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Neurodevelopmental disorders affect millions of children in Europe and worldwide. A large body of literature indicates that inhibitory GABAergic transmission thorough Cl-permeable GABAA receptors is defective in many of these disorders. However, effective pharmaceutical treatments are still needed. There is increasing scientific evidence that varying the intracellular Cl concentration is one of the more physiological and effective ways to modulate GABAAergic transmission. This concentration is mainly established by the Cl importer NKCC1 and the Cl exporter KCC2. Importantly, the NKCC1/KCC2 ratio is defective in several brain disorders. Moreover, NKCC1 inhibition by the FDA-approved diuretic bumetanide rescues many symptoms in animal models. These findings have already led to clinical studies of bumetanide to treat a broad range of brain disorders. However, this requires chronic treatment, which poses serious issues for drug compliance, given the diuretic effect of bumetanide caused by the inhibition of the kidney-specific Cl transporter NKCC2. Crucially, these issues could be solved by selective NKCC1 inhibitors, which would have no diuretic effect. Yet there is still very little knowledge of the structure-function relationship of NKCC1 in terms of ion transportation and how bumetanide acts on NKCC1. The main goal of this fellowship is to resolve NKCC1’s structure using X-Ray crystallography and/or cryo-electron microscopy. This effort will be coupled to the functional characterization of NKCC1 using in vitro and in silico approaches. The fellow will thus integrate her research skills with key expertise in the structural and molecular biology of ion transporters, allowing her to grow into an independent group leader. Ultimately, this project will provide unprecedented insights into the structure-function relationships of NKCC1 in terms of ion transportation. This will critically accelerate the discovery of new and urgently needed drugs for brain disorders.

Our long-term vision is that AVATAR therapy is optimised for delivery in clinical settings, with the impact that a novel effective treatment for distressing voices is readily adopted in UK and international clinical settings. As a result of the current study we expect the impact to be: - Software platform tested and optimised for use in NHS settings - Further evidence of effectiveness and the relative cost effectiveness of two therapy levels, including a further elaboration of the participants for whom the simpler phase 1 approach would be sufficient. The advantage of this being that the therapy would be more rapidly disseminated as the more straightforward skills needed for this phase are widely available and at lower cost both in the UK and internationally compared to the specialised psychological therapy skills necessary for phase 2 - Clarity about optimal therapy content and training, with published therapy operational and clinical manuals - Evidence sufficient for a NICE recommendation of AVATAR as a treatment in the NHS. This is a key next step in the wider dissemination of this therapy in the UK and will also be helpful data for similar clinical guideline and policy recommendations in the US and elsewhere AVATAR therapy is a brief intervention aimed at reducing the frequency of auditory verbal hallucinations (AVH, henceforth ‘voices’). It involves the use of a digital simulation (avatar) of the entity the person believes is the source of the voice in a three-way discussion between participant, avatar and therapist, focussing initially on managing anxiety and helping the participant to stand up to the avatar (phase 1) followed by a realistic enactment of the ascribed character of the voice, targeting processes that are specific to an individualised formulation (phase 2). The first fully powered RCT found AVATAR therapy resulted in a rapid and substantial fall in frequency and associated distress of voices that was superior to a supportive counselling control condition at 12 weeks. In the current study we have four main goals. First, a multicentre RCT to examine the effects of high and low intensity AVATAR therapy (where high intensity involves both phases and low intensity only phase 1) by comparing each to a treatment as usual comparator, and to identify who would be likely to benefit from the high intensity therapy versus those for whom low intensity alone would be sufficient. Second, to examine the relative cost-effectiveness of the two levels of AVATAR therapy and routine treatment. Third, to broaden the availability of AVATAR therapy by expanding the number of staff trained in geographically dispersed NHS settings. Finally, to provide the evidence on effects and cost-effectiveness necessary to take AVAVAR therapy to recommendation by guideline bodies such as NICE.

Understanding Earth’s climate system is a major aim of the H2020 work programme. The chemical weathering of silicate and carbonate minerals is a key component of Earth’s climate system by exchanging large volumes of carbon between atmospheric and geologic reservoirs. Commonly, weathering models focus on the steady production, chemical alteration, and erosion of regolith and soil. However, the majority of fresh, weatherable sediment on Earth’s surface is produced in active mountain ranges where unsteady bedrock landsliding is the dominant erosion process. There, existing weathering models do not apply. The lack of data and models for chemical weathering in bedrock landslide deposits presents a major knowledge gap that limits our predictions of weathering dynamics and, ultimately, our understanding of Earth’s climate system. The goal of WetSlide is to quantify the impact of landslide erosion on chemical weathering fluxes from mountain ranges with three research objectives: 1) Assess millennial-scale variations of weathering rates in landslide deposits with a unique dataset of landslide-seepage-water chemistry from New Zealand; 2) Quantify erosion timescales of landslide deposits by measuring and compiling deposit volumes of dated landslides; 3) Develop and calibrate a model for weathering in landslides based on data from 1-2. This model will be combined with a regolith weathering model to estimate landscape-scale weathering fluxes. By providing the first quantitative study of weathering in landslide deposits, WetSlide has the potential to re-define the impact of mountain belt uplift on the inorganic carbon cycle and to drive a step-change in the understanding of global chemical weathering dynamics. Moreover, interdisciplinary training by experts at two world-leading research institutions will shape a competitive young researcher with a rare combination of skills who can effectively contribute to EU research excellence in integrative natural sciences.

