Traveling Wave Fronts and Localized Traveling Wave Convection in Binary Fluid Mixtures

Nonlinear fronts between spatially extended traveling wave convection (TW) and quiescent fluid and spatially localized traveling waves (LTWs) are investigated in quantitative detail in the bistable regime of binary fluid mixtures heated from below. A finite-difference method is used to solve the full hydrodynamic field equations in a vertical cross section of the layer perpendicular to the convection roll axes. Results are presented for ethanol-water parameters with several strongly negative separation ratios where TW solutions bifurcate subcritically. Fronts and LTWs are compared with each other and similarities and differences are elucidated. Phase propagation out of the quiescent fluid into the convective structure entails a unique selection of the latter while fronts and interfaces where the phase moves into the quiescent state behave differently. Interpretations of various experimental observations are suggested.Comment: 46 pages, 11 figures. Accepted for publication in Phys. Rev.

Pattern selection in the absolutely unstable regime as a nonlinear eigenvalue problem: Taylor vortices in axial flow

A unique pattern selection in the absolutely unstable regime of a driven, nonlinear, open-flow system is analyzed: The spatiotemporal structures of rotationally symmetric vortices that propagate downstream in the annulus of the rotating Taylor-Couette system due to an externally imposed axial through-flow are investigated for two different axial boundary conditions at the in- and outlet. Unlike the stationary patterns in systems without through-flow the spatiotemporal structures of propagating vortices are independent of parameter history, initial conditions, and system's length. They do, however, depend on the axial boundary conditions, the driving rate of the inner cylinder and the through-flow rate. Our analysis of the amplitude equation shows that the pattern selection can be described by a nonlinear eigenvalue problem with the frequency being the eigenvalue. Approaching the border between absolute and convective instability the eigenvalue problem becomes effectively linear and the selection mechanism approaches that one of linear front propagation. PACS:47.54.+r,47.20.Ky,47.32.-y,47.20.FtComment: 15 pages (LateX-file), 8 figures (Postscript

MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa

Epigenetic variance in dopamine D2 receptor: A marker of IQ malleability?

Genetic and environmental factors both contribute to cognitive test performance. A substantial increase in average intelligence test results in the second half of the previous century within one generation is unlikely to be explained by genetic changes. One possible explanation for the strong malleability of cognitive performance measure is that environmental factors modify gene expression via epigenetic mechanisms. Epigenetic factors may help to understand the recent observations of an association between dopamine-dependent encoding of reward prediction errors and cognitive capacity, which was modulated by adverse life events. The possible manifestation of malleable biomarkers contributing to variance in cognitive test performance, and thus possibly contributing to the “missing heritability” between estimates from twin studies and variance explained by genetic markers, is still unclear. Here we show in 1475 healthy adolescents from the IMaging and GENetics (IMAGEN) sample that general IQ (gIQ) is associated with (1) polygenic scores for intelligence, (2) epigenetic modification of DRD2 gene, (3) gray matter density in striatum, and (4) functional striatal activation elicited by temporarily surprising reward-predicting cues. Comparing the relative importance for the prediction of gIQ in an overlapping subsample, our results demonstrate neurobiological correlates of the malleability of gIQ and point to equal importance of genetic variance, epigenetic modification of DRD2 receptor gene, as well as functional striatal activation, known to influence dopamine neurotransmission. Peripheral epigenetic markers are in need of confirmation in the central nervous system and should be tested in longitudinal settings specifically assessing individual and environmental factors that modify epigenetic structure

Linking the Epigenome to the Genome: Correlation of Different Features to DNA Methylation of CpG Islands

DNA methylation of CpG islands plays a crucial role in the regulation of gene expression. More than half of all human promoters contain CpG islands with a tissue-specific methylation pattern in differentiated cells. Still today, the whole process of how DNA methyltransferases determine which region should be methylated is not completely revealed. There are many hypotheses of which genomic features are correlated to the epigenome that have not yet been evaluated. Furthermore, many explorative approaches of measuring DNA methylation are limited to a subset of the genome and thus, cannot be employed, e.g., for genome-wide biomarker prediction methods. In this study, we evaluated the correlation of genetic, epigenetic and hypothesis-driven features to DNA methylation of CpG islands. To this end, various binary classifiers were trained and evaluated by cross-validation on a dataset comprising DNA methylation data for 190 CpG islands in HEPG2, HEK293, fibroblasts and leukocytes. We achieved an accuracy of up to 91% with an MCC of 0.8 using ten-fold cross-validation and ten repetitions. With these models, we extended the existing dataset to the whole genome and thus, predicted the methylation landscape for the given cell types. The method used for these predictions is also validated on another external whole-genome dataset. Our results reveal features correlated to DNA methylation and confirm or disprove various hypotheses of DNA methylation related features. This study confirms correlations between DNA methylation and histone modifications, DNA structure, DNA sequence, genomic attributes and CpG island properties. Furthermore, the method has been validated on a genome-wide dataset from the ENCODE consortium. The developed software, as well as the predicted datasets and a web-service to compare methylation states of CpG islands are available at http://www.cogsys.cs.uni-tuebingen.de/software/dna-methylation/