Complex cellular networks regulate regeneration, detoxification and differentiation of hepatocytes. By combining experimental data with mathematical modelling, systems biology holds great promises to elucidate the key regulatory mechanisms involved and predict targets for efficient intervention. For the generation of high-quality quantitative data suitable for mathematical modelling a standardised in vitro system is essential. Therefore the authors developed standard operating procedures for the preparation and cultivation of primary mouse hepatocytes. To reliably monitor the dynamic induction of signalling pathways, the authors established starvation conditions and evaluated the extent of starvation-associated stress by quantifying several metabolic functions of cultured primary hepatocytes, namely activities of glutathione-S-transferase, glutamine synthetase, CYP3A as well as secretion of lactate and urea into the culture medium. Establishment of constant metabolic activities after an initial decrease compared with freshly isolated hepatocytes showed that the cultured hepatocytes achieve a new equilibrium state that was not affected by our starving conditions. To verify the highly reproducible dynamic activation of signalling pathways in the in vitro system, the authors examined the JAK-STAT, SMAD, PI3 kinase, MAP kinase, NF-kappaB and Wnt/beta-catenin signalling pathways. For the induction of gp130, JAK1 and STAT3 phosphorylation IL6 was used, whereas TGFbeta was applied to activate the phosphorylation of SMAD1, SMAD2 and SMAD3. Both Akt/PKB and ERK1/2 phosphorylation were stimulated by the addition of hepatocyte growth factor. The time-dependent induction of a pool of signalling competent beta-catenin was monitored in response to the inhibition of GSK3beta. To analyse whether phosphorylation is actually leading to transcriptional responses, luciferase reporter gene constructs driven by multiple copies of TGFbeta-responsive motives were applied, demonstrating a dose-dependent increase in luciferase activity. Moreover, the induction of apoptosis by the TNF-like cytokine Fas ligand was studied in the in vitro system. Thus, the mouse hepatocyte in vitro system provides an important basis for the generation of high-quality quantitative data under standardised cell culture conditions that is essential to elucidate critical hepatocellular functions by the systems biology approach.
ABO-incompatible living donor kidney transplantation utilizing a combination of rituximab and antigen-specific immunoadsorption yielded results identical to ABO-compatible transplantation despite a significantly higher number of human leukocyte antigen mismatches.
Recently, the iridate double perovskite Sr 2 YIrO 6 has attracted considerable attention due to the report of unexpected magnetism in this Ir 5+ (5d 4 ) material, in which according to the J eff model, a nonmagnetic ground state is expected. However, in recent works on polycrystalline samples of the series Ba 2−x Sr x YIrO 6 no indication of magnetic transitions have been found. We present a structural, magnetic, and thermodynamic characterization of Sr 2 YIrO 6 single crystals, with emphasis on the temperature and magnetic field dependence of the specific heat. As determined by x-ray diffraction, the Sr 2 YIrO 6 single crystals have a cubic structure, with space group F m3m. In agreement with the expected nonmagnetic ground state of Ir 5+ (5d 4 ) in Sr 2 YIrO 6 , no magnetic transition is observed down to 430 mK. Moreover, our results suggest that the low-temperature anomaly observed in the specific heat is not related to the onset of long-range magnetic order. Instead, it is identified as a Schottky anomaly caused by paramagnetic impurities present in the sample, of the order of n ∼ 0.5(2)%. These impurities lead to non-negligible spin correlations, which nonetheless, are not associated with long-range magnetic ordering.
The use of antigen-specific immunoadsorption and an immunosuppressive regimen consisting of a conventional triple immunosuppressive therapy has shown excellent short-term results. The immunoadsorption treatment using antigen-specific columns is highly effective and even patients with high isoagglutinin titers can be transplanted. This protocol is an option for end-stage renal disease patients who have no blood group-compatible donor.
Our results show that the end stage of ADPKD is associated with increased markers of EMT, suggesting that EMT contributes to the progressive loss of renal function in ADPKD.
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