mmView: a web-based viewer of the mmCIF format

<p>Abstract</p> <p>Background</p> <p>Structural biomolecular data are commonly stored in the PDB format. The PDB format is widely supported by software vendors because of its simplicity and readability. However, the PDB format cannot fully address many informatics challenges related to the growing amount of structural data. To overcome the limitations of the PDB format, a new textual format mmCIF was released in June 1997 in its version 1.0. mmCIF provides extra information which has the advantage of being in a computer readable form. However, this advantage becomes a disadvantage if a human must read and understand the stored data. While software tools exist to help to prepare mmCIF files, the number of available systems simplifying the comprehension and interpretation of the mmCIF files is limited.</p> <p>Findings</p> <p>In this paper we present mmView - a cross-platform web-based application that allows to explore comfortably the structural data of biomacromolecules stored in the mmCIF format. The mmCIF categories can be easily browsed in a tree-like structure, and the corresponding data are presented in a well arranged tabular form. The application also allows to display and investigate biomolecular structures via an integrated Java application Jmol.</p> <p>Conclusions</p> <p>The mmView software system is primarily intended for educational purposes, but it can also serve as a useful research tool. The mmView application is offered in two flavors: as an open-source stand-alone application (available from <url>http://sourceforge.net/projects/mmview</url>) that can be installed on the user's computer, and as a publicly available web server.</p

Variation in the Ovine Abomasal Lymph Node Transcriptome between Breeds Known to Differ in Resistance to the Gastrointestinal Nematode

Texel lambs are known to be more resistant to gastrointestinal nematode (GIN) infection than Suffolk lambs, with a greater ability to limit infection. The objectives of this study were to: 1) profile the whole transcriptome of abomasal lymph node tissue of GIN-free Texel and Suffolk lambs; 2) identify differentially expressed genes and characterize the immune-related biological pathways and networks associated with these genes. Abomasal lymph nodes were collected from Texel (n = 6) and Suffolk (n = 4) lambs aged 19 weeks that had been GIN-free since 6 weeks of age. Whole transcriptome profiling was performed using RNA-seq on the Illumina platform. At the time of conducting this study, a well annotated Ovine genome was not available and hence the sequence reads were aligned with the Bovine (UMD3.1) genome. Identification of differentially expressed genes was followed by pathway and network analysis. The Suffolk breed accounted for significantly more of the differentially expressed genes, (276 more highly expressed in Suffolk v 162 in Texel; P < 0.001). The four most significant differentially expressed pathways were all related to immunity and were classified as: Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses, Activation of IRF by Cytosolic Pattern Recognition Receptors, Role of RIG-I-like Receptors in Antiviral Innate Immunity, and Interferon Signaling. Of significance is the fact that all of these four pathways were more highly expressed in the Suffolk. These data suggest that in a GIN-free environment, Suffolk lambs have a more active immune profile relative to the Texel: this immune profile may contribute to the poorer efficiency of response to a GIN challenge in the Suffolk breed compared to the Texel breed

A pilot survey of post-deployment health care needs in small community-based primary care clinics

<p>Abstract</p> <p>Background</p> <p>Relatively little is known regarding to what extent community-based primary care physicians are encountering post-deployment health care needs among veterans of the Afghanistan or Iraq conflicts and their family members.</p> <p>Methods</p> <p>This pilot study conducted a cross-sectional survey of 37 primary care physicians working at small urban and suburban clinics belonging to a practice-based research network in the south central region of Texas.</p> <p>Results</p> <p>Approximately 80% of the responding physicians reported caring for patients who have been deployed to the Afghanistan or Iraq war zones, or had a family member deployed. Although these physicians noted a variety of conditions related to physical trauma, mental illnesses and psychosocial disruptions such as marital, family, financial, and legal problems appeared to be even more prevalent among their previously deployed patients and were also noted among family members of deployed veterans.</p> <p>Conclusions</p> <p>Community-based primary care physicians should be aware of common post-deployment health conditions and the resources that are available to meet these needs.</p

Identification and Characterization of Novel Mutations in the Human Gene Encoding the Catalytic Subunit Calpha of Protein Kinase A (PKA)

