The Protein Naming Utility: a rules database for protein nomenclature

Generation of syntactically correct and unambiguous names for proteins is a challenging, yet vital task for functional annotation processes. Proteins are often named based on homology to known proteins, many of which have problematic names. To address the need to generate high-quality protein names, and capture our significant experience correcting protein names manually, we have developed the Protein Naming Utility (PNU, http://www.jcvi.org/pn-utility). The PNU is a web-based database for storing and applying naming rules to identify and correct syntactically incorrect protein names, or to replace synonyms with their preferred name. The PNU allows users to generate and manage collections of naming rules, optionally building upon the growing body of rules generated at the J. Craig Venter Institute (JCVI). Since communities often enforce disparate conventions for naming proteins, the PNU supports grouping rules into user-managed collections. Users can check their protein names against a selected PNU rule collection, generating both statistics and corrected names. The PNU can also be used to correct GenBank table files prior to submission to GenBank. Currently, the database features 3080 manual rules that have been entered by JCVI Bioinformatics Analysts as well as 7458 automatically imported names

Towards Viral Genome Annotation Standards, Report from the 2010 NCBI Annotation Workshop

Improvements in DNA sequencing technologies portend a new era in virology and could possibly lead to a giant leap in our understanding of viral evolution and ecology. Yet, as viral genome sequences begin to fill the world’s biological databases, it is critically important to recognize that the scientific promise of this era is dependent on consistent and comprehensive genome annotation. With this in mind, the NCBI Genome Annotation Workshop recently hosted a study group tasked with developing sequence, function, and metadata annotation standards for viral genomes. This report describes the issues involved in viral genome annotation and reviews policy recommendations presented at the NCBI Annotation Workshop

Draft Genome of the Filarial Nematode Parasite \u3ci\u3eBrugia malayi\u3c/i\u3e

Parasitic nematodes that cause elephantiasis and river blindness threaten hundreds of millions of people in the developing world. We have sequenced the ∼90 megabase (Mb) genome of the human filarial parasite Brugia malayi and predict ∼11,500 protein coding genes in 71 Mb of robustly assembled sequence. Comparative analysis with the free-living, model nematode Caenorhabditis elegans revealed that, despite these genes having maintained little conservation of local synteny during ∼350 million years of evolution, they largely remain in linkage on chromosomal units. More than 100 conserved operons were identified. Analysis of the predicted proteome provides evidence for adaptations of B. malayi to niches in its human and vector hosts and insights into the molecular basis of a mutualistic relationship with its Wolbachia endosymbiont. These findings offer a foundation for rational drug design

Acute ketamine dysregulates task-related gamma-band oscillations in thalamo-cortical circuits in schizophrenia

Hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1–90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63–80 Hz) in occipital regions and upregulated low frequency (5–28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia

Pathema: a clade-specific bioinformatics resource center for pathogen research

Pathema (http://pathema.jcvi.org) is one of the eight Bioinformatics Resource Centers (BRCs) funded by the National Institute of Allergy and Infectious Disease (NIAID) designed to serve as a core resource for the bio-defense and infectious disease research community. Pathema strives to support basic research and accelerate scientific progress for understanding, detecting, diagnosing and treating an established set of six target NIAID Category A–C pathogens: Category A priority pathogens; Bacillus anthracis and Clostridium botulinum, and Category B priority pathogens; Burkholderia mallei, Burkholderia pseudomallei, Clostridium perfringens and Entamoeba histolytica. Each target pathogen is represented in one of four distinct clade-specific Pathema web resources and underlying databases developed to target the specific data and analysis needs of each scientific community. All publicly available complete genome projects of phylogenetically related organisms are also represented, providing a comprehensive collection of organisms for comparative analyses. Pathema facilitates the scientific exploration of genomic and related data through its integration with web-based analysis tools, customized to obtain, display, and compute results relevant to ongoing pathogen research. Pathema serves the bio-defense and infectious disease research community by disseminating data resulting from pathogen genome sequencing projects and providing access to the results of inter-genomic comparisons for these organisms

The viral genomics revolution: Big data approaches to basic viral research, surveillance, and vaccine development

Since the decoding of the first RNA virus in 1976, the field of viral genomics has exploded, first through the use of Sanger sequencing technologies and later with the use next-generation sequencing approaches. With the development of these sequencing technologies, viral genomics has entered an era of big data. New challenges for analyzing these data are now apparent. Here, we describe novel methods to extend the current capabilities of viral comparative genomics. Through the use of antigenic distancing techniques, we have examined the relationship between the antigenic phenotype and the genetic content of influenza virus to establish a more systematic approach to viral surveillance and vaccine selection. Distancing of Antigenicity by Sequence-based Hierarchical Clustering (DASH) was developed and used to perform a retrospective analysis of 22 influenza seasons. Our methods produced vaccine candidates identical to or with a high concordance of antigenic similarity with those selected by the WHO. In a second effort, we have developed VirComp and OrionPlot: two independent yet related tools. These tools first generate gene-based genome constellations, or genotypes, of viral genomes, and second create visualizations of the resultant genome constellations. VirComp utilizes sequence-clustering techniques to infer genome constellations and prepares genome constellation data matrices for visualization with OrionPlot. OrionPlot is a java application for tailoring genome constellation figures for publication. OrionPlot allows for color selection of gene cluster assignments, customized box sizes to enable the visualization of gene comparisons based on sequence length, and label coloring. We have provided five analyses designed as vignettes to illustrate the utility of our tools for performing viral comparative genomic analyses. Study three focused on the analysis of respiratory syncytial virus (RSV) genomes circulating during the 2012- 2013 RSV season. We discovered a correlation between a recent tandem duplication within the G gene of RSV-A and a decrease in severity of infection. Our data suggests that this duplication is associated with a higher infection rate in female infants than is generally observed. Through these studies, we have extended the state of the art of genotype analysis, phenotype/genotype studies and established correlations between clinical metadata and RSV sequence data

Host CD3+ T-cells can significantly modulate phage treatment effects on bacterial bioburden in mouse models

Wound healing is a complex system including such key players as host, microbe, and treatments. However, little is known about their dynamic interactions. Here we explored the interplay between: (1) bacterial bioburden and host immune responses, (2) bacterial bioburden and wound size, and (3) treatments and wound size, using murine models and various treatment modalities: Phosphate buffer saline (PBS or vehicle, negative control), doxycycline, and two doses of A. baumannii phage mixtures. We uncovered that the interplay between bacterial bioburden and host immune system may be bidirectional, and that there is an interaction between host CD3+ T-cells and phage dosage, which significantly impacts bacterial bioburden. Furthermore, the bacterial bioburden and wound size association is significantly modulated by the host CD3+ T-cells. When the host CD3+ T-cells (x on log10 scale) are in the appropriate range (1.35 < x < = 1.5), we observed a strong association between colony forming units (CFU) and wound size, indicating a hallmark of wound healing. On the basis of the findings and our previous work, we proposed an integrated parallel systems biology model

Avian Influenza: Mixed Infections and Missing Viruses

A high prevalence and diversity of avian influenza (AI) viruses were detected in a population of wild mallards sampled during summer 2011 in California, providing an opportunity to compare results obtained before and after virus culture. We tested cloacal swab samples prior to culture by matrix real-time PCR, and by amplifying and sequencing a 640bp portion of the hemagglutinin (HA) gene. Each sample was also inoculated into embryonated chicken eggs, and full genome sequences were determined for cultured viruses. While low matrix Ct values were a good predictor of virus isolation from eggs, samples with high or undetectable Ct values also yielded isolates. Furthermore, a single passage in eggs altered the occurrence and detection of viral strains, and mixed infections (different HA subtypes) were detected less frequently after culture. There is no gold standard or perfect reference comparison for surveillance of unknown viruses, and true negatives are difficult to distinguish from false negatives. This study showed that sequencing samples prior to culture increases the detection of mixed infections and enhances the identification of viral strains and sequences that may have changed or even disappeared during culture

Complete Genome Sequence of a Reassortant H14N2 Avian Influenza Virus from California.

We report the complete genome sequence of a reassortant H14N2 avian influenza virus isolated in 2011 from a northern shoveler in California. This introduced Eurasian subtype acquired seven segments from North American viruses and circulated in the Pacific Flyway 1 year after its detection in the Mississippi Flyway