Description: Comparative functional genomics studies the evolution of biological processes by analyzing functional data, such as gene expression profiles, across species. A major challenge is to compare profiles collected in a complex phylogeny. Here, we present Arboretum, a novel scalable computational algorithm that integrates expression data from multiple species with species and gene phylogenies to infer modules of coexpressed genes in extant species and their evolutionary histories. We also develop new, generally applicable measures of conservation and divergence in gene regulatory modules to assess the impact of changes in gene content and expression on module evolution. We used Arboretum to study the evolution of the transcriptional response to heat shock in eight species of Ascomycota fungi and to reconstruct modules of the ancestral environmental stress response (ESR). We found substantial conservation in the stress response across species and in the reconstructed components of the ancestral ESR modules. The greatest divergence was in the most induced stress, primarily through module expansion. The divergence of the heat stress response exceeds that observed in the response to glucose depletion in the same species. Arboretum and its associated analyses provide a comprehensive framework to systematically study regulatory evolution of condition-specific responses.

Description: Purpose To evaluate the presentation of inflammatory hepatocellular adenomas (HCAs) on hepatocyte phase MRI. Materials and Methods We retrospectively reviewed the MRI features of histologically proven HCAs on hepatocyte phase imaging. Twenty-one lesions (17 with inflammatory subtype) were scanned with gadobenate dimeglumine. Signal intensities of the lesions were assessed in the hepatocyte phase and on the T1-weighted sequences before contrast. Results After gadobenate dimeglumine injection, 71% (12/17) of the inflammatory HCAs showed areas of iso- or hyperintensity to the surrounding liver in the hepatocyte phase. In 82% (10/12) of the iso- or hyperintense lesions, this was found over more than 75% of the lesion surface. None of the noninflammatory HCAs showed areas of iso- or hyperintensity to the surrounding liver in the hepatocyte phase. From these 12, 7 were hyperintense on T1-weighting before contrast due to liver steatosis, 2 due to intrinsic hyperintensity (on the in-phase sequence), and 3 were isointense. Conclusion In contrast to noninflammatory HCAs, inflammatory HCAs can show areas of iso- to hyperintensity to the surrounding liver in the hepatocyte phase; therefore, other typical imaging features should also be used to distinguish between HCAs and FNHs. J. Magn. Reson. Imaging 2013 . © 2013 Wiley Periodicals, Inc .

Description: Questions What is the role of nutrient limitation of dominant species in maintaining plant species diversity at small spatial scales, particularly in biodiversity hotspots? Location Southwest of Western Australia. Methods The extent of nutrient limitation was determined by measuring variation in the foliar nutrients of dominant plant species and total above-ground biomass in relation to soil N and P across 16 plots. Plant species richness and evenness for the same plots were then regressed against foliar N:P and δ 15 N of the dominant species. Results Foliar N and P content as well as above-ground biomass increased, while foliar N:P decreased with increasing soil N and P, suggesting that dominant species are limited by both N and P in southwest Australia. In contrast, foliar δ 15 N values only increased with decreasing soil P, indicating that δ 15 N enrichment reflects low P availability. Species richness increased at sites where foliar N:P was higher and δ 15 N more enriched, suggesting that a relatively greater number of rare plant species co-exist where the growth of dominant vegetation is more nutrient-limited. Conclusions The mechanisms that allow an exceptionally high number of plant species to co-exist at small spatial scales in a southwest Australian biodiversity hotspot are linked to the extent to which the dominant plant species are limited in N and P. In addition, on nutrient-impoverished soils, a foliar N:P ratio 〉16 can reflect N as well as P limitation. While foliar δ 15 N also reflects availability of soil P, it is not necessarily a reliable indicator of nutrient limitation in southwest Australia, and perhaps in other environments where plants are highly adapted to low-nutrient conditions.

