Drug therapy of primary biliary diseases: classical and modern strategies

Definition: Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are both cholestatic liver diseases. A common feature of these disorders is the accumulation of bile acids in the liver and blood, presumably because of decreased biliary secretion and reduced bile flow. Etiology: Etiology and pathogenesis of PBC and PSC are still unknown. PBC is considered to be an autoimmune disease. Immunological mechanisms may also be involved in PSC since there is an association with ulcerative colitis and autoantibodies can be detected. Furthermore, genetic factors seem to play an important role in both diseases. Therapy: Since the pathogenesis of both diseases is unclear, there is no definite causal treatment. However, ursodeoxycholic acid (UDCA) was shown to be highly effective. Other drugs which can be used alone or in combination with UDCA are promising and might further improve the outcome of the diseases

When countries do not do what they say: Systematic discrepancies between exchange rate regime announcements and de facto policies

We study the apparent disconnect between what countries announce to be their exchange rate regime and what they de facto implement. Even though discrepancies between announcements and de facto polices are frequent, there is a lack of understanding of actual patterns and underlying reasons. We contribute to the literature by identifying a number of robust stylized facts by means of an in-depth analysis of a large cross-country dataset. A key insight is that countries that operate under intermediate de facto regimes tend to announce fixed or flexible exchange rate regimes. The exact nature of deviations is related to country characteristics such as trade structure, financial development, and financial openness. Furthermore, regime discrepancies have followed secular trends, which are most likely related to financial globalization and changes in monetary policy design

When countries do not do what they say: Systematic discrepancies between exchange rate regime announcements and de facto policies

We study the apparent disconnect between what countries announce to be their exchange rate regime and what they de facto implement. Even though discrepancies between announcements and de facto polices are frequent, there is a lack of understanding of actual patterns and underlying reasons. We contribute to the literature by identifying a number of robust stylized facts by means of an in-depth analysis of a large cross-country dataset. A key insight is that countries that operate under intermediate de facto regimes tend to announce fixed or flexible exchange rate regimes. The exact nature of deviations is related to country characteristics such as trade structure, financial development, and financial openness. Furthermore, regime discrepancies have followed secular trends, which are most likely related to financial globalization and changes in monetary policy design.Exchange rate regimes; de facto versus de jure; exchange rate policy

Application of RNA Interference for the Study of Lethal Genes and Dynamic Processes

RNA interference (RNAi) is a highly conserved cellular mechanism and in the last years it has become to a major tool for functional analyses of genes in different species. Moreover, RNAi has recently been suggested as a novel and promising approach for pest control. Transgenic plants can be engineered to express double stranded RNAs (dsRNAs) targeting essential genes of a pest species. Upon feeding, the dsRNAs induce gene silencing in the pest, resulting in its death. However, the main challenge of RNAi-mediated plant protection is the identification of efficient RNAi target genes. In most pest species, the screening for RNAi target genes by a whole-animal-high-throughput-approach is not feasible due to missing genomic tools and limited breeding capacity. Therefore, the first aim of this thesis was to use Tribolium castaneum (Tc) as a screening platform in order to identify the most efficient RNAi target genes. By employing the data from the iBeetle RNAi screen, some novel and highly efficient RNAi target genes were identified that induced organism death most rapidly after knockdown. The orthologs of these genes are hence excellent candidates for RNAi based pest control methods in other pest insects. Based on this set of RNAi targets, Gene Ontology term (GO term) combinations were identified that are predictive for efficient RNAi target genes and which detect proteasomal genes as prime targets. Further, I could show that the efficiency of RNAi mediated pest control cannot be increased by synergistic action in double knockdowns. Finally, an off target analysis revealed that protein sequence conservation does not strongly correlate with the number of potential off target sites, indicating that it will be difficult to design dsRNAs without potential off-target sites in non-target organisms. In the second part of this thesis, I aimed to establish a method to regulate the RNAi response. Ubiquitous gene silencing can sometimes lead to pleiotropic effects, hampering the identification of specific phenotypes. Temporal and/or spatial regulation of RNAi can circumvent such effects. The viral RNAi suppressor protein CrPV1A can be used for this purpose. The expression of CrPV1A effectively blocks the RNAi mechanism and does not impair the development or viability of Tribolium. Probably, it also does not interfere with the microRNA (miRNA) pathway. Furthermore, temporal activation of CrPV1A is able to terminate the RNAi response of a previously silenced gene, resulting in a rescued RNAi phenotype. Temporally controlled RNAi by CrPV1A activation is therefore an effective approach to investigate genetic interactions of further genes

Automatic conversion of PDF-based, layout-oriented typesetting data to DAISY: potentials and limitations

Only two percent of new books released in Germany are professionally edited for visually impaired people. However, more and more print publications are made available to the public in digital formats through online content delivery platforms like “libreka!”. The automatic conversion of such contents into DAISY would considerably increase the number of publications available in accessible formats. Still, most data available on “libreka!” is published as non-tagged PDF. In this paper, we examine the potential for automatic conversion of “libreka!”-based content into DAISY, while also analyzing the potentials and limitations of current conversion tools

Late Pliocene lakes and soils: a global data set for the analysis of climate feedbacks in a warmer world

The global distribution of late Pliocene soils and lakes has been reconstructed using a synthesis of geological data. These reconstructions are then used as boundary conditions for the Hadley Centre General Circulation Model (HadCM3) and the BIOME4 mechanistic vegetation model. By combining our novel soil and lake reconstructions with a fully coupled climate model we are able to explore the feedbacks of soils and lakes on the climate of the late Pliocene. Our experiments reveal regionally confined changes of local climate and vegetation in response to the new boundary conditions. The addition of late Pliocene soils has the largest influence on surface air temperatures, with notable increases in Australia, the southern part of northern Africa and in Asia. The inclusion of late Pliocene lakes increases precipitation in central Africa and at the locations of lakes in the Northern Hemisphere. When combined, the feedbacks on climate from late Pliocene lakes and soils improve the data to model fit in western North America and the southern part of northern Africa

Late Pliocene lakes and soils: a data-model comparison for the analysis of climate feedbacks in a warmer world

Based on a synthesis of geological data we have reconstructed the global distribution of Late Pliocene soils and lakes which are then used as boundary conditions in a series of model experiments using the Hadley Centre General Circulation Model (HadCM3) and the BIOME4 mechanistic vegetation model. By combining our novel soil and lake reconstructions with a fully coupled climate model we are able to explore the feedbacks of soils and lakes on the climate of the Late Pliocene. Our experiments reveal regionally confined changes of local climate and vegetation in response to the new boundary conditions. The addition of Late Pliocene soils has the largest influence on surface air temperatures, with notable increases in Australia, southern North Africa and Asia. The inclusion of Late Pliocene lakes generates a significant increase in precipitation in central Africa, as well as seasonal increases in the Northern Hemisphere. When combined, the feedbacks on climate from Late Pliocene lakes and soils improve the data to model fit in western North America and southern North Africa

IL-13R alpha 2 reverses the effects of IL-13 and IL-4 on bronchial reactivity and acetylcholine-induced Ca2+ signaling

Background: The interleukins IL-4 and IL-13 play a key role in the pathophysiology of asthma. The interleukin receptor IL-13R alpha 2 is believed to act as a decoy receptor, but until now, the functional significance of IL-13R alpha 2 remains vague. Methods: Bronchial reactivity was quantified in murine lung slices by digital video microscopy and acetylcholine (ACH)-induced Ca2+ signaling was measured in human airway smooth muscle cells (ASMC) using fluorescence microscopy. Results: IL-4 or IL-13 up to 50 ng/ml induced bronchial hyperreactivity. But after incubation with 100 ng/ml this effect was lost and bronchial responsiveness was again comparable to the control level. The effects of IL-4 and IL-13 on bronchial reactivity were paralleled by the effects on ASMC proliferation. Fifty nanograms per milliliter of IL-4 and IL-13 increased the Ca2+ response of human ASMC to ACH. At 100 ng/ml, however, the effects of the cytokines on the Ca2+ response were no longer evident. The expression of IL-13R alpha 2 increased with increasing concentrations of IL-4 or IL-13, reaching its maximum at 100 ng/ml. Blocking IL-13R alpha 2, the loss of the effect of IL-4 and IL-13 at 100 ng/ml on human ASMC proliferation and the ACH-induced Ca2+ response were no longer present. Conclusions: IL-4 and IL-13 induce bronchial hyperreactivity by changing the Ca2+ homeostasis of ASMC. These effects are counteracted by IL-13R alpha 2. The biological significance of IL-13R alpha 2 might be a protective function by regulating IL-13- and IL-4-mediated signal transduction and thereby limiting pathological alterations in Th2-mediated inflammatory diseases. Copyright (c) 2007 S. Karger AG, Basel