Amyotrophic Lateral Sclerosis is a severe neurodegenerative disease characterized by the degeneration of the upper and lower motor neurons (MN), ultimately leading to patient death by respiratory failure. Despite being the most common adult-onset motor neuron disease, the drugs available till now are symptomatic and only extend patients life expectancy a few months without changing the onset of the disease. Recent studies revealed that NF-κB transcription factor is the major regulator of neuroinflammation in ALS. Therefore, inhibitors of NF-κB signalling pathway can be considered key tools for the development of novel therapies for ALS. Additionally, the use of iron chelators have also shown potential to increase ALS survival through the regulation of iron redox activity and by triggering MN cell survival mechanisms through the mild activation of HIF transcriptional factor. In this project we propose an innovative therapeutic solution for ALS based on the design and syntheses of multitarget small-molecules capable to modulate NF-κB activity through inhibition of IKKβ protein and prevent/minimize the iron induced oxidative damage and/or stabilize HIF. The project encompasses the rational design and synthesis of a library of small molecules that will be submitted to an initial cascade of biophysical and chemical assays to evaluate their binding affinity and iron chelation properties. Subsequently ALS cellular models will be used in order to validate target engagement inside cells, as well as, to identify the small-molecules that could protect MN from oxidative-stress and inflation driven apoptosis. At the end of the project it is expected to propose a novel lead compound that will be optimized and its performance evaluated in ALS animal models. This project combines the expertise available in academia and industry to validate a new therapeutic approach for ALS and, provides an exceptional training opportunity to prepare a young researcher for his future career.

The present project aims at the preparation of synthetic nanoreceptors exhibiting glycan epitope recognition in glycoproteins, identified to play a critical role in cell biology and diseases. Such nanoreceptors, behaving like antibodies, may cope with the current limitations in the essential step of enrichment of specific glycan subclasses, within studies of the glycoproteome. The preparation of the receptors will proceed through solid-phase synthesis of imprinted polymer nanoparticles, with the potential to deliver entities with size, specificity and solubility characteristics comparable to antibodies. The solid-phase synthesis of NanoMIP will require the immobilization of important monosaccharides (N-acetylglucosamine, N-acetlgalactosamine, mannose), widely found in glycoproteins, onto supporting beads. Several synthetic routes will be studied for the immobilization onto silica or plastic beads . In a reactor, built as a controlled temperature glass column filled with the beads containing immobilized monosaccharide, criteriously selected polymerization or sol-gel mixtures will generate the nanoMIPs, with subsequent selection of the highest affinity particles. The optimum combinations of solid-phase/imprinting protocol will be screened from a myriad of nanoMIPs prepared in different conditions. The performance of the nanoMIPs will be ascertained by setting a competitive enrichment protocol consisting of the incubation with a mixture of N-acetylglucosamine-, N-acetylgalactosamine- and mannose-containing glyproteins and a non-glycoprotein. Sorption isotherm data will be used to derive important binding features such as capacity, binding affinity and selectivity. Patentable robust solid-phases and imprinting protocols, either in standalone or combined manner, are planned outputs of the project, which may, in the near future, be incorporated into existing automated solid-phase synthesis instrumentation, for increased throughput and batch reproducibility.