Description: Using a dual-frequency high-resolution software-based GPS receiver, TEC and phase have been monitored from Calcutta, India situated near the northern crest of the Equatorial Ionization Anomaly for studying some Space Weather events during 2008–2010. Data from a dual-frequency Ionospheric TEC and Scintillation Monitor operational at this station under the international SCINDA program of the U.S. Air Force have also been used. This paper presents two cases of intense Space Weather events occurring in the equatorial latitudes under magnetically quiet conditions during the abnormally prolonged minimum of solar cycle 24. High values of S4 with maximum ∼0.8 were noted on GPS links located almost due south of Calcutta (22.58°N, 88.38°E geographic; magnetic dip: 32°N) when the look angles of the satellites are more-or-less aligned with the axis of the anisotropic field-aligned irregularities over the magnetic equator. Associated bite-outs in TEC of amplitude 40 units were recorded in the local post-sunset hours. Well-defined patches of phase scintillations and associated cycle slips were identified. On these days, higher values of ambient ionization were noted and the diurnal maximum of the electrojet strength was found to be delayed followed by a significant rise of the F region with a high upward drift velocity over the magnetic equator around sunset indicated by ionosonde. Measurements of in situ ion density using LEO DMSP corroborate the F region height rise. Presence of irregularities in ionization density distributions around 450km was found from C/NOFS measurements.

Description: Questions: How does the abundance and richness of plant assemblages with different functional (regeneration and nutrient acquisition) traits vary with fire regime, moisture availability and substrate fertility? What is the role of different functional traits in maintaining plant diversity under changing environmental conditions in seasonally dry and fire-prone environments? Location: Southwest Western Australia. Methods: Plant species abundance and soil nutrients were determined at 16 forest sites with variable fire histories across an aridity gradient. All plant species were classified based on their functional traits as (1) perennial or annual, (2) ectomycorrhizal, arbuscular mycorrhizal, ericoid mycorrhizal, orchid mycorrhizal, proteoid or other non-mycorrhizal, (3) resprouters or seeder, and (4) nitrogen fixer or non-fixer. We used a multivariate (fourth-corner) technique to simultaneously test the significance and direction of the relationship between each of these traits and fire frequency, fire interval length, aridity, and soil N, P and C fractions. Results: The functional response of the vegetation to fire regime was minor and restricted to annual species, which comprised only ∼4% of taxa. Proteoid and ectomycorrhizal species dominated over species with arbuscular and orchid mycorrhizal roots, N-fixers dominated over non-fixers, and seeders dominated over resprouters when N fertility was low but organic labile P was high. Further, proteoid and ectomycorrhizal species richness increased with aridity, while arbuscular mycorrhizal species richness decreased. Conclusions: While the functional composition of southwest Australian vegetation is largely insensitive to changes in fire regime, nutrient acquisition and, to a lesser extent, regeneration traits provide mechanisms for the vegetation community to adjust to changes in resource availability. Thus, diversity responses to environmental change in seasonally dry and fire-prone ecosystems are likely to be primarily mediated by the composition of nutrient acquisition traits in the vegetation community.

Description: Questions What is the role of nutrient limitation of dominant species in maintaining plant species diversity at small spatial scales, particularly in biodiversity hotspots? Location Southwest of Western Australia. Methods The extent of nutrient limitation was determined by measuring variation in the foliar nutrients of dominant plant species and total above-ground biomass in relation to soil N and P across 16 plots. Plant species richness and evenness for the same plots were then regressed against foliar N:P and δ 15 N of the dominant species. Results Foliar N and P content as well as above-ground biomass increased, while foliar N:P decreased with increasing soil N and P, suggesting that dominant species are limited by both N and P in southwest Australia. In contrast, foliar δ 15 N values only increased with decreasing soil P, indicating that δ 15 N enrichment reflects low P availability. Species richness increased at sites where foliar N:P was higher and δ 15 N more enriched, suggesting that a relatively greater number of rare plant species co-exist where the growth of dominant vegetation is more nutrient-limited. Conclusions The mechanisms that allow an exceptionally high number of plant species to co-exist at small spatial scales in a southwest Australian biodiversity hotspot are linked to the extent to which the dominant plant species are limited in N and P. In addition, on nutrient-impoverished soils, a foliar N:P ratio 〉16 can reflect N as well as P limitation. While foliar δ 15 N also reflects availability of soil P, it is not necessarily a reliable indicator of nutrient limitation in southwest Australia, and perhaps in other environments where plants are highly adapted to low-nutrient conditions.

