DNA Methylation and Genome Evolution in Honeybee: Gene Length, Expression, Functional Enrichment Covary with the Evolutionary Signature of DNA Methylation

A growing body of evidence suggests that DNA methylation is functionally divergent among different taxa. The recently discovered functional methylation system in the honeybee Apis mellifera presents an attractive invertebrate model system to study evolution and function of DNA methylation. In the honeybee, DNA methylation is mostly targeted toward transcription units (gene bodies) of a subset of genes. Here, we report an intriguing covariation of length and epigenetic status of honeybee genes. Hypermethylated and hypomethylated genes in honeybee are dramatically different in their lengths for both exons and introns. By analyzing orthologs in Drosophila melanogaster, Acyrthosiphon pisum, and Ciona intestinalis, we show genes that were short and long in the past are now preferentially situated in hyper- and hypomethylated classes respectively, in the honeybee. Moreover, we demonstrate that a subset of high-CpG genes are conspicuously longer than expected under the evolutionary relationship alone and that they are enriched in specific functional categories. We suggest that gene length evolution in the honeybee is partially driven by evolutionary forces related to regulation of gene expression, which in turn is associated with DNA methylation. However, lineage-specific patterns of gene length evolution suggest that there may exist additional forces underlying the observed interaction between DNA methylation and gene lengths in the honeybee

The Random Nature of Genome Architecture: Predicting Open Reading Frame Distributions

Background: A better understanding of the size and abundance of open reading frames (ORFS) in whole genomes may shed light on the factors that control genome complexity. Here we examine the statistical distributions of open reading frames (i.e. distribution of start and stop codons) in the fully sequenced genomes of 297 prokaryotes, and 14 eukaryotes. Methodology/Principal Findings: By fitting mixture models to data from whole genome sequences we show that the size-frequency distributions for ORFS are strikingly similar across prokaryotic and eukaryotic genomes. Moreover, we show that i) a large fraction (60–80%) of ORF size-frequency distributions can be predicted a priori with a stochastic assembly model based on GC content, and that (ii) size-frequency distributions of the remaining “non-random” ORFs are well-fitted by log-normal or gamma distributions, and similar to the size distributions of annotated proteins. Conclusions/Significance: Our findings suggest stochastic processes have played a primary role in the evolution of genome complexity, and that common processes govern the conservation and loss of functional genomics units in both prokaryotes and eukaryotes.8 page(s

Principles of strategic drug delivery to the brain (SDDB): Development of anorectic and orexigenic analogs of leptin

The blood-brain barrier (BBB) presents a tremendous challenge for the delivery of drugs to the central nervous system (CNS). This includes drugs that target brain receptors for the treatment of obesity and anorexia. Strategic drug delivery to brain (SDDB) is an approach that considers in depth the relations among the BBB, the candidate therapeutic, the CNS target, and the disease state to be treated. Here, we illustrate principles of SDDB with two different approaches to developing drugs based on leptin. In normal body weight humans and in non-obese rodents, leptin is readily transported across the BBB and into the CNS where it inhibits feeding and enhances thermogenesis. However, in obesity, the transport of leptin across the BBB is impaired, resulting in a resistance to leptin. As a result, it is difficult to treat obesity with leptin or its analogs that depend on the leptin transporter for access to the CNS. To treat obesity, we developed a leptin agonist modified by the addition of pluronic block copolymers (P85-leptin). P85-leptin retains biological activity and is capable of crossing the BBB by a mechanism that is not dependent on the leptin transporter. As such, P85-leptin is able to cross the BBB of obese mice at a rate similar to that of native leptin in lean mice. To treat anorexia, we developed a leptin antagonist modified by pegylation (PEG-MLA) that acts primarily by blocking the BBB transporter for endogenous, circulating leptin. This prevents blood-borne, endogenous leptin from entering the CNS, essentially mimicking the leptin resistance seen in obesity, and resulting in a significant increase in adiposity. These examples illustrate two strategies in which an understanding of the interactions among the BBB, CNS targets, and candidate therapeutics under physiologic and diseased conditions can be used to develop drugs effective for the treatment of brain disease

What are the determinants of gene expression levels and breadths in the human genome?

In complex organisms, different tissues express different genes, which ultimately shape the function and phenotype of each tissue. An important goal of modern biology is to understand how some genes are turned on and off in specific tissues and how the numbers of different gene expression products are determined. These aspects are named ‘expression breadth’ (or ‘tissue specificity’) and ‘expression level’, respectively. Here, we show that we can predict substantial amount of variation in levels and breadths of gene expression using genomic information of each gene. Interestingly, many genomic traits are correlated with both aspects of gene expression in similar directions, suggesting shared molecular pathways. However, to elucidate distinctive molecular mechanisms governing gene expression levels and breadths, we need to identify the relative significance of each genomic trait on these two aspects of gene expression. To this end, we developed a novel multivariate multiple regression method. Using this new method, we show that gene compactness (in particular, the mean size of exons), codon usage bias and non-synonymous rates have a stronger influence on expression levels compared with their effects on expression breadths. In contrast, the propensity of promoter DNA methylation is a stronger indicator of expression breadths than of expression levels. Interestingly, intron DNA methylation exhibits an opposite pattern to the promoter DNA methylation in the human genome, suggesting that DNA methylation may play multiple roles depending upon its genomic targets. Furthermore, synonymous rates have stronger associations with expression breadths than with expression levels in the human genome. These findings provide clues toward distinctive molecular mechanisms regulating different aspects of gene expression

