ALBERT

Description: Seismic waves sensitive to the outermost part of the Earth's liquid core seem to be affected by a stably stratified layer at the core–mantle boundary. Such a layer could have an observable signature in both long-term and short-term variations of the magnetic field of the Earth, which are used to probe the flow at the top of the core. Indeed, with the recent SWARM mission, it seems reasonable to be able to identify waves propagating in the core with period of several months, which may play an important role in the large-scale dynamics. In this paper, we characterize the influence of a stratified layer at the top of the core on deep quasi-geostrophic (Rossby) waves. We compute numerically the quasi-geostrophic eigenmodes of a rapidly rotating spherical shell, with a stably stratified layer near the outer boundary. Two simple models of stratification are taken into account, which are scaled with commonly adopted values of the Brunt–Väisälä frequency in the Earth's core. In the absence of magnetic field, we find that both azimuthal wavelength and frequency of the eigenmodes control their penetration into the stratified layer: the higher the phase speed, the higher the permeability of the stratified layer to the wave motion. We also show that the theory developed by Takehiro & Lister for thermal convection extends to the whole family of Rossby waves in the core. Adding a magnetic field, the penetrative behaviour of the quasi-geostrophic modes (the so-called fast branch) is insensitive to the imposed magnetic field and only weakly sensitive to the precise shape of the stratification. Based on these results, the large-scale and high-frequency modes (1–2 month periods) may be detectable in the geomagnetic data measured at the Earth's surface, especially in the equatorial area where the modes can be trapped.

Description: Recent releases of genome three-dimensional (3D) structures have the potential to transform our understanding of genomes. Nonetheless, the storage technology and visualization tools need to evolve to offer to the scientific community fast and convenient access to these data. We introduce simultaneously a database system to store and query 3D genomic data ( 3DBG ), and a 3D genome browser to visualize and explore 3D genome structures ( 3DGB ). We benchmark 3DBG against state-of-the-art systems and demonstrate that it is faster than previous solutions, and importantly gracefully scales with the size of data. We also illustrate the usefulness of our 3D genome Web browser to explore human genome structures. The 3D genome browser is available at http://3dgb.cs.mcgill.ca/ .

Description: Identification of transcription units (TUs) encoded in a bacterial genome is essential to elucidation of transcriptional regulation of the organism. To gain a detailed understanding of the dynamically composed TU structures, we have used four strand-specific RNA-seq (ssRNA-seq) datasets collected under two experimental conditions to derive the genomic TU organization of Clostridium thermocellum using a machine-learning approach. Our method accurately predicted the genomic boundaries of individual TUs based on two sets of parameters measuring the RNA-seq expression patterns across the genome: expression-level continuity and variance. A total of 2590 distinct TUs are predicted based on the four RNA-seq datasets. Among the predicted TUs, 44% have multiple genes. We assessed our prediction method on an independent set of RNA-seq data with longer reads. The evaluation confirmed the high quality of the predicted TUs. Functional enrichment analyses on a selected subset of the predicted TUs revealed interesting biology. To demonstrate the generality of the prediction method, we have also applied the method to RNA-seq data collected on Escherichia coli and achieved high prediction accuracies. The TU prediction program named SeqTU is publicly available at https://code.google.com/p/seqtu/ . We expect that the predicted TUs can serve as the baseline information for studying transcriptional and post-transcriptional regulation in C. thermocellum and other bacteria.

Description: Detecting genetic variation is one of the main applications of high-throughput sequencing, but is still challenging wherever aligning short reads poses ambiguities. Current state-of-the-art variant calling approaches avoid such regions, arguing that it is necessary to sacrifice detection sensitivity to limit false discovery. We developed a method that links candidate variant positions within repetitive genomic regions into clusters. The technique relies on a resource, a thesaurus of genetic variation, that enumerates genomic regions with similar sequence. The resource is computationally intensive to generate, but once compiled can be applied efficiently to annotate and prioritize variants in repetitive regions. We show that thesaurus annotation can reduce the rate of false variant calls due to mappability by up to three orders of magnitude. We apply the technique to whole genome datasets and establish that called variants in low mappability regions annotated using the thesaurus can be experimentally validated. We then extend the analysis to a large panel of exomes to show that the annotation technique opens possibilities to study variation in hereto hidden and under-studied parts of the genome.

Description: A 3-D magnetotelluric (MT) inversion code using unstructured tetrahedral elements has been developed in order to correct the topographic effect by directly incorporating it into computational grids. The electromagnetic field and response functions get distorted at the observation sites of MT surveys because of the undulating surface topography, and without correcting this distortion, the subsurface structure can be misinterpreted. Of the two methods proposed to correct the topographic effect, the method incorporating topography explicitly in the inversion is applicable to a wider range of surveys. For forward problems, it has been shown that the finite element method using unstructured tetrahedral elements is useful for the incorporation of topography. Therefore, this paper shows the applicability of unstructured tetrahedral elements in MT inversion using the newly developed code. The inversion code is capable of using the impedance tensor, the vertical magnetic transfer function (VMTF), and the phase tensor as observational data, and it estimates the subsurface resistivity values and the distortion tensor of each observation site. The forward part of the code was verified using two test models, one incorporating topographic effect and one without, and the verifications showed that the results were almost the same as those of previous works. The developed inversion code was then applied to synthetic data from a MT survey, and was verified as being able to recover the resistivity structure as well as other inversion codes. Finally, to confirm its applicability to the data affected by topography, inversion was performed using the synthetic data of the model that included two overlapping mountains. In each of the cases using the impedance tensor, the VMTF and the phase tensor, by including the topography in the mesh, the subsurface resistivity was determined more proficiently than in the case using the flat-surface mesh. Although the locations of the anomalies were not accurately estimated by the inversion using distorted impedance tensors due to the slightly undervalued gain, these locations were correctly estimated by using undistorted impedance tensors or adding VMTFs in the data. Therefore, it can be concluded that the inversion using the unstructured tetrahedral element effectively prevents the misinterpretation of subsurface resistivity and recovers subsurface resistivity proficiently by representing the topography in the computational mesh.

Description: Separating the contribution of different hematite coercivity grains to the magnetic fabric is a standing problem in rock magnetism because of the common occurrence of thermochemical alterations when measuring the anisotropy of thermal remanence. A technique that eliminates this bias is presented, which is useful when there is a need to separate the fabric of detrital from pigmentary hematite, for example. The method is based on stepwise thermal demagnetization of saturation isothermal remanent magnetizations (IRMs) applied orthogonally on three sister specimens, allowing calculation of the anisotropy tensor from the three components of each demagnetized IRM vector, avoiding the necessity of having to apply IRMs to thermochemically altered specimens. Vector subtraction allows determining the anisotropy tensor for specific unblocking-temperature ranges. The anisotropies of the pigmentary, specular and total hematite of the Mauch Chunk Formation red beds of Pennsylvania have been measured from an oriented block sample and results are compared to previous anisotropy measurements performed using the high-field anisotropy of isothermal remanence technique (hf-AIR), which measures total undifferentiated hematite. Experiments were conducted using non-saturating 1 T and fully saturating 5.5 T fields: both experimental sets seem capable of measuring the orientation of the specularite anisotropy principal axes, but 5.5 T are needed to capture the orientation of the higher coercivity pigmentary grains. The magnitudes of the principal axes, instead, are only faithfully measured using 5.5 T fields and yield somewhat higher anisotropies than those measured by hf-AIR. The fundamental requirement for this technique is homogeneous material among the three sister specimens, which is a significant limitation; homogeneity tests allow assessment of applicability of the method and reliability of the results.

Description: Archaeomagnetic field models cover longer timescales than historical models and may therefore resolve the motion of geomagnetic features on the core–mantle boundary (CMB) in a more meaningful statistical sense. Here we perform a detailed appraisal of archaeomagnetic field models to infer some aspects of the physics of the outer core. We characterize and compare the identification and tracking of reversed flux patches (RFPs) in order to assess the RFPs robustness. We find similar behaviour within a family of models but differences among different families, suggesting that modelling strategy is more influential than data set. Similarities involve recurrent positions of RFPs, but no preferred direction of motion is found. The tracking of normal flux patches shows similar qualitative behaviour confirming that RFPs identification and tracking is not strongly biased by their relative weakness. We also compare the tracking of RFPs with that of the historical field model gufm1 and with seismic anomalies of the lowermost mantle to explore the possibility that RFPs have preferred locations prescribed by lower mantle lateral heterogeneity. The archaeomagnetic field model that most resembles the historical field is interpreted in terms of core dynamics and core–mantle thermal interactions. This model exhibits correlation between RFPs and low seismic shear velocity in co-latitude and a shift in longitude. These results shed light on core processes, in particular we infer toroidal field lines with azimuthal orientation below the CMB and large fluid upwelling structures with a width of about 80° (Africa) and 110° (Pacific) at the top of the core. Finally, similar preferred locations of RFPs in the past 9 and 3 kyr of the same archaeomagnetic field model suggest that a 3 kyr period is sufficiently long to reliably detect mantle control on core dynamics. This allows estimating an upper bound of 220–310 km for the magnetic boundary layer thickness below the CMB.

Description: Post-depositional reductive diagenesis usually results in partial or entire cleansing of the pristine palaeomagnetic signal, therefore, its intensity is important to be assessed for sediments that are in the purpose of retrieving palaeomagnetic information. Grain size, rock magnetic and geochemical studies on the entire core, along with scanning electron microscope observations and X-ray diffraction analyses for representative samples were carried out on a Holocene sediment core retrieved from the deep water part of Huguangyan maar lake (HGY), southeast China. The pristine magnetic mineral assemblage of the studied core is domianted by superparamagnetic (SP) and stable single domain titanomagnetite, and high coercivity minerals are not detectable. Based on down-core variations of the average grain size ( M Z ), total organic carbon (TOC), detrital elements (Al, Ti, Fe and Mn) and the concentration and mineralogy of magnetic minerals, the studied core could be divided into three subsections. The uppermost subsection is the least affected by diagenesis, with detrital titanomagnetite as the dominant magnetic mineral. This is owing to low TOC contents, but high detrital input generated by weak Asian summer monsoon intensity during the late Holocene. The intermediate subsection shows down-core progressively enhanced dissolution of detrital titanomagnetite, and concomitant formation of authigenic pyrite and siderite, which indicates down-core progressively enhanced diagenesis generated by down-core progressive increasing TOC content, but decreasing detrital input as the result of down-core progressively strengthened Asian summer monsoon intensity. The pristine magnetic mineral assemblage has been profoundly modified in the lowermost subsection. At certain positions of the lowermost subsection, detrital titanomagnetite has been even completely dissolved via diagenesis, giving place to authigenic pyrite and siderite. High TOC content, but low detrital input generated from strong Asian summer monsoon intensity during the early Holocene are accountable for intensive diagenesis in the lowermost subsection. Complete erasing of detrital magnetic input signal at certain positions of the lowermost subsection, and considerable formation of authigenic siderite indicate that palaeomagnetic records of the studied core have been significantly compromised. The studied core has relatively higher TOC content, lower detrital matter content, calmer sedimentary environments, and less DO available at its water–sediment interface than the cores retrieved at relatively shallower water depths, which all contribute to its relatively stronger diagenesis. Progressive thickening of the upper two subsections with increasing water depth is owing to progressive increase in sedimentation rate with increasing water depth, which is the key factor in determining the thickness of each diagenetic subsection of cores from HGY. It would be better that lake sediments for palaeomagnetic investigations collected at a water depth shallower than the depth of its thermocline.

Description: Assigning cancer patients to the most effective treatments requires an understanding of the molecular basis of their disease. While DNA-based molecular profiling approaches have flourished over the past several years to transform our understanding of driver pathways across a broad range of tumors, a systematic characterization of key driver pathways based on RNA data has not been undertaken. Here we introduce a new approach for predicting the status of driver cancer pathways based on signature functions derived from RNA sequencing data. To identify the driver cancer pathways of interest, we mined DNA variant data from TCGA and nominated driver alterations in seven major cancer pathways in breast, ovarian and colon cancer tumors. The activation status of these driver pathways were then characterized using RNA sequencing data by constructing classification signature functions in training datasets and then testing the accuracy of the signatures in test datasets. The signature functions differentiate well tumors with nominated pathway activation from tumors with no signs of activation: average AUC equals to 0.83. Our results confirm that driver genomic alterations are distinctively displayed at the transcriptional level and that the transcriptional signatures can generally provide an alternative to DNA sequencing methods in detecting specific driver pathways.

