Perspectives on Viral RNA Genomes and the RNA Folding Problem

Viral RNA genomes change shape as virus particles disassemble, form replication complexes, attach to ribosomes for translation, evade host defense mechanisms, and assemble new virus particles. These structurally dynamic RNA shapeshifters present a challenging RNA folding problem, because the RNA sequence adopts multiple structures and may sometimes contain regions of partial disorder. Recent advances in high resolution asymmetric cryoelectron microscopy and chemical probing provide new ways to probe the degree of structure and disorder, and have identified more than one conformation in dynamic equilibrium in viral RNA. Chemical probing and the Detection of RNA Folding Ensembles using Expectation Maximization (DREEM) algorithm has been applied to studies of the dynamic equilibrium conformations in HIV RNA in vitro, in virio, and in vivo. This new type of data provides insight into important questions about virus assembly mechanisms and the fundamental physical forces driving virus particle assembly.This research was funded by a seed grant from the Oklahoma Health Science Center Office of the Vice President for Research and the Presbyterian Health Foundation. Open Access fees paid for in whole or in part by the University of Oklahoma Libraries.Ye

Making Sense of the Legendre Transform

The Legendre transform is an important tool in theoretical physics, playing a critical role in classical mechanics, statistical mechanics, and thermodynamics. Yet, in typical undergraduate or graduate courses, the power of motivation and elegance of the method are often missing, unlike the treatments frequently enjoyed by Fourier transforms. We review and modify the presentation of Legendre transforms in a way that explicates the formal mathematics, resulting in manifestly symmetric equations, thereby clarifying the structure of the transform algebraically and geometrically. Then we bring in the physics to motivate the transform as a way of choosing independent variables that are more easily controlled. We demonstrate how the Legendre transform arises naturally from statistical mechanics and show how the use of dimensionless thermodynamic potentials leads to more natural and symmetric relations.Comment: 11 pages, 3 figure

Crumple: A Method for Complete Enumeration of All Possible Pseudoknot-Free RNA Secondary Structures

The computing for this project was performed at the OU Supercomputing Center for Education & Research (OSCER) at the University of Oklahoma (OU). OSCER director Henry Neeman and OSCER staff provided valuable technical expertise. The authors acknowledge and appreciate the discussions about this work with Dr. Changwook Kim, Adam Heck, Sean Lavelle, and Jui-wen Liu.Conceived and designed the experiments: SB SJS. Performed the experiments: SB JWS. Analyzed the data: SB JWS SJS. Wrote the paper: SB JWS SJS.The diverse landscape of RNA conformational space includes many canyons and crevices that are distant from the lowest minimum free energy valley and remain unexplored by traditional RNA structure prediction methods. A complete description of the entire RNA folding landscape can facilitate identification of biologically important conformations. The Crumple algorithm rapidly enumerates all possible non-pseudoknotted structures for an RNA sequence without consideration of thermodynamics while filtering the output with experimental data. The Crumple algorithm provides an alternative approach to traditional free energy minimization programs for RNA secondary structure prediction. A complete computation of all non-pseudoknotted secondary structures can reveal structures that would not be predicted by methods that sample the RNA folding landscape based on thermodynamic predictions. The free energy minimization approach is often successful but is limited by not considering RNA tertiary and protein interactions and the possibility that kinetics rather than thermodynamics determines the functional RNA fold. Efficient parallel computing and filters based on experimental data make practical the complete enumeration of all non-pseudoknotted structures. Efficient parallel computing for Crumple is implemented in a ring graph approach. Filters for experimental data include constraints from chemical probing of solvent accessibility, enzymatic cleavage of paired or unpaired nucleotides, phylogenetic covariation, and the minimum number and lengths of helices determined from crystallography or cryo-electron microscopy. The minimum number and length of helices has a significant effect on reducing conformational space. Pairing constraints reduce conformational space more than single nucleotide constraints. Examples with Alfalfa Mosaic Virus RNA and Trypanosome brucei guide RNA demonstrate the importance of evaluating all possible structures when pseduoknots, RNA-protein interactions, and metastable structures are important for biological function. Crumple software is freely available at http://adenosine.chem.ou.edu/software.html.Yeshttp://www.plosone.org/static/editorial#pee

