Aquifer recharge in the Piedmont Alpine zone: Historical trends and future scenarios

The spatial and temporal variability of air temperature, precipitation, actual evapotranspiration (AET) and their related water balance components, as well as their responses to anthropogenic climate change, provide fundamental information for an effective management of water resources and for a proactive involvement of users and stakeholders, in order to develop and apply adaptation and mitigation strategies at the local level. In this study, using an interdisciplinary research approach tailored to water management needs, we evaluate the past, present and future quantity of water potentially available for drinking supply in the water catchments feeding the about 2.3 million inhabitants of the Turin metropolitan area (the former Province of Turin, north-western Italy), considering climatologies at the quarterly and yearly timescales. Observed daily maximum surface air temperature and precipitation data from 1959 to 2017 were analysed to assess historical trends, their significance and the possible cross-correlations between the water balance components. Regional climate model (RCM) simulations from a small ensemble were analysed to provide mid-century projections of the difference between precipitation and AET for the area of interest in the future CMIP5 scenarios RCP4.5 (stabilization) and RCP8.5 (business as usual). Temporal and spatial variations in recharge were approximated with variations of drainage. The impact of irrigation, and of snowpack variability, on the latter was also assessed. The other terms of water balance were disregarded because they are affected by higher uncertainty. The analysis over the historical period indicated that the driest area of the study region displayed significant negative annual (and spring) trends of both precipitation and drainage. Results from field experiments were used to model irrigation, and we found that relatively wetter watersheds in the northern and in the southern parts behave differently, with a significant increase of AET due to irrigation. The analysis of future projections suggested almost stationary conditions for annual data. Regarding quarterly data, a slight decrease in summer drainage was found in three out of five models in both emission scenarios. The RCM ensemble exhibits a large spread in the representation of the future drainage trends. The large interannual variability of precipitation was also quantified and identified as a relevant risk factor for water management, expected to play a major role also in future decades

A water-filled garment to protect astronauts during interplanetary missions tested on board the ISS

Abstract As manned spaceflights beyond low Earth orbit are in the agenda of Space Agencies, the concerns related to space radiation exposure of the crew are still without conclusive solutions. The risk of long-term detrimental health effects needs to be kept below acceptable limits, and emergency countermeasures must be planned to avoid the short-term consequences of exposure to high particle fluxes during hardly predictable solar events. Space habitat shielding cannot be the ultimate solution: the increasing complexity of future missions will require astronauts to protect themselves in low-shielded areas, e.g. during emergency operations. Personal radiation shielding is promising, particularly if using available resources for multi-functional shielding devices. In this work we report on all steps from the conception, design, manufacturing, to the final test on board the International Space Station (ISS) of the first prototype of a water-filled garment for emergency radiation shielding against solar particle events. The garment has a good shielding potential and comfort level. On-board water is used for filling and then recycled without waste. The successful outcome of this experiment represents an important breakthrough in space radiation shielding, opening to the development of similarly conceived devices and their use in interplanetary missions as the one to Mars

Understanding the Central Limit Theorem the Easy Way: A Simulation Experiment

Using a simulation approach, and with collaboration among peers, this paper is intended to improve the understanding of sampling distributions (SD) and the Central Limit Theorem (CLT) as the main concepts behind inferential statistics. By demonstrating with a hands-on approach how a simulated sampling distribution performs when the data used has different probability distributions, we expect to clarify the notion of the Central Limit Theorem, and the use of samples in the hypothesis testing process for populations. This paper will discuss an initial stage to create random samples from a given population (using Excel) with collaboration of the students, which has been tested in the classroom. Then, based on that experience, a second stage in which we created an online simulation, controlled by the professor, and in which the students will participate during class time using an electronic device connected to internet. Students will create simple random samples from a variety of probability distributions simulated online in a collaborative way. Once the samples are generated, the instructor will combine and summarize the resulting sample statistics using histograms and the results will be discussed with the students. The objective is to teach some of the central topics of introductory statistics, the Central Limit Theorem and sampling distributions with an interactive and engaging approach

Verification of Quantitative Precipitation Forecasts by Stochastic Downscaling

The use of dense networks of rain gauges to verify the skill of quantitative numerical precipitation forecasts requires bridging the scale gap between the finite resolution of the forecast fields and the point measurements provided by each gauge. This is usually achieved either by interpolating the numerical forecasts to the rain gauge positions, or by upscaling the rain gauge measurements by averaging techniques. Both approaches are affected by uncertainties and sampling errors due to the limited density of most rain gauge networks and to the high spatiotemporal variability of precipitation. For this reason, an estimate of the sampling errors is crucial for obtaining a meaningful comparison. This work presents the application of a stochastic rainfall downscaling technique that allows a quantitative comparison between numerical forecasts and rain gauge measurements, in both downscaling and upscaling approaches, and allows a quanti- tative assessment of the significance of the results of the verification procedure

Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors

The synthesis, structure–activity relationships (SAR) and structural data of a series of indolin-2-one inhibitors of RET tyrosine kinase are described. These compounds were designed to explore the available space around the indolinone scaffold within RET active site. Several substitutions at different positions were tested and biochemical data were used to draw a molecular model of steric and electrostatic interactions, which can be applied to design more potent and selective RET inhibitors. The crystal structures of RET kinase domain in complex with three inhibitors were solved. All three compounds bound in the ATP pocket and formed two hydrogen bonds with the kinase hinge region. Crystallographic analysis confirmed predictions from molecular modelling and helped refine SAR results. These data provide important information for the development of indolinone inhibitors for the treatment of RET-driven cancers

Characterization of compound 584, an Abl kinase inhibitor with lasting effects

BACKGROUND: Resistance to imatinib is an important clinical issue in the treatment of Philadelphia chromosome-positive leukemias which is being tackled by the development of new, more potent drugs, such as the dual Src/Abl tyrosine kinase inhibitors dasatinib and bosutinib and the imatinib analog nilotinib. In the current study we describe the design, synthesis and biological properties of an imatinib analog with a chlorine-substituted benzamide, namely compound 584 (cmp-584). DESIGN AND METHODS: To increase the potency, we rationally designed cmp-584, a compound with enhanced shape complementarity with the kinase domain of Abl. cmp-584 was synthesized and characterized in vitro against a panel of 67 serine/threonine and tyrosine kinases using radioactive and enzyme-linked immunosorbent kinase assays. We studied inhibitory cellular activity using Bcr/Abl-positive human cell lines, murine transfectants in proliferation experiments, and a murine xenotrans-planted model. Kinase assays on isolated Bcr/Abl protein were also performed. Finally, we used a wash-out approach on whole cells to study the binding kinetics of the inhibitor. RESULTS: cmp-584 showed potent anti-Abl activity both on recombinant protein (IC(50): 8 nM) and in cell-based assays (IC(50): 0.1-10 nM). The drug maintained inhibitory activity against platelet-derived growth factor receptors and c-KIT and was also active against Lyn (IC(50): 301 nM). No other kinase of the panel was inhibited at nanomolar doses. cmp-584 was 20- to 300-fold more active than imatinib in cells. This superior activity was evident in intact cells, in which full-length Bcr-Abl is present. In vivo experiments confirmed the activity of cmp-584. Wash-out experiments showed that short exposure to the drug impaired cell proliferation and Bcr-Abl phosphorylation for a substantially longer period of time than imatinib. CONCLUSIONS: The present results suggest a slower off-rate (dissociation rate) of cmp-584 compared to imatinib as an explanation for the increased cellular activity of the former

Characterization of coumpound 584, an Abl kinase inhibitor with lasting effects

Background: Resistance to imatinib is an important clinical issue in the treatment of Philadelphia chromosomepositive leukemias which is being tackled by the development of new, more potent drugs, such as the dual Src/Abl tyrosine kinase inhibitors dasatinib and bosutinib and the imatinib analog nilotinib. In the current study we describe the design, synthesis and biological properties of an imatinib analog with a chlorine-substituted benzamide, namely compound 584 (cmp-584). Design and Methods: To increase the potency, we rationally designed cmp-584, a compound with enhanced shape complementarity with the kinase domain of Abl. cmp-584 was synthesized and characterized in vitro against a panel of 67 serine/threonine and tyrosine kinases using radioactive and enzyme-linked immunosorbent kinase assays. We studied inhibitory cellular activity using Bcr/Abl-positive human cell lines, murine transfectants in proliferation experiments, and a murine xenotransplanted model. Kinase assays on isolated Bcr/Abl protein were also performed. Finally, we used a wash-out approach on whole cells to study the binding kinetics of the inhibitor. Results: cmp-584 showed potent anti-Abl activity both on recombinant protein (IC50: 8 nM) and in cell-based assays (IC50: 0.1-10 nM). The drug maintained inhibitory activity against platelet-derived growth factor receptors and c-KIT and was also active against Lyn (IC50: 301 nM). No other kinase of the panel was inhibited at nanomolar doses. cmp-584 was 20- to 300-fold more active than imatinib in cells. This superior activity was evident in intact cells, in which full-length Bcr-Abl is present. In vivo experiments confirmed the activity of cmp-584. Wash-out experiments showed that short exposure to the drug impaired cell proliferation and Bcr-Abl phosphorylation for a substantially longer period of time than imatinib. Conclusions: The present results suggest a slower off-rate (dissociation rate) of cmp-584 compared to imatinib as an explanation for the increased cellular activity of the former. ©2008 Ferrata Storti Foundation