TGR(mREN2)27 rats develop non-alcoholic fatty liver disease-associated portal hypertension responsive to modulations of Janus-kinase 2 and Mas receptor

Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl4 inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2/Arhgef1/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and in vivo. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl4) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas

Self Aligned Concentric Nanostructures Formed by E-beam Overexposure of PMMA and Single Post Processing Steps

We demonstrate the ability to control the creation of self aligned nanostructures by e-beam lithography, where a central nanopillar with circular rim is created in a single e-beam exposure [1,2]. This characteristic shape is formed by the energy density distribution of incident, forwardscattered and backscattered electrons [3] and reflects the dual behavior of PMMA as positive and negative e-beam resist. In addition, the high energy incident electrons have a confined heating effect on the PMMA and carbonize the polymer from top to bottom. At the same time, electrons backscattered from the underlying material will break the polymeric bonds around thiscarbonized region and render the PMMA soluble in developer solution

Fabrication of Heterogeneous Nanogaps for Characterizing Electrochemical Metal Deposition Processes

We present a much simpler and high-throughput method compared to mechanically break junctions (MBJ) and electro-migration, to produce a heterogeneous nanogap, directly using electron beam lithography and metal lift-off technology. Au – Pt and Au – Pt silicide electrodes pairs are fabricated using two-step electron beam lithography. The shape of the electrode apex and the distance between the electrodes are well controlled

Nanomechanical Membrane-type Surface Stress Sensor

Nanomechanical cantilever sensors have been emerging as a key device for real-time and label-free detection of various analytes ranging from gaseous to biological molecules. The major sensing principle is based on the analyte-induced surface stress, which makes a cantilever bend. In this letter, we present a membrane-type surface stress sensor (MSS), which is based on the piezoresistive read-out integrated in the sensor chip. The MSS is not a simple "cantilever," rather it consists of an "adsorbate membrane" suspended by four piezoresistive "sensing beams," composing a full Wheatstone bridge. The whole analyte-induced isotropic surface stress on the membrane is efficiently transduced to the piezoresistive beams as an amplified uniaxial stress. Evaluation of a prototype MSS used in the present experiments demonstrates a high sensitivity which is comparable with that of optical methods and a factor of more than 20 higher than that obtained with a standard piezoresistive cantilever. The finite element analyses indicate that changing dimensions of the membrane and beams can substantially increase the sensitivity further. Given the various conveniences and advantages of the integrated piezoresistive read-out, this platform is expected to open a new era of surface stress-based sensing