Evaluation of Methods to Detect Shifts in Directional Selection at the Genome Scale.

Identifying the footprints of selection in coding sequences can inform about the importance and function of individual sites. Analyses of the ratio of nonsynonymous to synonymous substitutions (dN/dS) have been widely used to pinpoint changes in the intensity of selection, but cannot distinguish them from changes in the direction of selection, that is, changes in the fitness of specific amino acids at a given position. A few methods that rely on amino-acid profiles to detect changes in directional selection have been designed, but their performances have not been well characterized. In this paper, we investigate the performance of six of these methods. We evaluate them on simulations along empirical phylogenies in which transition events have been annotated and compare their ability to detect sites that have undergone changes in the direction or intensity of selection to that of a widely used dN/dS approach, codeml's branch-site model A. We show that all methods have reduced performance in the presence of biased gene conversion but not CpG hypermutability. The best profile method, Pelican, a new implementation of Tamuri AU, Hay AJ, Goldstein RA. (2009. Identifying changes in selective constraints: host shifts in influenza. PLoS Comput Biol. 5(11):e1000564), performs as well as codeml in a range of conditions except for detecting relaxations of selection, and performs better when tree length increases, or in the presence of persistent positive selection. It is fast, enabling genome-scale searches for site-wise changes in the direction of selection associated with phenotypic changes.

CAARS: comparative assembly and annotation of RNA-Seq data.

MOTIVATION: RNA sequencing (RNA-Seq) is a widely used approach to obtain transcript sequences in non-model organisms, notably for performing comparative analyses. However, current bioinformatic pipelines do not take full advantage of pre-existing reference data in related species for improving RNA-Seq assembly, annotation and gene family reconstruction. RESULTS: We built an automated pipeline named CAARS to combine novel data from RNA-Seq experiments with existing multi-species gene family alignments. RNA-Seq reads are assembled into transcripts by both de novo and assisted assemblies. Then, CAARS incorporates transcripts into gene families, builds gene alignments and trees and uses phylogenetic information to classify the genes as orthologs and paralogs of existing genes. We used CAARS to assemble and annotate RNA-Seq data in rodents and fishes using distantly related genomes as reference, a difficult case for this kind of analysis. We showed CAARS assemblies are more complete and accurate than those assembled by a standard pipeline consisting of de novo assembly coupled with annotation by sequence similarity on a guide species. In addition to annotated transcripts, CAARS provides gene family alignments and trees, annotated with orthology relationships, directly usable for downstream comparative analyses. AVAILABILITY AND IMPLEMENTATION: CAARS is implemented in Python and Ocaml and is freely available at https://github.com/carinerey/caars. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Structural and Lattice-Dynamical Properties of Tb2O3 under Compression: A Comparative Study with Rare Earth and Related Sesquioxides.

We report a joint experimental and theoretical investigation of the high pressure structural and vibrational properties of terbium sesquioxide (Tb2O3). Powder X-ray diffraction and Raman scattering measurements show that cubic Ia3̅ (C-type) Tb2O3 undergoes two phase transitions up to 25 GPa. We observe a first irreversible reconstructive transition to the monoclinic C2/m (B-type) phase at ∼7 GPa and a subsequent reversible displacive transition from the monoclinic to the trigonal P3̅m1 (A-type) phase at ∼12 GPa. Thus, Tb2O3 is found to follow the well-known C → B → A phase transition sequence found in other cubic rare earth sesquioxides with cations of larger atomic mass than Tb. Our ab initio theoretical calculations predict phase transition pressures and bulk moduli for the three phases in rather good agreement with experimental results. Moreover, Raman-active modes of the three phases have been monitored as a function of pressure, while lattice-dynamics calculations have allowed us to confirm the assignment of the experimental phonon modes in the C- and A-type phases as well as to make a tentative assignment of the symmetry of most vibrational modes in the B-type phase. Finally, we extract the bulk moduli and the Raman-active mode frequencies together with their pressure coefficients for the three phases of Tb2O3. These results are thoroughly compared and discussed in relation to those reported for rare earth and other related sesquioxides as well as with new calculations for selected sesquioxides. It is concluded that the evolution of the volume and bulk modulus of all the three phases of these technologically relevant compounds exhibit a nearly linear trend with respect to the third power of the ionic radii of the cations and that the values of the bulk moduli for the three phases depend on the filling of the f orbitals.

