems by revolutionising how we think about test automation. Our key idea is to frame testing on models rather than operational systems. We refer to such testing as model testing. The models that underlie model testing are executable representations of the relevant aspects of a system and its environment, alongside the risks of system failures. Such models inevitably have uncertainties due to complex, dynamic environment behaviours and the unknowns about the system. This necessitates that model testing be uncertainty-aware. We propose to develop scalable, practical and uncertainty-aware techniques for test automation, leveraging our expertise on model-driven engineering and automated testing. Our solutions will synergistically combine metaheuristic search with system and risk models to drive the search for critical faults that entail the most risk. TUNE is the first initiative with the specific goal of raising the level of abstraction of testing from operational systems to models. The project will bring early and cost-effective automation to the testing of many critical systems that defy existing automation techniques, thus significantly improving the dependability of such systems.