Ortho2ExpressMatrix—a web server that interprets cross-species gene expression data by gene family information

<p>Abstract</p> <p>Background</p> <p>The study of gene families is pivotal for the understanding of gene evolution across different organisms and such phylogenetic background is often used to infer biochemical functions of genes. Modern high-throughput experiments offer the possibility to analyze the entire transcriptome of an organism; however, it is often difficult to deduct functional information from that data.</p> <p>Results</p> <p>To improve functional interpretation of gene expression we introduce Ortho2ExpressMatrix, a novel tool that integrates complex gene family information, computed from sequence similarity, with comparative gene expression profiles of two pre-selected biological objects: gene families are displayed with two-dimensional matrices. Parameters of the tool are object type (two organisms, two individuals, two tissues, etc.), type of computational gene family inference, experimental meta-data, microarray platform, gene annotation level and genome build. Family information in Ortho2ExpressMatrix bases on computationally different protein family approaches such as EnsemblCompara, InParanoid, SYSTERS and Ensembl Family. Currently, respective all-against-all associations are available for five species: human, mouse, worm, fruit fly and yeast. Additionally, microRNA expression can be examined with respect to miRBase or TargetScan families. The visualization, which is typical for Ortho2ExpressMatrix, is performed as matrix view that displays functional traits of genes (differential expression) as well as sequence similarity of protein family members (BLAST e-values) in colour codes. Such translations are intended to facilitate the user's perception of the research object.</p> <p>Conclusions</p> <p>Ortho2ExpressMatrix integrates gene family information with genome-wide expression data in order to enhance functional interpretation of high-throughput analyses on diseases, environmental factors, or genetic modification or compound treatment experiments. The tool explores differential gene expression in the light of orthology, paralogy and structure of gene families up to the point of ambiguity analyses. Results can be used for filtering and prioritization in functional genomic, biomedical and systems biology applications. The web server is freely accessible at <url>http://bioinf-data.charite.de/o2em/cgi-bin/o2em.pl</url>.</p

A novel nuclear receptor/coregulator complex controls C. elegans lipid metabolism, larval development, and aging

Environmental cues transduced by an endocrine network converge on Caenorhabditis elegans nuclear receptor DAF-12 to mediate arrest at dauer diapause or continuous larval development. In adults, DAF-12 selects long-lived or short-lived modes. How these organismal choices are molecularly specified is unknown. Here we show that coregulator DIN-1 and DAF-12 physically and genetically interact to instruct organismal fates. Homologous to human corepressor SHARP, DIN-1 comes in long (L) and short (S) isoforms, which are nuclear localized but have distinct functions. DIN-1L has embryonic and larval developmental roles. DIN-1S, along with DAF-12, regulates lipid metabolism, larval stage-specific programs, diapause, and longevity. Epistasis experiments reveal that din-1S acts in the dauer pathways downstream of lipophilic hormone, insulin/IGF, and TGFβ signaling, the same point as daf-12. We propose that the DIN-1S/DAF-12 complex serves as a molecular switch that implements slow life history alternatives in response to diminished hormonal signals

Metabolic profiles of six African cultivars of cassava (Manihot esculenta Crantz) highlight bottlenecks of root yield

Cassava is an important staple crop in sub-Saharan Africa, due to its high productivity even on nutrient poor soils. The metabolic characteristics underlying this high productivity are poorly understood including the mode of photosynthesis, reasons for the high rate of photosynthesis, the extent of source/sink limitation, the impact of environment, and the extent of variation between cultivars. Six commercial African cassava cultivars were grown in a greenhouse in Erlangen, Germany, and in the field in Ibadan, Nigeria. Source leaves, sink leaves, stems and storage roots were harvested during storage root bulking and analyzed for sugars, organic acids, amino acids, phosphorylated intermediates, minerals, starch, protein, activities of enzymes in central metabolism and yield traits. High ratios of RuBisCO:phosphoenolpyruvate carboxylase activity support a C3 mode of photosynthesis. The high rate of photosynthesis is likely to be attributed to high activities of enzymes in the Calvin–Benson cycle and pathways for sucrose and starch synthesis. Never- theless, source limitation is indicated because root yield traits correlated with metabolic traits in leaves rather than in the stem or storage roots. This situation was especially so in greenhouse-grown plants, where irradiance will have been low. In the field, plants produced more storage roots. This was associated with higher AGPase activity and lower sucrose in the roots, indicating that feedforward loops enhanced sink capacity in the high light and low nitrogen environment in the field. Overall, these results indicated that car- bon assimilation rate, the K battery, root starch synthesis, trehalose, and chlorogenic acid accumulation are potential target traits for genetic improvement

