Exploring the NANOG-TET2 interaction interface. Effects of a selected mutation and hypothesis on the clinical correlation with anemias

In this study, we focused on the computational analysis of a selected single-point mutation identified by a NGS screening panel in the TET2 enzyme classified as “variant of uncertain clinical significance.” The mutation, namely Q1084P, occurs at the interface between TET2, an important epigenetic regulator, and NANOG, a transcription factor fundamental for hematopoietic cells differentiation. Notably, the mutation occurs in a protein region distant from the active site; moreover, the experimental structures of the interacting region of both proteins are unknown, making it difficult to validate the impact of TET2 mutation on its binding with NANOG. To address these challenges, we employed an integrated computational approach combining molecular docking, molecular dynamics simulations and protein-protein interaction prediction. Our findings indicate that the single-point mutation might effectively reduce the TET2-NANOG interaction, which would consequently impair cells differentiation and hematopoiesis process, consistent with the clinical presentation of pure red cell aplastic anemia. These results, along with the proposed computational method, provide insights for establishing clinical correlations between variants of uncertain significance and anemias in general, comprising common hematological problems widespread in the world population and for which dedicated NGS panels are still not available

Chemical and isotopic (δ18O‰, δ²H‰, δ¹³C‰, Rn-222) multi-tracing for groundwater conceptual model of carbonate aquifer (Gran Sasso INFN underground laboratory - central Italy)

A hydrochemical and isotope study was conducted on the drainage waters of an underground laboratory, located inside the Gran Sasso massif (central Italy). The study was expected to improve the conceptual model of groundwater circulation at the base of an over 1000-thick unsaturated zone in the Gran Sasso partitioned karst aquifer. This lithostratigraphically and tectonically complex aquifer is typical of Africa-Europe thrust-and-fold collision belt in the Mediterranean area. In this case, investigations on water-rock interactions during recharge in complex aquifers, overlaid by a thick unsaturated zone, have been made thanks to the strategic location of the Gran Sasso underground laboratories, located in the core of a huge carbonate aquifer. Knowledge of the local basic hydrogeological setting was the starting point for a detailed hydrogeochemical and isotopic study, which was carried out at the aquifer scale and at the fine scale in the underground laboratories. The water-rock interaction processes were investigated both spatially and in temporal sequences, analysing recharge waters and groundwater in the underground laboratories by multitracing techniques, including major ions and ?18O‰, ?2H‰ and ?13C‰ stable isotopes. Use of 222Rn provides information on transit time in the aquifer. Processes proved to be typical of carbonate rocks, with clear influence of vertical movement of water on chemical-physical parameters through the unsaturated zone. Conversely, in the saturated zone, these processes proved to be dominantly affected by local geological-structural conditions. A conceptual model with dual flow velocity is proposed, directly related to the local geological-structural setting. 222Rn decay enables to calculate an effective velocity of around 10 m/day for the fracture network, through the sequence of less permeable dolomites and underlying limestone. Lag time between recharge and chemical changes in the saturated zone testifies to an effective velocity of about 35 m/day for fast flow through recent and active extensional faults

Isotope hydrology and geochemical modeling: new insights into the recharge processes and water-rock interactions of a fissured carbonate aquifer (Gran Sasso, central Italy)

