Wall roughness induces asymptotic ultimate turbulence

Turbulence is omnipresent in Nature and technology, governing the transport of heat, mass, and momentum on multiple scales. For real-world applications of wall-bounded turbulence, the underlying surfaces are virtually always rough; yet characterizing and understanding the effects of wall roughness for turbulence remains a challenge, especially for rotating and thermally driven turbulence. By combining extensive experiments and numerical simulations, here, taking as example the paradigmatic Taylor-Couette system (the closed flow between two independently rotating coaxial cylinders), we show how wall roughness greatly enhances the overall transport properties and the corresponding scaling exponents. If only one of the walls is rough, we reveal that the bulk velocity is slaved to the rough side, due to the much stronger coupling to that wall by the detaching flow structures. If both walls are rough, the viscosity dependence is thoroughly eliminated in the boundary layers and we thus achieve asymptotic ultimate turbulence, i.e. the upper limit of transport, whose existence had been predicted by Robert Kraichnan in 1962 (Phys. Fluids {\bf 5}, 1374 (1962)) and in which the scalings laws can be extrapolated to arbitrarily large Reynolds numbers

A computational approach to identify point mutations associated with occult hepatitis B: significant mutations affect coding regions but not regulative elements of HBV

<p>Abstract</p> <p>Background</p> <p>Occult Hepatitis B Infection (OBI) is characterized by absence of serum HBsAg and persistence of HBV-DNA in liver tissue, with low to undetectable serum HBV-DNA. The mechanisms underlying OBI remain to be clarified. To evaluate if specific point mutations of HBV genome may be associated with OBI, we applied an approach based on bioinformatics analysis of complete genome HBV sequences. In addition, the feasibility of bioinformatics prediction models to classify HBV infections into OBI and non-OBI by molecular data was evaluated.</p> <p>Methods</p> <p>41 OBI and 162 non-OBI complete genome sequences were retrieved from GenBank, aligned and subjected to univariable analysis including statistical evaluation. Their S coding region was analyzed for Stop codon mutations too, while S amino acid variability could be evaluated for genotype D only, due to the too small number of available complete genome OBI sequences from other genotypes.</p> <p>Prediction models were derived by multivariable analysis using Logistic Regression, Rule Induction and Random Forest approaches, with extra-sample error estimation by Multiple ten-fold Cross-Validation (MCV). Models were compared by t-test on the Area Under the Receiver Operating Characteristic curve (AUC) distributions obtained from the MCV runs for each model against the best-performing model.</p> <p>Results</p> <p>Variations in seven nucleotide positions were significantly associated with OBI, and occurred in 11 out of 41 OBI sequences (26.8%): likely, other mutations did not reach statistical significance due to the small size of OBI dataset. All variations affected at least one HBV coding region, but none of them mapped to regulative elements. All viral proteins, with the only exception of the X, were affected. Stop codons in the S, that might account for absence of serum HBsAg, were not significantly enriched in OBI sequences. In genotype D, amino acid variability in the S was higher in OBI than non-OBI, particularly in the immunodominant region. A Random Forest prediction model showed the best performance, but all models were not satisfactory in terms of specificity, due to the small sample size of OBIs; however results are promising in the perspective of a broader dataset of complete genome OBI sequences.</p> <p>Conclusions</p> <p>Data suggest that point mutations rarely occur in regulative elements of HBV, if ever, and contribute to OBI by affecting different viral proteins, suggesting heterogeneous mechanisms may be responsible for OBI, including, at least in genotype D, an escape mutation mechanism due to imperfect immune control. It appears possible to derive prediction models based on molecular data when a larger set of complete genome OBI sequences will become available.</p

Identification of Type 1 Diabetes-Associated DNA Methylation Variable Positions That Precede Disease Diagnosis

Monozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is similar to 50%, implicating roles for genetic and non-genetic factors in the aetiology of this complex autoimmune disease. Although significant progress has been made in elucidating the genetics of T1D in recent years, the non-genetic component has remained poorly defined. We hypothesized that epigenetic variation could underlie some of the non-genetic component of T1D aetiology and, thus, performed an epigenome-wide association study (EWAS) for this disease. We generated genome-wide DNA methylation profiles of purified CD14(+) monocytes (an immune effector cell type relevant to T1D pathogenesis) from 15 T1D-discordant MZ twin pairs. This identified 132 different CpG sites at which the direction of the intra-MZ pair DNA methylation difference significantly correlated with the diabetic state, i.e. T1D-associated methylation variable positions (T1D-MVPs). We confirmed these T1D-MVPs display statistically significant intra-MZ pair DNA methylation differences in the expected direction in an independent set of T1D-discordant MZ pairs (P = 0.035). Then, to establish the temporal origins of the T1D-MVPs, we generated two further genome-wide datasets and established that, when compared with controls, T1D-MVPs are enriched in singletons both before (P = 0.001) and at (P = 0.015) disease diagnosis, and also in singletons positive for diabetes-associated autoantibodies but disease-free even after 12 years follow-up (P = 0.0023). Combined, these results suggest that T1D-MVPs arise very early in the etiological process that leads to overt T1D. Our EWAS of T1D represents an important contribution toward understanding the etiological role of epigenetic variation in type 1 diabetes, and it is also the first systematic analysis of the temporal origins of disease-associated epigenetic variation for any human complex disease

Nuclear Export and Import of Human Hepatitis B Virus Capsid Protein and Particles

It remains unclear what determines the subcellular localization of hepatitis B virus (HBV) core protein (HBc) and particles. To address this fundamental issue, we have identified four distinct HBc localization signals in the arginine rich domain (ARD) of HBc, using immunofluorescence confocal microscopy and fractionation/Western blot analysis. ARD consists of four tight clustering arginine-rich subdomains. ARD-I and ARD-III are associated with two co-dependent nuclear localization signals (NLS), while ARD-II and ARD-IV behave like two independent nuclear export signals (NES). This conclusion is based on five independent lines of experimental evidence: i) Using an HBV replication system in hepatoma cells, we demonstrated in a double-blind manner that only the HBc of mutant ARD-II+IV, among a total of 15 ARD mutants, can predominantly localize to the nucleus. ii) These results were confirmed using a chimera reporter system by placing mutant or wild type HBc trafficking signals in the heterologous context of SV40 large T antigen (LT). iii) By a heterokaryon or homokaryon analysis, the fusion protein of SV40 LT-HBc ARD appeared to transport from nuclei of transfected donor cells to nuclei of recipient cells, suggesting the existence of an NES in HBc ARD. This putative NES is leptomycin B resistant. iv) We demonstrated by co-immunoprecipitation that HBc ARD can physically interact with a cellular factor TAP/NXF1 (Tip-associated protein/nuclear export factor-1), which is known to be important for nuclear export of mRNA and proteins. Treatment with a TAP-specific siRNA strikingly shifted cytoplasmic HBc to nucleus, and led to a near 7-fold reduction of viral replication, and a near 10-fold reduction in HBsAg secretion. v) HBc of mutant ARD-II+IV was accumulated predominantly in the nucleus in a mouse model by hydrodynamic delivery. In addition to the revised map of NLS, our results suggest that HBc could shuttle rapidly between nucleus and cytoplasm via a novel TAP-dependent NES

DNA methylation and methyl-CpG binding proteins: developmental requirements and function

DNA methylation is a major epigenetic modification in the genomes of higher eukaryotes. In vertebrates, DNA methylation occurs predominantly on the CpG dinucleotide, and approximately 60% to 90% of these dinucleotides are modified. Distinct DNA methylation patterns, which can vary between different tissues and developmental stages, exist on specific loci. Sites of DNA methylation are occupied by various proteins, including methyl-CpG binding domain (MBD) proteins which recruit the enzymatic machinery to establish silent chromatin. Mutations in the MBD family member MeCP2 are the cause of Rett syndrome, a severe neurodevelopmental disorder, whereas other MBDs are known to bind sites of hypermethylation in human cancer cell lines. Here, we review the advances in our understanding of the function of DNA methylation, DNA methyltransferases, and methyl-CpG binding proteins in vertebrate embryonic development. MBDs function in transcriptional repression and long-range interactions in chromatin and also appear to play a role in genomic stability, neural signaling, and transcriptional activation. DNA methylation makes an essential and versatile epigenetic contribution to genome integrity and function