A new consistent modeling framework for the competitive adsorption of humic nanoparticles and oxyanions to metal (hydr)oxides: Multiple modes of heterogeneity, fractionation, and conformational change.

HYPOTHESIS: The competitive interaction of oxyanions and humic nanoparticles (HNPs) with metal (hydr)oxide surfaces can be used to trace the ligand and charge distribution of adsorbed HNPs in relation to heterogeneity, fractionation, and conformational change. EXPERIMENTS: Batch adsorption experiments of HNPs on goethite were performed in the absence and presence of phosphate. The size of HNPs was measured with size exclusion chromatography. The Ligand and Charge Distribution (LCD) model framework was further developed to describe the simultaneous interaction of HNPs and phosphate with goethite. FINDINGS: Preferential adsorption decreases the mean molar mass of adsorbed HNPs, independent of the phosphate presence, showing a linear dependency on the adsorbed HNPs fraction. Phosphate ion can be used as a probe to trace the distribution of functional groups and the variation in affinity of HNPs. The spatial distribution of adsorbed HNPs is driven by the potential gradients in the electrical double layer, which changes the conformation of the adsorbed HNPs. At the particle level, the adsorption of heterogeneous HNPs has an affinity distribution, which can be explained by the variation in molar mass (kDa) and density of the functional groups (mol kg-1) of the HNPs. The presented model can simultaneously describe the competitive adsorption of HNPs and phosphate in a consistent manner.

Modelling porcine NAFLD by deletion of leptin and defining the role of AMPK in hepatic fibrosis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic hepatic disease and results in non-alcoholic steatohepatitis (NASH), which progresses to fibrosis and cirrhosis. Although the Leptin deficient rodent models are widely used in study of metabolic syndrome and obesity, they fail to develop liver injuries as in patients. METHODS: Due to the high similarity with humans, we generated Leptin-deficient (Leptin-/-) pigs to investigate the mechanisms and clinical trials of obesity and NAFLD caused by Leptin. RESULTS: The Leptin-/- pigs showed increased body fat and significant insulin resistance at the age of 12 months. Moreover, Leptin-/- pig developed fatty liver, non-alcoholic steatohepatitis and hepatic fibrosis with age. Absence of Leptin in pig reduced the phosphorylation of JAK2-STAT3 and AMPK. The inactivation of JAK2-STAT3 and AMPK enhanced fatty acid ß-oxidation and leaded to mitochondrial autophagy respectively, and both contributed to increased oxidative stress in liver cells. In contrast with Leptin-/- pig, although Leptin deletion in rat liver inhibited JAK2-STAT3 phosphorylation, the activation of AMPK pathway might prevent liver injury. Therefore, ß-oxidation, mitochondrial autophagy and hepatic fibrosis did not occurred in Leptin-/- rat livers. CONCLUSIONS: The Leptin-deficient pigs presents an ideal model to illustrate the full spectrum of human NAFLD. The activity of AMPK signaling pathway suggests a potential target to develop new strategy for the diagnosis and treatment of NAFLD.

PKD1 deficiency induces Bronchiectasis in a porcine ADPKD model.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent genetic disorder, mainly characterized by the development of renal cysts, as well as various extrarenal manifestations. Previous studies have shown that ADPKD is related to bronchiectasis, while its pathogenic mechanism is unclear. In previous studies, we have generated the PKD1+/- pigs to simulate the progression of cyst formation and physiological alterations similar to those seen in ADPKD patients. METHODS: Phenotypic changes to airway epithelial cell and mesenchymal cell in PKD1+/- pigs were assessed by histological analysis. The molecular mechanisms driving these processes were investigated by using PKD1+/- pig lungs, human mesenchymal cells, and generating PKD1 deficient human epithelial cells. RESULTS: We identified bronchiectasis in PKD1+/- pigs, which is consistent with the clinical symptoms in ADPKD patients. The deficiency of PKD1 suppressed E-cadherin expression in the airway epithelial barrier, which aggravated invasion and leaded to a perpetuated inflammatory response. During this process, extracellular matrix (ECM) components were altered, which contributed to airway smooth muscle cell phenotype switch from a contractile phenotype to a proliferative phenotype. The effects on smooth muscle cells resulted in airway remodeling and establishment of bronchiectasis. CONCLUSION: To our knowledge, the PKD1+/- pig provides the first model recapitulating the pathogenesis of bronchiectasis in ADPKD. The role of PKD1 in airway epithelial suggests a potential target for development of new strategies for the diagnosis and treatment of bronchiectasis.

Key factors in the adsorption of natural organic matter to metal (hydr)oxides: Fractionation and conformational change.

Adsorption of natural organic matter (NOM) to mineral surfaces is an important process determining the environmental fate and biogeochemical cycling of many elements. Natural organic matter consists of a heterogeneous mixture of soft and flexible organic molecules. Upon adsorption, size fractionation may occur, as well as changes in molecular conformation. Although very important, these phenomena have been omitted in existing adsorption models. Filling this gap, a novel framework for NOM adsorption to metal (hydr)oxides is presented. Humic acid (HA) was used as an analog for studying experimentally the NOM adsorption to goethite and its size fractionation as a function of pH, ionic strength, and surface loading. Size fractionation was evaluated for adsorption isotherms collected at pH 4 and 6, showing HA molecules of low molar mass were preferentially adsorbed. This phenomenon was incorporated into the new model. Consistent description of the HA adsorption data over the entire range of pH (3-11), ionic strength (2-100 mM), and surface loading (0.1-3 mg m-2) indicated that the spatial distribution of HA molecules adsorbed in the interface is a trade-off between maximizing the interaction of the HA ligands with the oxide surface and minimizing the electrostatic repulsion between HA particles as a result of interfacial crowding. Our advanced consistent framework is able to quantify changes in molar mass and molecular conformation, thereby significantly contributing to an improved understanding of the competitive power of HA for interacting on oxides with other adsorbed small organic acids as well as environmentally important oxyanions, such as phosphate, arsenate, and others.