Coupling approach in shallow, unconfined aquifers in the Po Plain area: A preliminary study for future ground monitoring purposes.

The use of the coupling approach in analyzing the interaction between the flow field and the stress field in shallow, unconsolidated aquifers allows a better description of the involved phenomena. We perform our study on an area in the Po Plain (northern Italy) in the province of Bologna in Emilia-Romagna based on intended future studies on ground movements due to the superposition of shallow water production with deep underground gas storage. The static geological model of the alluvial sediments, locally exceeding 500 meters of thickness, is developed via a stochastic approach in order to manage the high degree of uncertainty in the system spatial continuity and heterogeneities. Corresponding water production data and piezometric measurements are collected for simulating the dynamic behavior of the shallow aquifer. The high uncertainty in water production data are managed considering a maximum and minimum scenarios on the basis of punctual well measurements and regional trend information. Correlation law between petrophysical parameters and deformation variables are derived for technical literature. The coupling technique is then applied and some sensitivity analysis are developed to assess the effects of the correlation laws. The results are finally compared with the output from the uncoupled techniques

Fluid Production Dataset for the Assessment of the Anthropogenic Subsidence in the Po Plain Area (Northern Italy)

Fluid produced/injected volumes from/into underground natural formations and their spatial allocation play a key role in addressing the superposition of anthropogenic subsidence effects, but the definition of coherent datasets is usually very challenging. In this paper, the creation of a gas and water production dataset for the Po Plain area in northern Italy is presented, focusing on the Emilia-Romagna region (an industrialized, highly-populated area characterized by rapid subsidence). The produced volumes and their spatial/temporal allocation are gathered from different sources, analyzed, and organized via dedicated georeferenced maps. The geological framework of the Po Plain is delineated, with attention to the superficial aquifers. Reference ranges of petrophysical and pseudo-elastic parameters are reported for both aquifer and reservoir formations. Water extractions from the superficial unconsolidated sediments are widespread, both in space and time; instead, primary gas production and underground storage of natural gas, involving deeper formations, are spatially and temporally well constrained. Drastic increases in water production and high concentrations of gas production temporally coincided between the 1950s and 1970s. The ‘hotspots’ of the strongest superposition are recognized in Piacenza, Ferrara, Bologna, and Ravenna provinces. Qualitative and quantitative information represent a reference source for both Oil and Gas Societies and Regional/National authorities in addressing the subsidence analysis to plan the field production life and predict the environmental consequences

CRISPR-Cas9 Gene Editing of Hematopoietic Stem Cells from Patients with Friedreich's Ataxia.

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by expansion of GAA repeats in intron 1 of the frataxin (FXN) gene, leading to significant decreased expression of frataxin, a mitochondrial iron-binding protein. We previously reported that syngeneic hematopoietic stem and progenitor cell (HSPC) transplantation prevented neurodegeneration in the FRDA mouse model YG8R. We showed that the mechanism of rescue was mediated by the transfer of the functional frataxin from HSPC-derived microglia/macrophage cells to neurons/myocytes. In this study, we report the first step toward an autologous HSPC transplantation using the CRISPR-Cas9 system for FRDA. We first identified a pair of CRISPR RNAs (crRNAs) that efficiently removes the GAA expansions in human FRDA lymphoblasts, restoring the non-pathologic level of frataxin expression and normalizing mitochondrial activity. We also optimized the gene-editing approach in HSPCs isolated from healthy and FRDA patients' peripheral blood and demonstrated normal hematopoiesis of gene-edited cells in vitro and in vivo. The procedure did not induce cellular toxic effect or major off-target events, but a p53-mediated cell proliferation delay was observed in the gene-edited cells. This study provides the foundation for the clinical translation of autologous transplantation of gene-corrected HSPCs for FRDA

Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis.

Inflammation is involved in the pathogenesis of many disorders. However, the underlying mechanisms are often unknown. Here, we test whether cystinosin, the protein involved in cystinosis, is a critical regulator of galectin-3, a member of the β-galactosidase binding protein family, during inflammation. Cystinosis is a lysosomal storage disorder and, despite ubiquitous expression of cystinosin, the kidney is the primary organ impacted by the disease. Cystinosin was found to enhance lysosomal localization and degradation of galectin-3. In Ctns-/- mice, a mouse model of cystinosis, galectin-3 is overexpressed in the kidney. The absence of galectin-3 in cystinotic mice ameliorates pathologic renal function and structure and decreases macrophage/monocyte infiltration in the kidney of the Ctns-/-Gal3-/- mice compared to Ctns-/- mice. These data strongly suggest that galectin-3 mediates inflammation involved in kidney disease progression in cystinosis. Furthermore, galectin-3 was found to interact with the pro-inflammatory cytokine Monocyte Chemoattractant Protein-1, which stimulates the recruitment of monocytes/macrophages, and proved to be significantly increased in the serum of Ctns-/- mice and also patients with cystinosis. Thus, our findings highlight a new role for cystinosin and galectin-3 interaction in inflammation and provide an additional mechanistic explanation for the kidney disease of cystinosis. This may lead to the identification of new drug targets to delay cystinosis progression

Combined PI3K and CDK2 inhibition induces cell death and enhances in vivo antitumour activity in colorectal cancer

Background: The phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway is commonly deregulated in human cancer, hence many PI3K and mTOR inhibitors have been developed and have now reached clinical trials. Similarly, CDKs have been investigated as cancer drug targets. Methods: We have synthesised and characterised a series of 6-aminopyrimidines identified from a kinase screen that inhibit PI3K and/or mTOR and/or CDK2. Kinase inhibition, tumour cell growth, cell cycle distribution, cytotoxicity and signalling experiments were undertaken in HCT116 and HT29 colorectal cancer cell lines, and in vivo HT29 efficacy studies. Results: 2,6-Diaminopyrimidines with an O4-cyclohexylmethyl substituent and a C-5-nitroso or cyano group (1,2,5) induced cell cycle phase alterations and were growth inhibitory (GI50<20 μM). Compound 1, but not 2 or 5, potently inhibits CDK2 (IC50=0.1 nM) as well as PI3K, and was cytotoxic at growth inhibitory concentrations. Consistent with kinase inhibition data, compound 1 reduced phospho-Rb and phospho-rS6 at GI50 concentrations. Combination of NU6102 (CDK2 inhibitor) and pictilisib (GDC-0941; pan-PI3K inhibitor) resulted in synergistic growth inhibition, and enhanced cytotoxicity in HT29 cells in vitro and HT29 tumour growth inhibition in vivo. Conclusions: These studies identified a novel series of mixed CDK2/PI3K inhibitors and demonstrate that dual targeting of CDK2 and PI3K can result in enhanced antitumour activity