On the statistical mechanics of prion diseases

We simulate a two-dimensional, lattice based, protein-level statistical mechanical model for prion diseases (e.g., Mad Cow disease) with concommitant prion protein misfolding and aggregation. Our simulations lead us to the hypothesis that the observed broad incubation time distribution in epidemiological data reflect fluctuation dominated growth seeded by a few nanometer scale aggregates, while much narrower incubation time distributions for innoculated lab animals arise from statistical self averaging. We model `species barriers' to prion infection and assess a related treatment protocol.Comment: 5 Pages, 3 eps figures (submitted to Physical Review Letters

Non-perturbative dynamics of hot non-Abelian gauge fields: beyond leading log approximation

Many aspects of high-temperature gauge theories, such as the electroweak baryon number violation rate, color conductivity, and the hard gluon damping rate, have previously been understood only at leading logarithmic order (that is, neglecting effects suppressed only by an inverse logarithm of the gauge coupling). We discuss how to systematically go beyond leading logarithmic order in the analysis of physical quantities. Specifically, we extend to next-to-leading-log order (NLLO) the simple leading-log effective theory due to Bodeker that describes non-perturbative color physics in hot non-Abelian plasmas. A suitable scaling analysis is used to show that no new operators enter the effective theory at next-to-leading-log order. However, a NLLO calculation of the color conductivity is required, and we report the resulting value. Our NLLO result for the color conductivity can be trivially combined with previous numerical work by G. Moore to yield a NLLO result for the hot electroweak baryon number violation rate.Comment: 20 pages, 1 figur

Annotation of two large contiguous regions from the Haemonchus contortus genome using RNA-seq and comparative analysis with Caenorhabditis elegans

The genomes of numerous parasitic nematodes are currently being sequenced, but their complexity and size, together with high levels of intra-specific sequence variation and a lack of reference genomes, makes their assembly and annotation a challenging task. Haemonchus contortus is an economically significant parasite of livestock that is widely used for basic research as well as for vaccine development and drug discovery. It is one of many medically and economically important parasites within the strongylid nematode group. This group of parasites has the closest phylogenetic relationship with the model organism Caenorhabditis elegans, making comparative analysis a potentially powerful tool for genome annotation and functional studies. To investigate this hypothesis, we sequenced two contiguous fragments from the H. contortus genome and undertook detailed annotation and comparative analysis with C. elegans. The adult H. contortus transcriptome was sequenced using an Illumina platform and RNA-seq was used to annotate a 409 kb overlapping BAC tiling path relating to the X chromosome and a 181 kb BAC insert relating to chromosome I. In total, 40 genes and 12 putative transposable elements were identified. 97.5% of the annotated genes had detectable homologues in C. elegans of which 60% had putative orthologues, significantly higher than previous analyses based on EST analysis. Gene density appears to be less in H. contortus than in C. elegans, with annotated H. contortus genes being an average of two-to-three times larger than their putative C. elegans orthologues due to a greater intron number and size. Synteny appears high but gene order is generally poorly conserved, although areas of conserved microsynteny are apparent. C. elegans operons appear to be partially conserved in H. contortus. Our findings suggest that a combination of RNA-seq and comparative analysis with C. elegans is a powerful approach for the annotation and analysis of strongylid nematode genomes

Comparison of C. elegans and C. briggsae Genome Sequences Reveals Extensive Conservation of Chromosome Organization and Synteny

To determine whether the distinctive features of Caenorhabditis elegans chromosomal organization are shared with the C. briggsae genome, we constructed a single nucleotide polymorphism–based genetic map to order and orient the whole genome shotgun assembly along the six C. briggsae chromosomes. Although these species are of the same genus, their most recent common ancestor existed 80–110 million years ago, and thus they are more evolutionarily distant than, for example, human and mouse. We found that, like C. elegans chromosomes, C. briggsae chromosomes exhibit high levels of recombination on the arms along with higher repeat density, a higher fraction of intronic sequence, and a lower fraction of exonic sequence compared with chromosome centers. Despite extensive intrachromosomal rearrangements, 1:1 orthologs tend to remain in the same region of the chromosome, and colinear blocks of orthologs tend to be longer in chromosome centers compared with arms. More strikingly, the two species show an almost complete conservation of synteny, with 1:1 orthologs present on a single chromosome in one species also found on a single chromosome in the other. The conservation of both chromosomal organization and synteny between these two distantly related species suggests roles for chromosome organization in the fitness of an organism that are only poorly understood presently

Methods and strategies for gene structure curation in WormBase

The Caenorhabditis elegans genome sequence was published over a decade ago; this was the first published genome of a multi-cellular organism and now the WormBase project has had a decade of experience in curating this genome's sequence and gene structures. In one of its roles as a central repository for nematode biology, WormBase continues to refine the gene structure annotations using sequence similarity and other computational methods, as well as information from the literature- and community-submitted annotations. We describe the various methods of gene structure curation that have been tried by WormBase and the problems associated with each of them. We also describe the current strategy for gene structure curation, and introduce the WormBase ‘curation tool’, which integrates different data sources in order to identify new and correct gene structures

Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B

Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a β-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-β-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae-dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone

Rec-DCM-Eigen: Reconstructing a Less Parsimonious but More Accurate Tree in Shorter Time

Maximum parsimony (MP) methods aim to reconstruct the phylogeny of extant species by finding the most parsimonious evolutionary scenario using the species' genome data. MP methods are considered to be accurate, but they are also computationally expensive especially for a large number of species. Several disk-covering methods (DCMs), which decompose the input species to multiple overlapping subgroups (or disks), have been proposed to solve the problem in a divide-and-conquer way

Policy ideas through the prism of knowledge regimes and framing

Policymakers are often confronted with problems that involve ambiguity and uncertainty (Zahariadis, 2003). In order to make sense of such problems and to identify possible solutions, they are on the lookout for policy ideas