Subfamily specific conservation profiles for proteins based on n-gram patterns

<p>Abstract</p> <p>Background</p> <p>A new algorithm has been developed for generating conservation profiles that reflect the evolutionary history of the subfamily associated with a query sequence. It is based on n-gram patterns (NP{<it>n,m</it>}) which are sets of <it>n </it>residues and <it>m </it>wildcards in windows of size <it>n+m</it>. The generation of conservation profiles is treated as a signal-to-noise problem where the signal is the count of n-gram patterns in target sequences that are similar to the query sequence and the noise is the count over all target sequences. The signal is differentiated from the noise by applying singular value decomposition to sets of target sequences rank ordered by similarity with respect to the query.</p> <p>Results</p> <p>The new algorithm was used to construct 4,248 profiles from 120 randomly selected Pfam-A families. These were compared to profiles generated from multiple alignments using the consensus approach. The two profiles were similar whenever the subfamily associated with the query sequence was well represented in the multiple alignment. It was possible to construct subfamily specific conservation profiles using the new algorithm for subfamilies with as few as five members. The speed of the new algorithm was comparable to the multiple alignment approach.</p> <p>Conclusion</p> <p>Subfamily specific conservation profiles can be generated by the new algorithm without aprioi knowledge of family relationships or domain architecture. This is useful when the subfamily contains multiple domains with different levels of representation in protein databases. It may also be applicable when the subfamily sample size is too small for the multiple alignment approach.</p

Stalking influenza by vaccination with pre-fusion headless HA mini-stem.

Inaccuracies in prediction of circulating viral strain genotypes and the possibility of novel reassortants causing a pandemic outbreak necessitate the development of an anti-influenza vaccine with increased breadth of protection and potential for rapid production and deployment. The hemagglutinin (HA) stem is a promising target for universal influenza vaccine as stem-specific antibodies have the potential to be broadly cross-reactive towards different HA subtypes. Here, we report the design of a bacterially expressed polypeptide that mimics a H5 HA stem by protein minimization to focus the antibody response towards the HA stem. The HA mini-stem folds as a trimer mimicking the HA prefusion conformation. It is resistant to thermal/chemical stress, and it binds to conformation-specific, HA stem-directed broadly neutralizing antibodies with high affinity. Mice vaccinated with the group 1 HA mini-stems are protected from morbidity and mortality against lethal challenge by both group 1 (H5 and H1) and group 2 (H3) influenza viruses, the first report of cross-group protection. Passive transfer of immune serum demonstrates the protection is mediated by stem-specific antibodies. Furthermore, antibodies indudced by these HA stems have broad HA reactivity, yet they do not have antibody-dependent enhancement activity

A comparison of benzodiazepine and related drug use in Nova Scotia and Australia

Objective: Benzodiazepines can be a problem if used for long periods, or in at-risk populations, such as the elderly. We compared the use of benzodiazepine and related prescription medicines in Nova Scotia and Australia

Experiencing uncertainty – on the potential of groups and a group analytic approach for making management education more critical.

This document is the Accepted Manuscript. The final, definitive version of this paper has been published in Management Learning, November 2017, DOI: https://doi.org/10.1177/1350507617697868. Published by SAGE Publishing. All rights reserved.This article points to the potential of methods derived from group analytic practice for making management education more critical. It draws on the experience of running a professional doctorate for more experienced managers in a university in the UK over a 16 year period. Group analysis is informed by the highly social theories of S.H. Foulkes and draws heavily on psychoanalytic theory as well as sociology. First and foremost, though, it places our interdependence at the heart of the process of inquiry, and suggests that the most potent place for learning about groups, where we spend most of our lives, is in a group. The article prioritises three areas of management practice for which group analytic methods, as adapted for research environment, are most helpful: coping with uncertainty and the feelings of anxiety which this often arouses; thinking about leadership as a relational and negotiated activity, and encouraging reflexivity in managers. The article also points to some of the differences between the idea of the learning community and psychodynamic perspectives more generally and the limitations of group analytic methods in particular, which may pathologise resistance in the workplace.Peer reviewe