Robust Fit of Toxicokinetic-Toxicodynamic Models Using Prior Knowledge Contained in the Design of Survival Toxicity Tests.

Toxicokinetics-toxicodynamic (TKTD) models have emerged as a powerful means to describe survival as a function of time and concentration in ecotoxicology. They are especially powerful to extrapolate survival observed under constant exposure conditions to survival predicted under realistic fluctuating exposure conditions. But despite their obvious benefits, these models have not yet been adopted as a standard to analyze data of survival toxicity tests. Instead simple dose-response models are still often used although they only exploit data observed at the end of the experiment. We believe a reason precluding a wider adoption of TKTD models is that available software still requires strong expertise in model fitting. In this work, we propose a fully automated fitting procedure that extracts prior knowledge on parameters of the model from the design of the toxicity test (tested concentrations and observation times). We evaluated our procedure on three experimental and 300 simulated data sets and showed that it provides robust fits of the model, both in the frequentist and the Bayesian framework, with a better robustness of the Bayesian approach for the sparsest data sets.

RAR/RXR binding dynamics distinguish pluripotency from differentiation associated cis-regulatory elements.

In mouse embryonic cells, ligand-activated retinoic acid receptors (RARs) play a key role in inhibiting pluripotency-maintaining genes and activating some major actors of cell differentiation. To investigate the mechanism underlying this dual regulation, we performed joint RAR/RXR ChIP-seq and mRNA-seq time series during the first 48 h of the RA-induced Primitive Endoderm (PrE) differentiation process in F9 embryonal carcinoma (EC) cells. We show here that this dual regulation is associated with RAR/RXR genomic redistribution during the differentiation process. In-depth analysis of RAR/RXR binding sites occupancy dynamics and composition show that in undifferentiated cells, RAR/RXR interact with genomic regions characterized by binding of pluripotency-associated factors and high prevalence of the non-canonical DR0-containing RA response element. By contrast, in differentiated cells, RAR/RXR bound regions are enriched in functional Sox17 binding sites and are characterized with a higher frequency of the canonical DR5 motif. Our data offer an unprecedentedly detailed view on the action of RA in triggering pluripotent cell differentiation and demonstrate that RAR/RXR action is mediated via two different sets of regulatory regions tightly associated with cell differentiation status.

T-cell factor 4 and ß-catenin chromatin occupancies pattern zonal liver metabolism in mice.

UNLABELLED: ß-catenin signaling can be both a physiological and oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20%-40% of hepatocellular carcinomas (HCCs) with specific metabolic features. We decipher the molecular determinants of ß-catenin-dependent zonal transcription using mice with ß-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by T-cell factor (Tcf)-4 and ß-catenin, transcriptome, and metabolome. We find that Tcf-4 DNA bindings depend on ß-catenin. Tcf-4/ß-catenin binds Wnt-responsive elements preferentially around ß-catenin-induced genes. In contrast, genes repressed by ß-catenin bind Tcf-4 on hepatocyte nuclear factor 4 (Hnf-4)-responsive elements. ß-Catenin, Tcf-4, and Hnf-4α interact, dictating ß-catenin transcription, which is antagonistic to that elicited by Hnf-4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by ß-catenin, partly through xenobiotic nuclear receptors. CONCLUSIONS: ß-catenin patterns the zonal liver together with Tcf-4, Hnf-4α, and xenobiotic nuclear receptors. This network represses lipid metabolism and exacerbates glutamine, drug, and bile metabolism, mirroring HCCs with ß-catenin mutational activation.

Discussion on the structure stability and the luminescence switch under irradiation of a Ce-doped elpasolite compound.