Description: Modeling the properties and functions of DNA sequences is an important, but challenging task in the broad field of genomics. This task is particularly difficult for non-coding DNA, the vast majority of which is still poorly understood in terms of function. A powerful predictive model for the function of non-coding DNA can have enormous benefit for both basic science and translational research because over 98% of the human genome is non-coding and 93% of disease-associated variants lie in these regions. To address this need, we propose DanQ, a novel hybrid convolutional and bi-directional long short-term memory recurrent neural network framework for predicting non-coding function de novo from sequence. In the DanQ model, the convolution layer captures regulatory motifs, while the recurrent layer captures long-term dependencies between the motifs in order to learn a regulatory ‘grammar’ to improve predictions. DanQ improves considerably upon other models across several metrics. For some regulatory markers, DanQ can achieve over a 50% relative improvement in the area under the precision-recall curve metric compared to related models. We have made the source code available at the github repository http://github.com/uci-cbcl/DanQ .

Description: Molecular sequences in public databases are mostly annotated by the submitting authors without further validation. This procedure can generate erroneous taxonomic sequence labels. Mislabeled sequences are hard to identify, and they can induce downstream errors because new sequences are typically annotated using existing ones. Furthermore, taxonomic mislabelings in reference sequence databases can bias metagenetic studies which rely on the taxonomy. Despite significant efforts to improve the quality of taxonomic annotations, the curation rate is low because of the labor-intensive manual curation process. Here, we present SATIVA, a phylogeny-aware method to automatically identify taxonomically mislabeled sequences (‘mislabels’) using statistical models of evolution. We use the Evolutionary Placement Algorithm (EPA) to detect and score sequences whose taxonomic annotation is not supported by the underlying phylogenetic signal, and automatically propose a corrected taxonomic classification for those. Using simulated data, we show that our method attains high accuracy for identification (96.9% sensitivity/91.7% precision) as well as correction (94.9% sensitivity/89.9% precision) of mislabels. Furthermore, an analysis of four widely used microbial 16S reference databases (Greengenes, LTP, RDP and SILVA) indicates that they currently contain between 0.2% and 2.5% mislabels. Finally, we use SATIVA to perform an in-depth evaluation of alternative taxonomies for Cyanobacteria. SATIVA is freely available at https://github.com/amkozlov/sativa .

Description: DNA microarrays and RNAseq are complementary methods for studying RNA molecules. Current computational methods to determine alternative exon usage (AEU) using such data require impractical visual inspection and still yield high false-positive rates. Integrated Gene and Exon Model of Splicing (iGEMS) adapts a gene-level residuals model with a gene size adjusted false discovery rate and exon-level analysis to circumvent these limitations. iGEMS was applied to two new DNA microarray datasets, including the high coverage Human Transcriptome Arrays 2.0 and performance was validated using RT-qPCR. First, AEU was studied in adipocytes treated with ( n = 9) or without ( n = 8) the anti-diabetes drug, rosiglitazone. iGEMS identified 555 genes with AEU, and robust verification by RT-qPCR (~90%). Second, in a three-way human tissue comparison (muscle, adipose and blood, n = 41) iGEMS identified 4421 genes with at least one AEU event, with excellent RT-qPCR verification (95%, n = 22). Importantly, iGEMS identified a variety of AEU events, including 3'UTR extension, as well as exon inclusion/exclusion impacting on protein kinase and extracellular matrix domains. In conclusion, iGEMS is a robust method for identification of AEU while the variety of exon usage between human tissues is 5–10 times more prevalent than reported by the Genotype-Tissue Expression consortium using RNA sequencing.

Description: The rocks in the crust and the upper mantle of the Earth are believed to exhibit electrical anisotropy to some extent. It is beneficial to further understand and recognize the propagation of the electromagnetic waves in the Earth by investigating the magnetotelluric (which is one of the main geophysical techniques to probe the deep structures in the Earth) responses of the media with anisotropic conductivity structures. In this study, we examine the magnetotelluric fields over an idealized 2-D model consisting of two segments with axially anisotropic conductivity structures overlying a perfect conductor basement by a quasi-static analytic approach. The resulting analytic solution could not only contribute to the electromagnetic induction theory in the anisotropic Earth but also serve as at least an initial standard solution which could be used to validate the reliability and accuracy of the numerical algorithms developed for modelling the magnetotelluric responses of the 2-D media with much more general anisotropic conductivity.

Description: Several works have reported that haematite has non-linear initial susceptibility at room temperature, like pyrrhotite or titanomagnetite, but there is no explanation for the observed behaviours yet. This study sets out to determine which physical property (grain size, foreign cations content and domain walls displacements) controls the initial susceptibility. The performed measurements include microprobe analysis to determine magnetic phases different to haematite; initial susceptibility (300 K); hysteresis loops, SIRM and backfield curves at 77 and 300 K to calculate magnetic parameters and minor loops at 77 K, to analyse initial susceptibility and magnetization behaviours below Morin transition. The magnetic moment study at low temperature is completed with measurements of zero field cooled–field cooled and AC susceptibility in a range from 5 to 300 K. The minor loops show that the non-linearity of initial susceptibility is closely related to Barkhausen jumps. Because of initial magnetic susceptibility is controlled by domain structure it is difficult to establish a mathematical model to separate magnetic subfabrics in haematite-bearing rocks.

Description: The Cancer Genome Atlas (TCGA) research network has made public a large collection of clinical and molecular phenotypes of more than 10 000 tumor patients across 33 different tumor types. Using this cohort, TCGA has published over 20 marker papers detailing the genomic and epigenomic alterations associated with these tumor types. Although many important discoveries have been made by TCGA's research network, opportunities still exist to implement novel methods, thereby elucidating new biological pathways and diagnostic markers. However, mining the TCGA data presents several bioinformatics challenges, such as data retrieval and integration with clinical data and other molecular data types (e.g. RNA and DNA methylation). We developed an R/Bioconductor package called TCGAbiolinks to address these challenges and offer bioinformatics solutions by using a guided workflow to allow users to query, download and perform integrative analyses of TCGA data. We combined methods from computer science and statistics into the pipeline and incorporated methodologies developed in previous TCGA marker studies and in our own group. Using four different TCGA tumor types (Kidney, Brain, Breast and Colon) as examples, we provide case studies to illustrate examples of reproducibility, integrative analysis and utilization of different Bioconductor packages to advance and accelerate novel discoveries.

Description: Single cell RNA-seq experiments provide valuable insight into cellular heterogeneity but suffer from low coverage, 3' bias and technical noise. These unique properties of single cell RNA-seq data make study of alternative splicing difficult, and thus most single cell studies have restricted analysis of transcriptome variation to the gene level. To address these limitations, we developed SingleSplice, which uses a statistical model to detect genes whose isoform usage shows biological variation significantly exceeding technical noise in a population of single cells. Importantly, SingleSplice is tailored to the unique demands of single cell analysis, detecting isoform usage differences without attempting to infer expression levels for full-length transcripts. Using data from spike-in transcripts, we found that our approach detects variation in isoform usage among single cells with high sensitivity and specificity. We also applied SingleSplice to data from mouse embryonic stem cells and discovered a set of genes that show significant biological variation in isoform usage across the set of cells. A subset of these isoform differences are linked to cell cycle stage, suggesting a novel connection between alternative splicing and the cell cycle.

Description: The recent super-exponential growth in the amount of sequencing data generated worldwide has put techniques for compressed storage into the focus. Most available solutions, however, are strictly tied to specific bioinformatics formats, sometimes inheriting from them suboptimal design choices; this hinders flexible and effective data sharing. Here, we present CARGO (Compressed ARchiving for GenOmics), a high-level framework to automatically generate software systems optimized for the compressed storage of arbitrary types of large genomic data collections. Straightforward applications of our approach to FASTQ and SAM archives require a few lines of code, produce solutions that match and sometimes outperform specialized format-tailored compressors and scale well to multi-TB datasets. All CARGO software components can be freely downloaded for academic and non-commercial use from http://bio-cargo.sourceforge.net .

Description: Phasing of single nucleotide (SNV), and structural variations into chromosome-wide haplotypes in humans has been challenging, and required either trio sequencing or restricting phasing to population-based haplotypes. Selvaraj et al . demonstrated single individual SNV phasing is possible with proximity ligated (HiC) sequencing. Here, we demonstrate HiC can phase structural variants into phased scaffolds of SNVs. Since HiC data is noisy, and SV calling is challenging, we applied a range of supervised classification techniques, including Support Vector Machines and Random Forest, to phase deletions. Our approach was demonstrated on deletion calls and phasings on the NA12878 human genome. We used three NA12878 chromosomes and simulated chromosomes to train model parameters. The remaining NA12878 chromosomes withheld from training were used to evaluate phasing accuracy. Random Forest had the highest accuracy and correctly phased 86% of the deletions with allele-specific read evidence. Allele-specific read evidence was found for 76% of the deletions. HiC provides significant read evidence for accurately phasing 33% of the deletions. Also, eight of eight top ranked deletions phased by only HiC were validated using long range polymerase chain reaction and Sanger. Thus, deletions from a single individual can be accurately phased using a combination of shotgun and proximity ligation sequencing. InPhaDel software is available at: http://l337x911.github.io/inphadel/.

Description: Many genomes display high levels of heterozygosity (i.e. presence of different alleles at the same loci in homologous chromosomes), being those of hybrid organisms an extreme such case. The assembly of highly heterozygous genomes from short sequencing reads is a challenging task because it is difficult to accurately recover the different haplotypes. When confronted with highly heterozygous genomes, the standard assembly process tends to collapse homozygous regions and reports heterozygous regions in alternative contigs. The boundaries between homozygous and heterozygous regions result in multiple assembly paths that are hard to resolve, which leads to highly fragmented assemblies with a total size larger than expected. This, in turn, causes numerous problems in downstream analyses such as fragmented gene models, wrong gene copy number, or broken synteny. To circumvent these caveats we have developed a pipeline that specifically deals with the assembly of heterozygous genomes by introducing a step to recognise and selectively remove alternative heterozygous contigs. We tested our pipeline on simulated and naturally-occurring heterozygous genomes and compared its accuracy to other existing tools. Our method is freely available at https://github.com/Gabaldonlab/redundans .

Description: A series of important geological events occurred in the Tibetan Plateau area during the Jurassic, such as the collision of the Lhasa and Qiangtang Terranes, the closure of the Meso-Tethyan Ocean, the opening of the Neo-Tethyan Ocean and the cessation of the mega-monsoon. The ~3000 m thick Jurassic sedimentary sequence in the Qiangtang Basin on the central Tibetan Plateau, which is called the Yanshiping (YSP) Group, recorded these geological events. However, the chronology of the sequence is surprisingly poorly constrained. Here, we perform a detailed palaeomagnetic analysis on the ~1060 m thick middle and upper portions of the YSP Group (the Xiali and Suowa Formations) in the YSP section of the eastern Qiangtang Basin. Three bivalve zones at stratigraphic intervals of ~40–140, 640–800 and 940–1040 m are identified, which yield a Bathonian–Callovian age for the Lower Xiali Fm., a Callovian–Oxfordian age for the Lower Suowa Fm. and an Oxfordian–Kimmeridgian age for the Upper Suowa Fm. A total of 544 oriented palaeomagnetic samples were collected from the section. By combining thermal and alternating field demagnetizations, clear characteristic remanent magnetization (ChRM) directions are isolated for most of the samples. The robust ChRM directions pass fold and reversals tests, which support the primary nature of the ChRMs and yield a palaeopole at 76.8°N/297.2°E (dp = 2.2°, dm = 3.7°). A total of 27 normal and 26 reversed polarity zones were successfully recorded in the section. Combined with fossil age constraints, results suggest that the section is plausibly composed of a Callovian-Early Kimmeridgian age sedimentary sequence.

