Hepatocyte KLF6 expression affects FXR signalling and the clinical course of primary sclerosing cholangitis

Background & Aims: Primary sclerosing cholangitis (PSC) is characterized by chronic cholestasis and inflammation, which promotes cirrhosis and an increased risk of cholangiocellular carcinoma (CCA). The transcription factor Krueppel-like-factor-6 (KLF6) is a mediator of liver regeneration, steatosis, and hepatocellular carcinoma (HCC), but no data are yet available on its potential role in cholestasis. Here, we aimed to identify the impact of hepatic KLF6 expression on cholestatic liver injury and PSC and identify potential effects on farnesoid-X-receptor (FXR) signalling. Methods: Hepatocellular KLF6 expression was quantified by immunohistochemistry (IHC) in liver biopsies of PSC patients and correlated with serum parameters and clinical outcome. Liver injury was analysed in hepatocyte-specific Klf6-knockout mice following bile duct ligation (BDL). Chromatin-immunoprecipitation-assays (ChIP) and KLF6-overexpressing HepG2 cells were used to analyse the interaction of KLF6 and FXR target genes such as NR0B2. Results: Based on IHC, PSC patients could be subdivided into two groups showing either low (80%) hepatocellular KLF6 expression. In patients with high KLF6 expression, we observed a superior survival in Kaplan-Meier analysis. Klf6-knockout mice showed reduced hepatic necrosis following BDL when compared to controls. KLF6 suppressed NR0B2 expression in HepG2 cells mediated through binding of KLF6 to the NR0B2 promoter region. Conclusion: Here, we show an association between KLF6 expression and the clinical course and overall survival in PSC patients. Mechanistically, we identified a direct interaction of KLF6 with the FXR target gene NR0B2

The Epistemic Status of Processing Fluency as Source for Judgments of Truth

This article combines findings from cognitive psychology on the role of processing fluency in truth judgments with epistemological theory on justification of belief. We first review evidence that repeated exposure to a statement increases the subjective ease with which that statement is processed. This increased processing fluency, in turn, increases the probability that the statement is judged to be true. The basic question discussed here is whether the use of processing fluency as a cue to truth is epistemically justified. In the present analysis, based on Bayes’ Theorem, we adopt the reliable-process account of justification presented by Goldman (1986) and show that fluency is a reliable cue to truth, under the assumption that the majority of statements one has been exposed to are true. In the final section, we broaden the scope of this analysis and discuss how processing fluency as a potentially universal cue to judged truth may contribute to cultural differences in commonsense beliefs

On the fallibility of human memory for future actions

Human memory is a system that is inherently fallible and prone to distortion, and our memory for future actions is no exception. Prospective memory is defined either as remembering to carry out a task at a particular moment in the future or as the timely execution of a previously formed intention. For a variety of reasons, one may miss this prearranged moment and thus fail to fulfill an intention. This thesis focuses on the factors that may affect the fulfilment of a delayed intention and contribute to prospective memory failures. As the rather scant literature on the effect of stress on prospective memory functioning has produced contradictory findings, Part One of this Thesis investigates the role of stress in prospective memory failures in a strict sense, namely forgetting to carry out intended actions at the appointed time and place. One study involving healthy participants examines the disruptive effect of daily stress on prospective memory functioning and explores the moderating role of individual factors in modulating the harmful consequences associated with stress in everyday life. Another study carried out with healthcare workers investigates how work stress and burnout may contribute to forgetting clinical tasks, which may result in potential adverse events jeopardizing patient safety. Besides stress, misremembering future intentions may also arise from the lingering effect of misinformation on our memory, attitudes, and behaviors. Part Two of this Thesis, encompassing 6 experiments on healthy participants, shows how inaccurate and invalid information survive despite sophisticated correction attempts, influencing memory and reported future intentions. Overall, the results of the studies presented in this Thesis prove the fallibility of our memory for future actions. Various techniques to reduce the risks associated with memory failures are discussed

The truth about the truth : a meta-analytic review of the truth effect

Repetition has been shown to increase subjective truth ratings of trivia statements. This truth effect can be measured in two ways: (a) as the increase in subjective truth from the first to the second encounter (within-items criterion) and (b) as the difference in truth ratings between repeated and other new statements (between-items criterion). Qualitative differences are assumed between the processes underlying both criteria. A meta-analysis of the truth effect was conducted that compared the two criteria. In all, 51 studies of the repetition-induced truth effect were included in the analysis. Results indicate that the between-items effect is larger than the within-items effect. Moderator analyses reveal that several moderators affect both effects differentially. This lends support to the notion that different psychological comparison processes may underlie the two effects. The results are discussed within the processing fluency account of the truth effect