Reproductive factors and hormone use and risk of adult gliomas

Previous research suggests there may be a hormonal influence on glioma risk as evidenced by lower rates in females, change in incidence rates around ages at menarche and menopause and presence of hormone receptors in glial tumors. Using the large San Francisco Bay Area Adult Glioma Study, we investigated whether reported reproductive factors and hormone use were associated with gliomas overall or with histologic subtypes among female cases (n=619) and controls (n=650). We found that reproductive factors were generally not associated with gliomas. Weak to moderately elevated odds ratios were observed for self-reported later age at menarche (14+ years old versus 12–13 years old: adjusted odds ratio (AOR) = 1.39, 95% confidence interval (CI): 1.02 –1.89), particularly for non-glioblastoma histologies (AOR = 1.64, 95% CI: 1.11–2.43). Inverse associations were observed for ever self-reported use of exogenous hormones (oral contraceptive use: AOR = 0.72, 95% CI: 0.53–0.99; postmenopausal hormone use: AOR = 0.56, CI: 0.37–0.84). However, cumulative hormone exposure defined multiple ways demonstrated no clear pattern of association. The results of this study suggest that any protective effect of hormones on gliomas may be limited to exogenous hormones, but a more detailed history of exogenous hormone use are needed to confirm findings

From venture idea to venture formation:The role of sensemaking, sensegiving and sense receiving

This article explores the sensemaking processes entrepreneurs use when transitioning between venture ideas and venture formation. Adopting a sensemaking/sensegiving approach and utilising an interpretivist methodology, we use sensemaking to analyse the entrepreneurial journey of four diverse entrepreneurs. In so doing, we make three contributions: first, we locate the early stages of the entrepreneurial context as a primary site where sensemaking occurs as entrepreneurs deal with the differences between expectations and reality. Second, we show how sensemaking occurs when entrepreneurs build a causal map of the problem they wish to address and how social exchanges are crucial as entrepreneurs then refine that idea with other sensegivers. Finally, we extend scholarly understanding through explaining the ways in which sensemaking, sensegiving and sense receiving contribute to the entrepreneurs' decision to act and create a new venture

Unraveling the sequence of serpentinization reactions : petrography, mineral chemistry, and petrophysics of serpentinites from MAR 15°N (ODP Leg 209, Site 1274)

Author Posting. © American Geophysical Union, 2006. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 33 (2006): L13306, doi:10.1029/2006GL025681.The results of detailed textural, mineral chemical, and petrophysical studies shed new light on the poorly constrained fluid-rock reaction pathways during retrograde serpentinization at mid-ocean ridges. Uniformly depleted harzburgites and dunites from the Mid-Atlantic Ridge at 15°N show variable extents of static serpentinization. They reveal a simple sequence of reactions: serpentinization of olivine and development of a typical mesh texture with serpentine-brucite mesh rims, followed by replacement of olivine mesh centers by serpentine and brucite. The serpentine mesh rims on relic olivine are devoid of magnetite. Conversely, domains in the rock that are completely serpentinized show abundant magnetite. We propose that low-fluid-flux serpentinization of olivine to serpentine and ferroan brucite is followed by later stages of serpentinization under more open-system conditions and formation of magnetite by the breakdown of ferroan brucite. Modeling of this sequence of reactions can account for covariations in magnetic susceptibility and grain density of the rocks.Funding for this research was provided by USSSP and NSF-OCE grant 9986135. WB acknowledges support through a fellowship by the Deep Ocean Exploration Institute

Annotation of the Drosophila melanogaster euchromatic genome: a systematic review

BACKGROUND: The recent completion of the Drosophila melanogaster genomic sequence to high quality and the availability of a greatly expanded set of Drosophila cDNA sequences, aligning to 78% of the predicted euchromatic genes, afforded FlyBase the opportunity to significantly improve genomic annotations. We made the annotation process more rigorous by inspecting each gene visually, utilizing a comprehensive set of curation rules, requiring traceable evidence for each gene model, and comparing each predicted peptide to SWISS-PROT and TrEMBL sequences. RESULTS: Although the number of predicted protein-coding genes in Drosophila remains essentially unchanged, the revised annotation significantly improves gene models, resulting in structural changes to 85% of the transcripts and 45% of the predicted proteins. We annotated transposable elements and non-protein-coding RNAs as new features, and extended the annotation of untranslated (UTR) sequences and alternative transcripts to include more than 70% and 20% of genes, respectively. Finally, cDNA sequence provided evidence for dicistronic transcripts, neighboring genes with overlapping UTRs on the same DNA sequence strand, alternatively spliced genes that encode distinct, non-overlapping peptides, and numerous nested genes. CONCLUSIONS: Identification of so many unusual gene models not only suggests that some mechanisms for gene regulation are more prevalent than previously believed, but also underscores the complex challenges of eukaryotic gene prediction. At present, experimental data and human curation remain essential to generate high-quality genome annotations