The recently approved drugs for Alzheimer’s disease (AD), targeting amyloid plaques removal, only mildly slow patients’ cognitive decline as neuronal loss starts decades before plaque deposition. To delay AD onset before symptoms development, prevention of neuronal death should be prioritised instead. An early AD pathological event is intraneuronal accumulation of amyloids (intraAβ) which can cause neuronal death at the pre-plaque stage. IntraAβ is only found in specific neuronal subtypes first to be lost in AD, suggesting it might underly their selective vulnerability. Reactive microglia could contribute to intraAβ as blocking neuroinflammatory processes in early AD reduces its accumulation. Whether microglia also contribute to intraAβ+ neurons selective loss is still unknown but could suggest repurposing of already available microglia targeting drugs for early neuroprotective therapies. I will test this hypothesis in 5xFAD mice, first confirming intraAβ accumulates in the neuronal subtypes selectively lost, as it occurs in humans. I will analyse the contribution of reactive microglia to intraAβ neurons death by pharmaceutically rescuing their reactivity and determine if intraAβ neurons-associated microglia express AD high-risk genes, which drive late AD pathology. Because AD affects women more, possibly due to their higher inflammatory response, the sex-specificity in the previous analyses will also be tested. Finally, I will establish microglia-containing human brain organoids to recapitulate this synergy in a in vitro human AD model, providing a foundation for future drug testing. By determining the potentially detrimental interplay between microglia reactivity and intraAβ+ neurons, using both in vivo and in vitro models, my project will lay the basis of extensive future work while defining my research niche. In the long term, my results will impact development of novel neuroprotective therapies for treating AD before neuronal loss.

Colorectal cancer (CRC) is one of the most diagnosed cancer worldwide. Though several treatment strategies are available today, around a million people die of this disease each year worldwide. Thus, there is still a pivotal need for new and more effective treatments. Intra-tumor cellular heterogeneity has emerged lately as an intrinsic feature of malignancies and as one of the factors responsible for therapy resistance or tolerance. However, the role that phenotypically distinct subpopulations have on tumor biology is far from being understood. This multi-disciplinary proposal is based on the use of cutting-edge techniques to unravel the basic features of intra-tumor phenotypic heterogeneity and subpopulations interactions. The goals are to (1) identify and characterize phenotypically distinct subpopulations on a set of metastatic CRC human-derived organoids by single-cell RNA sequencing; (2) monitor their plasticity (transitions) by generation of fluorescent reporter lines and live-imaging lineage tracing; (3) study the impact of each subpopulation on tumor growth, and identify underlying molecular pathways by live-imaging. Ambitiously, this project aims at witnessing phenotypic transitions in living cells, a challenging task that has not been fully accomplished yet, with relevant therapeutic consequences. It is expected that this project will provide the scientific community with a deeper understanding on subpopulations dynamics in colorectal cancer, that could ultimately result in the discovery of novel treatment strategies, such as targeting a specific subpopulation or interfering with molecular determinants of transitions. Moreover, it will foster the independent career of the applicant as a researcher by expanding her skills and international network. This project tackles a relevant problem of modern cancer biology by employing innovative techniques, complemented with state-of-the-art facilities and high quality training and mentoring.

In cultures with a strong Catholic tradition saints represent models of life perfection, dialectically elaborated by a plurality of subjects and expressed in a thick intertextual network. Since the Second Vatican Council (1962-1965), when the Church promoted a policy of adaptation of her tradition to the modern world, the modeling of sanctity has undergone a deep transformation. In a context of global change, new models of sanctity have assumed a central role in guiding the faithful by proposing a renewed religious alternative to growing secularization. NeMoSanctI intends to study how models of sanctity have changed after the Second Vatican Council and their relationship with the culture of a country exemplum of strong Catholicism: Italy. To this end, it will apply a pioneering semiotic method based on the study of values, which will allow the comparative analysis of a corpus of texts of different genres: - normative texts regulating sanctity emanating from the Church; - judicial texts, i.e. causes of canonization of three famous Italian saints (Padre Pio, Gianna Beretta Molla, and Gerardo Maiella), with a focus on the dialectics between the models proposed by laic witnesses and by ecclesiastic inquirers; - narrative texts, i.e. a sample of popular hagiography about the three saints, of official hagiographic collections, and of Italian literary texts, where the theme of sanctity tends to be unconventionally elaborated and dissociated from Catholic values. Despite its relevance for a deeper understanding of the role of religion in today’s culture, a systematic research on new models of sanctity and on their intertextual codification is still missing. By carrying out this research and by proposing an innovative semiotic method for the analysis of models of life perfection, NeMoSanctI will have a significant impact on numerous disciplines, especially semiotics, religious and cultural studies, critical studies of hagiography and canon law, literary and Italian studies.

Strigolactones (SLs) are a class of plant hormones that participate in many plant environmental interactions, including responses to drought. Much still has to be understood about how they mediate plant responses to abiotic stresses, but their mapping and quantification in plant tissues is extremely difficult. Some SL biosensors have been developed in recent years, but they all suffer from some technical limitations: namely they are negative sensors whose signal is degraded in the presence of SLs, and they require laborious and invasive techniques for signal detection. The aim of this fellowship is thus to combine knowledge in the fields of plant synthetic biology and plant molecular physiology to construct a novel SL biosensor, called StrigoSense, which is positively activated in the presence of SLs. StrigoSense will be constructed using the principles of modularity and reusability: this will allow to pair it with many customisable reporter systems, creating a tool which can accomodate a variety of users and research applications. In this project, StrigoSense is coupled to fluorescent and bioluminescent reporters for the non-invasive monitoring of plant SL responses at the cell and system level. The biosensor will be developed in Arabidopsis and tomato plants, seeking to transfer the research conducted on model organisms to a crop of enormous relevance, narrowing the gap between basic research and the development of SL-based agricultural solutions. After fine-tuning, the biosensor will be used to monitor plant responses to different abiotic stresses and to an array of SL-like compounds and biostimulants with the potential of acting as priming agents that help plants cope with recurring water deficits. This will be the first example of the testing of a SL biosensor under physiological stress conditions. The technical advantages of StrigoSense will make SL biosensors faster, cheaper and more high-throughput, with benefits for basic and applied research.