Ce-doped Rb2 KInF6 elpasolite has the potential for tunable luminescence due to an unusual reversible redox process between the cerium and indium cations. Coupled with a deep understanding of the luminescence properties, XRD analysis and DFT calculations are used to locate the doping elements in the host lattice. The origin explanation of the charge-transfer mechanism that causes a decrease or increase in the blue-green cerium emission in opposition to the red indium emission is discussed regarding the crystallographic structure, the connection of the metallic cations and their equilibrium valence. Still detectable after nineteen years, the optical contrast created under irradiation makes this material a good candidate as photosensor for data storage.

Statistical handling of reproduction data for exposure-response modeling.

Reproduction data collected through standard bioassays are classically analyzed by regression in order to fit exposure-response curves and estimate ECx values (x% effective concentration). But regression is often misused on such data, ignoring statistical issues related to (i) the special nature of reproduction data (count data), (ii) a potential inter-replicate variability, and (iii) a possible concomitant mortality. This paper offers new insights in dealing with those issues. Concerning mortality, particular attention was paid not to waste any valuable data-by dropping all the replicates with mortality-or to bias ECx values. For that purpose we defined a new covariate summing the observation periods during which each individual contributes to the reproduction process. This covariate was then used to quantify reproduction-for each replicate at each concentration-as a number of offspring per individual-day. We formulated three exposure-response models differing by their stochastic part. Those models were fitted to four data sets and compared using a Bayesian framework. The individual-day unit proved to be a suitable approach to use all the available data and prevent bias in the estimation of ECx values. Furthermore, a nonclassical negative-binomial model was shown to correctly describe the inter-replicate variability observed in the studied data sets.

High-Frequency Linear Array (20 MHz) Based on Lead-Free BCTZ Crystal.

Centimeter-sized BaTiO3-based crystals grown by top-seeded solution growth from the BaTiO3-CaTiO3-BaZrO3 system were used to process a high-frequency (HF) lead-free linear array. Piezoelectric plates with (110)pc cut within 1° accuracy were used to manufacture two 1-3 piezo-composites with thicknesses of 270 and [Formula: see text] for resonant frequencies in air of 10 and 30 MHz, respectively. The electromechanical characterization of the BCTZ crystal plates and the 10-MHz piezocomposite yielded the thickness coupling factors of 40% and 50%, respectively. We quantified the electromechanical performance of the second piezocomposite (30 MHz) according to the reduction in the pillar sizes during the fabrication process. The dimensions of the piezocomposite at 30 MHz were sufficient for a 128-element array with a 70- [Formula: see text] element pitch and a 1.5-mm elevation aperture. The transducer stack (backing, matching layers, lens, and electrical components) was tuned with the characteristics of the lead-free materials to deliver optimal bandwidth and sensitivity. The probe was connected to a real-time HF 128-channel echographic system for acoustic characterization (electroacoustic response and radiation pattern) and to acquire high-resolution in vivo images of human skin. The center frequency of the experimental probe was 20 MHz, and the fractional bandwidth at -6 dB was 41%. Skin images were compared against those obtained with a lead-based 20-MHz commercial imaging probe. Despite significant differences in sensitivity between elements, in vivo images obtained with a BCTZ-based probe convincingly demonstrated the potential of integrating this piezoelectric material in an imaging probe.

Laser demonstration with highly doped Yb:Gd2O3 and Yb:Y2O3 crystals grown by an original flux method.

We present, to the best of our knowledge, the first laser demonstration of an Yb-doped Gd(2)O(3) cubic crystal. This crystal was obtained by the flux method using an original borate-based solvent, which was particularly well suited to the growth of rare earth sesquioxide crystals at half the working temperature of classical growth techniques. This flux method is a very interesting alternative for the production of laser sesquioxide crystals, not only because it provides access to new matrices of the cubic polymorph, but also because it permits high Yb(3+)-doping levels for these crystals. The first laser results of two highly Yb(3+)-doped sesquioxides, namely Gd(2)O(3) and Y(2)O(3), grown by this flux method are presented here, including the Ti:sapphire and diode pumping configurations. Laser efficiencies and emission spectra for these two crystals were studied and compared.

