MenT nucleotidyltransferase toxins extend tRNA acceptor stems and can be inhibited by asymmetrical antitoxin binding

Mycobacterium tuberculosis, the bacterium responsible for human tuberculosis, has a genome encoding a remarkably high number of toxin-antitoxin systems of largely unknown function. We have recently shown that the M. tuberculosis genome encodes four of a widespread, MenAT family of nucleotidyltransferase toxin-antitoxin systems. In this study we characterize MenAT1, using tRNA sequencing to demonstrate MenT1 tRNA modification activity. MenT1 activity is blocked by MenA1, a short protein antitoxin unrelated to the MenA3 kinase. X-ray crystallographic analysis shows blockage of the conserved MenT fold by asymmetric binding of MenA1 across two MenT1 protomers, forming a heterotrimeric toxin-antitoxin complex. Finally, we also demonstrate tRNA modification by toxin MenT4, indicating conserved activity across the MenT family. Our study highlights variation in tRNA target preferences by MenT toxins, selective use of nucleotide substrates, and diverse modes of MenA antitoxin activity

GeneBins: a database for classifying gene expression data, with application to plant genome arrays

BACKGROUND: To interpret microarray experiments, several ontological analysis tools have been developed. However, current tools are limited to specific organisms. RESULTS: We developed a bioinformatics system to assign the probe set sequences of any organism to a hierarchical functional classification modelled on KEGG ontology. The GeneBins database currently supports the functional classification of expression data from four Affymetrix arrays; Arabidopsis thaliana, Oryza sativa, Glycine max and Medicago truncatula. An online analysis tool to identify relevant functions is also provided. CONCLUSION: GeneBins provides resources to interpret gene expression results from microarray experiments. It is available a

Endeavour update: a web resource for gene prioritization in multiple species

Endeavour (http://www.esat.kuleuven.be/endeavourweb; this web site is free and open to all users and there is no login requirement) is a web resource for the prioritization of candidate genes. Using a training set of genes known to be involved in a biological process of interest, our approach consists of (i) inferring several models (based on various genomic data sources), (ii) applying each model to the candidate genes to rank those candidates against the profile of the known genes and (iii) merging the several rankings into a global ranking of the candidate genes. In the present article, we describe the latest developments of Endeavour. First, we provide a web-based user interface, besides our Java client, to make Endeavour more universally accessible. Second, we support multiple species: in addition to Homo sapiens, we now provide gene prioritization for three major model organisms: Mus musculus, Rattus norvegicus and Caenorhabditis elegans. Third, Endeavour makes use of additional data sources and is now including numerous databases: ontologies and annotations, protein–protein interactions, cis-regulatory information, gene expression data sets, sequence information and text-mining data. We tested the novel version of Endeavour on 32 recent disease gene associations from the literature. Additionally, we describe a number of recent independent studies that made use of Endeavour to prioritize candidate genes for obesity and Type II diabetes, cleft lip and cleft palate, and pulmonary fibrosis

Gravity, Geodesy and Fundamental Physics with BepiColombo’s MORE Investigation

open40siThe Mercury Orbiter Radio Science Experiment (MORE) of the ESA mission BepiColombo will provide an accurate estimation of Mercury’s gravity field and rotational state, improved tests of general relativity, and a novel deep space navigation system. The key experimental setup entails a highly stable, multi-frequency radio link in X and Ka band, enabling two-way range rate measurements of 3 micron/s at nearly all solar elongation angles. In addition, a high chip rate, pseudo-noise ranging system has already been tested at 1-2 cm accuracy. The tracking data will be used together with the measurements of the Italian Spring Accelerometer to provide a pseudo drag free environment for the data analysis. We summarize the existing literature published over the past years and report on the overall configuration of the experiment, its operations in cruise and at Mercury, and the expected scientific results.openIess L.; Asmar S.W.; Cappuccio P.; Cascioli G.; De Marchi F.; di Stefano I.; Genova A.; Ashby N.; Barriot J.P.; Bender P.; Benedetto C.; Border J.S.; Budnik F.; Ciarcia S.; Damour T.; Dehant V.; Di Achille G.; Di Ruscio A.; Fienga A.; Formaro R.; Klioner S.; Konopliv A.; Lemaitre A.; Longo F.; Mercolino M.; Mitri G.; Notaro V.; Olivieri A.; Paik M.; Palli A.; Schettino G.; Serra D.; Simone L.; Tommei G.; Tortora P.; Van Hoolst T.; Vokrouhlicky D.; Watkins M.; Wu X.; Zannoni M.Iess L.; Asmar S.W.; Cappuccio P.; Cascioli G.; De Marchi F.; di Stefano I.; Genova A.; Ashby N.; Barriot J.P.; Bender P.; Benedetto C.; Border J.S.; Budnik F.; Ciarcia S.; Damour T.; Dehant V.; Di Achille G.; Di Ruscio A.; Fienga A.; Formaro R.; Klioner S.; Konopliv A.; Lemaitre A.; Longo F.; Mercolino M.; Mitri G.; Notaro V.; Olivieri A.; Paik M.; Palli A.; Schettino G.; Serra D.; Simone L.; Tommei G.; Tortora P.; Van Hoolst T.; Vokrouhlicky D.; Watkins M.; Wu X.; Zannoni M

Integrating Computational Biology and Forward Genetics in Drosophila

Genetic screens are powerful methods for the discovery of gene–phenotype associations. However, a systems biology approach to genetics must leverage the massive amount of “omics” data to enhance the power and speed of functional gene discovery in vivo. Thus far, few computational methods for gene function prediction have been rigorously tested for their performance on a genome-wide scale in vivo. In this work, we demonstrate that integrating genome-wide computational gene prioritization with large-scale genetic screening is a powerful tool for functional gene discovery. To discover genes involved in neural development in Drosophila, we extend our strategy for the prioritization of human candidate disease genes to functional prioritization in Drosophila. We then integrate this prioritization strategy with a large-scale genetic screen for interactors of the proneural transcription factor Atonal using genomic deficiencies and mutant and RNAi collections. Using the prioritized genes validated in our genetic screen, we describe a novel genetic interaction network for Atonal. Lastly, we prioritize the whole Drosophila genome and identify candidate gene associations for ten receptor-signaling pathways. This novel database of prioritized pathway candidates, as well as a web application for functional prioritization in Drosophila, called Endeavour-HighFly, and the Atonal network, are publicly available resources. A systems genetics approach that combines the power of computational predictions with in vivo genetic screens strongly enhances the process of gene function and gene–gene association discovery

Rare variants in NR2F2 cause congenital heart defects in humans

Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p = 7.7 × 10?7) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via luciferase assays, we showed that all six coding sequence variants observed in individuals significantly alter the activity of NR2F2 on target promoters