Description: Tandem repeats (TRs) are often present in proteins with crucial functions, responsible for resistance, pathogenicity and associated with infectious or neurodegenerative diseases. This motivates numerous studies of TRs and their evolution, requiring accurate multiple sequence alignment. TRs may be lost or inserted at any position of a TR region by replication slippage or recombination, but current methods assume fixed unit boundaries, and yet are of high complexity. We present a new global graph-based alignment method that does not restrict TR unit indels by unit boundaries. TR indels are modeled separately and penalized using the phylogeny-aware alignment algorithm. This ensures enhanced accuracy of reconstructed alignments, disentangling TRs and measuring indel events and rates in a biologically meaningful way. Our method detects not only duplication events but also all changes in TR regions owing to recombination, strand slippage and other events inserting or deleting TR units. We evaluate our method by simulation incorporating TR evolution, by either sampling TRs from a profile hidden Markov model or by mimicking strand slippage with duplications. The new method is illustrated on a family of type III effectors, a pathogenicity determinant in agriculturally important bacteria Ralstonia solanacearum. We show that TR indel rate variation contributes to the diversification of this protein family.

Description: The introduction of next generation sequencing methods in genome studies has made it possible to shift research from a gene-centric approach to a genome wide view. Although methods and tools to detect single nucleotide polymorphisms are becoming more mature, methods to identify and visualize structural variation (SV) are still in their infancy. Most genome browsers can only compare a given sequence to a reference genome; therefore, direct comparison of multiple individuals still remains a challenge. Therefore, the implementation of efficient approaches to explore and visualize SVs and directly compare two or more individuals is desirable. In this article, we present a visualization approach that uses space-filling Hilbert curves to explore SVs based on both read-depth and pair-end information. An interactive open-source Java application, called Meander , implements the proposed methodology, and its functionality is demonstrated using two cases. With Meander , users can explore variations at different levels of resolution and simultaneously compare up to four different individuals against a common reference. The application was developed using Java version 1.6 and Processing.org and can be run on any platform. It can be found at http://homes.esat.kuleuven.be/~bioiuser/meander .

Description: This study investigates pressure effects on the magnetic properties of non-interacting single-domain (SD) magnetite. Using a high-pressure cell specially designed for a Magnetic Property Measurement System, magnetic hysteresis measurements were conducted under high pressures of up to 1 GPa on natural plagioclase crystals containing much acicular SD magnetite. Coercivity and saturation magnetization were nearly constant with pressure, while saturation remanent magnetization and coercivity of remanence decreased with pressure at moderate rates of –8 per cent GPa –1 and –18 per cent GPa –1 , respectively. These results suggest that temperature effects govern the magnetic behaviour of acicular SD magnetite grains in the middle and lower crusts.

Description: Inversion polymorphisms have important phenotypic and evolutionary consequences in humans. Two different methodologies have been used to infer inversions from SNP dense data, enabling the use of large cohorts for their study. One approach relies on the differences in linkage disequilibrium across breakpoints; the other one captures the internal haplotype groups that tag the inversion status of chromosomes. In this article, we assessed the convergence of the two methods in the detection of 20 human inversions that have been reported in the literature. The methods converged in four inversions including inv-8p23, for which we studied its association with low-BMI in American children. Using a novel haplotype tagging method with control on inversion ancestry, we computed the frequency of inv-8p23 in two American cohorts and observed inversion haplotype admixture. Accounting for haplotype ancestry, we found that the European inverted allele in children carries a recessive risk of underweight, validated in an independent Spanish cohort (combined: OR= 2.00, P = 0.001). While the footprints of inversions on SNP data are complex, we show that systematic analyses, such as convergence of different methods and controlling for ancestry, can reveal the contribution of inversions to the ancestral composition of populations and to the heritability of human disease.

Description: The Metabolic Models Reconstruction Using Genome-Scale Information ( merlin ) tool is a user-friendly Java application that aids the reconstruction of genome-scale metabolic models for any organism that has its genome sequenced. It performs the major steps of the reconstruction process, including the functional genomic annotation of the whole genome and subsequent construction of the portfolio of reactions. Moreover, merlin includes tools for the identification and annotation of genes encoding transport proteins, generating the transport reactions for those carriers. It also performs the compartmentalisation of the model, predicting the organelle localisation of the proteins encoded in the genome and thus the localisation of the metabolites involved in the reactions promoted by such enzymes. The gene-proteins-reactions (GPR) associations are automatically generated and included in the model. Finally, merlin expedites the transition from genomic data to draft metabolic models reconstructions exported in the SBML standard format, allowing the user to have a preliminary view of the biochemical network, which can be manually curated within the environment provided by merlin .

Description: For eukaryotic cells, the biological processes involving regulatory DNA elements play an important role in cell cycle. Understanding 3D spatial arrangements of chromosomes and revealing long-range chromatin interactions are critical to decipher these biological processes. In recent years, chromosome conformation capture (3C) related techniques have been developed to measure the interaction frequencies between long-range genome loci, which have provided a great opportunity to decode the 3D organization of the genome. In this paper, we develop a new Bayesian framework to derive the 3D architecture of a chromosome from 3C-based data. By modeling each chromosome as a polymer chain, we define the conformational energy based on our current knowledge on polymer physics and use it as prior information in the Bayesian framework. We also propose an expectation-maximization (EM) based algorithm to estimate the unknown parameters of the Bayesian model and infer an ensemble of chromatin structures based on interaction frequency data. We have validated our Bayesian inference approach through cross-validation and verified the computed chromatin conformations using the geometric constraints derived from fluorescence in situ hybridization (FISH) experiments. We have further confirmed the inferred chromatin structures using the known genetic interactions derived from other studies in the literature. Our test results have indicated that our Bayesian framework can compute an accurate ensemble of 3D chromatin conformations that best interpret the distance constraints derived from 3C-based data and also agree with other sources of geometric constraints derived from experimental evidence in the previous studies. The source code of our approach can be found in https://github.com/wangsy11/InfMod3DGen .

Description: Characterization of cell type specific regulatory networks and elements is a major challenge in genomics, and emerging strategies frequently employ high-throughput genome-wide assays of transcription factor (TF) to DNA binding, histone modifications or chromatin state. However, these experiments remain too difficult/expensive for many laboratories to apply comprehensively to their system of interest. Here, we explore the potential of elucidating regulatory systems in varied cell types using computational techniques that rely on only data of gene expression, low-resolution chromatin accessibility, and TF–DNA binding specificities (‘motifs’). We show that static computational motif scans overlaid with chromatin accessibility data reasonably approximate experimentally measured TF–DNA binding. We demonstrate that predicted binding profiles and expression patterns of hundreds of TFs are sufficient to identify major regulators of ~200 spatiotemporal expression domains in the Drosophila embryo. We are then able to learn reliable statistical models of enhancer activity for over 70 expression domains and apply those models to annotate domain specific enhancers genome-wide. Throughout this work, we apply our motif and accessibility based approach to comprehensively characterize the regulatory network of fruitfly embryonic development and show that the accuracy of our computational method compares favorably to approaches that rely on data from many experimental assays.

Description: Characterization of geomagnetic field behaviour on timescales of centuries to millennia is necessary to understand the mechanisms that sustain the geodynamo and drive its evolution. As Holocene paleomagnetic and archeomagnetic data have become more abundant, strategies for regularized inversion of modern field data have been adapted to produce numerous time-varying global field models. We evaluate the effectiveness of several approaches to inversion and data handling, by assessing both global and regional properties of the resulting models. Global Holocene field models cannot resolve Southern hemisphere regional field variations without the use of sediments. A standard data set is used to construct multiple models using two different strategies for relative paleointensity calibration and declination orientation and a selection of starting models in the inversion procedure. When data uncertainties are considered, the results are similar overall regardless of whether we use iterative calibration and reorientation, or co-estimation of the calibration and orientation parameters as part of the inversion procedure. In each case the quality of the starting model used for initial relative paleointensity calibration and declination orientation is crucial and must be based on the best absolute information available. Without adequate initial calibration the morphology of dipole moment variations can be recovered but its absolute value will be correlated with the initial intensity calibrations, an effect that might be mitigated by ensuring an appropriate fit to enough high quality absolute intensity data with low uncertainties. The declination reorientation mainly impacts regional field structure and in the presence of non-zonal fields will result in a non-zero local average. The importance of declination orientation is highlighted by inconsistencies in the West Pacific and Australian sediment records in CALS10k.1b model. Great care must also be taken to assess uncertainties associated with both paleomagnetic and age data and to evaluate the effects of poor data distribution. New consistently allocated uncertainty estimates for sediment paleomagnetic records highlight the importance of adequate uncertainties in the inversion process, as they determine the relative weighting among the data and overall normalized misfit levels which in turn influence the complexity of the inferred field models. Residual distributions suggest that the most appropriate misfit measure is the L 1 norm (minimum absolute deviation) rather than L 2 (least squares), but this seems to have relatively minor impact on the overall results. For future Holocene field modelling we see a need for comprehensive methods to assess uncertainty in individual archeomagnetic data so that these data or models derived from them can be used for reliable initial relative paleointensity calibration and declination orientation in sediments. More work will be needed to assess whether co-estimation or an iterative approach to inversion is more efficient overall. This would be facilitated by realistic and globally consistent data and age uncertainties from the paleomagnetic community.

Description: Galvanic distortion of magnetotelluric (MT) data due to small-scale surficial bodies or due to topography is one of the major factors that prevents accurate imaging of the subsurface. We present a 3-D algorithm for joint inversion of MT impedance tensor data and a frequency-independent full distortion matrix that circumvents this problem. We perform several tests of our algorithm on synthetic data affected by different amounts of distortion. These tests show that joint inversion leads to a better conductivity model compared to the inversion of the MT impedance tensor without any correction for distortion effects. For highly distorted data, inversion without any distortion correction results in strong artefacts and we cannot fit the data to the specified noise level. When the distortion is reduced, we can fit the data to an RMS of one, but still observe artefacts in the shallow part of the model. In contrast, in both cases our joint inversion can fit the data within the assumed noise level and the resulting models are comparable to the inversion of undistorted data. In addition, we show that the elements of the full distortion matrix can be well resolved by our algorithm. Finally, when inverting undistorted data, including the distortion matrix in the inversion only results in a minor loss of resolution. We therefore consider our new approach a promising tool for the general analysis of field MT data.

Description: The magnetic field that originates in the earth's core is transformed across the electrically conducting mantle before being observed, at the earth's surface or above. Assuming that the conductivity depends only on radius, it has been customary to treat the mantle as a linear time-invariant filter for the core magnetic field, with properties (as a function of the frequency ) specified by the transfer function (). An high-frequency approximation to (), which is derived from a three terms WKBJ expansion with –1/2 as small parameter, is found here to reproduce adequately, for low harmonic degrees and/or thin conducting layers, the exact solution, which is evaluated numerically. It is contrasted with the low-frequency estimation of , which consists in a perturbation procedure and in writing () as a series in powers of ( -〉 0). The low-frequency theory is applied to the magnetic variations produced by the geostrophic core flows with about 6 yr period as the phase of these flows is independently determined from their effect on the length of the day. Apart from that, the low-frequency approximation overestimates the screening by the mantle of high-frequency signals, especially the low harmonic degree ones. In practice, the attenuating factor defined from the O ( 2 ) term in the expansion of as -〉 0 cannot be retrieved from analyses of geomagnetic time-series. Application of the mantle filter theory hinges on our knowledge about the time spectrum of the magnetic field at the core surface. The low-frequency theory had been previously applied to observatory series on the assumption that geomagnetic jerks occurring in the core are rare and isolated events. Rather than following up these earlier studies, I note that the spectral density function for the second time derivative of the main magnetic field coefficients is approximately independent of in a frequency range for which the mantle has undoubtedly negligible influence. In the absence of any other information, this scaling law is extrapolated to higher frequencies.

Description: Surface nuclear magnetic resonance (surface-NMR) is a promising technique for exploring shallow subsurface aquifer structures. Surface-NMR can be applied in environments that are characterized as a 1-D layered Earth. The technique utilizes a single loop and is referred to as magnetic resonance sounding. The technique referred to as magnetic resonance tomography (MRT) allows complex 2-D aquifer structures to be explored. Currently, MRT requires multiple loops and a roll along measurement scheme, which causes long survey time. We propose a loop layout using an elongated transmitter and an in-loop receiver arrays (ETRA) to conduct a 2-D survey with just one measurement. We present a comprehensive comparison between the new layout and the common approaches based on sensitivity and resolution analyses and show synthetic and field data. The results show that ETRA generates subsurface images at sufficient resolution with significantly lower survey times than other loop layouts.