Phylogeography and demographic history of Epomophorus gambianus: contrasting nuclear and mitochondrial DNA

The Gambian epauletted fruit bat (Epomophorus gambianus) is an abundant species that roosts in both urban and rural settings. The possible role of E. gambianus as a reservoir host of zoonotic diseases underlines the need to better understand the species movement patterns. So far, neither observational nor phylogenetic studies have identified the dispersal range or behavior of this species. Comparative analyses of mitochondrial and nuclear markers from 20 localities across the known distribution of E. gambianus showed population panmixia, except for the populations in Ethiopia and southern Ghana (Accra and Ve‐Golokwati). The Ethiopian population may be ancestral and is highly divergent to the species across the rest of its range, possibly reflecting isolation of an ancient colonization along an east–west axis. Mitochondrial haplotypes in the Accra population display a strong signature of a past bottleneck event; evidence of either an ancient or recent bottleneck using microsatellite data, however, was not detected. Demographic analyses identified population expansion in most of the colonies, except in the female line of descent in the Accra population. The molecular analyses of the colonies from Ethiopia and southern Ghana show gender dispersal bias, with the mitochondrial DNA fixation values over ten times those of the nuclear markers. These findings indicate free mixing of the species across great distances, which should inform future epidemiological studies

Modified Vaccinia Virus Ankara Preferentially Targets Antigen Presenting Cells In Vitro, Ex Vivo and In Vivo

Modified Vaccinia virus Ankara (MVA) is a promising vaccine vector with an excellent safety profile. However, despite extensive pre-clinical and clinical testing, surprisingly little is known about the cellular tropism of MVA, especially in relevant animal species. Here, we performed in vitro, ex vivo and in vivo experiments with recombinant MVA expressing green fluorescent protein (rMVA-GFP). In both human peripheral blood mononuclear cells and mouse lung explants, rMVA-GFP predominantly infected antigen presenting cells. Subsequent in vivo experiments performed in mice, ferrets and non-human primates indicated that preferential targeting of dendritic cells and alveolar macrophages was observed after respiratory administration, although subtle differences were observed between the respective animal species. Following intramuscular injection, rMVA-GFP was detected in interdigitating cells between myocytes, but also in myocytes themselves. These data are important in advancing our understanding of the basis for the immunogenicity of MVA-based vaccines and aid rational vaccine design and delivery strategies

Contrasting responses of mean and extreme snowfall to climate change

Snowfall is an important element of the climate system, and one that is expected to change in a warming climate. Both mean snowfall and the intensity distribution of snowfall are important, with heavy snowfall events having particularly large economic and human impacts. Simulations with climate models indicate that annual mean snowfall declines with warming in most regions but increases in regions with very low surface temperatures. The response of heavy snowfall events to a changing climate, however, is unclear. Here I show that in simulations with climate models under a scenario of high emissions of greenhouse gases, by the late twenty-first century there are smaller fractional changes in the intensities of daily snowfall extremes than in mean snowfall over many Northern Hemisphere land regions. For example, for monthly climatological temperatures just below freezing and surface elevations below 1,000 metres, the 99.99th percentile of daily snowfall decreases by 8% in the multimodel median, compared to a 65% reduction in mean snowfall. Both mean and extreme snowfall must decrease for a sufficiently large warming, but the climatological temperature above which snowfall extremes decrease with warming in the simulations is as high as −9 °C, compared to −14 °C for mean snowfall. These results are supported by a physically based theory that is consistent with the observed rain–snow transition. According to the theory, snowfall extremes occur near an optimal temperature that is insensitive to climate warming, and this results in smaller fractional changes for higher percentiles of daily snowfall. The simulated changes in snowfall that I find would influence surface snow and its hazards; these changes also suggest that it may be difficult to detect a regional climate-change signal in snowfall extremes.National Science Foundation (U.S.) (Grant AGS-1148594)United States. National Aeronautics and Space Administration (ROSES Grant 09-IDS09-0049