The goal of this paper was to characterize the recharge process and water-rock interactions in a regional homogeneous fractured carbonate aquifer in the Mediterranean environment (Gran Sasso, central Italy) through isotope data (δ2H, δ18O and δ13C-DIC) collected between 2006 and 2010. Samples were collected from the springs of the Gran Sasso aquifer and from the Underground Nuclear Physics Laboratories, located within the aquifer. Additionally, the hydrochemical data and the reference hydrogeological frameworks of previous studies have been used as a starting point for the geochemical modeling. The Gran Sasso aquifer, which is bounded by terrigenous and clastic units acting as aquitards, accommodates a uniquely broad regional groundwater, which feeds springs mainly at its border with high, steady discharge. In total, these springs discharge of more than 18 m3/s. At a local scale for the aquifer core and at a regional scale for the overall aquifer, δ 2H, δ18O and δ13C-DIC isotope data, the geochemical inverse modeling through PHREEQC and the δ13C-DIC fractionation modeling through NETPATH 2.0 show the following. (1) Clear processes of evaporation and related isotope enrichment may be ruled out. (2) Groundwater flow is active and extends to the overall aquifer without clear signs of layering and partitioning. (3) Groundwater flowpaths radiate from the core toward the periphery. (4) In L'Aquila Plain, Gran Sasso groundwater mixes with shallow Quaternary water at a ratio of one half. (5) The main geochemical processes are the dissolution of calcite and dolomite, and in some cases, ion exchange occurs (Mg2+ and SO4 2- release, Ca2+ adsorption). (6) In the less mineralized recharge groundwater, the δ13C-DIC value is influenced by the δ13C-DIC value of rainfall, while in more evolved groundwater, the final δ13C-DIC value is reached by fractionation during the flowpaths, indicating a lengthy interaction with limestone. © 2014 Springer-Verlag Berlin Heidelberg

Changes on groundwater flow and hydrochemistry of the Gran Sasso carbonate aquifer due to the 2009 L'Aquila earthquake

The earthquake that struck L’Aquila on April 6 2009 (Mw 6.3) directly affected the Gran Sasso aquifer. Co-seismic and post-seismic changes in groundwater discharge and in hydrochemistry, possibly induced by the earthquake, were observed. Spot and monitoring measurements of the spring discharge, of water table level and of the main physico-chemical parameters of spring waters (T, pH, electrical conductivity, major ions and 222Rn) were thus carried out to determine the effects of the L’Aquila earthquake on groundwater at regional and local scale, to be compared with available data collected since the 1990s. Short- and mid-term effects have been observed in the groundwater flow at recharge and discharge areas. The following short-term effects have been observed: i) the sudden disappearance of some springs located along the surface trace of the Paganica Fault; ii) an immediate discharge increase of the Gran Sasso highway tunnel drainages (+20%) and of other springs (+10%); iii) a progressive increase of the water table elevation (+1m) at the boundary of the Gran Sasso aquifer during the following month; iv) a sudden lowering of the water table in the recharge area. Similar post-seismic effects have been recorded in the following 20 months, when spring discharge and water table remain higher than the pre-seismic ones in discharge zones. A conceptual model of the earthquake consequences on the Gran Sasso aquifer is proposed herein. The short-term hydrologic effects registered immediately after the mainshock have been caused by a pore pressure increase related to aquifer deformation. Apart from the contribution of seasonal recharge observed in 2009-10, mid-term effects observed in the 20 months following the mainshock suggest that there was a change in groundwater hydrodynamics. Supplementary groundwater that flows toward aquifer boundaries and springs in discharge areas reflects a possible increase in hydraulic conductivity in the recharge area. This increase is probably related to fracture cleaning and/or dilatancy. Additional monitoring including hydrochemical data allows a refinement of the proposed model. The outcomes of the hydrochemical spot sampling of the pre-seismic (2001 – 2007), post-seismic (April 2009) and after-seismic (July and September 2009, may 2010) periods, give the following insights: i) post-seismic groundwater of Tempera spring group was more mineralised and richer in 222Rn than the pre-seismic one; ii) transient changes in pH and calcite saturation index involve the whole aquifer, moving from Tempera springs and spreading from the recharge to discharge areas, causing changes in groundwater hydrochemistry; iii) post-seismic gradual return to previous hydrochemical equilibrium. Both hydrodynamic and hydrochemical observation converge towards a non-permanent increase of the bulk hydraulic conductivity in the aquifer portion close to the Paganica Fault (recharge area and local discharge zone). This fact has caused a lowering of the water table and calcite saturation index in recharge areas and simultaneously an increase of water table and flow rate in discharge zones. Complete interpretation of both quantitative and hydrochemical data allows to determine the long-term consequences of this earthquake on the groundwater flow of the Gran Sasso carbonate massif