Description: A new functional gene database, FOAM (Functional Ontology Assignments for Metagenomes), was developed to screen environmental metagenomic sequence datasets. FOAM provides a new functional ontology dedicated to classify gene functions relevant to environmental microorganisms based on Hidden Markov Models (HMMs). Sets of aligned protein sequences (i.e. ‘profiles’) were tailored to a large group of target KEGG Orthologs (KOs) from which HMMs were trained. The alignments were checked and curated to make them specific to the targeted KO. Within this process, sequence profiles were enriched with the most abundant sequences available to maximize the yield of accurate classifier models. An associated functional ontology was built to describe the functional groups and hierarchy. FOAM allows the user to select the target search space before HMM-based comparison steps and to easily organize the results into different functional categories and subcategories. FOAM is publicly available at http://portal.nersc.gov/project/m1317/FOAM/ .

Description: We studied ionospheric responses to the 2012 April 11 M w 8.6 North Sumatra earthquake using total electron content (TEC) measurements with the regional Global Navigation Satellite System network. This earthquake ruptured the oceanic lithosphere off the Indian Ocean coast of North Sumatra, and is known as the largest strike-slip earthquake ever recorded. Coseismic ionospheric disturbances (CIDs) with rapid TEC enhancement of a few TEC units propagated northward with a speed of acoustic waves (~1 km s –1 ). Resonant atmospheric oscillation with a frequency ~4 mHz have been found as monochromatic oscillation of TEC lasting for an hour after the main shock and the largest aftershock. We compared CID amplitudes of 21 earthquakes world-wide with moment magnitudes ( M w ) 6.6–9.2. They roughly obeyed a law such that CID amplitude increases by two orders of magnitude for the M w increase of three. The 2012 North Sumatra earthquakes slightly deviated negatively from the trend possibly reflecting their strike-slip mechanisms, that is small vertical crustal movements for their magnitudes.

Description: The magnetic field of the Earth's lithosphere arises from rock magnetization contrasts that were shaped over geological times. The field can be described mathematically in spherical harmonics or with distributions of magnetization. We exploit this dual representation and assume that the lithospheric field is induced by spatially varying susceptibility values within a shell of constant thickness. By introducing a statistical assumption about the power spectrum of the susceptibility, we then derive a statistical expression for the spatial power spectrum of the crustal magnetic field for the spatial scales ranging from 60 to 2500 km. This expression depends on the mean induced magnetization, the thickness of the shell, and a power law exponent for the power spectrum of the susceptibility. We test the relevance of this form with a misfit analysis to the observational NGDC-720 lithospheric magnetic field model power spectrum. This allows us to estimate a mean global apparent induced magnetization value between 0.3 and 0.6 A m –1 , a mean magnetic crustal thickness value between 23 and 30 km, and a root mean square for the field value between 190 and 205 nT at 95 per cent. These estimates are in good agreement with independent models of the crustal magnetization and of the seismic crustal thickness. We carry out the same analysis in the continental and oceanic domains separately. We complement the misfit analyses with a Kolmogorov–Smirnov goodness-of-fit test and we conclude that the observed power spectrum can be each time a sample of the statistical one.

Description: Data on the evolution of Earth's magnetic field intensity are important for understanding the geodynamo and planetary evolution. However, the paleomagnetic record in rocks may be adversely affected by many physical processes, which must be taken into account when analysing the palaeointensity database. This is especially important in the light of an ongoing debate regarding core thermal conductivity values, and how these relate to the Precambrian geodynamo. Here, we demonstrate that several data sets in the Precambrian palaeointensity database overestimate the true paleofield strength due to the presence of non-ideal carriers of palaeointensity signals and/or viscous re-magnetizations. When the palaeointensity overestimates are removed, the Precambrian database does not indicate a robust change in geomagnetic field intensity during the Mesoproterozoic. These findings call into question the recent claim that the solid inner core formed in the Mesoproterozoic, hence constraining the thermal conductivity in the core to ‘moderate’ values. Instead, our analyses indicate that the presently available palaeointensity data are insufficient in number and quality to constrain the timing of solid inner core formation, or the outstanding problem of core thermal conductivity. Very young or very old inner core ages (and attendant high or low core thermal conductivity values) are consistent with the presently known history of Earth's field strength. More promising available data sets that reflect long-term core structure are geomagnetic reversal rate and field morphology. The latter suggests changes that may reflect differences in Archean to Proterozoic core stratification, whereas the former suggest an interval of geodynamo hyperactivity at ca. 550 Ma.

Description: Red Clay underlying the loess-palaeosol sequences on the Chinese Loess Plateau is an eolian deposit. There is a controversy over whether magnetic susceptibility ( ) variations in Red Clay sequence can be used as an indicator of summer palaeomonsoon intensity. This study investigates the magnetic mineralogy, magnetic concentration and magnetic grain size distribution of Jiaxian Red Clay with multimagnetic methods. Our results indicate that the magnetic properties of Jiaxian Red Clay are similar to those of the Quaternary loess-palaeosol sequences, and ultrafine ferrimagnetic grains produced during pedogenesis are responsible for an increase in susceptibility, therefore the enhancement mechanism of Red Clay is similar to that of the overlying loess-palaeosol sequences. This paper explores variations in the Red Clay sequence through spatial and temporal analysis. The susceptibility variation of six sites along a NNE to SSW transect correlate to palaeoclimatic cycles, so can be used to trace the summer palaeomonsoon intensity from a spatial perspective. However, a simple loess-derived calibration function cannot be used to quantitative reconstruct the palaeomonsoon intensity variations thought time. An adjusted calibration function for palaeosols from Red Clay sequence needs to be developed, so that can be used to quantitative reconstruct palaeomonsoon intensity. Further study is necessary to develop such a transfer function.

Description: Palaeointensity experiments were carried out to a sample collection from two sections of basalt lava flow sequences of Pliocene age in north central Iceland (Chron C2An) to further refine the knowledge of the behaviour of the palaeomagnetic field. Selection of samples was mainly based on their stability of remanence to thermal demagnetization as well as good reversibility in variations of magnetic susceptibility and saturation magnetization with temperature, which would indicate the presence of magnetite as a product of deuteric oxidation of titanomagnetite. Among 167 lava flows from two sections, 44 flows were selected for the Königsberger–Thellier–Thellier experiment in vacuum. In spite of careful pre-selection of samples, an Arai plot with two linear segments, or a concave-up appearance, was often encountered during the experiments. This non-ideal behaviour was probably caused by an irreversible change in the domain state of the magnetic grains of the pseudo-single-domain (PSD) range. This is assumed because an ideal linear plot was obtained in the second run of the palaeointensity experiment in which a laboratory thermoremanence acquired after the final step of the first run was used as a natural remanence. This experiment was conducted on six selected samples, and no clear difference between the magnetic grains of the experimented and pristine sister samples was found by scanning electron microscope and hysteresis measurements, that is, no occurrence of notable chemical/mineralogical alteration, suggesting that no change in the grain size distribution had occurred. Hence, the two-segment Arai plot was not caused by the reversible multidomain/PSD effect in which the curvature of the Arai plot is dependent on the grain size. Considering that the irreversible change in domain state must have affected data points at not only high temperatures but also low temperatures, f v ≥ 0.5 was adopted as one of the acceptance criteria where f v is a vectorially defined fraction of the linear segment. A measure of curvature k ' was also used to check the linearity of the selected linear segment. It was avoided, however, to reject the result out of hand by the large curvature k of the entire data points because it might still include a linear segment with a large fraction. Combining with the results of Shaw's experiments, 52 palaeointensities were obtained out of 192 specimens, or 11 flow means were obtained out of the 44 lava flows. Most of the palaeointensities were from the upper part of the lava section (Chron C2An.1n) and ranged between 30 and 66 μT. Including two results from the bottom part of the lava section, the mean virtual dipole moment for 2.5–3.5 Ma is 6.3 ± 1.4  x  10 22 Am 2 ( N  = 11), which is ~19 per cent smaller than the present-day dipole moment.

Description: The sedimentary sequence deposited during the deglaciation phase following the last glacial maximum in the Storfjorden trough, on the northwestern Barents Sea south of Svalbard, was sampled with 10 piston and gravity cores during the SVAIS and EGLACOM cruises. Three cores (SV-02, SV-03 and SV-05) collected on the upper continental slope are characterized by a thin (20–40 cm) Holocene interval and a thick (up to 4.5 m in core SV-03) late Pleistocene sequence of finely laminated fine-grained sediments that have been interpreted as plumites deposited during the Melt Water Pulse 1a (MWP-1a). Radiocarbon ages obtained at the top and bottom of this stratigraphic interval revealed that deposition occurred during less than two centuries at around 15 ka ago, with a very high sedimentary rate exceeding 3 cm a –1 . We studied the palaeomagnetic and rock magnetic properties of this interval, by taking magnetic measurements at 1 cm spacing on u-channel samples collected from the three cores. The data show that this sequence is characterized by good palaeomagnetic properties and the palaeomagnetic and rock magnetic trends may be correlated at high resolution from core to core. The obtained palaeomagnetic data therefore offer the unique opportunity to investigate in detail the rate of geomagnetic palaeosecular variation (PSV) in the high northern latitudes at a decadal scale. Notwithstanding the palaeomagnetic trends of the three cores may be closely matched, the amplitude of directional PSV and the consequent virtual geomagnetic pole (VGP) scatter (S) is distinctly higher in one core (SV-05) than in the other two cores (SV-02 and SV-03). This might result from a variable proportion of two distinct populations of magnetic minerals in core SV-05, as suggested by the variable tendency to acquire a gyromagnetic remanent magnetization at high fields during the AF demagnetization treatment. For the plumite interval of cores SV-02 and SV-03, where the magnetic mineralogy is uniform and magnetite is the main magnetic carrier, a S value of about 9° is obtained. We consider this value as a reliable approximation of palaeomagnetic secular variation at a latitude of 75°N over a time interval spanning a couple of centuries around 15 ka ago.

Description: A recent study of the Matuyama–Brunhes (M-B) geomagnetic field reversal recorded in exposed lacustrine sediments from the Sulmona Basin (Italy) provided a continuous, high-resolution record indicating that the reversal of the field direction at the terminus of the M-B boundary (MBB) occurred in less than a century, about 786 ka ago. In the sediment, thin (4–6 cm) remagnetized horizons were recognized above two distinct tephra layers—SUL2-19 and SUL2-20—that occur ~25 and ~35 cm below the MBB, respectively. Also, a faint, millimetre-thick tephra (SUL2-18) occurs 2–3 cm above the MBB. With the aim of improving the temporal resolution of the previous Sulmona MBB record and understanding the possible influence of cryptotephra on the M-B record in the Sulmona Basin, we performed more detailed sampling and analyses of overlapping standard and smaller samples from a 50 cm-long block that spans the MBB. The new data indicate that (i) the MBB is even sharper than previously reported and occurs ~2.5 cm below tephra SUL2-18, in agreement with the previous study; (ii) the MBB coincides with the rise of an intensity peak of the natural remanent magnetization (NRM) intensity, which extends across SUL2-18; (iii) except for a 2-cm-thick interval just above tephra SUL2-18, the rock magnetic parameters ( k , ARM, M r , M s , B c , B cr ) indicate exactly the same magnetic mineralogy throughout the sampled sequence. We conclude that either SUL2-18 resulted in the remagnetization of an interval of about 6 cm (i.e. during the NRM intensity peak spanning ~260 ± 110 yr, according to the estimated local sedimentation rate), and thus the detailed MBB record is lost because it is overprinted, or the MBB is well recorded, occurred abruptly about 2.5 cm below SUL2-18 and lasted less than 13 ± 6 yr. Both hypotheses challenge our understanding of the geomagnetic field behaviour during a polarity transition and/or of the NRM acquisition process in the Sulmona lacustrine sediment.

