Fabertrevino0406

The Na+/H+ exchanger-1 (NHE1) supports tumour growth, making NHE1 inhibitors of interest in anticancer therapy, yet their molecular effects are incompletely characterized. Here, we demonstrate that widely used pyrazinoylguanidine-type NHE1 inhibitors potently inhibit growth and survival of cancer cell spheroids, in a manner unrelated to NHE1 inhibition. Cancer and non-cancer cells were grown as 3-dimensional (3D) spheroids and treated with pyrazinoylguanidine-type (amiloride, 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), 5-(N,N-dimethyl)-amiloride (DMA), and 5-(N,N-hexamethylene)-amiloride (HMA)) or benzoylguanidine-type (eniporide, cariporide) NHE1 inhibitors for 2-7 days, followed by analyses of viability, compound accumulation, and stress- and death-associated signalling. EIPA, DMA and HMA dose-dependently reduced breast cancer spheroid viability while cariporide and eniporide had no effect. Although both compound types inhibited NHE1, the toxic effects were NHE1-independent, as inhibitor-induced viability loss was unaffected by NHE1 CRISPR/Cas9 knockout. EIPA and HMA accumulated extensively in spheroids, and this was associated with marked vacuolization, apparent autophagic arrest, ER stress, mitochondrial- and DNA damage and poly-ADP-ribose-polymerase (PARP) cleavage, indicative of severe stress and paraptosis-like cell death. Pyrazinoylguanidine-induced cell death was partially additive to that induced by conventional anticancer therapies and strongly additive to extracellular-signal-regulated-kinase (ERK) pathway inhibition. Thus, in addition to inhibiting NHE1, pyrazinoylguanidines exert potent, NHE1-independent cancer cell death, pointing to a novel relevance for these compounds in anticancer therapy.Research in recent decades has confirmed that biodiversity influences ecosystem productivity; however, the potential mechanisms regulating this process remain subject to controversy, due to variation across ecosystems. Here, the effects of biodiversity on ecosystem productivity were evaluated using three variables of biodiversity (taxonomic diversity, functional identity, and functional diversity) and surrounding environmental conditions in a coastal saline meadow located on the south coast of Laizhou Bay, China. At this site, the shrub and field layers were primarily dominated by Tamarix chinensis and natural mesic grasses, respectively. Our results showed that functional identity, which is quantified as the community weighted mean of trait values, had greater explanatory ability than taxonomic and functional diversity. Thus, ecosystem productivity was determined disproportionately by the specific traits of dominant species. T. chinensis coverage was a biotic environmental factor that indirectly affected ecosystem productivity by increasing the community weighted mean of plant maximum height, which simultaneously declined with species richness. The present study advances our understanding of the mechanisms driving variation in the productivity of temperate coastal saline meadows, providing evidence supporting the "mass ratio" hypothesis.Crohn's disease is an inflammatory bowel disease that is characterized by chronic inflammation of any part of the gastrointestinal tract, has a progressive and destructive course and is increasing in incidence worldwide. Several factors have been implicated in the cause of Crohn's disease, including a dysregulated immune system, an altered microbiota, genetic susceptibility and environmental factors, but the cause of the disease remains unknown. The onset of the disease at a young age in most cases necessitates prompt but long-term treatment to prevent disease flares and disease progression with intestinal complications. Thus, earlier, more aggressive treatment with biologic therapies or novel small molecules could profoundly change the natural history of the disease and decrease complications and the need for hospitalization and surgery. Although less invasive biomarkers are in development, diagnosis still relies on endoscopy and histological assessment of biopsy specimens. Crohn's disease is a complex disease, and treatment should be personalized to address the underlying pathogenetic mechanism. In the future, disease management might rely on severity scores that incorporate prognostic factors, bowel damage assessment and non-invasive close monitoring of disease activity to reduce the severity of complications.Tissue engineering allows to combine biomaterials and seeded cells to experimentally replace urinary bladder wall. The normal bladder wall however, includes branched neuronal network propagating signals which regulate urine storage and voiding. In this study we introduced a novel biocomposite built from amniotic membrane (Am) and graphene which created interface between cells and external stimuli replacing neuronal network. Graphene layers were transferred without modifying Am surface. Applied method allowed to preserve the unique bioactive characteristic of Am. Tissue engineered constructs composed from biocomposite seeded with smooth muscle cells (SMC) derived from porcine detrusor and porcine urothelial cells (UC) were used to evaluate properties of developed biomaterial. The presence of graphene layer significantly increased electrical conductivity of biocomposite. UCs and SMCs showed an organized growth pattern on graphene covered surfaces. Electrical filed stimulation (EFS) applied in vitro led additionally to increased SMCs growth and linear arrangement. 3D printed chamber equipped with 3D printed graphene based electrodes was fabricated to deliver EFS and record pressure changes caused by contracting SMCs seeded biocomposite. Observed contractile response indicated on effective SMCs stimulation mediated by graphene layer which constituted efficient cell to biomaterial interface.Research on smart grid technologies is expected to result in effective climate change mitigation. PI3K inhibitor Non-Intrusive Load Monitoring (NILM) is seen as a key technique for enabling innovative smart-grid services. By breaking down the energy consumption of households and industrial facilities into its components, NILM techniques provide information on present appliances and can be applied to perform diagnostics. As with related Machine Learning problems, research and development requires a sufficient amount of data to train and validate new approaches. As a viable alternative to collecting datasets in buildings during expensive and time-consuming measurement campaigns, the idea of generating synthetic datasets for NILM gain momentum recently. With SynD, we present a synthetic energy dataset with focus on residential buildings. We release 180 days of synthetic power data on aggregate level (i.e. mains) and individual appliances. SynD is the result of a custom simulation process that relies on power traces of real household appliances.