Larval crowding accelerates C-elegans development and reduces lifespan

Environmental conditions experienced during animal development are thought to have sustained impact on maturation and adult lifespan. Here we show that in the model organism C. elegans developmental rate and adult lifespan depend on larval population density, and that this effect is mediated by excreted small molecules. By using the time point of first egg laying as a marker for full maturity, we found that wildtype hermaphrodites raised under high density conditions developed significantly faster than animals raised in isolation. Population density-dependent acceleration of development (Pdda) was dramatically enhanced in fatty acid beta-oxidation mutants that are defective in the biosynthesis of ascarosides, small-molecule signals that induce developmental diapause. In contrast, Pdda is abolished by synthetic ascarosides and steroidal ligands of the nuclear hormone receptor DAF-12. We show that neither ascarosides nor any known steroid hormones are required for Pdda and that another chemical signal mediates this phenotype, in part via the nuclear hormone receptor NHR-8. Our results demonstrate that C. elegans development is regulated by a push-pull mechanism, based on two antagonistic chemical signals: chemosensation of ascarosides slows down development, whereas population-density dependent accumulation of a different chemical signal accelerates development. We further show that the effects of high larval population density persist through adulthood, as C. elegans larvae raised at high densities exhibit significantly reduced adult lifespan and respond differently to exogenous chemical signals compared to larvae raised at low densities, independent of density during adulthood. Our results demonstrate how inter-organismal signaling during development regulates reproductive maturation and longevity

Population density dependent acceleration of development (Pdda) in <i>C</i>. <i>elegans</i> hermaphrodites.

<p><b>A)</b> Time point of first egg laying on plates with different population densities, set up according to protocol A (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006717#sec008" target="_blank">Methods</a>). First egg laying was scored from 60 h after plating. <b>B)</b> Schematic of experimental protocol B used for measuring the effect of population density on the time point of first egg laying. <b>C)</b> Time point of first egg laying of worms isolated throughout development (ISO) or kept at high density for 48 h or 59 h (HD) before transfer onto new plates at one worm per plate. <b>D)</b> Developmental stage of isolated worms and groups of 100 worms at 52 h. <b>E)</b> Pdda is unaffected by mutation of <i>eat-2 and egl-4</i>, (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006717#sec008" target="_blank">Methods</a> for calculating percent wildtype Pdda). Error bars, STD; ***<i>P</i> < 0.0001; **<i>P</i> < 0.001; *<i>P</i> < 0.05.</p

Population density affects lifespan of <i>C</i>. <i>elegans</i> hermaphrodites and a model for Pdda.

<p><b>A)</b> Mean lifespan of hermaphrodites at different population densities, set up as eggs on mock treated plates (black bars) or set up as eggs on plates containing 100 nM dafa#3 (grey bars), or raised on plates of >100 animals and moved onto mock-treated assay plates at indicated densities at 62 h (red bars). <b>B)</b> Aging curves for hermaphrodites kept at 1 worm/plate, set up by isolating worms from plates with >100 hermaphrodites at 62 h (protocol I, red) or as eggs (protocol II, black [control] and grey dashed [with 100 nM dafa#3]). Error bars, SEM; ***<i>P</i> < 0.0001; **<i>P</i> < 0.001; *<i>P</i> < 0.05. <b>C)</b> Model for the roles of small molecule signaling in Pdda. Population density controls development via two competing small-molecule cascades. High population density results in accumulation of ascarosides that downregulate DA biosynthesis and thereby retard developmental progression. This effect is antagonized by a second chemical signal, here named compound X, that accelerates development and represents the proximal cause of Pdda.</p

Sex-specificity of the C. elegans metabolome

Biological sex affects all aspects of animal physiology. Using the model C. elegans, the authors show that metabolomes are highly sex-specific and include a vast space of yet unidentified metabolites that may control development and lifespan

Broad anti-pathogen potential of DEAD box RNA helicase eIF4A-targeting rocaglates

Abstract Inhibition of eukaryotic initiation factor 4A has been proposed as a strategy to fight pathogens. Rocaglates exhibit the highest specificities among eIF4A inhibitors, but their anti-pathogenic potential has not been comprehensively assessed across eukaryotes. In silico analysis of the substitution patterns of six eIF4A1 aa residues critical to rocaglate binding, uncovered 35 variants. Molecular docking of eIF4A:RNA:rocaglate complexes, and in vitro thermal shift assays with select recombinantly expressed eIF4A variants, revealed that sensitivity correlated with low inferred binding energies and high melting temperature shifts. In vitro testing with silvestrol validated predicted resistance in Caenorhabditis elegans and Leishmania amazonensis and predicted sensitivity in Aedes sp., Schistosoma mansoni, Trypanosoma brucei, Plasmodium falciparum, and Toxoplasma gondii. Our analysis further revealed the possibility of targeting important insect, plant, animal, and human pathogens with rocaglates. Finally, our findings might help design novel synthetic rocaglate derivatives or alternative eIF4A inhibitors to fight pathogens