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.

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.

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.

Several works by Ernesto Neto present huge, warm-colored, pleasantly smelling Lycra tunnels. They are cases of installation art (IA): the public is supposed to enter the tunnels and interact with the physical environment, experiencing the works from within. Works of IA resemble buildings because they envelop the public, but they differ in that, as with paintings and sculptures, they do not have a sheltering function. This raises a philosophical question: what states of mind are distinctive of our engagement with IA? The goal of this project is to develop the first full-fledged philosophical account of our engagement with IA, arguing that, typically, the imagination plays a crucial role in it, by pursuing 5 research and innovation objectives: (1) showing that IA prompts imaginings of a specific kind; (2) arguing that IA can be defined in terms of its imagining-arousing function; (3) arguing against the prevalent view that IA doesn't have a representational or fictional dimension; (4) investigating the link between the imaginings aroused by IA, on the one hand, and abstract painting, on the other hand; (5) integrating the proposal within a broader account of fiction. The project’s goal is relevant to aestheticians and art theorists, because IA dominates contemporary art, and to art practitioners and public, because it can help improve the design, exhibition, and communication of IA. I, Elisa Caldarola (Philosophy PhD), will carry out the proposed research through investigations in the philosophy of fiction and of art, in art theory, in depiction theory, and the philosophy of mind, working at The Graduate Center, City University of New York (Philosophy Program) under the supervision of Prof. Jonathan Gilmore, and at the Department of Philosophy and Education Sciences, University of Turin, under the supervision of Prof. Alberto Voltolini. I shall publish 5 papers in top-level journals, present my work at 8 conferences and at outreach events.

With the enforcement of EU regulations 2024/573, the production and usage of Tetrafluoroethane (R134a) has been strongly regulated. This gas is a key component in the gas mixture of Resistive Plate Chambers, a detector technology widely employed in high-energy physics. A potential, more environment-friendly, substitute for this gas is Tetrafluoropropene (HFO) and several promising HFO-based mixtures have been proposed. The long-term behavior (aging) of RPCs operated with these mixtures is typically studied by exposing several detectors flushed with an HFO-based gas mixture to a radioactive source and by studying the stability of the absorbed current and RPC performance over time Experimental tests are crucial to spot and quantify aging effects, but can rarely provide an explanation for their origin. This requires a deeper understanding of the microscopical modifications of the materials induced by the HFO decomposition when exposed to irradiation. This project aims at breaking down the aging phenomena of several RPC components in their basic building blocks by comparing the chemical (EDX spectroscopy and SEM analyses) and electrical (resistivity) features of new and aged samples of RPC materials. The results of these analyses will be used to formulate a model to describe the observed effects and develop a simulation code, allowing for a systematic test of the aging properties of different HFO-based gas mixtures. I will carry out my research at the High Voltage Laboratory of the ETH Zurich University and at the Physics Department at the University of Torino, with the guidance of Prof. Christian Franck and Martino Gagliardi, leading experts on eco-friendly high-voltage gaseous insulation and RPC detectors respectively, while the chemical analyses will be performed at the CERN chemical laboratory. On a personal level, this project will strengthen my academic profile significantly and provide an ideal training ground for my project- and time-management skills.