Microscopic model of diffusion limited aggregation and electrodeposition in the presence of levelling molecules

A microscopic model of the effect of unbinding in diffusion limited aggregation based on a cellular automata approach is presented. The geometry resembles electrochemical deposition - ``ions'' diffuse at random from the top of a container until encountering a cluster in contact with the bottom, to which they stick. The model exhibits dendritic (fractal) growth in the diffusion limited case. The addition of a field eliminates the fractal nature but the density remains low. The addition of molecules which unbind atoms from the aggregate transforms the deposit to a 100% dense one (in 3D). The molecules are remarkably adept at avoiding being trapped. This mimics the effect of so-called ``leveller'' molecules which are used in electrochemical deposition

Sensitive Detection of Organophosphorus Pesticides Using a Needle Type Amperometric Acetylcholinesterase-based Bioelectrode. Thiocholine Electrochemistry and Immobilised Enzyme Inhibition

International audienceAn acetylcholinesterase (AChE) based amperometric bioelectrode for a selective detection of low concen¬ trations of organophosphorus pesticides has been developed. The amperometric needle type bioelectrode consists of a bare cavity in a PTFE isolated Pt-Ir wire, where the AChE was entrapped into a photopolymerised polymer of polyvinyl alcohol bearing styrylpyridinium groups (PVA-SbQ). Cyclic voltammetry, performed at Pt and AChE/Pt disk electrodes, confirmed the irreversible, monoelectronic thiocholine oxidation process and showed that a working potential of + 0.410 V vs. Ag/AgCl, KClSat was suitable for a selective and sensitive amperometric detection of thiocholine. The acetylthio-choline detection under enzyme kinetic control was found in the range of 0.01-0.3 U cm~" of immobilised AChE. The detection limit, calculated for an inhibition ratio of 10%, was found to reach 5 jxM for dipterex and 0.4 jaIVI for paraoxon. A kinetic analysis of the AChE-pesticide interaction process using Hanes-Woolf or Lineweaver-Burk linearisations and secondary plots allowed identification of the immobilised enzyme inhibition process as a mixed one (non/uncompetitive) for both dipterex and paraoxon. The deviation from classical Michaelis Menten kinetics induced from the studied pesticides was evaluated using Hill plots

Gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the STAM™ model of NASH

<div><p>Background and aims</p><p>Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) can advance, if untreated, to liver fibrosis, cirrhosis, hepatocellular carcinoma, liver failure and liver-related death. In the United States, NASH affects approximately 2–5% of the population and an additional 10–30% have NAFLD. The number of drugs in development for NASH is growing steadily, along with nonclinical models to support prediction of clinical success. Here we evaluate gemcabene, a first-in-class clinical candidate for dyslipidemia, for its potential utility, based on its combined lipid-lowering and anti-inflammatory efficacy in clinical trials, in a preclinical model of NASH.</p><p>Methods</p><p>Gemcabene was evaluated in the STAM™ murine model of NASH. Gemcabene intervention in mice made diabetic with streptozotocin and fed a high fat high-caloric diet was assessed for changes in plasma, and hepatic histological and mRNA markers of lipid metabolism and inflammation.</p><p>Results</p><p>Gemcabene significantly downregulated hepatic mRNA markers of inflammation (TNF-α, MCP-1, MIP-1β, CCR5, CCR2, NF-κB), lipogenesis and lipid modulation (ApoC-III, ACC1, ADH-4, Sulf-2), and fibrosis (TIMP-1 and MMP-2). These effects are important for the prevention of steatosis, inflammation, and hepatocyte ballooning (<i>i</i>.<i>e</i>., the components of the NAFLD Activity Score or NAS), and inhibition of fibrosis progression, and were observed following treatment with gemcabene.</p><p>Conclusions</p><p>These non-clinical findings corroborate with existing clinical data to support the clinical evaluation of gemcabene as a potential new treatment for NASH.</p></div

Gene expression analysis.

<p>Gene expression analysis.</p

Gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the STAM™ model of NASH - Fig 5

<p>A) NAS Score; B) Fibrosis area.</p

Representative photomicrographs of Sirius red-stained liver sections.

<p>Representative photomicrographs of Sirius red-stained liver sections.</p

Gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the STAM™ model of NASH - Fig 6

<p>Oil Red-O Staining Analysis: A—Representative photomicrographs of Oil Red Stained Liver Sections; B—Fat Deposition Area.</p

Representative photomicrographs of hematoxylin and eosin-stained liver sections.

<p>Representative photomicrographs of hematoxylin and eosin-stained liver sections.</p

Overview of the NAFLD Activity Score (NAS).

<p>Overview of the NAFLD Activity Score (NAS).</p