Description: We test the ability of large-scale velocity fields inferred from geomagnetic secular variation data to produce the global magnetic field of the Earth. Our kinematic dynamo calculations use quasi-geostrophic (QG) flows inverted from geomagnetic field models which, as such, incorporate flow structures that are Earth-like and may be important for the geodynamo. Furthermore, the QG hypothesis allows straightforward prolongation of the flow from the core surface to the bulk. As expected from previous studies, we check that a simple QG flow is not able to sustain the magnetic field against ohmic decay. Additional complexity is then introduced in the flow, inspired by the action of the Lorentz force. Indeed, on centennial timescales, the Lorentz force can balance the Coriolis force and strict quasi-geostrophy may not be the best ansatz. When our columnar flow is modified to account for the action of the Lorentz force, magnetic field is generated for Elsasser numbers larger than 0.25 and magnetic Reynolds numbers larger than 100. This suggests that our large-scale flow captures the relevant features for the generation of the Earth's magnetic field and that the invisible small-scale flow may not be directly involved in this process. Near the threshold, the resulting magnetic field is dominated by an axial dipole, with some reversed flux patches. Time dependence is also considered, derived from principal component analysis applied to the inverted flows. We find that time periods from 120 to 50 yr do not affect the mean growth rate of the kinematic dynamos. Finally, we note that the footprint of the inner core in the magnetic field generated deep in the bulk of the shell, although we did not include one in our computations.

Description: The Auca Mahuida volcano (2.03–0.88 Ma) located east of the Andean thrust front in the Neuquén basin (Argentina) hosts an oil system of thermogenic origin and is affected by the NW–SE striking-faults. Intrusive bodies and the underlying Jurassic sediments constitute the reservoir rocks. Aeromagnetic data collected in the Auca Mahuida area detected multiple dipolar magnetic anomalies, many of which have reverse polarity. Palaeomagnetic measurements on rock samples collected in the field together with available age determinations indicate that the reversely magnetized sources were mainly emplaced during the Matuyama reverse polarity chron while the normal polarity sources were emplaced during the Olduvai and/or Jaramillo subchrons. The location and geometry of the intrusive bodies is poorly known and the customary magnetic inversion is rendered difficult because of multiple natural remanent magnetization directions. To address these difficulties, a voxel inversion was applied to model the vector residual magnetic intensity (VRMI) transformation of the observed total magnetic intensity data. The modelling showed a 1.5 km deep, subcircular ring-shaped intrusion below the summit of the volcano and a series of NW–SE elongated, fault-controlled intrusive bodies to depths up to 3–4 km. Our results show that magnetic data and VRMI modelling help resolve the geometry of the shallow plumbing system of volcanoes with remanently magnetized sources, and estimate the depth and geometry of potential oil reservoirs in volcanic areas.

Description: Much of the inter-individual variation in gene expression is triggered via perturbations of signaling networks by DNA variants. We present a novel probabilistic approach for identifying the particular pathways by which DNA variants perturb the signaling network. Our procedure, called PINE, relies on a systematic integration of established biological knowledge of signaling networks with data on transcriptional responses to various experimental conditions. Unlike previous approaches, PINE provides statistical aspects that are critical for prioritizing hypotheses for followup experiments. Using simulated data, we show that higher accuracy is attained with PINE than with existing methods. We used PINE to analyze transcriptional responses of immune dendritic cells to several pathogenic stimulations. PINE identified statistically significant genetic perturbations in the pathogen-sensing signaling network, suggesting previously uncharacterized regulatory mechanisms for functional DNA variants.

Description: Variations in sample quality are frequently encountered in small RNA-sequencing experiments, and pose a major challenge in a differential expression analysis. Removal of high variation samples reduces noise, but at a cost of reducing power, thus limiting our ability to detect biologically meaningful changes. Similarly, retaining these samples in the analysis may not reveal any statistically significant changes due to the higher noise level. A compromise is to use all available data, but to down-weight the observations from more variable samples. We describe a statistical approach that facilitates this by modelling heterogeneity at both the sample and observational levels as part of the differential expression analysis. At the sample level this is achieved by fitting a log-linear variance model that includes common sample-specific or group-specific parameters that are shared between genes. The estimated sample variance factors are then converted to weights and combined with observational level weights obtained from the mean–variance relationship of the log-counts-per-million using ‘voom’. A comprehensive analysis involving both simulations and experimental RNA-sequencing data demonstrates that this strategy leads to a universally more powerful analysis and fewer false discoveries when compared to conventional approaches. This methodology has wide application and is implemented in the open-source ‘limma’ package.

Description: Most mammalian genes have mRNA variants due to alternative promoter usage, alternative splicing, and alternative cleavage and polyadenylation. Expression of alternative RNA isoforms has been found to be associated with tumorigenesis, proliferation and differentiation. Detection of condition-associated transcription variation requires association methods. Traditional association methods such as Pearson chi-square test and Fisher Exact test are single test methods and do not work on count data with replicates. Although the Cochran Mantel Haenszel (CMH) approach can handle replicated count data, our simulations showed that multiple CMH tests still had very low power. To identify condition-associated variation of transcription, we here proposed a ranking analysis of chi-squares (RAX2) for large-scale association analysis. RAX2 is a nonparametric method and has accurate and conservative estimation of FDR profile. Simulations demonstrated that RAX2 performs well in finding condition-associated transcription variants. We applied RAX2 to primary T-cell transcriptomic data and identified 1610 (16.3%) tags associated in transcription with immune stimulation at FDR 〈 0.05. Most of these tags also had differential expression. Analysis of two and three tags within genes revealed that under immune stimulation short RNA isoforms were preferably used.

Description: Was the Yukon-Tanana Terrane (YTT), a California-sized part of south-central Yukon, an autochthonous or para-autochthonous part of northern British Columbia in the Early Cretaceous or was it part of a proposed allochthonous ‘Baja B.C.’ continent offshore of southern California? To answer this fundamental question, a paleomagnetic study has been completed on 347 specimens from 24 sites in the 114.7 ± 1.1 Ma Quiet Lake batholith. This 1300 km 2 pluton is composed mostly of massive medium-to-coarse grained biotite quartz monzonite that exhibits no evidence of either deformation or metamorphism, and that intrudes metamorphosed pre-Cretaceous basement rocks of the YTT in southern Yukon. The paleomagnetic analysis utilized thermal and alternating field step demagnetization, and saturation isothermal remanence methods. A well-defined characteristic remanent magnetization (ChRM) direction was isolated throughout the 500–585 °C temperature range at Decl. = 340.6°, Incl. = 77.4° ( N = 14 sites, k = 51.2, A 95 = 5.6°). The ChRM resides in magnetite with a low titanium content and is interpreted to be a primary thermoremanent magnetization. After correction for 490 km of geologically demonstrable dextral displacement on the inboard Tintina fault zone, the Quiet Lake batholith's paleopole is not significantly different at 95 per cent confidence from the co-eval 115 Ma reference paleopole for North America, giving non-significant translation and rotation estimates of 1.4° ± 5.1° (1) northwestwards and 10° ± 13° (1) clockwise, respectively. Thus, this is the first Early Cretaceous paleopole to show clearly that the YTT in Yukon is a para-autochthon that was part of North America's continental margin at that time. Further, after correction for Tintina fault displacement, the eight available Mesozoic YTT paleopoles agree closely with the North American apparent polar wander path (APWP). In contrast, the 22 paleopoles from the Intermontane Belt show the expected behaviour of an allochthonous thin-skin of terranes (i.e. ‘Baja B.C.’ behaviour) and record ~8° of northward translation and ~50° of clockwise rotation relative to both the YTT and North American APWPs during the Mesozoic and Paleogene.

Description: There exists a fundamental as well as practical interest in being able to accurately forecast the future evolution of Earth's magnetic field at decadal to secular ranges. This work enables such forecasts by combining geomagnetic data with an Earth-like numerical model of a convection-driven fluid dynamo. The underlying data assimilation framework builds on recent progress in inverse geodynamo modelling, a method which estimates an internal dynamic structure for Earth's core from a snapshot of the magnetic field and its instantaneous rate of change at the surface, and takes advantage of linear relationships and long-range correlations between observed and hidden state variables. Here the method is further evolved into a single-epoch ensemble Kalman filter, in order to initialise at a given epoch an ensemble of states compatible with the observations and representative of the uncertainties in the estimation of hidden quantities. The ensemble dynamics, obtained by subsequent numerical integration of the prognostic model equations, are found to be governed by a thermal wind balance or equilibrium between buoyancy forces, the Coriolis force and the pressure gradient. The resulting core fluid flow pattern is a quasi-steady eccentric gyre organised in a column parallel to Earth's rotation axis, in equilibrium with a longitudinal hemispheric convective density anomaly pattern. The flow provides induction for the magnetic field, which also undergoes a realistic amount of diffusion. Predictions of the present magnetic field from data taken within the past century show that the ensemble has an average retaining good consistency with the true geomagnetic evolution and an acceptable spread well representative of prediction errors, up to at least a secular range. The predictability of the geodynamo thus appears to significantly exceed previous theoretical expectations based on the chaotic divergence of ensemble members. The assimilation generally outperforms the linear mathematical extrapolations from a 30-yr prediction range onwards, with a 40 per cent improvement in Earth-surface error at a secular range. The geomagnetic axial dipole decay observed over the past two centuries is predicted to continue at a similar pace in the next century, with a further loss of $1.1\pm 0.3 \hspace{2.84526pt}\mathrm{\mu T}$ by year 2115. The focal (or minimum intensity) point of the South Atlantic geomagnetic anomaly is predicted to enter the South Pacific region in the next century, with the anomaly itself further deepening and widening. By year 2065, the minimum intensity is predicted to decrease by $1.46\pm 0.4 \hspace{2.84526pt}\mathrm{\mu T}$ at the Earth surface and the focal point to move 12.8 ± 1.4 deg westwards with a slight northward component. This corresponds to a drift rate of 0.26 deg yr –1 , similar to the typical geomagnetic westward drift observed over the past four centuries. The same drift rate is also predicted until 2115 with a further (but more uncertain) intensity decrease.

Description: Understanding the contribution of biogenic magnetic particles into sedimentary assemblages is a current challenge in palaeomagnetism. It has been demonstrated recently that magnetic particles produced through biologically controlled mineralization processes, such as magnetosomes from magnetotactic bacteria, contribute to the recording of natural remanent magnetization in marine and lacustrian sediments. Contributions from other, biologically induced, mineralization types, which are known from multiple laboratory experiments to include magnetic minerals, remain largely unknown. Here, we report magnetic properties of iron minerals formed by a community of iron- and manganese-reducing bacteria isolated from a natural groundwater deposit during a 2 yr long incubation experiment. The main iron phases of the biomineralized mass are lepidocrocite, goethite and magnetite, each of which has environmental significance. Unlike the majority of the previous studies that reported superparamagnetic grain size, and thus no remanence carrying capacity of biologically induced magnetite, hysteresis and first-order reversal curves measurements in our study have not detected significant superparamagnetic contribution. The biomineralized mass, instead, contains a mixture of single-domain to pseudo-single-domain and multidomain magnetite particles that are capable of carrying a stable chemical remanent magnetization. Isothermal remanent magnetization acquisition parameters and first-order reversal curves signatures of the biomineralized samples deviate from previously proposed criteria for the distinction of extracellular (biologically induced) magnetic particles in mixtures. Given its potential significance as a carrier of natural remanent magnetization, environmental requirements, distribution in nature and the efficiency in the geomagnetic field recording by biologically induced mineralization need comprehensive investigation.