A Quantitative, Genome-Wide Analysis in Drosophila Reveals Transposable Elements' Influence on Gene Expression Is Species-Specific.

Transposable elements (TEs) are parasite DNA sequences that are able to move and multiply along the chromosomes of all genomes. They can be controlled by the host through the targeting of silencing epigenetic marks, which may affect the chromatin structure of neighboring sequences, including genes. In this study, we used transcriptomic and epigenomic high-throughput data produced from ovarian samples of several Drosophila melanogaster and Drosophila simulans wild-type strains, in order to finely quantify the influence of TE insertions on gene RNA levels and histone marks (H3K9me3 and H3K4me3). Our results reveal a stronger epigenetic effect of TEs on ortholog genes in D. simulans compared with D. melanogaster. At the same time, we uncover a larger contribution of TEs to gene H3K9me3 variance within genomes in D. melanogaster, which is evidenced by a stronger correlation of TE numbers around genes with the levels of this chromatin mark in D. melanogaster. Overall, this work contributes to the understanding of species-specific influence of TEs within genomes. It provides a new light on the considerable natural variability provided by TEs, which may be associated with contrasted adaptive and evolutionary potentials.

BioNLP Shared Task--The Bacteria Track.

BACKGROUND: We present the BioNLP 2011 Shared Task Bacteria Track, the first Information Extraction challenge entirely dedicated to bacteria. It includes three tasks that cover different levels of biological knowledge. The Bacteria Gene Renaming supporting task is aimed at extracting gene renaming and gene name synonymy in PubMed abstracts. The Bacteria Gene Interaction is a gene/protein interaction extraction task from individual sentences. The interactions have been categorized into ten different sub-types, thus giving a detailed account of genetic regulations at the molecular level. Finally, the Bacteria Biotopes task focuses on the localization and environment of bacteria mentioned in textbook articles. We describe the process of creation for the three corpora, including document acquisition and manual annotation, as well as the metrics used to evaluate the participants' submissions. RESULTS: Three teams submitted to the Bacteria Gene Renaming task; the best team achieved an F-score of 87%. For the Bacteria Gene Interaction task, the only participant's score had reached a global F-score of 77%, although the system efficiency varies significantly from one sub-type to another. Three teams submitted to the Bacteria Biotopes task with very different approaches; the best team achieved an F-score of 45%. However, the detailed study of the participating systems efficiency reveals the strengths and weaknesses of each participating system. CONCLUSIONS: The three tasks of the Bacteria Track offer participants a chance to address a wide range of issues in Information Extraction, including entity recognition, semantic typing and coreference resolution. We found common trends in the most efficient systems: the systematic use of syntactic dependencies and machine learning. Nevertheless, the originality of the Bacteria Biotopes task encouraged the use of interesting novel methods and techniques, such as term compositionality, scopes wider than the sentence.

Cation ordering in the double tungstate LiFe(WO4)2.

Single crystals of lithium iron tungstate, LiFe(WO(4))(2), were obtained using a high-temperature solution growth method. The analysis was conducted using the monoclinic space group C2/c, with ß = 90.597 (2)°, giving R1 = 0.0177. The Li and Fe atoms lie on twofold axes. The structure can also be refined using the orthorhombic space group Cmcm, giving slightly higher residuals. The experimental value of ß and the residuals mitigate in favour of the monoclinic description of the structure. Calculated bond-valence sums for the present results are closer to expected values than those obtained using the results of a previously reported analysis of this structure.

High Stability of the Epigenome in Drosophila Interspecific Hybrids.

