The evolution of Homo sapiens has always benefited from its ability to adapt to the most diverse environments. The subject of the adaptation of human groups to the environment has been of interest to scholars, whose attention is often turned to cases of adaptation to environments with extreme conditions and to the so-called ecological niches. However, little attention has been given to the choice of human groups to occupy extremely different environments (high mountains, higher than 2000 meter asl vs lowlands) and how high altitude settlements relate to the lowland sites in the framework of the land management. This is particularly the case of the Finale Pleistocene to Mid-Holocene period in the Horn of Africa. HUMA will be the first project to fully explore the contribution of a multidisciplinary and integrated approach to the understanding of human adaptation to the different environments in the Later Stone Age of the Horn of Africa. This will be achieved by integrating the most up-to-date approaches in lithic techno-functional analysis with organic and inorganic residues analysis on lithic artefacts and dental calculus analysis. Focusing on archaeological sites from Ethiopian highlands (Beefa Cave, a site discovered in 2019) and Somali highlands and plains, Huma will investigate the role played by the climate played in the development of the cultural traits and how environmental factors may have fostered specific adaptations to different ecological niches and encouraged seasonal use of them. Lithic techno-functional analysis, Residues analysis, Archaeobotany, Experimental Archaeology, Dental Calculus analysis, and aDNA analysis will be applied in order to answer the research questions. Both the University of Florence and the University of Connecticut are the ideal environments for undertaking the proposed cross-disciplinary research, as they will contribute with their theoretical, methodological, and professional resources to reaching the project's goals.

Chronic pain, characterized by increased sensitivity to innocuous/mild stimuli (allodynia), afflicts 25% of the European adult population. Efficacy and/or safety of analgesic medicines is limited, and the treatment of chronic pain associated with inflammation, peripheral and central neuropathies and cancer remains unsatisfactory. Thus, identification of novel targets for better and safer analgesics is a major medical need. Transient receptor potential ankyrin 1 (TRPA1) channel, expressed by a subpopulation of primary sensory neurons (nociceptors), has been proposed as a major transducer of acute pain. We have, recently, identified that TRPA1 is expressed in Schwann cells that ensheath peripheral nerve fibres. In a prototypical model of neuropathic pain (sciatic nerve ligation in mice), we discovered that Schwann cell-TRPA1 exerts a hitherto unknown role that, via amplification of the oxidative stress message, sustains neuroinflammation and chronic pain (allodynia). Thus, Schwann cells, through their own repertoire of channels and enzymes orchestrate in the injured/inflamed tissue an autocrine/paracrine signalling pathway to sustain chronic pain. The purpose of the present project is to extend this observation to other models of inflammatory, neuropathic and cancer pain to identify a general paradigm based on Schwann cell/TRPA1/oxidative stress as the pathway that sustains chronic pain. We aim also at identifying in oligodendrocytes (the Schwann cells of the brain) whether the TRPA1/oxidative stress pathway sustains pain in the central nervous system. In mouse, rat and human Schwann cells/oligodendrocytes we aim at identifying biomarkers and combine them into biosignatures predictive of the susceptibility to the development of chronic pain. We anticipate that each molecular step that entails the TRPA1/oxidative stress pathway in Schwann cell lineages is an eligible target for discovering new effective and safer medicines for the treatment of chronic pain.

Acute kidney injury (AKI) is a global public health concern which results in 1.7 million deaths per year. If not lethal in the acute phase, AKI is considered reversible as suggested by recovery of renal function. However, even mild AKI episodes carry substantial risk of developing subsequent chronic kidney disease (CKD). The pathophysiological basis for this phenomenon remains unclear. Injury and death of tubular cells are recognized as the main factors in the pathogenesis of AKI and functional recovery from AKI was traditionally attributed to the regenerative capacity of tubular epithelial cells (TECs) which are believed to re-enter the cell cycle and repair the damage. Nevertheless, my preliminary data provide evidence that an endocycle-mediated response of remnant TECs may represent a critical mechanism of response to AKI. Endocycles are cell cycle variants consisting of G and S phases alone that repeatedly proceed without cytokinesis and its role in repair of mammalian tissues is mostly unknown and totally unexplored in the kidney. This proposal will be structured into 3 distinct objectives to address: 1. The physiologic relevance of endocycle for kidney function recovery after AKI 2. The role of endocycle in the progression of AKI to CKD; 3. The mechanism by which YAP1 drives endocycle and contributes to CKD development. To this end I will use lineage tracing techniques based on the FUCCI2aR reporter applied in different transgenic animal models of AKI, together with in vitro experiments in human primary cultures of renal tubular cells. Collectively, the outcomes of this proposal are expected to provide an entirely novel view of the kidney’s response to AKI, to further our understanding of the processes that drive CKD following AKI, as well as to describe for the first time endocycle as a critical response mechanism to tissue injury in the mammalian kidney.