Description: Gaining insights on gene regulation from large-scale functional data sets is a grand challenge in systems biology. In this article, we develop and apply methods for transcriptional regulatory network inference from diverse functional genomics data sets and demonstrate their value for gene function and gene expression prediction. We formulate the network inference problem in a machine-learning framework and use both supervised and unsupervised methods to predict regulatory edges by integrating transcription factor (TF) binding, evolutionarily conserved sequence motifs, gene expression, and chromatin modification data sets as input features. Applying these methods to Drosophila melanogaster, we predict ~300,000 regulatory edges in a network of ~600 TFs and 12,000 target genes. We validate our predictions using known regulatory interactions, gene functional annotations, tissue-specific expression, protein–protein interactions, and three-dimensional maps of chromosome conformation. We use the inferred network to identify putative functions for hundreds of previously uncharacterized genes, including many in nervous system development, which are independently confirmed based on their tissue-specific expression patterns. Last, we use the regulatory network to predict target gene expression levels as a function of TF expression, and find significantly higher predictive power for integrative networks than for motif or ChIP-based networks. Our work reveals the complementarity between physical evidence of regulatory interactions (TF binding, motif conservation) and functional evidence (coordinated expression or chromatin patterns) and demonstrates the power of data integration for network inference and studies of gene regulation at the systems level.

Description: BACKGROUND The identification of molecular alterations has an important therapeutic implication in patients with lung adenocarcinomas. In the current study, the authors evaluated their experience with the identification of epidermal growth factor receptor ( EGFR ), Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutation, and anaplastic lymphoma kinase ( ALK ) gene rearrangement using cytological specimens of primary and metastatic lung adenocarcinoma. METHODS A total of 54 cases of lung adenocarcinomas (11 primary and 43 metastatic tumors) in which molecular tests were performed were retrieved. Molecular tests were performed on the cell block material of 19 effusions and 35 fine-needle aspirates. EGFR mutation was evaluated by polymerase chain reaction sequencing analysis of exons 18, 19, 20, and 21. KRAS mutation was tested using polymerase chain reaction–single-strand conformational polymorphism analysis of codons 12 and 13. ALK gene rearrangement was evaluated by fluorescence in situ hybridization using an ALK break apart probe. RESULTS Molecular tests were successful in 49 of 54 cases (91%). Evaluation of EGFR mutation, KRAS mutation, and ALK gene rearrangement were performed in 49 cases, 14 cases, and 22 cases, respectively. EGFR mutations were found in 14 of 49 cases (29%), including 5 primary and 9 metastatic tumors. Three metastatic/recurrent adenocarcinomas demonstrated an additional EGFR T790M mutation that was not identified in the original specimens. KRAS mutation was detected in 3 of 14 cases (21%) including 1 primary and 2 metastatic tumors. ALK gene rearrangement was evident in 3 of 22 cases (14%), all of which were metastatic tumors. CONCLUSIONS The results of the current study have demonstrated the feasibility of using cytological specimens for EGFR mutation, KRAS mutation, and ALK gene rearrangement analysis. Repeating molecular testing in metastatic/recurrent lung adenocarcinomas may uncover newly acquired molecular alterations. Cancer (Cancer Cytopathol) 2013; © 2013 American Cancer Society .

Description: The order of genes in eukaryotic genomes has generally been assumed to be neutral, since gene order is largely scrambled over evolutionary time. Only a handful of exceptional examples are known, typically involving deeply conserved clusters of tandemly duplicated genes (e.g., Hox genes and histones). Here we report the first systematic survey of microsynteny conservation across metazoans, utilizing 17 genome sequences. We identified nearly 600 pairs of unrelated genes that have remained tightly physically linked in diverse lineages across over 600 million years of evolution. Integrating sequence conservation, gene expression data, gene function, epigenetic marks, and other genomic features, we provide extensive evidence that many conserved ancient linkages involve (1) the coordinated transcription of neighboring genes, or (2) genomic regulatory blocks (GRBs) in which transcriptional enhancers controlling developmental genes are contained within nearby bystander genes. In addition, we generated ChIP-seq data for key histone modifications in zebrafish embryos, which provided further evidence of putative GRBs in embryonic development. Finally, using chromosome conformation capture (3C) assays and stable transgenic experiments, we demonstrate that enhancers within bystander genes drive the expression of genes such as Otx and Islet , critical regulators of central nervous system development across bilaterians. These results suggest that ancient genomic functional associations are far more common than previously thought—involving ~12% of the ancestral bilaterian genome—and that cis -regulatory constraints are crucial in determining metazoan genome architecture.