Developing and applying heterogeneous phylogenetic models with XRate

Modeling sequence evolution on phylogenetic trees is a useful technique in computational biology. Especially powerful are models which take account of the heterogeneous nature of sequence evolution according to the "grammar" of the encoded gene features. However, beyond a modest level of model complexity, manual coding of models becomes prohibitively labor-intensive. We demonstrate, via a set of case studies, the new built-in model-prototyping capabilities of XRate (macros and Scheme extensions). These features allow rapid implementation of phylogenetic models which would have previously been far more labor-intensive. XRate's new capabilities for lineage-specific models, ancestral sequence reconstruction, and improved annotation output are also discussed. XRate's flexible model-specification capabilities and computational efficiency make it well-suited to developing and prototyping phylogenetic grammar models. XRate is available as part of the DART software package: http://biowiki.org/DART .Comment: 34 pages, 3 figures, glossary of XRate model terminolog

Maximum principle and mutation thresholds for four-letter sequence evolution

A four-state mutation-selection model for the evolution of populations of DNA-sequences is investigated with particular interest in the phenomenon of error thresholds. The mutation model considered is the Kimura 3ST mutation scheme, fitness functions, which determine the selection process, come from the permutation-invariant class. Error thresholds can be found for various fitness functions, the phase diagrams are more interesting than for equivalent two-state models. Results for (small) finite sequence lengths are compared with those for infinite sequence length, obtained via a maximum principle that is equivalent to the principle of minimal free energy in physics.Comment: 25 pages, 16 figure

Active flow control systems architectures for civil transport aircraft

Copyright @ 2010 American Institute of Aeronautics and AstronauticsThis paper considers the effect of choice of actuator technology and associated power systems architecture on the mass cost and power consumption of implementing active flow control systems on civil transport aircraft. The research method is based on the use of a mass model that includes a mass due to systems hardware and a mass due to the system energy usage. An Airbus A320 aircraft wing is used as a case-study application. The mass model parameters are based on first-principle physical analysis of electric and pneumatic power systems combined with empirical data on system hardware from existing equipment suppliers. Flow control methods include direct fluidic, electromechanical-fluidic, and electrofluidic actuator technologies. The mass cost of electrical power distribution is shown to be considerably less than that for pneumatic systems; however, this advantage is reduced by the requirement for relatively heavy electrical power management and conversion systems. A tradeoff exists between system power efficiency and the system hardware mass required to achieve this efficiency. For short-duration operation the flow control solution is driven toward lighter but less power-efficient systems, whereas for long-duration operation there is benefit in considering heavier but more efficient systems. It is estimated that a practical electromechanical-fluidic system for flow separation control may have a mass up to 40% of the slat mass for a leading-edge application and 5% of flap mass for a trailing-edge application.This work is funded by the Sixth European Union Framework Programme as part of the AVERT project (Contract No. AST5-CT-2006-030914

Nocardia kroppenstedtii sp. nov., a novel actinomycete isolated from a lung transplant patient with a pulmonary infection

An actinomycete, strain N1286T, isolated from a lung transplant patient with a pulmonary infection, was provisionally assigned to the genus Nocardia. The strain had chemotaxonomic and morphological properties typical of members of the genus Nocardia and formed a distinct phyletic line in the Nocardia 16S rRNA gene tree. It was most closely related to Nocardia farcinica DSM 43665T (99.8% gene similarity) but was distinguished from the latter by a low level of DNA:DNA relatedness. These strains were also distinguished by a broad range of phenotypic properties. On the basis of these data, it is proposed that isolate N1286T (=DSM 45810T = NCTC 13617T) should be classified as the type strain of a new Nocardia species for which the name Nocardia kroppenstedtii is proposed

