RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state

RNF43/ZNRF3 negatively regulate WNT signalling. Both genes are mutated in several types of cancers, however, their contribution to liver disease is unknown. Here we describe that hepatocyte-specific loss of Rnf43/Znrf3 results in steatohepatitis and in increase in unsaturated lipids, in the absence of dietary fat supplementation. Upon injury, Rnf43/Znrf3 deletion results in defective hepatocyte regeneration and liver cancer, caused by an imbalance between differentiation/proliferation. Using hepatocyte-, hepatoblast- and ductal cell-derived organoids we demonstrate that the differentiation defects and lipid alterations are, in part, cell-autonomous. Interestingly, ZNRF3 mutant liver cancer patients present poorer prognosis, altered hepatic lipid metabolism and steatohepatitis/NASH signatures. Our results imply that RNF43/ZNRF3 predispose to liver cancer by controlling the proliferative/differentiation and lipid metabolic state of hepatocytes. Both mechanisms combined facilitate the progression towards malignancy. Our findings might aid on the management of those RNF43/ZNRF3 mutated individuals at risk of developing fatty liver and/or liver cancer

Mouse liver assembloids model periportal architecture and biliary fibrosis

Modelling liver disease requires in vitro systems that replicate disease progression1,2. Current tissue-derived organoids fail to reproduce the complex cellular composition and tissue architecture observed in vivo3. Here, we describe a multicellular organoid system composed of adult hepatocytes, cholangiocytes and mesenchymal cells that recapitulates the architecture of the liver periportal region and, when manipulated, models aspects of cholestatic injury and biliary fibrosis. We first generate reproducible hepatocyte organoids with functional bile canaliculi network that retain morphological features of in vivo tissue. By combining these with cholangiocytes and portal fibroblasts, we generate assembloids that mimic the cellular interactions of the periportal region. Assembloids are functional, consistently draining bile from bile canaliculi into the bile duct. Strikingly, manipulating the relative number of portal mesenchymal cells is sufficient to induce a fibrotic-like state, independently of an immune compartment. By generating chimeric assembloids of mutant and wild-type cells, or after gene knockdown, we show proof-of-concept that our system is amenable to investigating gene function and cell-autonomous mechanisms. Taken together, we demonstrate that liver assembloids represent a suitable in vitro system to study bile canaliculi formation, bile drainage, and how different cell types contribute to cholestatic disease and biliary fibrosis, in an all-in-one model

Cytotoxicity and ion release of alloy nanoparticles

It is well-known that nanoparticles could cause toxic effects in cells. Alloy nanoparticles with yet unknown health risk may be released from cardiovascular implants made of Nickel–Titanium or Cobalt–Chromium due to abrasion or production failure. We show the bio-response of human primary endothelial and smooth muscle cells exposed to different concentrations of metal and alloy nanoparticles. Nanoparticles having primary particle sizes in the range of 5–250 nm were generated using laser ablation in three different solutions avoiding artificial chemical additives, and giving access to formulations containing nanoparticles only stabilized by biological ligands. Endothelial cells are found to be more sensitive to nanoparticle exposure than smooth muscle cells. Cobalt and Nickel nanoparticles caused the highest cytotoxicity. In contrast, Titanium, Nickel–Iron, and Nickel–Titanium nanoparticles had almost no influence on cells below a nanoparticle concentration of 10 μM. Nanoparticles in cysteine dissolved almost completely, whereas less ions are released when nanoparticles were stabilized in water or citrate solution. Nanoparticles stabilized by cysteine caused less inhibitory effects on cells suggesting cysteine to form metal complexes with bioactive ions in media