Description: Monthly means of the magnetic field measurements at ground observatories are a key data source for studying temporal changes of the core magnetic field. However, when they are calculated in the usual way, contributions of external (magnetospheric and ionospheric) origin may remain, which make them less favourable for studying the field generated by dynamo action in the core. We remove external field predictions, including a new way of characterizing the magnetospheric ring current, from the data and then calculate revised monthly means using robust methods. The geomagnetic secular variation (SV) is calculated as the first annual differences of these monthly means, which also removes the static crustal field. SV time-series based on revised monthly means are much less scattered than those calculated from ordinary monthly means, and their variances and correlations between components are smaller. On the annual to decadal timescale, the SV is generated primarily by advection in the fluid outer core. We demonstrate the utility of the revised monthly means by calculating models of the core surface advective flow between 1997 and 2013 directly from the SV data. One set of models assumes flow that is constant over three months; such models exhibit large and rapid temporal variations. For models of this type, less complex flows achieve the same fit to the SV derived from revised monthly means than those from ordinary monthly means. However, those obtained from ordinary monthly means are able to follow excursions in SV that are likely to be external field contamination rather than core signals. Having established that we can find models that fit the data adequately, we then assess how much temporal variability is required. Previous studies have suggested that the flow is consistent with torsional oscillations (TO), solid body-like oscillations of fluid on concentric cylinders with axes aligned along the Earth's rotation axis. TO have been proposed to explain decadal timescale changes in the length-of-day. We invert for flow models where the only temporal changes are consistent with TO, but such models have an unacceptably large data misfit. However, if we relax the TO constraint to allow a little more temporal variability, we can fit the data as well as with flows assumed constant over three months, demonstrating that rapid SV changes can be reproduced by rather small flow changes. Although the flow itself changes slowly, its time derivative can be locally (temporally and spatially) large, in particular when and where core surface secular acceleration peaks. Spherical harmonic expansion coefficients of the flows are not well resolved, and many of them are strongly correlated. Averaging functions, a measure of our ability to determine the flow at a given location from the data distribution available, are poor approximations to the ideal, even when centred on points of the core surface below areas of high observatory density. Both resolution and averaging functions are noticeably worse for the toroidal flow component, which dominates the flow, than the poloidal flow component, except around the magnetic equator where averaging functions for both components are poor.

Description: The electrical rock conductivity is a sensitive indicator for carbon dioxide (CO 2 ) injection and migration processes. For a reliable balancing of the free CO 2 in pore space with petrophysical models such as Archie's law or for the detection of migrating CO 2 , detailed knowledge of the pore water conductivity during interaction with CO 2 is essential but not available yet. Contrary to common assumptions, pore water conductivity cannot be assumed constant since CO 2 is a reactive gas that dissolves into the pore water in large amounts and provides additional charge carriers due to the dissociation of carbonic acid. We consequently carried out systematic laboratory experiments to quantify and analyse the changes in saline pore water conductivity caused by CO 2 at thermodynamic equilibrium. Electrical conductivity is measured on pore water samples for pressures up to 30 MPa and temperatures up to 80 °C. The parameter range covers the gaseous, liquid and supercritical state of the CO 2 involved. Pore water salinities from 0.006 up to 57.27 g L –1 sodium chloride were investigated as well as selective other ion species. At the same time, the CO 2 concentration in the salt solution was determined by a wet-chemical procedure. A two-regime behaviour appears: for small salinities, we observe an increase of up to more than factor 3 in the electrical pore water conductivity, which strongly depends on the solution salinity (low-salinity regime). This is an expected behaviour, since the additional ions originating from the dissociation of carbonic acid positively contribute to the solution conductivity. However, when increasing salinities are considered this effect is completely diminished. For highly saline solutions, the increased mutual impeding causes the mobility of all ions to decrease, which may result in a significant reduction of conductivity by up to 15 per cent despite the added CO 2 (high-salinity regime). We present the data set covering the pressure, temperature, salinity and ion species dependence of the CO 2 effect. Furthermore, the observations are analysed and predicted with a semi-analytical formulation for the electrical pore water conductivity taking into account the species’ interactions. For the applicability of our results in practice of exploration and monitoring, we additionally provide a purely empirical formulation to compute the impact of CO 2 on pore water conductivity at equilibrium which only requires the input of pressure, temperature and salinity information.

Description: Although the Matuyama–Brunhes boundary (MBB) in the Chinese Loess Plateau (CLP) is very important in reliably correlating Quaternary loess with other sediments in the world, particularly with marine and polar ice cores, its exact stratigraphic position remains controversial. Previous investigations usually placed the MBB between paleosol unit S8 and loess unit L8 in various locations. To better understand the spatial differences in the MBB position, a high-resolution paleomagnetic study was conducted in a loess section of the Lantian Basin at the southern margin of the CLP. The results show that the MBB is situated in the middle of the relatively weak paleosol unit S7, consistent with a recent report on the MBB based on a 10 Be study from the Xifeng and Luochuan loess sections of the central CLP. However, the regional anomalously low magnetic susceptibility in paleosols S7 and S8 indicates that it is more reliable to determine the paleoclimate boundaries between loess and paleosol horizons of this segment with median grain size. Then, the MBB in the Yushan section can be correlated with the bottom of paleosol S7, corresponding to the older part of interglacial marine isotope stage 19. This result temporally reconciles the striking discrepancy of the position of the MBB recorded in between loess and other typical sedimentary sequences, and further confirms that the stratigraphic position of the MBB could spatially vary to a certain extent due to regional sedimentary or paleoclimatic conditions in the marginal areas of the CLP. In the Yushan section, the high-frequency variations of paleomagnetic directions during a long period of ~31 ka before the MBB, however, could not be attributed to a genuine response to the true geomagnetic behaviour. Moreover, the climate offset defined by the magnetic susceptibility and median grain size of the section can be preliminarily attributed to the regional geology and paleoenvironment background. A multiproxy-based stratigraphic division is considered very necessary when paleomagnetic and climatic boundaries are defined exactly in a specific area of the southern CLP.

Description: To understand how transposon landscapes (TLs) vary across animal genomes, we describe a new method called the Transposon Insertion and Depletion AnaLyzer (TIDAL) and a database of 〉300 TLs in Drosophila melanogaster (TIDAL-Fly). Our analysis reveals pervasive TL diversity across cell lines and fly strains, even for identically named sub-strains from different laboratories such as the ISO1 strain used for the reference genome sequence. On average, 〉500 novel insertions exist in every lab strain, inbred strains of the Drosophila Genetic Reference Panel (DGRP), and fly isolates in the Drosophila Genome Nexus (DGN). A minority (〈25%) of transposon families comprise the majority (〉70%) of TL diversity across fly strains. A sharp contrast between insertion and depletion patterns indicates that many transposons are unique to the ISO1 reference genome sequence. Although TL diversity from fly strains reaches asymptotic limits with increasing sequencing depth, rampant TL diversity causes unsaturated detection of TLs in pools of flies. Finally, we show novel transposon insertions negatively correlate with Piwi-interacting RNA (piRNA) levels for most transposon families, except for the highly-abundant roo retrotransposon. Our study provides a useful resource for Drosophila geneticists to understand how transposons create extensive genomic diversity in fly cell lines and strains.

Description: We study rotating thermal convection in spherical shells as prototype for flow in the cores of terrestrial planets, gas planets or in stars. We base our analysis on a set of about 450 direct numerical simulations of the (magneto)hydrodynamic equations under the Boussinesq approximation. The Ekman number ranges from 10 –3 to 10 –5 . The supercriticality of the convection reaches about 1000 in some models. Four sets of simulations are considered: non-magnetic simulations and dynamo simulations with either free-slip or no-slip flow boundary conditions. The non-magnetic setup with free-slip boundaries generates the strongest zonal flows. Both non-magnetic simulations with no-slip flow boundary conditions and self-consistent dynamos with free-slip boundaries have drastically reduced zonal-flows. Suppression of shear leads to a substantial gain in heat-transfer efficiency, increasing by a factor of 3 in some cases. Such efficiency enhancement occurs as long as the convection is significantly influenced by rotation. At higher convective driving the heat-transfer efficiency tends towards that of the classical non-rotating Rayleigh–Bénard system. Analysis of the latitudinal distribution of heat flow at the outer boundary reveals that the shear is most effective at suppressing heat-transfer in the equatorial regions. Simulations with convection zones of different thickness show that the zonal flows become less energetic in thicker shells, and, therefore, their effect on heat-transfer efficiency decreases. Furthermore, we explore the influence of the magnetic field on the non-zonal flow components of the convection. For this we compare the heat-transfer efficiency of no-slip non-magnetic cases with that of the no-slip dynamo simulations. We find that at E = 10 –5 magnetic field significantly affects the convection and a maximum gain of about 30 per cent (as compared to the non-magnetic case) in heat-transfer efficiency is obtained for an Elsasser number of about 3. Our analysis motivates us to speculate that convection in the polar regions in dynamos at E = 10 –5 is probably in a ‘magnetostrophic’ regime.

Description: ‘Anomalous’ magnetic fabrics in dikes that appear to indicate flow into the wall confound many workers. Here, we present extensive magnetic data on five dikes from Tenerife, Canary Islands, and use these to interpret the causes of the anomalous fabrics. Comparison of the anisotropy of magnetic susceptibility (AMS) and anhysteretic magnetization (AARM) results show that, in some cases, the anomalous fabrics are caused by single-domain grains, which produce AMS fabrics perpendicular to the grain elongation, whereas AARM fabrics are parallel. To check this, hysteresis experiments were used to characterize the domain state. These show most are mixtures of pseudo-single-domain or single-domain plus multi-domain particles, but many have wasp-waisted hysteresis loops, likely indicating mixed populations of stable single-domain and superparamagnetic grains. First-order reversal curves were used to better characterize this and show mixtures of stable single-domain and superparamagnetic grains dominate the magnetic signal. Magnetic particles at the stable single-domain/superparamagnetic threshold are unstable at timespans relevant to the analytical techniques, so they produce complicated results. This suggests that anomalous AMS fabrics in dikes cannot simply be attributed to elongated stable single-domain particles and that mixtures of the different grain types can produce hybrid fabrics, in which the fabrics are neither perpendicular or parallel to the dike plane, that are difficult to interpret without extensive magnetic analysis.

Description: Understanding telomere length maintenance mechanisms is central in cancer biology as their dysregulation is one of the hallmarks for immortalization of cancer cells. Important for this well-balanced control is the transcriptional regulation of the telomerase genes. We integrated Mixed Integer Linear Programming models into a comparative machine learning based approach to identify regulatory interactions that best explain the discrepancy of telomerase transcript levels in yeast mutants with deleted regulators showing aberrant telomere length, when compared to mutants with normal telomere length. We uncover novel regulators of telomerase expression, several of which affect histone levels or modifications. In particular, our results point to the transcription factors Sum1, Hst1 and Srb2 as being important for the regulation of EST1 transcription, and we validated the effect of Sum1 experimentally. We compiled our machine learning method leading to a user friendly package for R which can straightforwardly be applied to similar problems integrating gene regulator binding information and expression profiles of samples of e.g. different phenotypes, diseases or treatments.

Description: The ability to integrate ‘omics’ (i.e. transcriptomics and proteomics) is becoming increasingly important to the understanding of regulatory mechanisms. There are currently no tools available to identify differentially expressed genes (DEGs) across different ‘omics’ data types or multi-dimensional data including time courses. We present fCI (f-divergence Cut-out Index), a model capable of simultaneously identifying DEGs from continuous and discrete transcriptomic, proteomic and integrated proteogenomic data. We show that fCI can be used across multiple diverse sets of data and can unambiguously find genes that show functional modulation, developmental changes or misregulation. Applying fCI to several proteogenomics datasets, we identified a number of important genes that showed distinctive regulation patterns. The package fCI is available at R Bioconductor and http://software.steenlab.org/fCI/ .

Description: Next generation sequencing of cellular RNA is making it possible to characterize genes and alternative splicing in unprecedented detail. However, designing bioinformatics tools to accurately capture splicing variation has proven difficult. Current programs can find major isoforms of a gene but miss lower abundance variants, or are sensitive but imprecise. CLASS2 is a novel open source tool for accurate genome-guided transcriptome assembly from RNA-seq reads based on the model of splice graph. An extension of our program CLASS, CLASS2 jointly optimizes read patterns and the number of supporting reads to score and prioritize transcripts, implemented in a novel, scalable and efficient dynamic programming algorithm. When compared against reference programs, CLASS2 had the best overall accuracy and could detect up to twice as many splicing events with precision similar to the best reference program. Notably, it was the only tool to produce consistently reliable transcript models for a wide range of applications and sequencing strategies, including ribosomal RNA-depleted samples. Lightweight and multi-threaded, CLASS2 requires 〈3GB RAM and can analyze a 350 million read set within hours, and can be widely applied to transcriptomics studies ranging from clinical RNA sequencing, to alternative splicing analyses, and to the annotation of new genomes.

