The valuation of forest ecosystem services as a tool for management planning – A choice experiment

Forest owners and managers deal with an increasing demand for forest ecosystem services (ES). In addition, a recent change can be observed from a governmental top-down approach to bottom-up initiatives, including efforts of the local population to have a say in forest management decisions. Matching supply and demand is seen as a basic condition for the sustainable utilization of forest ES. Against this background, we address the following research questions: (i) How can the preferences on the supply and demand side of forest ES be consistently determined? (ii) In how far do these preferences vary due to regional and societal differences? (iii) How can the supply and demand of forest ES be matched by forest management alternatives? We conducted a survey in Switzerland with foresters and the wider population to compare attitudes and preferences of the supply and demand side of forest ES. The core of the study is a choice experiment (CE) to elicit the population’s willingness to pay (WTP) for specific forest management alternatives, and the respective will- ingness to accept (WTA) on the foresters’ side. To address spatial and societal heterogeneity, we compare different geographic forest zones and settlement areas

Loss of Tet1 associated 5-hydroxymethylcytosine is concomitant with aberrant promoter hypermethylation in liver cancer

Aberrant hypermethylation of CpG islands (CGI) in human tumors occurs predominantly at repressed genes in the host tissue, but the preceding events driving this phenomenon are poorly understood. In this study, we temporally tracked epigenetic and transcriptomic perturbations which occur in a mouse model of liver carcinogenesis. Hypermethylated CGI events in the model were predicted by enrichment of the DNA modification 5-hydroxymethylcytosine (5hmC) and the histone H3 modification H3K27me3 at silenced promoters in the host tissue. During cancer progression, CGI underwent hypo-hydroxymethylation prior to hypermethylation, whilst retaining H3K27me3. In livers from mice deficient in Tet1, a tumor suppressor involved in cytosine demethylation, we observed a similar loss of promoter core 5hmC, suggesting that reduced Tet1 activity at CGI may contribute to epigenetic dysregulation observed during hepatocarcinogenesis. Consistent with this possibility, mouse liver tumors exhibited reduced Tet1 protein levels. Similar to humans, DNA methylation changes at CGI in mice did not appear to be direct drivers of hepatocellular carcinoma progression, rather, dynamic changes in H3K27me3 promoter deposition correlated strongly with tumor-specific activation and repression of transcription. Overall, our results suggest that loss of promoter-associated 5hmC in liver tumors licenses reprogramming of DNA methylation at silent CGI during progression

A Helminth Immunomodulator Exploits Host Signaling Events to Regulate Cytokine Production in Macrophages

Parasitic worms alter their host's immune system to diminish the inflammatory responses directed against them, using very efficient immunomodulating molecules. We have previously shown that the helminth immunomodulator cystatin (AvCystatin) profoundly reduces the progression of inflammatory diseases via modulation of macrophages. Here we elucidate the signaling events in macrophages triggered by AvCystatin. Labeled AvCystatin was predominantly taken up by macrophages and subsequently induced the phosphorylation of the mitogen-activated protein kinases (MAPK) ERK1/2 and p38. IL-10 expression induced by AvCystatin in macrophages was tyrosine kinase sensitive and dependent on activation of both MAP kinases, in clear contrast to expression of IL-12/23p40. In addition, phosphorylation of the transcription factors CREB and STAT3 was induced by AvCystatin and regulated by phospho-ERK. Chemical inhibition of phosphoinositide 3-kinase (PI3K) reduced AvCystatin-induced cytokine release; however, AKT, the downstream target of PI3K, was not activated following AvCystatin exposure. To characterize signaling elements involved in alteration of the macrophage phenotype we applied mathematical modeling. Experimental testing of the in silico generated hypotheses identified dual specificity phosphatase (DUSP) 1 and 2, as regulators in AvCystatin triggered macrophages in vitro and in vivo. In particular, DUSP1 was subsequently found to be responsible for regulation of ERK- and p38-phosphorylation and controlled the IL-10 expression in macrophages by AvCystatin. Thus, we show that AvCystatin exploits activation and deactivation pathways of MAP kinases to induce regulatory macrophages. This study provides insights into molecular mechanisms of macrophage manipulation by parasites and highlights the utility of mathematical modeling for the elucidation of regulatory circuits of immune cells

Identification of Dlk1-Dio3 imprinted gene cluster non-coding RNAs as novel candidate biomarkers for liver tumor promotion

The molecular events during non-genotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital-mediated liver tumor promotion in vivo. Molecular profiling (mRNA, miRNA, DNA methylation & proteins) of mouse liver during 13 weeks of phenobarbital treatment revealed progressive increases in hepatic expression of long non-coding RNAs and microRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. Phenobarbital-induction of the Dlk1-Dio3 cluster non-coding RNA Meg3 was localised to glutamine synthetase positive hypertrophic perivenous hepatocytes suggesting a role for β-catenin signaling in the dysregulation of Dlk1-Dio3 non-coding RNAs. The carcinogenic relevance of Dlk1-Dio3 locus non-coding RNA induction was further supported by in vivo genetic dependence on Constitutive Androstane Receptor (CAR) and β-catenin pathways. Our data identify Dlk1-Dio3 non-coding RNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds