ALBERT

Description: The extracellular matrix protein Laminin B1 (LamB1) regulates tumor cell migration and invasion. Carcinoma cells acquire invasive properties by epithelial to mesenchymal transition (EMT), which is a fundamental step in dissemination of metastatic cells from the primary tumor. Recently, we showed that enhanced translation of LamB1 upon EMT of malignant hepatocytes is mediated by an internal ribosome entry site (IRES). We demonstrated that the IRES transacting factor La binds the minimal IRES motif and positively modulates IRES activity of LamB1. Here, we show that platelet-derived growth factor (PDGF) enhances IRES activity of LamB1 by the increasing cytoplasmic localization of La during EMT. Accordingly, cells expressing dominant negative PDGF receptor display reduced cytoplasmic accumulation of La and show no elevation of IRES activity or endogenous LamB1 levels after stimulation with PDGF. Furthermore, La-mediated regulation of LamB1 IRES activity predominantly depends on MAPK/ERK signaling downstream of PDGF. Notably, LamB1 expression is not significantly downregulated by the impairment of the translation initiation factor eIF4E. In vivo , knockdown of La associated with decreased LamB1 expression and reduced tumor growth. Together, these data suggest that PDGF is required for the cytoplasmic accumulation of La that triggers IRES-dependent translation of LamB1 during EMT.

Description: In humans, the Crumbs homolog-1 ( CRB1 ) gene is mutated in progressive types of autosomal recessive retinitis pigmentosa and Leber congenital amaurosis. However, there is no clear genotype–phenotype correlation for CRB1 mutations, which suggests that other components of the CRB complex may influence the severity of retinal disease. Therefore, to understand the physiological role of the Crumbs complex proteins, we generated and analysed conditional knockout mice lacking CRB2 in the developing retina. Progressive disorganization was detected during late retinal development. Progressive thinning of the photoreceptor layer and sites of cellular mislocalization was detected throughout the CRB2-deficient retina by confocal scanning laser ophthalmoscopy and spectral domain optical coherence tomography. Under scotopic conditions using electroretinography, the attenuation of the a-wave was relatively stronger than that of the b-wave, suggesting progressive degeneration of photoreceptors in adult animals. Histological analysis of newborn mice showed abnormal lamination of immature rod photoreceptors and disruption of adherens junctions between photoreceptors, Müller glia and progenitor cells. The number of late-born progenitor cells, rod photoreceptors and Müller glia cells was increased, concomitant with programmed cell death of rod photoreceptors. The data suggest an essential role for CRB2 in proper lamination of the photoreceptor layer and suppression of proliferation of late-born retinal progenitor cells.

Description: : S weep F inder is a widely used program that implements a powerful likelihood-based method for detecting recent positive selection, or selective sweeps. Here, we present S weep F inder 2, an extension of S weep F inder with increased sensitivity and robustness to the confounding effects of mutation rate variation and background selection. Moreover, S weep F inder 2 has increased flexibility that enables the user to specify test sites, set the distance between test sites and utilize a recombination map. Availability and implementation: S weep F inder 2 is a freely-available ( www.personal.psu.edu/mxd60/sf2.html ) software package that is written in C and can be run from a Unix command line. Contact: mxd60@psu.edu

Description: Detecting positive selection in species with heterogeneous habitats and complex demography is notoriously difficult and prone to statistical biases. The model plant Arabidopsis thaliana exemplifies this problem: In spite of the large amounts of data, little evidence for classic selective sweeps has been found. Moreover, many aspects of the demography are unclear, which makes it hard to judge whether the few signals are indeed signs of selection, or false positives caused by demographic events. Here, we focus on Swedish A. thaliana and we find that the demography can be approximated as a two-population model. Careful analysis of the data shows that such a two island model is characterized by a very old split time that significantly predates the last glacial maximum followed by secondary contact with strong migration. We evaluate selection based on this demography and find that this secondary contact model strongly affects the power to detect sweeps. Moreover, it affects the power differently for northern Sweden (more false positives) as compared with southern Sweden (more false negatives). However, even when the demographic history is accounted for, sweep signals in northern Sweden are stronger than in southern Sweden, with little or no positional overlap. Further simulations including the complex demography and selection confirm that this is not compatible with global selection acting on both populations, and thus can be taken as evidence for local selection within subpopulations of Swedish A. thaliana . This study demonstrates the necessity of combining demographic analyses and sweep scans for the detection of selection, particularly when selection acts predominantly local.

Description: This article aims to quantify the effects of energy policy on power prices. A fundamental model is used to replicate wholesale market prices and to analyse the impact of a change in single price drivers such as coal prices or subsidies for new renewables. It is shown that approximately 50 per cent of the wholesale power price decrease in Germany of the last few years is due to market effects such as the decrease of coal and gas prices as well as the decrease in electricity demand. Only approximately 30 per cent of the price decrease can be directly associated with the subsidies for new renewable energies such as wind and solar. The first part of this article reviews the three policy objectives which guide energy strategy in Europe. In the second part two theoretic models of energy policy governance, namely the direct and multiple steering approach are introduced. Moreover, the article quantifies the impacts of the policy instruments on wholesale power prices and challenges the current energy policies. The third part briefly discusses the effect of the energy policy impact of Fukushima, before the results of the fundamental model and the market effects are analysed in the fourth chapter. The last chapter quantifies all different drivers of power prices and concludes that market effects such as coal and gas prices are at least as important as all policy effects, such as subsidizing renewables or abandoning nuclear power, combined.

Description: Timescales of magma chamber assembly and recharge are investigated here by applying 1D and 2D diffusion modeling techniques to high-resolution maps of titanium in quartz from a large-volume ignimbrite eruption in the Taupo Volcanic Zone, New Zealand. We compare quartz zonation patterns and associated diffusion timescales from the ~340 ka Whakamaru super-eruption (magma volume ~1000 km 3 ) with the Younger Toba Tuff super-eruption, 74 ka (2000 km 3 ), Sumatra, and the smaller volume ~50 ka Earthquake Flat eruption (10 km 3 ), Okataina Caldera Complex, New Zealand. Two principal timescales are presented: that of chamber recharge and eruption triggering events, and that of magma generation (involving long-term assembly, stirring and reactivation). Synchrotron micro-X-ray fluorescence maps of core–rim quartz transects provide a high-resolution record of magma chamber conditions throughout quartz crystallization. Quartz crystals from the Whakamaru magma display complex zonation patterns indicating fluctuating pressure–temperature conditions throughout the crystallization history. Toba and Earthquake Flat, in contrast, display simple quartz-zoning patterns and record slightly longer periods of crystal residence in the chamber that fed the eruption. We apply Lattice Boltzmann 2D diffusion modeling to reconstruct the timescales of quartz crystal zonation, accounting for crystal boundary complexities. Quartz crystal orientation is also accounted for by using geometry constraints from the synchrotron data. Our calculations suggest that crystal-mush reactivation for the main Whakamaru magma reservoir occured over a period of the order of 10 3 –10 4 years. Both the Earthquake Flat and Toba eruptions experienced a significant recharge event (causing a temperature and pressure change), which occurred within ~100 years of eruption. In comparison, the complex Whakamaru quartz zoning patterns suggest that the magma body experienced numerous thermal and compositional fluctuations in the lead-up to eruption. The final magma recharge event, which most probably triggered the eruption, occurred within ~10–60 years of the eruption. Even though the volume of these systems spans two orders of magnitude, there does not appear to be a relationship between magma volume and diffusion timescale, suggesting similar histories before eruption.

Description: DNA methylation of cytosine in eukaryotic cells is a common epigenetic modification, which plays an important role in gene expression and thus affects various cellular processes like development and carcinogenesis. The occurrence of 5-methyl-2'-deoxycytosine (5mC) as well as the distribution pattern of this epigenetic marker were shown to be crucial for gene regulation and can serve as important biomarkers for diagnostics. DNA polymerases distinguish little, if any, between incorporation opposite C and 5mC, which is not surprising since the site of methylation is not involved in Watson–Crick recognition. Here, we describe the development of a DNA polymerase variant that incorporates the canonical 2'-deoxyguanosine 5'-monophosphate (dGMP) opposite C with higher efficiency compared to 5mC. The variant of Thermococcus kodakaraensis (KOD) exo- DNA polymerase was discovered by screening mutant libraries that were built by rational design. We discovered that an amino acid substitution at a single site that does not directly interact with the templating nucleobase, may alter the ability of the DNA polymerase in processing C in comparison to 5mC. Employing these findings in combination with a nucleotide, which is fluorescently labeled at the terminal phosphate, indicates the potential use of the mutant DNA polymerase in the detection of 5mC.