The genes PRKACA and PRKACB encode the principal catalytic (C) subunits of protein kinase A (PKA) Cα and Cβ, respectively. Cα is expressed in all eukaryotic tissues examined and studies of Cα knockout mice demonstrate a crucial role for Cα in normal physiology. We have sequenced exon 2 through 10 of PRKACA from the genome of 498 Norwegian donors and extracted information about PRKACA mutations from public databases. We identified four interesting nonsynonymous point mutations, Arg45Gln, Ser109Pro, Gly186Val, and Ser263Cys, in the Cα1 splice variant of the kinase. Cα variants harboring the different amino acid mutations were analyzed for kinase activity and regulatory (R) subunit binding. Whereas mutation of residues 45 and 263 did not alter catalytic activity or R subunit binding, mutation of Ser109 significantly reduced kinase activity while R subunit binding was unaltered. Mutation of Cα Gly186 completely abrogated kinase activity and PKA type I but not type II holoenzyme formation. Gly186 is located in the highly conserved DFG motif of Cα and mutation of this residue to Val was predicted to result in loss of binding of ATP and Mg2+, which may explain the kinetic inactivity. We hypothesize that individuals born with mutations of Ser109 or Gly186 may be faced with abnormal development and possibly severe disease

BLAST Ring Image Generator (BRIG): simple prokaryote genome comparisons

<p>Abstract</p> <p>Background</p> <p>Visualisation of genome comparisons is invaluable for helping to determine genotypic differences between closely related prokaryotes. New visualisation and abstraction methods are required in order to improve the validation, interpretation and communication of genome sequence information; especially with the increasing amount of data arising from next-generation sequencing projects. Visualising a prokaryote genome as a circular image has become a powerful means of displaying informative comparisons of one genome to a number of others. Several programs, imaging libraries and internet resources already exist for this purpose, however, most are either limited in the number of comparisons they can show, are unable to adequately utilise draft genome sequence data, or require a knowledge of command-line scripting for implementation. Currently, there is no freely available desktop application that enables users to rapidly visualise comparisons between hundreds of draft or complete genomes in a single image.</p> <p>Results</p> <p>BLAST Ring Image Generator (BRIG) can generate images that show multiple prokaryote genome comparisons, without an arbitrary limit on the number of genomes compared. The output image shows similarity between a central reference sequence and other sequences as a set of concentric rings, where BLAST matches are coloured on a sliding scale indicating a defined percentage identity. Images can also include draft genome assembly information to show read coverage, assembly breakpoints and collapsed repeats. In addition, BRIG supports the mapping of unassembled sequencing reads against one or more central reference sequences. Many types of custom data and annotations can be shown using BRIG, making it a versatile approach for visualising a range of genomic comparison data. BRIG is readily accessible to any user, as it assumes no specialist computational knowledge and will perform all required file parsing and BLAST comparisons automatically.</p> <p>Conclusions</p> <p>There is a clear need for a user-friendly program that can produce genome comparisons for a large number of prokaryote genomes with an emphasis on rapidly utilising unfinished or unassembled genome data. Here we present BRIG, a cross-platform application that enables the interactive generation of comparative genomic images via a simple graphical-user interface. BRIG is freely available for all operating systems at <url>http://sourceforge.net/projects/brig/</url>.</p

Pilot study of Lokomat versus manual-assisted treadmill training for locomotor recovery post-stroke

<p>Abstract</p> <p>Background</p> <p>While manually-assisted body-weight supported treadmill training (BWSTT) has revealed improved locomotor function in persons with post-stroke hemiparesis, outcomes are inconsistent and it is very labor intensive. Thus an alternate treatment approach is desirable. Objectives of this pilot study were to: 1) compare the efficacy of body-weight supported treadmill training (BWSTT) combined with the Lokomat robotic gait orthosis versus manually-assisted BWSTT for locomotor training post-stroke, and 2) assess effects of fast versus slow treadmill training speed.</p> <p>Methods</p> <p>Sixteen volunteers with chronic hemiparetic gait (0.62 ± 0.30 m/s) post-stroke were randomly allocated to Lokomat (n = 8) or manual-BWSTT (n = 8) 3×/wk for 4 weeks. Groups were also stratified by fast (mean 0.92 ± 0.15 m/s) or slow (0.58 ± 0.12 m/s) training speeds. The primary outcomes were self-selected overground walking speed and paretic step length ratio. Secondary outcomes included: fast overground walking speed, 6-minute walk test, and a battery of clinical measures.</p> <p>Results</p> <p>No significant differences in primary outcomes were revealed between Lokomat and manual groups as a result of training. However, within the Lokomat group, self-selected walk speed, paretic step length ratio, and four of the six secondary measures improved (<it>p </it>= 0.04–0.05, effect sizes = 0.19–0.60). Within the manual group, only balance scores improved (<it>p </it>= 0.02, effect size = 0.57). Group differences between fast and slow training groups were not revealed (<it>p </it>≥ 0.28).</p> <p>Conclusion</p> <p>Results suggest that Lokomat training may have advantages over manual-BWSTT following a modest intervention dose in chronic hemiparetic persons and further, that our training speeds produce similar gait improvements. Suggestions for a larger randomized controlled trial with optimal study parameters are provided.</p