Stops making sense: translational trade-offs and stop codon reassignment

Background Efficient gene expression involves a trade-off between (i) premature termination of protein synthesis; and (ii) readthrough, where the ribosome fails to dissociate at the terminal stop. Sense codons that are similar in sequence to stop codons are more susceptible to nonsense mutation, and are also likely to be more susceptible to transcriptional or translational errors causing premature termination. We therefore expect this trade-off to be influenced by the number of stop codons in the genetic code. Although genetic codes are highly constrained, stop codon number appears to be their most volatile feature. Results In the human genome, codons readily mutable to stops are underrepresented in coding sequences. We construct a simple mathematical model based on the relative likelihoods of premature termination and readthrough. When readthrough occurs, the resultant protein has a tail of amino acid residues incorrectly added to the C-terminus. Our results depend strongly on the number of stop codons in the genetic code. When the code has more stop codons, premature termination is relatively more likely, particularly for longer genes. When the code has fewer stop codons, the length of the tail added by readthrough will, on average, be longer, and thus more deleterious. Comparative analysis of taxa with a range of stop codon numbers suggests that genomes whose code includes more stop codons have shorter coding sequences. Conclusions We suggest that the differing trade-offs presented by alternative genetic codes may result in differences in genome structure. More speculatively, multiple stop codons may mitigate readthrough, counteracting the disadvantage of a higher rate of nonsense mutation. This could help explain the puzzling overrepresentation of stop codons in the canonical genetic code and most variants

eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5'UTR

Background: Regulation of the mRNA life cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood.Results: Here, we show that eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex. We demonstrate that while DDX6 interacts with Ccr4-Not, its effects in the mechanism are not as pronounced. Through its interaction with the Ccr4-Not complex, eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar RNA selectivity to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5'UTR of target mRNAs directly upstream of the AUG start codon.Conclusions: Our data support a model whereby purine motifs towards the 3' end of the 5'UTR are associated with increased ribosome occupancy and possible uORF activation upon eIF4A2 binding.</p

Phylogeny of snakes (Serpentes): combining morphological and molecular data in likelihood Bayesian and parsimony analyses

Copyright © 2007 The Natural history MuseumThe phylogeny of living and fossil snakes is assessed using likelihood and parsimony approaches and a dataset combining 263 morphological characters with mitochondrial (2693 bp) and nuclear (1092 bp) gene sequences. The ‘no common mechanism’ (NCMr) and ‘Markovian’ (Mkv) models were employed for the morphological partition in likelihood analyses; likelihood scores in the NCMr model were more closely correlated with parsimony tree lengths. Both models accorded relatively less weight to the molecular data than did parsimony, with the effect being milder in the NCMr model. Partitioned branch and likelihood support values indicate that the mtDNA and nuclear gene partitions agree more closely with each other than with morphology. Despite differences between data partitions in phylogenetic signal, analytic models, and relative weighting, the parsimony and likelihood analyses all retrieved the following widely accepted groups: scolecophidians, alethinophidians, cylindrophiines, macrostomatans (sensu lato) and caenophidians. Anilius alone emerged as the most basal alethinophidian; the combined analyses resulted in a novel and stable position of uropeltines and cylindrophiines as the second-most basal clade of alethinophidians. The limbed marine pachyophiids, along with Dinilysia and Wonambi, were always basal to all living snakes. Other results stable in all combined analyses include: Xenopeltis and Loxocemus were sister taxa (fide morphology) but clustered with pythonines (fide molecules), and Ungaliophis clustered with a boine-erycine clade (fide molecules). Tropidophis remains enigmatic; it emerges as a basal alethinophidian in the parsimony analyses (fide molecules) but a derived form in the likelihood analyses (fide morphology), largely due to the different relative weighting accorded to data partitions.Michael S. Y. Lee, Andrew F. Hugall, Robin Lawson & John D. Scanlo

Immunology in the Clinic Review Series ; focus on host responses : invariant natural killer T cell activation following transplantation

OTHER THEMES PUBLISHED IN THIS IMMUNOLOGY IN THE CLINIC REVIEW SERIES Allergy, Metabolic Diseases, Cancer, Autoinflammatory Diseases, Type 1 diabetes and viruses. Invariant natural killer T (iNKT) cells have been shown to play a key role in the regulation of immunity in health and disease. However, iNKT cell responses have also been found to influence both rejection and the induction of tolerance following transplantation of allogeneic cells or organs. Although a number of mechanisms have been identified that lead to iNKT cell activation, how iNKT cells are activated following transplantation remains unknown. This review will attempt to identify potential mechanisms of iNKT cell activation in the context of transplantation by applying knowledge garnered from other disease situations. Furthermore, we put forward a novel mechanism of iNKT cell activation which we believe may be the dominant mechanism responsible for iNKT activation in this setting, i.e. bystander activation by interleukin-2 secreted by recently activated conventional T cells