Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2)

Funding: Supported by grants MR/J001465/1 (JDH, MLJA, JFD and RJMcC) and MR/N009851/1 (JDH, MLJA, ATD-K and DJH) from the Medical Research Council of the UK and grants from Stony Brook Foundation and Reata Pharmaceuticals, Inc. (TH)Background & Aims:  Nonalcoholic steatohepatitis (NASH) is associated with oxidative stress. We surmised that pharmacological activation of NF-E2 p45-related factor 2 (Nrf2) using the acetylenic tricyclic bis(cyano-enone) TBE-31 would suppress NASH because Nrf2 is a transcriptional master regulator of intracellular redox homeostasis. Methods:  Nrf2+/+ and Nrf2-/- C57BL/6 mice were fed a high-fat plus fructose (HFFr) or regular chow (RC) diet for 16 weeks or 30 weeks, and then treated for the final 6 weeks, whilst still being fed the same HFFr or RC diets, with either TBE-31 or DMSO vehicle control. Measures of whole body glucose homeostasis, histological assessment of liver, and biochemical and molecular measurements of steatosis, endoplasmic reticulum (ER) stress, inflammation, apoptosis, fibrosis and oxidative stress were performed in livers from these animals. Results:  TBE-31−treatment reversed insulin resistance in HFFr-fed wild-type mice, but not in HFFr-fed Nrf2-null mice. TBE-31−treatment of HFFr-fed wild-type mice substantially decreased liver steatosis and expression of lipid synthesis genes, whilst increasing hepatic expression of fatty acid oxidation and lipoprotein assembly genes. Also, TBE-31−treatment decreased ER stress, expression of inflammation genes, and markers of apoptosis, fibrosis and oxidative stress in the livers of HFFr-fed wild-type mice. By comparison, TBE-31 did not decrease steatosis, ER stress, lipogenesis, inflammation, fibrosis or oxidative stress in livers of HFFr-fed Nrf2-null mice. Conclusions:  Pharmacological activation of Nrf2 in mice that had already been rendered obese and insulin resistant reversed insulin resistance, suppressed hepatic steatosis, and mitigated against NASH and liver fibrosis, effects that we principally attribute to inhibition of ER, inflammatory and oxidative stress.Publisher PDFPeer reviewe

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Endogenous (In)Formal Institutions.

Despite the huge evidence documenting the relevance of inclusive political institutions and a culture of cooperation, we still lack a framework that identifies their origins and interaction. In a model in which an elite and a citizenry try to cooperate in consumption risk-sharing and investment, we show that a rise in the investment value encourages the elite to introduce more inclusive political institutions to convince the citizenry that a sufficient part of the returns on joint investments will be shared. In addition, accumulation of culture rises with the severity of consumption risk if this is not too large and thus cheating is not too appealing. Finally, the citizenry may over-accumulate culture to credibly commit to cooperate in investment when its value falls and so inclusive political institutions are at risk. These predictions are consistent with the evolution of activity-specific geographic factors, monasticism, and political institutions in a panel of 90 European regions spanning the 1000-1600 period. Evidence from several identification strategies suggests that the relationships we uncover are causal