Expression of phosphorylated eIF4E-binding protein 1, but not of eIF4E itself, predicts survival in male breast cancer

Background: Male breast cancer is rare and treatment is based on data from females. High expression/activity of eukaryotic initiation factor 4E (eIF4E) denotes a poor prognosis in female breast cancer, and the eIF4E pathway has been targeted therapeutically. eIF4E activity in female breast cancer is deregulated by eIF4E over-expression and by phosphorylation of its binding protein, 4E-BP1, which relieves inhibitory association between eIF4E and 4E-BP1. The relevance of the eIF4E pathway in male breast cancer is unknown. Methods: We have assessed expression levels of eIF4E, 4E-BP1, 4E-BP2 and phosphorylated 4E-BP1 (p4E-BP1) using immunohistochemistry in a large cohort of male breast cancers (n=337) and have examined correlations with prognostic factors and survival. Results: Neither eIF4E expression or estimated eIF4E activity were associated with prognosis. However, a highly significant correlation was found between p4E-BP1 expression and disease-free survival, linking any detectable p4E-BP1 with poor survival (univariate log rank p=0.001; multivariate HR 8.8, p=0.0001). Conclusions: Our data provide no support for direct therapeutic targeting of eIF4E in male breast cancer, unlike in females. However, as p4E-BP1 gives powerful prognostic insights that are unrelated to eIF4E function, p4E-BP1 may identify male breast cancers potentially suitable for therapies directed at the upstream kinase, mTOR

KB-Rank: efficient protein structure and functional annotation identification via text query

The KB-Rank tool was developed to help determine the functions of proteins. A user provides text query and protein structures are retrieved together with their functional annotation categories. Structures and annotation categories are ranked according to their estimated relevance to the queried text. The algorithm for ranking first retrieves matches between the query text and the text fields associated with the structures. The structures are next ordered by their relative content of annotations that are found to be prevalent across all the structures retrieved. An interactive web interface was implemented to navigate and interpret the relevance of the structures and annotation categories retrieved by a given search. The aim of the KB-Rank tool is to provide a means to quickly identify protein structures of interest and the annotations most relevant to the queries posed by a user. Informational and navigational searches regarding disease topics are described to illustrate the tool’s utilities. The tool is available at the URL http://protein.tcmedc.org/KB-Rank

Assessing the Value of DNA Barcodes and Other Priority Gene Regions for Molecular Phylogenetics of Lepidoptera

BACKGROUND: Despite apparently abundant amounts of observable variation and species diversity, the order Lepidoptera exhibits a morphological homogeneity that has provided only a limited number of taxonomic characters and led to widespread use of nucleotides for inferring relationships. This study aims to characterize and develop methods to quantify the value of priority gene regions designated for Lepidoptera molecular systematics. In particular, I assess how the DNA barcode segment of the mitochondrial COI gene performs across a broad temporal range given its number one position of priority, most sequenced status, and the conflicting opinions on its phylogenetic performance. METHODOLOGY/PRINCIPAL FINDINGS: Gene regions commonly sequenced for lepidoptera phylogenetics were scored using multiple measures across three categories: practicality, which includes universality of primers and sequence quality; phylogenetic utility; and phylogenetic signal. I found that alternative measures within a category often appeared correlated, but high scores in one category did not necessarily translate into high scores in another. The DNA barcode was easier to sequence than other genes, and had high scores for utility but low signal above the genus level. CONCLUSIONS/SIGNIFICANCE: Given limited financial resources and time constraints, careful selection of gene regions for molecular phylogenetics is crucial to avoid wasted effort producing partially informative data. This study introduces an approach to assessing the value of gene regions prior to the initiation of new studies and presents empirical results to help guide future selections

Genetic Associations and Architecture of Asthma-COPD Overlap

BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10-6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10-8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma