Nuclear factor programming improves stem-cell-derived hepatocyte phenotype

In this issue of Cell Stem Cell, Ma et al. demonstrate that the activation of the nuclear receptor thyroid hormone receptor beta (NR1A2) improves the differentiation status of hepatocyte-like cells derived from human pluripotent stem cells

Implications of the Dirac CP phase upon parametric resonance for sub-GeV neutrinos

We perform an analytic and numerical study of parametric resonance in a three-neutrino framework for sub-GeV neutrinos which travel through a periodic density profile. Commensurate with the initial level of approximation, we develop a parametric resonance condition similar to the exact condition for two-neutrino systems. For a castle-wall density profile, the νe→νμ oscillation probability is enhanced significantly and bounded by cos2θ23. The CP phase δ enters into the oscillation probability as a phase shift. For several cases, we examine the interplay between the characteristics of the castle-wall profile and the CP phase and determine which profiles maximize the separation between oscillations with δ=0,±π2,π. We also consider neutrinos which travel along a chord through the Earth, passing from the mantle to core and back to mantle again. Significant enhancement of the oscillation probability is seen even in the case in which the neutrino energy is far from the MSW resonant energies. At 500 GeV, the difference between oscillation probabilities with δ=0 and δ=π2 is maximized

Metabolic control of gene transcription in non-alcoholic fatty liver disease: the role of the epigenome

Non-alcoholic fatty liver disease (NAFLD) is estimated to affect 24% of the global adult population. NAFLD is a major risk factor for the development of cirrhosis and hepatocellular carcinoma, as well as being strongly associated with type 2 diabetes and cardiovascular disease. It has been proposed that up to 88% of obese adults have NAFLD, and with global obesity rates increasing, this disease is set to become even more prevalent. Despite intense research in this field, the molecular processes underlying the pathology of NAFLD remain poorly understood. Hepatic intracellular lipid accumulation may lead to dysregulated tricarboxylic acid (TCA) cycle activity and associated alterations in metabolite levels. The TCA cycle metabolites alpha-ketoglutarate, succinate and fumarate are allosteric regulators of the alpha-ketoglutarate-dependent dioxygenase family of enzymes. The enzymes within this family have multiple targets, including DNA and chromatin, and thus may be capable of modulating gene transcription in response to intracellular lipid accumulation through alteration of the epigenome. In this review, we discuss what is currently understood in the field and suggest areas for future research which may lead to the development of novel preventative or therapeutic interventions for NAFLD

The Association between Partnership Financial Integration and Risky Audit Client Portfolios

This study examines whether profit-sharing arrangements within accounting firms are associated with the riskiness of their client portfolios. Our results use unique data about the profit-sharing arrangements of the Big 8 firms during the period 1985 to 1994. We investigate whether there is a correlation between profit-sharing and risky clients. Firms consist of the financially integrated firms, i.e., those that share their profits across a large pool of partners across the country and the financially independent firms that share their profits in a small pool on a local office basis. The large-pool firms provide more incentive for partners to cooperate to audit high-risk clients than the small-pool firms. Our results show that the large-pool firms are associated with riskier client portfolios; this is indicated by a higher proportion of fees from clients that later suffer from bankruptcies. In contrast, a smaller proportion of the clients of the small-pool firms go bankrupt. Tests using financial distress as alternative measures of client risk confirm this result

Early interferon lambda production is induced by double-stranded RNA in iPS-derived hepatocyte-like cells

Hepatotropic viruses are amongst the most ubiquitous pathogens worldwide, causing significant morbidity and mortality. As hepatocytes are among the primary targets of these viruses, their ability to mount early effective innate defence responses is of major research interest. Interferon lambda (IFNL) is produced early in response to viral stimulation in other cell types, but hepatocyte production of this interferon is little investigated. Due to the difficulty and significant costs in obtaining and culturing human primary hepatocytes, surrogate systems are widely sought. Here we used induced pluripotent stem (iPS)-derived hepatocyte-like cells (HLCs) to investigate hepatic IFNL expression in response to viral-like ligands. We demonstrate that hepatocytes rely on cytoplasmic pattern recognition receptors (PRRs) such as Protein Kinase RNA-dependent (PKR) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLR) for the detection of double stranded RNA. Stimulation of HLCs by viral-like RNA ligands activating cytosolic RNA sensors resulted in thousand fold increase of type III interferon gene expression. These results are in contrast with type I IFN expression, which was induced to a lower extent. Concomitant induction of interferon stimulated genes, such as interferon-stimulated gene 15 (ISG15) and CXCL10, indicated the ability of HLCs to activate interferon-dependent activity. These results demonstrate that HLCs mount an innate antiviral response upon stimulation with viral-like RNA characterized by the induction of type III IFN