Interspecific hybridization is often seen as a genomic stress that may lead to new gene expression patterns and deregulation of transposable elements (TEs). The understanding of expression changes in hybrids compared with parental species is essential to disentangle their putative role in speciation processes. However, to date we ignore the detailed mechanisms involved in genomic deregulation in hybrids. We studied the ovarian transcriptome and epigenome of the Drosophila buzzatii and Drosophila koepferae species together with their F1 hybrid females. We found a trend toward underexpression of genes and TE families in hybrids. The epigenome in hybrids was highly similar to the parental epigenomes and showed intermediate histone enrichments between parental species in most cases. Differential gene expression in hybrids was often associated only with changes in H3K4me3 enrichments, whereas differential TE family expression in hybrids may be associated with changes in H3K4me3, H3K9me3, or H3K27me3 enrichments. We identified specific genes and TE families, which their differential expression in comparison with the parental species was explained by their differential chromatin mark combination enrichment. Finally, cis-trans compensatory regulation could also contribute in some way to the hybrid deregulation. This work provides the first study of histone content in Drosophila interspecific hybrids and their effect on gene and TE expression deregulation.

Transcriptome-wide deregulation of gene expression by artificial light at night in tadpoles of common toads.

Artificial light at night (ALAN) affects numerous physiological and behavioural mechanisms in various species by potentially disturbing circadian timekeeping systems and modifying melatonin levels. However, given the multiple direct and indirect effects of ALAN on organisms, large-scale transcriptomic approaches are essential to assess the global effect of ALAN on biological processes. Moreover, although studies have focused mainly on variations in gene expression during the night in the presence of ALAN, it is necessary to investigate the effect of ALAN on gene expression during the day. In this study, we combined de novo transcriptome sequencing and assembly, and a controlled laboratory experiment to evaluate the transcriptome-wide gene expression response using high-throughput (RNA-seq) in Bufo bufo tadpoles exposed to ecologically relevant light levels. Here, we demonstrated for the first time that ALAN affected gene expression at night (3.5% and 11% of differentially expressed genes when exposed to 0.1 and 5 lx compared to controls, respectively), but also during the day (11.2% of differentially expressed genes when exposed to 5 lx compared to controls) with a dose-dependent effect. ALAN globally induced a downregulation of genes (during the night, 58% and 62% of the genes were downregulated when exposed to 0.1 and 5 lx compared to controls, respectively, and during the day, 61.2% of the genes were downregulated when exposed to 5 lx compared to controls). ALAN effects were detected at very low levels of illuminance (0.1 lx) and affected mainly genes related to the innate immune system and, to a lesser extend to lipid metabolism. These results provide new insights into understanding the effects of ALAN on organism. ALAN impacted the expression of genes linked to a broad range of physiological pathways at very low levels of ALAN during night-time and during daytime, potentially resulting in reduced immune capacity under environmental immune challenges.

Phase Transitions and Physical Properties of the Mixed Valence Iron Phosphate Fe3(PO3OH)4(H2O)4.

Iron phosphate materials have attracted a lot of attention due to their potential as cathode materials for lithium-ion rechargeable batteries. It has been shown that lithium insertion or extraction depends on the Fe mixed valence and reduction or oxidation of the Fe ions' valences. In this paper, we report a new synthesis method for the Fe3(PO3OH)4(H2O)4 mixed valence iron phosphate. In addition, we perform temperature-dependent measurements of structural and physical properties in order to obtain an understanding of electronic-structural interplay in this compound. Scanning electron microscope images show needle-like single crystals of 50 µm to 200 µm length which are stable up to approximately 200 °C, as revealed by thermogravimetric analysis. The crystal structure of Fe3(PO3OH)4(H2O)4 single crystals has been determined in the temperature range of 90 K to 470 K. A monoclinic isostructural phase transition was found at ~213 K, with unit cell volume doubling in the low temperature phase. While the local environment of the Fe2+ ions does not change significantly across the structural phase transition, small antiphase rotations occur for the Fe3+ octahedra, implying some kind of electronic order. These results are corroborated by first principle calculations within density functional theory, which also point to ordering of the electronic degrees of freedom across the transition. The structural phase transition is confirmed by specific heat measurements. Moreover, hints of 3D antiferromagnetic ordering appear below ~11 K in the magnetic susceptibility measurements. Room temperature visible light absorption is consistent with the Fe2+/Fe3+ mixed valence.

