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The concept of climate change has grown in recent decades, influencing the scientific community to conduct research on meteorological parameters and their variabilities. Research on global warming, as well as on its possible economic and environmental consequences, has spread over the last 20 years. Diffused changes in trends have been stated by several authors throughout the world, with different developments observed depending on the continent. Following a period of approximately 40 days of almost continuous rain that occurred from October to November 2019 across the Italian territory and caused several hazards (e.g., floods and landslides), a relevant question for decision-makers and civil protection actors emerged regarding the relative frequencies of given rainfall events in the Warning Hazard Zones (WHZs) of Italy. The derived products of this work could answer this question for both weather and hydrogeological operators thanks to the frequency and spatio-temporal distribution analyses conducted on 10-year daily rainfall data over the entire Italian territory. This work aspires to be an additional tool used to analyse events that have occurred, providing further information for a better understanding of the probability of occurrence and distribution of future events., (© 2021. The Author(s).)

Activating mutations of the BRAF gene are the most common genetic alterations in papillary thyroid carcinomas (PTCs) and the T1799A transversion, resulting in BRAFV600E, appeared virtually unique in this cancer type. Here, we report on the identification in a classic PTC of a novel BRAF mutation, namely a 1795GTT insertion, resulting in BRAFV599Ins, and describe its biochemical and molecular characterization. Kinase assays carried out on BRAFV599Ins and BRAFV600E revealed a three- to five-fold increase in the enzymatic activity of both mutants with respect to BRAFWT. Similarly, evaluation of BRAF-induced phosphorylation of MEK, MAPK and RSK revealed a significant MAPK cascade activation in cells expressing BRAFV599Ins or BRAFV600E, but not in cells expressing BRAFWT. Molecular dynamic simulations showed a destabilization of the inactive conformation of the enzyme in both BRAFV599Ins and BRAFV600E mutants, but not in BRAFWT. The analysis of the interaction energies inside the catalytic site allowed to demonstrate the presence of repulsive electrostatic forces acting on the activation loop and moving from inward to outward of the mutant enzymes. Finally, focus assays in NIH-3T3 cells confirmed a high transformation rate in the cells transfected either with BRAFV599Ins or BRAFV600E. In conclusion, this study demonstrated that BRAFV599Ins, as BRAFV600E, is a 'gain of function' mutation, characterized by a constitutive catalytic activation, which accounts for its causative role in the studied PTC.