In recent years, an increasing number of emerging pollutants were identified in aquatic ecosystems, and one of the major concerns is the presence of sex-steroid hormones and mimics which act on aquatic organisms as endocrine-disrupting compounds (EDCs). The proposed multidisciplinary project will have focus on in vitro testing of complex of EDCs mixtures: the EU watch listed pollutant ethinylestradiol with emergent progestins drugs (levonorgestrel and megestrol acetate), taking into account a standard versus a warming scenario, as a major global change issue. This will be done by developing and exploiting cutting edge in vitro fish toxicity test tools: single-cell and (new in fish studies) multi-cell type 3D spheroids of liver cells (hepatocytes, stellate cells and biliary epithelial cells) of brown trout (Salmo trutta). The project will explore the advantages of 3D cultures, which have been proved to be much more biologically realistic than common 2D cultures, in order to study: (i) their morphology and viability using light and electron microscopy, including immunocytochemistry; (ii) multi end-point biochemical assays in combination with Raman microspectroscopy (novel in 3D culture); (iii) mechanistic insights of disruption and eventual (still unavailable) biomarkers of fish exposure/effect as to progestins. Quantitative gene expression is the method of choice for this task, targeting specific genes related to lipid-metabolism, yolk and eggshell proteins and androgen/estrogen/progestin receptors. An additional innovative contribution of this project is developing new tolls for enforcing the 3Rs (Replacement, Reduction, and Refinement) in fish research. The project will bring to another level the collaboration between the applicant and the host mentor by bidirectional transfer of skills and expertise, while conducting a scientifically innovative project. The strategy will benefit persons while establishing grounds for long-term institutional benefits.

The transport sector is currently facing global economic uncertainty, tough market competition, stringent EU emission and efficiency targets, increased vehicle occupant safety requirements, and pollution and safety scandals which have damaged its reputation. These factors require engineers to increasingly adopt the use of composite materials, to come up with cheaper, safer, and more environmentally friendly solutions. However, even if these materials enable the production of light energy-efficient vehicles, most carbon fibre composites are expensive, and thus the majority of their current applications are limited to the aerospace and motorsport industries. Furthermore, conventional composites have a high manufacturing carbon footprint, and they are typically non-recyclable at the end of life of the components. Natural fibre composites (NFCs) are now being used in the automotive industry, as a cheaper and more environmentally friendly option to conventional carbon fibre composites, albeit limited to non-safety critical components, due to their poorer mechanical performance. The TEMPEST research programme aims to explore the possibility of using a novel NFC material offering improved mechanical performance (developed by partner organisation Bcomp) in safety-critical structural components. Furthermore, by collaborating with McLaren Racing, who have been developing composite crash structures for over two decades, the project aims to advance on the current state-of-the-art in the fields of experimental and numerical crashworthiness, all the while trying to reduce the carbon footprint of such structures. The project also aims to enhance the creative and innovative potential of the researcher, wishing to diversify his competences to include sustainable composite material development, while advancing his international and intersectoral mobility, through collaboration with four industrial partners from the transport and materials sectors.

With the rapid development of high speed rail system, ground vibration mitigation solutions are desperately needed. As a novel vibration mitigation method, metamaterial can theoretically yield excellent performance in shielding dynamic waves in broad frequency bands. However, the application of metamaterials in railway-induced vibration mitigation is a very recent and ongoing topic. Therefore, the XeRo project aims to establish new and practical contribution towards a better understanding of the mitigation effects by metamaterials for railway-induced environmental vibrations. The experienced researcher (ER) will: 1) investigate the dominant frequencies of railway environment based on a 3D coupled train-track-soil interaction model; 2) design and develop the metamaterial based on the locally resonant mechanism; 3) characterize and optimize the metamaterial with respect to viscoelastic multi-layered soils; and 4) demonstrate the mitigation effect of the metamaterial on railway environmental vibration. Implemented at the University of Porto, and supervised by Prof Rui Calcada, the XeRo project will allow the ER to diversify her individual competence by developing skills in railway dynamics, academic dissemination and networking; student supervision; and research management and leadership. The XeRo project will also strongly benefit the ER’s inter-sectoral and interdisciplinary expertise and strengthen her international network considering a secondment will be carried out at the University of Birmingham. A two-way transfer of knowledge is guaranteed since the XeRo project combines the ER’s expertise in metamaterial design and railway vibration evaluation and the host’s expertise in the numerical modelling and dynamic analysis of train-induced ground vibrations. Therefore, the XeRo project will contribute to Europe’s knowledge-based society, policy makers and rail industries by providing invaluable knowledge on the novel vibration mitigation solution in railways.