Nickel-Rare Earth (RE = Ce, Sm, Dy) Electrodes for H2O2 Reduction in Fuel Cells

The use of hydrogen peroxide (H2O2) as an oxidant is considered a good alternative to oxygen for the cathodic process in liquid fuel cells. Herein, we studied the reduction of H2O2 at nickel and at nickel-rare earth (RE = Ce, Sm, Dy) alloys containing 5 and 10 at.% of RE metal. The alloys were prepared by arc melting, starting from the stoichiometric amounts of the two parent metals, and analyzed by X-ray diffraction and scanning electron microscopy coupled with energy-dispersive spectroscopy. The electrochemical characterization was carried out by voltammetry and chronoamperometry measurements in alkaline media, in which main parameters were calculated, namely diffusion coefficients and number of exchanged electrons. Ni0.95Ce0.05 alloy exhibited the highest catalytic activity for H2O2 reduction reaction, with a number of exchanged electrons of 1.7. Additionally, activation energies were estimated according to Arrhenius equation

The thermodynamics of sequestration of toxic copper(II) metal ion pollutants from aqueous media by L-cysteine methyl ester modified glassy carbon spheres

l-Cysteine methyl ester modified glassy carbon powder (CysOMe-GC) has been shown to have potential for the removal of toxic heavy metal ions, such as copper(ii), cadmium(ii) and arsenic(iii), from "real" water samples. To develop this material for environmental applications we must develop an understanding of the thermodynamic parameters controlling the uptake of metal ions by the modified carbon powder. Here we characterise the material using X-ray photoelectron spectroscopy (XPS), before investigating the effect of varying the solution pH, the concentration of copper(ii) ions and the mass of CysOMe-GC powder added to the solution using square wave voltammetry (SWV). This data allows us to understand the thermodynamics controlling the copper(ii) ion uptake and elucidate that the adsorption of copper(ii) onto the CysOMe modified surface is controlled by a Freundlich isotherm

The thermodynamics of sequestration of toxic copper(II) metal ion pollutants from aqueous media by L-cysteine methyl ester modified glassy carbon spheres

l-Cysteine methyl ester modified glassy carbon powder (CysOMe-GC) has been shown to have potential for the removal of toxic heavy metal ions, such as copper(ii), cadmium(ii) and arsenic(iii), from "real" water samples. To develop this material for environmental applications we must develop an understanding of the thermodynamic parameters controlling the uptake of metal ions by the modified carbon powder. Here we characterise the material using X-ray photoelectron spectroscopy (XPS), before investigating the effect of varying the solution pH, the concentration of copper(ii) ions and the mass of CysOMe-GC powder added to the solution using square wave voltammetry (SWV). This data allows us to understand the thermodynamics controlling the copper(ii) ion uptake and elucidate that the adsorption of copper(ii) onto the CysOMe modified surface is controlled by a Freundlich isotherm

Nickel-rare earth electrodes for sodium borohydride electrooxidation

Binary alloys of nickel (Ni) and dysprosium (Dy) or samarium (Sm) of different composition were prepared. Their electrocatalytic activity in respect to borohydride oxidation in alkaline medium was investigated by cyclic voltammetry, chronoamperometry and chronopotentiometry. It was correlated to their morphological and structural properties examined by SEM/EDXS and XRPD. Ni0.95Dy0.05 alloy electrode showed the highest electrocatalytic activity for BOR, and Ni0.90Sm0.10 showed the lowest. The activity of the rare earth alloys was compared to other Ni- and Pt-based materials, with promising results being reported, which envisage application of these materials as electrodes in direct borohydride fuel cells

Electroanalytical sensing of trace amounts of As(III) in water resources by Gold\u2013Rare Earth alloys

Gold\u2013Rare Earth (Au-RE, RE = Sm, Dy, Ho, Y) alloys were prepared by co-melting stoichiometric amounts of metals. XRPD and SEM/EDX analysis revealed the formation of equiatomic compounds. These alloys were used for the preparation of electrodes for As(III) sensing in aqueous samples. All four electrodes gave a clear response in the presence of As(III) in weakly alkaline media (NaHCO3 + Na2CO3 buffer). Following optimisation of operating parameters (deposition potential of 120.9 V vs SCE and deposition time of 180 s), limits of detection of As(III) at four electrodes were determined to be in 0.8\u20132.3 ppb region. Au-RE electrodes gave a clear response in the presence of Cu(II) as model interferent and, finally, showed the ability for As(III) sensing in a real sample