Bile acid retention and activation of endogenous hepatic farnesoid-X-receptor in the pathogenesis of fatty liver disease in ob/ob-mice

The nuclear bile acid receptor FXR (farnesoid-X-receptor) has recently been implicated in the pathophysiology of non-alcoholic fatty liver disease because selective FXR-agonists improve glucose and lipid metabolism in rodent models of obesity. However, the regulation of FXR and other relevant nuclear receptors as well as their lipogenic target genes in fatty liver is still not revealed in detail. Livers were harvested from 14-week-old male ob/ob mice and wild-type controls. Serum bile acids were quantified by radioimmunoassay. mRNA and protein expression of transporters and nuclear receptors was analyzed by reverse transcriptase-polymerase chain reaction and Western blotting, whereas DNA binding to the IR-1 element was examined by electrophoretic mobility shift assay. In this study we show: (i) bile acid retention in ob/ob mice, (ii) a resulting FXR upregulation and binding to the IR-1 element in ob/ob animals and (iii) concomitant activation of the fatty acid synthase as a potential lipogenic FXR target gene in vivo. The present study suggests a potential role of hepatic bile acid retention and FXR activation in the induction of lipogenic target genes. Differences between intestinal and hepatic FXR could explain apparent contradictory information regarding its effects on fatty liver diseas

Bile acid retention and activation of endogenous hepatic farnesoid-X-receptor in the pathogenesis of fatty liver disease in ob/ob-mice

The nuclear bile acid receptor FXR (farnesoid-X-receptor) has recently been implicated in the pathophysiology of non-alcoholic fatty liver disease because selective FXR-agonists improve glucose and lipid metabolism in rodent models of obesity. However, the regulation of FXR and other relevant nuclear receptors as well as their lipogenic target genes in fatty liver is still not revealed in detail. Livers were harvested from 14-week-old male ob/ob mice and wild-type controls. Serum bile acids were quantified by radioimmunoassay. mRNA and protein expression of transporters and nuclear receptors was analyzed by reverse transcriptase-polymerase chain reaction and Western blotting, whereas DNA binding to the IR-1 element was examined by electrophoretic mobility shift assay. In this study we show: (i) bile acid retention in ob/ob mice, (ii) a resulting FXR upregulation and binding to the IR-1 element in ob/ob animals and (iii) concomitant activation of the fatty acid synthase as a potential lipogenic FXR target gene in vivo. The present study suggests a potential role of hepatic bile acid retention and FXR activation in the induction of lipogenic target genes. Differences between intestinal and hepatic FXR could explain apparent contradictory information regarding its effects on fatty liver disease

A Throughput-Optimized Optical Network for Data-Intensive Computing

Data-intensive computing increasingly involves operations at the scale of an entire computing system, requiring quick and efficient processing of massive datasets. In this article, the authors present a circuit-switched network architecture, together with requisite optical-switch and burst-mode transceiver technology, designed to support demanding graph algorithms in a distributed-memory system. The proposed optical network, configured as multiple planes of high-radix wavelength-division-multiplexed (WDM) switches, offers tremendous path diversity and is designed to deliver up to 10 terabytes per second of node bandwidth and predictable performance under heavy load with latencies well under a microsecond. With the optical core switch, the authors overcome pin-count and power-dissipation limitations of electrical networks with comparable bandwidth. To achieve this, they are developing new hardware, including nanosecond-scale silicon photonic switches with flip-chip-attached optical amplifiers, low-power parallel WDM transceivers operating at about 20-Gbps per channel, with burst-mode clock and data recovery circuits in advanced CMOS for link retraining in tens of nanoseconds. Network simulations predict that the proposed system could achieve graph performance on par with today's leading supercomputers, and its limited power consumption would result in several orders of magnitude of efficiency improvements that could allow the system to fit within a few racks.This work was supported by DARPA/ARL under contract W911NF-11-2-0059

Immediate early gene-X1 interferes with 26 S proteasome activity by attenuating expression of the 19 S proteasomal components S5a/Rpn10 and S1/Rpn2

The stress response gene IEX-1 (immediate early gene-X-1) is involved in the regulation of cell growth and cellular viability. To some extent, these effects include an interference with the proteasomal turnover of certain regulatory proteins. Here, we show that IEX-1 directly attenuates the activity and formation of the 26 S proteasome in HEK-293 cells (human embryonic kidney cells). We further demonstrate that IEX-1 reduces the overall expression levels of certain protein components of the 19 S proteasomal subunit such as S5a/Rpn10 and S1/Rpn2, whereas the expression of other proteasomal proteins was less or not affected. In contrast with direct apoptotic stimuli, such as the anti-cancer drug etoposide, leading to caspase-dependent degradation of S1 and S5a, the effect of IEX-1 is independent of proteolytic cleavage of these proteins. Furthermore, the decreasing effect of IEX-1 on S5a and S1 expression is still seen in the presence of cycloheximide, but not in the presence of actinomycin D, and quantitative real-time PCR revealed lower mRNA levels of S5a and S1 in IEX-1-overexpressing cells, suggesting an interference of IEX-1 with the gene transcription of S5a and S1. Additionally, luciferase assays confirmed an interference of IEX-1 with the activity of the S5a promoter. These findings indicate a role of IEX-1 in the maintenance and assembly of the 26 S proteasome, obviously involving an altered gene expression of certain proteasomal proteins. Thereby, IEX-1 may essentially modulate signalling pathways related to 26 S proteasome activity and involved in cellular growth control and apoptosis

Same-sex unions: the globalization of an idea

What explains why a majority of western democracies have adopted same-sex union (SSU) laws in the past decade and a half? I argue that this startling trend toward policy convergence in part can be explained by the rise of a human rights oriented transnational network of lesbian, gay, bisexual, and transgender (LGBT) activists as well as the transnationally networked policy elites these activists influence. These networks, however, do not fully determine policy outcomes as is evidenced by the fact that not all western democracies legally recognize same-sex relationships and those that do have adopted different models of SSU laws. To explain these differences, I show how the nature of national religious practices and the perceived legitimacy of international norms by national elites and publics mediate the influence of the transnational networks and the norms they promote