Asymmetric rolling of interstitial-free steel using differential roll diameters. Part II : microstructure and annealing effects

The effects of annealing on the microstructure, texture, tensile properties, and R value evolution of an IF steel sheet after room-temperature symmetric and asymmetric rolling were examined. Simulations were carried out to obtain R values from the experimental textures using the viscoplastic self-consistent polycrystal plasticity model. The investigation revealed the variations in the textures due to annealing and symmetric/asymmetric rolling and showed that the R values correlate strongly with the evolution of the texture. An optimum heat treatment for the balance of strength, ductility, and deep drawability was found to be at 873 K (600 _C) for 30 minutes

Production of phi mesons at mid-rapidity in sqrt(s_NN) = 200 GeV Au+Au collisions at RHIC

We present the first results of meson production in the K^+K^- decay channel from Au+Au collisions at sqrt(s_NN) = 200 GeV as measured at mid-rapidity by the PHENIX detector at RHIC. Precision resonance centroid and width values are extracted as a function of collision centrality. No significant variation from the PDG accepted values is observed. The transverse mass spectra are fitted with a linear exponential function for which the derived inverse slope parameter is seen to be constant as a function of centrality. These data are also fitted by a hydrodynamic model with the result that the freeze-out temperature and the expansion velocity values are consistent with the values previously derived from fitting single hadron inclusive data. As a function of transverse momentum the collisions scaled peripheral.to.central yield ratio RCP for the is comparable to that of pions rather than that of protons. This result lends support to theoretical models which distinguish between baryons and mesons instead of particle mass for explaining the anomalous proton yield.Comment: 326 authors, 24 pages text, 23 figures, 6 tables, RevTeX 4. To be submitted to Physical Review C as a regular article. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Multiplicity dependence of jet-like two-particle correlations in p-Pb collisions at sNN\sqrt{s_{NN}} = 5.02 TeV

Two-particle angular correlations between unidentified charged trigger and associated particles are measured by the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV. The transverse-momentum range 0.7 $< p_{\rm{T}, assoc} < p_{\rm{T}, trig} <$ 5.0 GeV/$c$ is examined, to include correlations induced by jets originating from low momen\-tum-transfer scatterings (minijets). The correlations expressed as associated yield per trigger particle are obtained in the pseudorapidity range $|\eta|<0.9$. The near-side long-range pseudorapidity correlations observed in high-multiplicity p-Pb collisions are subtracted from both near-side short-range and away-side correlations in order to remove the non-jet-like components. The yields in the jet-like peaks are found to be invariant with event multiplicity with the exception of events with low multiplicity. This invariance is consistent with the particles being produced via the incoherent fragmentation of multiple parton--parton scatterings, while the yield related to the previously observed ridge structures is not jet-related. The number of uncorrelated sources of particle production is found to increase linearly with multiplicity, suggesting no saturation of the number of multi-parton interactions even in the highest multiplicity p-Pb collisions. Further, the number scales in the intermediate multiplicity region with the number of binary nucleon-nucleon collisions estimated with a Glauber Monte-Carlo simulation.Comment: 23 pages, 6 captioned figures, 1 table, authors from page 17, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/161

Anisotropic flow of charged hadrons, pions and (anti-)protons measured at high transverse momentum in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}=2.76 TeV

The elliptic, $v_2$, triangular, $v_3$, and quadrangular, $v_4$, azimuthal anisotropic flow coefficients are measured for unidentified charged particles, pions and (anti-)protons in Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV with the ALICE detector at the Large Hadron Collider. Results obtained with the event plane and four-particle cumulant methods are reported for the pseudo-rapidity range $|\eta|<0.8$ at different collision centralities and as a function of transverse momentum, $p_{\rm T}$, out to $p_{\rm T}=20$ GeV/$c$. The observed non-zero elliptic and triangular flow depends only weakly on transverse momentum for $p_{\rm T}>8$ GeV/$c$. The small $p_{\rm T}$ dependence of the difference between elliptic flow results obtained from the event plane and four-particle cumulant methods suggests a common origin of flow fluctuations up to $p_{\rm T}=8$ GeV/$c$. The magnitude of the (anti-)proton elliptic and triangular flow is larger than that of pions out to at least $p_{\rm T}=8$ GeV/$c$ indicating that the particle type dependence persists out to high $p_{\rm T}$.Comment: 16 pages, 5 captioned figures, authors from page 11, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/186

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur