Neuronal loss is at the core of cognitive and functional failures of both acute brain injuries and neurodegenerative diseases. Direct neuronal reprogramming of local glial cells is emerging as a promising approach for restorative brain therapy. However, in order to use direct glia-to-neuron reprogramming for the treatment of neuronal loss we still need to address a number of challenges, namely reliable and long-term conversion into the desired neuron subtype. In this proposal we aim to generate specific neuronal subtypes using novel fate determinants in glia-to-neuron reprogramming, and to provide a detailed molecular analysis of the newly generated neurons over time. Our data indicate that ONECUT factors may represent excellent novel candidates for astrocyte reprogramming into neuronal fates. To address this possibility, in this proposal we will focus on the thalamocortical system, which represents the main input to the neocortex and it is essential to cortical processing. We hypothesize that the innovative combination of nuclei specific thalamic factors with ONECUT factors could reveal new avenues for the direct reprogramming of astrocytes into thalamic neurons of specific sensory modalities and may inform future strategies for brain repair. Here, we have unique expertise and molecular tools at hand that will allow us to reprogram astrocytes into specific neuron types in vitro and in vivo. Moreover, as our ultimate goal is to reprogram astrocytes to recover neuronal loss, we will test whether astrocytes from a sensory deprived thalamus can be reprogrammed. By using state-of-the-art techniques such as 3D light-sheet microscopy, calcium imaging and transcriptomic analysis, we will determine the fidelity and functionality of the newly generated neurons. This approach will offer us unparalleled advantages for the discovery of novel reprogramming combinations and address important questions about reliable and long-term conversion into the desired neuron type.

Global biodiversity loss is disproportionately rapid on islands, which despite being hotspots of biodiversity, comprise ~ 80% of world’s species extinctions. The vulnerability of insular ecosystems to global change has been historically related to the introduction of invasive species. Yet, we still lack a quantitative understanding of how other major threats such as climate change will jeopardise, not only species, but pivotal ecosystem functions derived from trophic interactions such as animal-mediated seed dispersal. To date, the scarce data and methodological limitations have entailed a lack of studies on the effect of climate change on seed dispersal in entire island communities. ECORISC implies a major step ahead previous work with its integration of a new global dataset on ~65 insular seed-dispersal networks, alongside methodological approaches from the fields of interaction networks, ecological niche modelling and future climate change projections. The combination of empirical knowledge on the structure and vulnerability of current insular communities with future climate, species extinctions and interaction rewiring simulations will provide an integrated understanding of the resilience of seed dispersal in insular systems to climate change. The main outcome of ECORISC (i.e. the quantification of structural and functional consequences derived from climate-driven biodiversity loss) will provide essential knowledge needed to restore Europe’s ecosystems and biodiversity, one of the main issue mainstreamed in the first Horizon Europe strategic plan. During the course of this project, I will receive essential training by world leading experts of the fields of island ecology, niche modelling and complex systems at three outstanding institutes from the disciplines of Ecology and Physics, thus paving my way towards establishing an independent and distinct research profile in the fields of global change and community ecology.

Catalysis is a key technology in the European economy, industry and sustainable growth for a resilient future. However, many catalytic methods in use today are not outstanding in fundamental aspects such as activity, selectivity, substrate scope, toxicity or even cost efficiency. The rich structural diversity and associated reactivity provided by heavy elements from the Main Group offer unique opportunities for the prospective substitution of traditional catalysts based on precious metals by less expensive, more abundant, and potentially less toxic Main Group compounds. Sub-valent Ge(II) and Sn(II) derivatives are particularly appealing due to their reduced HOMO-LUMO gaps and thus increased reactivity. Nevertheless, bond activation processes lead to very stable and unreactive products in higher oxidation states (+IV). As such, catalytic turnover via reductive regeneration of the active species is highly challenging. To address this problem, an interdisciplinary approach will be used combining fundamental aspects stemming from a priori independent areas of Chemistry. Rationally designed ambiphilic and bifunctional derivatives will be used as ligands for low-valent tetrylenes to induce cooperativity between Main Group elements and Transition Metals and promote novel reactivity in small molecule activation and functionalization. Another objective is to demonstrate that selective irradiation of well-designed mononuclear tetrylene will allow photoactivation of chemical bonds that are thermally inert towards many of these divalent species. However, we envision that the main advantage of using light will be in facilitating reductive elimination processes in the cases where thermal catalytic turnover is hampered by this rate-limiting step. For this reason, these studies will also be extended to our hybrid systems, in what constitutes a completely innovative research area, and where the possible synergies and cooperative mechanisms will be analyzed.

In eukaryotes, untranslated regions located at the 3′ end (3’UTRs) of messenger RNAs (mRNAs) have been proved to be key post-transcriptional regulatory elements controlling almost every single biological process. In contrast, in bacteria, most studies regarding post-transcriptional regulation have been mainly focused on specific non-coding RNAs and 5’UTRs, which often carry riboswitches or thermosensors. Remarkably, bacterial 3’UTRs have been largely disregarded and have not been considered as potential regulators. Recently, we found that a 3’UTR modulates biofilm formation in S. aureus through its interaction with the 5’UTR encoded in the same mRNA. This mechanism resembles eukaryotic mRNA circularization. Also, a 3’UTR that contributes to cellular homeostasis by promoting hilD mRNA turnover was recently shown in Salmonella. Although both studies are pioneering showing the potential of bacterial 3’UTRs as regulatory elements, many questions still remain to be answered. Are 3’UTRs roles conserved in bacterial species? Do 3’UTRs contain specific regulatory sequences or secondary RNA structures? Are transcriptional terminator sequences relevant for certain 3’UTRs? Are 3’UTRs specifically recognized by RNA-binding proteins? Might 3’UTRs be responsible for bacterial speciation? Might bacterial 3’UTRs be the ancestors of eukaryotic 3’UTR evolution? To achieve these questions, here we propose a high-throughput analysis based on the development of specialized dual-reporter libraries to identify in vivo functional 3’UTRs by fluorescence-activated cell sorting coupled to RNA sequencing. Also the pool of RNA-binding proteins associated to 3’UTRs will be identified by global MS2-tagging and mass spectrometry. Examples of 3’UTRs belonging to physiologically important genes will be selected to deeply study regulatory mechanisms at the molecular and single cell levels. We expect that this project will largely change the view of post-transcriptional regulation in bacteria.