Description: We derive scaling relationships for planetary dynamos based on a balance between energy production and Joule dissipation, and between the curl of the buoyancy and Coriolis forces. These scaling relationships are deduced for the particular case of dynamos driven by helical waves, but are shown to have a much broader applicability. They are consistent with the evidence of the numerical dynamos, yielding predictions consistent with published empirical scaling laws and also with the observed transition from dipolar to multipolar dynamos. A direct comparison with the observational evidence for the planets is hampered by the fact that we do not know what sets the smallest scale of the motion in the planets. Nevertheless, we use our scaling relationships to show that the traditional assumption that the Elsasser number is of order unity is inconsistent with the observation that the gas-giant dynamos are dipolar dynamos, as is the more recent suggestion that the strength of the dipole is independent of rotation rate and controlled by the buoyancy flux alone. On the other hand, we show that the observational data is consistent with the hypothesis that a dipolar dynamo saturates at the lowest permissible magnetic energy compatible with a given buoyancy flux.

Description: Allele-specific copy number analysis (ASCN) from next generation sequencing (NGS) data can greatly extend the utility of NGS beyond the identification of mutations to precisely annotate the genome for the detection of homozygous/heterozygous deletions, copy-neutral loss-of-heterozygosity (LOH), allele-specific gains/amplifications. In addition, as targeted gene panels are increasingly used in clinical sequencing studies for the detection of ‘actionable’ mutations and copy number alterations to guide treatment decisions, accurate, tumor purity-, ploidy- and clonal heterogeneity-adjusted integer copy number calls are greatly needed to more reliably interpret NGS-based cancer gene copy number data in the context of clinical sequencing. We developed FACETS, an ASCN tool and open-source software with a broad application to whole genome, whole-exome, as well as targeted panel sequencing platforms. It is a fully integrated stand-alone pipeline that includes sequencing BAM file post-processing, joint segmentation of total- and allele-specific read counts, and integer copy number calls corrected for tumor purity, ploidy and clonal heterogeneity, with comprehensive output and integrated visualization. We demonstrate the application of FACETS using The Cancer Genome Atlas (TCGA) whole-exome sequencing of lung adenocarcinoma samples. We also demonstrate its application to a clinical sequencing platform based on a targeted gene panel.

Description: We present SWAN, a statistical framework for robust detection of genomic structural variants in next-generation sequencing data and an analysis of mid-range size insertion and deletions (〈10 Kb) for whole genome analysis and DNA mixtures. To identify these mid-range size events, SWAN collectively uses information from read-pair, read-depth and one end mapped reads through statistical likelihoods based on Poisson field models. SWAN also uses soft-clip/split read remapping to supplement the likelihood analysis and determine variant boundaries. The accuracy of SWAN is demonstrated by in silico spike-ins and by identification of known variants in the NA12878 genome. We used SWAN to identify a series of novel set of mid-range insertion/deletion detection that were confirmed by targeted deep re-sequencing. An R package implementation of SWAN is open source and freely available.

Description: We present a detailed palaeomagnetic study from 35 sites on Holocene lava flows of the Tongariro Volcanic Centre, central North Island, New Zealand. Prior to the study the eruption ages of these flows were constrained to within a few thousand years by recently published high-precision 40 Ar/ 39 Ar geochronological data and tephrostratigraphic controls. Correlation of flow mean palaeomagnetic directions with a recently published continuous sediment record from Lake Mavora, Fiordland, allows us to reduce the age uncertainty to 300–500 yr in some cases. Our refined ages significantly improve the chronology of Holocene effusive eruptions of the volcanoes of the Tongariro Volcanic Centre. For instance, differences in the palaeomagnetic directions recorded by lavas from the voluminous Iwikau and Rangataua members suggest that individual effusive periods lasted up to thousands of years and that these bursts have been irregularly spaced over time. While over the last few millennia the effusive eruptive activity from Mt Ruapehu has been relatively quiet, the very young age (200–500 BP) of a Red Crater sourced flow suggests that effusive activity around Mt Tongariro lasted into the past few centuries. This adds an important hazard context to the historical record, which has otherwise comprised frequent relatively small, tephra producing, explosive eruptions without the production of lava flows.

Description: High-throughput screening (HTS) is an indispensable tool for drug (target) discovery that currently lacks user-friendly software tools for the robust identification of putative hits from HTS experiments and for the interpretation of these findings in the context of systems biology. We developed HiTSeekR as a one-stop solution for chemical compound screens, siRNA knock-down and CRISPR/Cas9 knock-out screens, as well as microRNA inhibitor and -mimics screens. We chose three use cases that demonstrate the potential of HiTSeekR to fully exploit HTS screening data in quite heterogeneous contexts to generate novel hypotheses for follow-up experiments: (i) a genome-wide RNAi screen to uncover modulators of TNFα, (ii) a combined siRNA and miRNA mimics screen on vorinostat resistance and (iii) a small compound screen on KRAS synthetic lethality. HiTSeekR is publicly available at http://hitseekr.compbio.sdu.dk . It is the first approach to close the gap between raw data processing, network enrichment and wet lab target generation for various HTS screen types.

Description: The inversion of magnetotelluric data into subsurface electrical conductivity poses an ill-posed problem. Smoothing constraints are widely employed to estimate a regularized solution. Here, we present an alternative inversion scheme that estimates a sparse representation of the model in a wavelet basis. The objective of the inversion is to determine the few non-zero wavelet coefficients which are required to fit the data. This approach falls into the class of sparsity constrained inversion schemes and minimizes the combination of the data misfit in a least-squares 2 sense and of a model coefficient norm in an 1 sense ( 2 - 1 minimization). The 1 coefficient norm renders the solution sparse in a suitable representation such as the multiresolution wavelet basis, but does not impose explicit structural penalties on the model as it is the case for 2 regularization. The presented numerical algorithm solves the mixed 2 - 1 norm minimization problem for the nonlinear magnetotelluric inverse problem. We demonstrate the feasibility of our algorithm on synthetic 2-D MT data as well as on a real data example. We found that sparse models can be estimated by inversion and that the spatial distribution of non-vanishing coefficients indicates regions in the model which are resolved.

Description: We examined the mathematical and computational aspects of the magnetic potential, vector and gradient tensor fields of a tesseroid in a geocentric spherical coordinate system (SCS). This work is relevant for 3-D modelling that is performed with lithospheric vertical scales and global, continent or large regional horizontal scales. The curvature of the Earth is significant at these scales and hence, a SCS is more appropriate than the usual Cartesian coordinate system (CCS). The 3-D arrays of spherical prisms (SP; ‘tesseroids’) can be used to model the response of volumes with variable magnetic properties. Analytical solutions do not exist for these model elements and numerical or mixed numerical and analytical solutions must be employed. We compared various methods for calculating the response in terms of accuracy and computational efficiency. The methods were (1) the spherical coordinate magnetic dipole method (MD), (2) variants of the 3-D Gauss–Legendre quadrature integration method (3-D GLQI) with (i) different numbers of nodes in each of the three directions, and (ii) models where we subdivided each SP into a number of smaller tesseroid volume elements, (3) a procedure that we term revised Gauss–Legendre quadrature integration (3-D RGLQI) where the magnetization direction which is constant in a SCS is assumed to be constant in a CCS and equal to the direction at the geometric centre of each tesseroid, (4) the Taylor's series expansion method (TSE) and (5) the rectangular prism method (RP). In any realistic application, both the accuracy and the computational efficiency factors must be considered to determine the optimum approach to employ. In all instances, accuracy improves with increasing distance from the source. It is higher in the percentage terms for potential than the vector or tensor response. The tensor errors are the largest, but they decrease more quickly with distance from the source. In our comparisons of relative computational efficiency, we found that the magnetic potential takes less time to compute than the vector response, which in turn takes less time to compute than the tensor gradient response. The MD method takes less time to compute than either the TSE or RP methods. The efficiency of the (GLQI and) RGLQI methods depends on the polynomial order, but the response typically takes longer to compute than it does for the other methods. The optimum method is a complex function of the desired accuracy, the size of the volume elements, the element latitude and the distance between the source and the observation. For a model of global extent with typical model element size (e.g. 1 degree horizontally and 10 km radially) and observations at altitudes of 10s to 100s of km, a mixture of methods based on the horizontal separation of the source and observation separation would be the optimum approach. To demonstrate the RGLQI method described within this paper, we applied it to the computation of the response for a global magnetization model for observations at 300 and 30 km altitude.

Description: Next-generation sequencing (NGS) approaches rapidly produce millions to billions of short reads, which allow pathogen detection and discovery in human clinical, animal and environmental samples. A major limitation of sequence homology-based identification for highly divergent microorganisms is the short length of reads generated by most highly parallel sequencing technologies. Short reads require a high level of sequence similarities to annotated genes to confidently predict gene function or homology. Such recognition of highly divergent homologues can be improved by reference-free ( de novo ) assembly of short overlapping sequence reads into larger contigs. We describe an ensemble strategy that integrates the sequential use of various de Bruijn graph and overlap-layout-consensus assemblers with a novel partitioned sub-assembly approach. We also proposed new quality metrics that are suitable for evaluating metagenome de novo assembly. We demonstrate that this new ensemble strategy tested using in silico spike-in, clinical and environmental NGS datasets achieved significantly better contigs than current approaches.

Description: Distinguishing between promoter-like sequences in bacteria that belong to true or abortive promoters, or to those that do not initiate transcription at all, is one of the important challenges in transcriptomics. To address this problem, we have studied the genome-reduced bacterium Mycoplasma pneumoniae , for which the RNAs associated with transcriptional start sites have been recently experimentally identified. We determined the contribution to transcription events of different genomic features: the –10, extended –10 and –35 boxes, the UP element, the bases surrounding the –10 box and the nearest-neighbor free energy of the promoter region. Using a random forest classifier and the aforementioned features transformed into scores, we could distinguish between true, abortive promoters and non-promoters with good –10 box sequences. The methods used in this characterization of promoters can be extended to other bacteria and have important applications for promoter design in bacterial genome engineering.

Description: Kamacite particles (Fe–Ni, Ni 〈 5 per cent), are very common in extra-terrestrial materials, such as meteorites. It is normally assumed that for kamacite particles to be reliable recorders of magnetic fields, they need to be magnetically uniform (single domain, SD) and thermally stable. Larger particles subdivide into non-uniform multidomain (MD) magnetic structures that produce weaker magnetic signals, while small SD particles become magnetically unstable due to thermal fluctuations and exhibit superparamagnetic behaviour. In this paper we determine the first micromagnetic calculation of the stable SD range domain-state phase diagram for metallic iron; previous calculations were analytical. There is a significant increase in the critical size for the SD/MD threshold size, for example, for cube-shaped iron particles, the critical SD/MD threshold has now been estimated to be 25 nm, compared to 17 nm for previous estimates. The larger critical SD/MD threshold size for iron, agrees better with previously published nanometric observations of domain state for FeNi particles, then early analytical models.

Description: This paper presents a distributed magnetotelluric inversion scheme based on adaptive finite-element method (FEM). The key novel aspect of the introduced algorithm is the use of automatic mesh refinement techniques for both forward and inverse modelling. These techniques alleviate tedious and subjective procedure of choosing a suitable model parametrization. To avoid overparametrization, meshes for forward and inverse problems were decoupled. For calculation of accurate electromagnetic (EM) responses, automatic mesh refinement algorithm based on a goal-oriented error estimator has been adopted. For further efficiency gain, EM fields for each frequency were calculated using independent meshes in order to account for substantially different spatial behaviour of the fields over a wide range of frequencies. An automatic approach for efficient initial mesh design in inverse problems based on linearized model resolution matrix was developed. To make this algorithm suitable for large-scale problems, it was proposed to use a low-rank approximation of the linearized model resolution matrix. In order to fill a gap between initial and true model complexities and resolve emerging 3-D structures better, an algorithm for adaptive inverse mesh refinement was derived. Within this algorithm, spatial variations of the imaged parameter are calculated and mesh is refined in the neighborhoods of points with the largest variations. A series of numerical tests were performed to demonstrate the utility of the presented algorithms. Adaptive mesh refinement based on the model resolution estimates provides an efficient tool to derive initial meshes which account for arbitrary survey layouts, data types, frequency content and measurement uncertainties. Furthermore, the algorithm is capable to deliver meshes suitable to resolve features on multiple scales while keeping number of unknowns low. However, such meshes exhibit dependency on an initial model guess. Additionally, it is demonstrated that the adaptive mesh refinement can be particularly efficient in resolving complex shapes. The implemented inversion scheme was able to resolve a hemisphere object with sufficient resolution starting from a coarse discretization and refining mesh adaptively in a fully automatic process. The code is able to harness the computational power of modern distributed platforms and is shown to work with models consisting of millions of degrees of freedom. Significant computational savings were achieved by using locally refined decoupled meshes.