Immunotherapy holds the potential to dramatically improve the curative prognosis of cancer patients. However, despite significant progress, a huge gap remains to be bridged to gain board success in the clinic. A first limiting factor in cancer immunotherapy is the low response rate in large fraction of the patients and an unmet need exists for more efficient - potentially synergistic - immunotherapies that improve upon or complement existing strategies. The second limiting factor is immune-related toxicity that can cause live-threatening situations as well as seriously impair the quality of life of patients. Therefore, there is an urgent need for safer immunotherapies that allow for a more target-specific engineering of the immune system. Strategies to engineer the immune system via a materials chemistry approach, i.e. immuno-engineering, have gathered major attention over the past decade and could complement or replace biologicals, and holds promise to contribute to resolving the current issues faced by the immunotherapy field. I hypothesize that synthetic biomaterials can play an important role in anti-cancer immunotherapy with regard to synergistic, safe, but potent, instruction of innate and adaptive anti-cancer immunity and to revert the tumor microenvironment from an immune-suppressive into an immune-susceptible state. Hereto, the overall scientific objective of this proposal is to fully embrace the potential of immuno-engineering and develop several highly synergistic biomaterials strategies to engineer the immune system to fight cancer. I will develop a series of biomaterials and address a number of fundamental questions with regard to optimal biomaterial design for immuno-engineering. Based on these findings, I will elucidate those therapeutic strategies that lead to synergistic engineering of innate and adaptive immunity in combination with remodeling the tumor microenvironment from an immune-suppressive into an immune-susceptible state.

What is the origin of the electromagnetic (EM) counterparts of gravitational waves observed from compact binary mergers? What makes short gamma ray bursts (GRBs)? What are the sources of IceCube’s high-energy neutrinos? Are all core-collapse supernovae exploding via the same mechanism? These are some of the puzzles that have emerged with the rapid progress of time domain astronomy. Relativistic jets in compact binary mergers and GRBs, and their interaction with the surrounding media hold the key to these, and other, seemingly unrelated broad-impact questions. Here I propose a new forefront study of how relativistic jets interact with their surrounding media and of its numerous implications, focusing on compact binary mergers and GRBs. The goal of this project is to study, first, the jet-media interaction, and the microphysics of the radiation-mediated shocks that it drives. I will then use the results, together with available observations, to learn about compact binary mergers, GRBs and SNe, sheding light on the questions listed above, and probing the nature of relativistic jets in general. Important goals will include: (i) General models for the propagation of relativistic jets in various media types. (ii) Modeling of the EM signal generated by jet-media interaction following compact binary mergers. (iii) Estimates of the neutrino signal from jet-media interaction in GRBs and SNe. (iv) Constraint the role of jets in SN explosions. This project is timey as it comes at the beginning of a new multi-messenger era where the EM counterparts of GW sources are going to be detected on a regular basis and where the face of transient astrophysics is going to be changed by a range of large scale surveys such as LSST, the SKA, and more. This project will set the theoretical base for understanding numerous known and yet-to be discovered transients that will be detected in the next decade.

Water scarcity is probably one of the biggest challenges of the 21st century. According to the United Nations, it affects more than 40 percent of the global population, and by 2050 more than 5 bn people could suffer water shortages. Europe is not an exemption, as one third of European countries have relatively low availability of water. In Mediterranean area there is both a severe lack and great demand for water. However, climate change and growing water demand is projected to increase water shortages in other EU regions. The ocean is seen as a promising source for providing drinking water to the more than 40% of EU population living in coastal areas. However, traditional technologies for water desalination are highly energy demanding and the capital and operation costs are not affordable for small to medium-sized applications. W2W-Water to Water is a state-of-the-art desalination system that tackles these two challenges. It has been originally conceived to be used with renewable energies (intermittent power) and to provide clean water from seawater or brackish groundwater. It is easily scalable, mobile and rapidly deployable even in remote areas. It is highly versatile, and it adapts to be used in multiple applications such as: drinking water delivery in low-income and developing countries, humanitarian aid and disaster relief operations or to support the water distribution in intense touristic areas during the dry season. We are Rainmaker, a Dutch SME focused on developing sustainable and decentralized water purification technologies to produce clean water. We have planned the activities required to build, install and validate the first W2W industrial unit, providing around 80 m3 of clean water daily. The market deployment of W2W will start in 2021 and by 2025, we expect having installed 200 units worldwide. This will make Rainmaker grow up (18 new jobs) and will place Rainmaker at the forefront of sustainable water supply.