The transforming growth factor-α and cyclin D1 genes are direct targets of ß-catenin signaling in hepatocyte proliferation.

BACKGROUND & AIMS: ß-Catenin is an oncogene frequently mutated in hepatocellular carcinoma. In this study, we investigated target genes of ß-catenin signaling in hepatocyte proliferation. METHODS: We studied transgenic mice displaying either inactivation or activation of the ß-catenin pathway, focusing on analysis of liver proliferation due to aberrant ß-catenin activation, and on the regeneration process during which ß-catenin signaling is transiently activated. We localized in situ the various partners involved in proliferation or identified as targets of ß-catenin in these transgenic and regenerating livers. We also performed comparative transcriptome analyses, using microarrays. Finally, we extracted, from deep-sequencing data, both the DNA regulatory elements bound to the ß-catenin/Tcf nuclear complex and the expression levels of critical targets identified in microarrays. RESULTS: ß-Catenin activation during liver regeneration occurred during G1/S cell cycle progression and allowed zonal extension of the normal territory of active ß-catenin and panlobular proliferation. We found that ß-catenin controlled both cell-autonomous and non-cell-autonomous hepatocyte proliferation, through direct transcriptional and complex control of cyclin D1 gene expression and of the expression of a new target gene, Tgfα. CONCLUSIONS: We propose that ß-catenin controls panlobular hepatocyte proliferation partly by controlling, together with its Tcf4 nuclear partner, expression of the pro-proliferation cyclin D1 and Tgfα genes. This study constitutes a first step toward understanding the oncogenic properties of this prominent signaling pathway in the liver.

Correlation between luminescence and EPR spectroscopy as evidence of ytterbium pair formation in Li6Ln(BO3)3:Yb3+ (Ln=Gd, Y) borate single crystals.

Synthesized powders and grown single crystals of nominal compositions Li(6)Ln(BO(3))(3):Yb(3+) (Ln=Y, Gd) were investigated by means of powder and single-crystal X-ray diffraction (XRD), as well as optical near-IR spectroscopy in conjunction with electron paramagnetic resonance (EPR) spectroscopy. The appearance of two distinct zero-phonon lines suggests the existence of two kinds of Yb(3+) ions in the single crystals. The XRD results exclude the possibility of a phase transition occurring between room and low temperatures. EPR spectra of single crystals show the presence of both isolated ions and pairs of ytterbium ions substituted for Y(3+). A strong temperature dependence of the intensity of Yb-Yb pairs resonance lines coincides with temperature dependence of emission peak at 978 nm, confirming a common origin of the defect giving rise to these spectra. Calculated from EPR spectra, the distance between pairs of Yb(3+) is in good agreement with crystallographic ones: R=3.856 Å, R(cryst) =3.849 Å.

A Transposon Story: From TE Content to TE Dynamic Invasion of Drosophila Genomes Using the Single-Molecule Sequencing Technology from Oxford Nanopore.

Transposable elements (TEs) are the main components of genomes. However, due to their repetitive nature, they are very difficult to study using data obtained with short-read sequencing technologies. Here, we describe an efficient pipeline to accurately recover TE insertion (TEI) sites and sequences from long reads obtained by Oxford Nanopore Technology (ONT) sequencing. With this pipeline, we could precisely describe the landscapes of the most recent TEIs in wild-type strains of Drosophila melanogaster and Drosophila simulans. Their comparison suggests that this subset of TE sequences is more similar than previously thought in these two species. The chromosome assemblies obtained using this pipeline also allowed recovering piRNA cluster sequences, which was impossible using short-read sequencing. Finally, we used our pipeline to analyze ONT sequencing data from a D. melanogaster unstable line in which LTR transposition was derepressed for 73 successive generations. We could rely on single reads to identify new insertions with intact target site duplications. Moreover, the detailed analysis of TEIs in the wild-type strains and the unstable line did not support the trap model claiming that piRNA clusters are hotspots of TE insertions.