Description: MicroRNAs (miRNAs) are involved in the regulation of gene expression at a post-transcriptional level. As such, monitoring miRNA expression has been increasingly used to assess their role in regulatory mechanisms of biological processes. In large scale studies, once miRNAs of interest have been identified, the target genes they regulate are often inferred using algorithms or databases. A pathway analysis is then often performed in order to generate hypotheses about the relevant biological functions controlled by the miRNA signature. Here we show that the method widely used in scientific literature to identify these pathways is biased and leads to inaccurate results. In addition to describing the bias and its origin we present an alternative strategy to identify potential biological functions specifically impacted by a miRNA signature. More generally, our study exemplifies the crucial need of relevant negative controls when developing, and using, bioinformatics methods.

Description: A spatially averaged mean-field model for fully or partially ordered members of the ilmenite–hematite solid solution series is rigorously derived from the Heisenberg Hamiltonian by first assuming no temporal correlation of atomic spins, and then by spatially averaging over spins at equivalent atomic positions. The model is based on the geometry of exchange interactions between nearest and next-nearest neighbours and predicts magnetization curves in homogenous solid solutions with variable degree of order. While the general framework presented can also be applied to atomic scale models, and to other solid solution series, here the symmetries of the ilmenite–hematite lattice are exploited to show that four different sublattice magnetizations and six independent combinations of exchange constants determine the temperature variation of the magnetization curves. Comparing measured Curie temperatures T C and M s ( T ) curves to model predictions results in accurate constraints for these combinations. It is also possible to calculate predictions for high-field magnetization slopes HF , which not only improve accurate experimental determination of the Curie temperature but also provide a new magnetic method to estimate the order parameter for ilmenite–hematite solid solution samples.

Description: Tibetan Plateau uplift and global cooling have generally been thought to have caused the drying of the Asian inland, but how and when these factors drove the aridification is unknown. The Xining Basin at the NE Tibetan Plateau received continuous Eocene–Miocene fine-grained sediments, providing an excellent opportunity to address this question. Here we present detailed rock magnetic and diffuse reflectance spectroscopy (DRS) analyses for a well-dated Cenozoic sedimentary record from the Xiejia section in the basin. Magnetic susceptibility ( ), saturation magnetization (Ms) and saturation isothermal remanent magnetization (SIRM) in this section show a long-term decreasing trend from ~52 to ~25 Ma, well coinciding with global cooling and drying in the region, and an increasing trend since ~25 Ma, which is in contrast to the further progressing aridification of the basin. Thermomagnetic results and DRS-determined hematite contents suggest that the relative content of magnetite and hematite is the main control on the , Ms and SIRM values. We argue that the long-term Eocene–Oligocene global cooling increased the drying of the Asian inland, lowering the lake level and exposing a larger area to low temperature oxidation for longer times, thus producing more hematite and leading to the decreasing trend of magnetic concentration parameters from ~52 to ~25 Ma. An intensive uplift of the NE Tibetan Plateau since ~25 Ma, associated with a change in the sedimentary source, might be responsible for the increase of , Ms and SIRM after 25 Ma.

Description: It is now known that unwanted noise and unmodeled artifacts such as batch effects can dramatically reduce the accuracy of statistical inference in genomic experiments. These sources of noise must be modeled and removed to accurately measure biological variability and to obtain correct statistical inference when performing high-throughput genomic analysis. We introduced surrogate variable analysis (sva) for estimating these artifacts by (i) identifying the part of the genomic data only affected by artifacts and (ii) estimating the artifacts with principal components or singular vectors of the subset of the data matrix. The resulting estimates of artifacts can be used in subsequent analyses as adjustment factors to correct analyses. Here I describe a version of the sva approach specifically created for count data or FPKMs from sequencing experiments based on appropriate data transformation. I also describe the addition of supervised sva (ssva) for using control probes to identify the part of the genomic data only affected by artifacts. I present a comparison between these versions of sva and other methods for batch effect estimation on simulated data, real count-based data and FPKM-based data. These updates are available through the sva Bioconductor package and I have made fully reproducible analysis using these methods available from: https://github.com/jtleek/svaseq .

Description: High-throughput techniques have considerably increased the potential of comparative genomics whilst simultaneously posing many new challenges. One of those challenges involves efficiently mining the large amount of data produced and exploring the landscape of both conserved and idiosyncratic genomic regions across multiple genomes. Domains of application of these analyses are diverse: identification of evolutionary events, inference of gene functions, detection of niche-specific genes or phylogenetic profiling. Insyght is a comparative genomic visualization tool that combines three complementary displays: (i) a table for thoroughly browsing amongst homologues, (ii) a comparator of orthologue functional annotations and (iii) a genomic organization view designed to improve the legibility of rearrangements and distinctive loci. The latter display combines symbolic and proportional graphical paradigms. Synchronized navigation across multiple species and interoperability between the views are core features of Insyght. A gene filter mechanism is provided that helps the user to build a biologically relevant gene set according to multiple criteria such as presence/absence of homologues and/or various annotations. We illustrate the use of Insyght with scenarios. Currently, only Bacteria and Archaea are supported. A public instance is available at http://genome.jouy.inra.fr/Insyght . The tool is freely downloadable for private data set analysis.

Description: The 54 promoters are unique in prokaryotic genome and responsible for transcripting carbon and nitrogen-related genes. With the avalanche of genome sequences generated in the postgenomic age, it is highly desired to develop automated methods for rapidly and effectively identifying the 54 promoters. Here, a predictor called ‘ iPro54-PseKNC ’ was developed. In the predictor, the samples of DNA sequences were formulated by a novel feature vector called ‘pseudo k -tuple nucleotide composition’, which was further optimized by the incremental feature selection procedure. The performance of iPro54-PseKNC was examined by the rigorous jackknife cross-validation tests on a stringent benchmark data set. As a user-friendly web-server, iPro54-PseKNC is freely accessible at http://lin.uestc.edu.cn/server/iPro54-PseKNC . For the convenience of the vast majority of experimental scientists, a step-by-step protocol guide was provided on how to use the web-server to get the desired results without the need to follow the complicated mathematics that were presented in this paper just for its integrity. Meanwhile, we also discovered through an in-depth statistical analysis that the distribution of distances between the transcription start sites and the translation initiation sites were governed by the gamma distribution, which may provide a fundamental physical principle for studying the 54 promoters.

Description: The Mt Amram igneous complex (AIC) represents northern tip of the Neoproterozoic Arabian Nubian Shield (ANS). For the first time the AIC deep structure was studied using the gravity, aero and ground magnetic, magnetic susceptibility and density measurements and geological data. Analysing all available data at the Amram area we concluded what only monzonite body can be reason for gravity high and coinciding reduced to pole (RTP) maximum. Geological knowledge allowed suggesting its intrusive character and compact body form. Cluster of inverse solutions (Werner deconvolution) localized this body as initial model for forward modelling. Further iterations (2 3/4 -D forward modelling) clarified the monzonite geometry and properties; the modelling allowed also to investigate the non-uniqueness and estimate also the confident intervals for final solution. The research consists three interconnected stages. At the detailed scale, ground magnetic data suggested three magmatic blocks of few hundred meters shifted dextral about 100 m along the Zefunut fault. Estimated accuracy for geometry of the magnetic bodies is a few tens metres. At the middle scale, quantitative gravity and magnetic interpretations provide model of the monzonite body, which is an order of magnitude more than the volume of the felsic rhyolites and granite rocks. Boundary of the whole monzonite body was estimated with accuracy as a hundred meters. As a result we suggest that the parent magma for the AIC is the monzonite, similar to the model suggested for the Timna Igneous Complex 12 km north of the AIC. The model developed can be applied to evaluate the subsurface volumes of the mafic magmatic rocks in adjacent locations. At the regional scale for exposed the Sinai and Arab Saudi Precambrian crystalline shield our approach allows to understand the apparent contradiction between geological predominantly granite composition (low magnetic rocks) and magnetic data. The aeromagnetic data show number strong magnetic anomalies suggesting the presence large volume of high magnetic (mainly basic) rocks at the depth. This problem is proposed for future research.

Description: 3-D electromagnetic (EM) studies of the Earth have advanced significantly over the past decade. Despite a certain success of the 3-D EM inversions of real data sets, the quantitative assessment of the recovered models is still a challenging problem. It is known that one can gain valuable information about model uncertainties from the analysis of Hessian matrix. However, even with modern computational capabilities the calculation of the Hessian matrix based on numerical differentiation is extremely time consuming. Much more efficient way to compute the Hessian matrix is provided by an ‘adjoint sources’ methodology. The computation of Hessian matrix (and Hessian-vector products) using adjoint formulation is now well-established approach, especially in seismic inverse modelling. As for EM inverse modelling we did not find in the literature a description of the approach, which would allow EM researchers to apply this methodology in a straightforward manner to their scenario of interest. In the paper, we present formalism for the efficient calculation of the Hessian matrix using adjoint sources approach. We also show how this technique can be implemented to calculate multiple Hessian-vector products very efficiently. The formalism is general in the sense that it allows to work with responses that arise in EM problem set-ups either with natural- or controlled-source excitations. The formalism allows for various types of parametrization of the 3-D conductivity distribution. Using this methodology one can readily obtain appropriate formulae for the specific sounding methods. To illustrate the concept we provide such formulae for two EM techniques: magnetotellurics and controlled-source sounding with vertical magnetic dipole as a source.

Description: Geomagnetic jerks are sudden changes of trend in the geomagnetic secular variation. The Earth's mantle behaves as a filter for the jerks, causing a delayed and a smoothed signal at the Earth's surface. Backus' mantle filter theory relies on approximating the impulse response function (IRF) of the mantle by a Gaussian. The advantage of this theory is the linear relation between jerks’ delay times and the mantle electrical conductivity, as expressed by kernels. However, the limitations of this theory arise when negative delay and/or smoothing times occur. The applicability of the mantle filter theory is examined by analysing the validity of the Gaussian as an approximation for the composite IRF (CIRF) at a given location. We show that the electrical conductivity of the lower mantle is mostly responsible for the jerk delay time. Alternating sign CIRFs might cause negative delay and/or smoothing times which prevents the use of the mantle filter theory. Adequate/inadequate Gaussian approximations to the CIRFs give small/large differences in the convolved jerk occurrence times. Most observatories yield positive time constants, but in most cases the difference in the jerk occurrence times exceeds 0.5 yr.

Description: We present a discriminative learning method for pattern discovery of binding sites in nucleic acid sequences based on hidden Markov models. Sets of positive and negative example sequences are mined for sequence motifs whose occurrence frequency varies between the sets. The method offers several objective functions, but we concentrate on mutual information of condition and motif occurrence. We perform a systematic comparison of our method and numerous published motif-finding tools. Our method achieves the highest motif discovery performance, while being faster than most published methods. We present case studies of data from various technologies, including ChIP-Seq, RIP-Chip and PAR-CLIP, of embryonic stem cell transcription factors and of RNA-binding proteins, demonstrating practicality and utility of the method. For the alternative splicing factor RBM10, our analysis finds motifs known to be splicing-relevant. The motif discovery method is implemented in the free software package Discrover. It is applicable to genome- and transcriptome-scale data, makes use of available repeat experiments and aside from binary contrasts also more complex data configurations can be utilized.

Description: A new method of estimating fluid flows near the core–mantle boundary is presented. Both the geomagnetic diffusion and dynamics in a boundary layer are taken into account under the no-slip condition at the core–mantle boundary. Below the boundary layer, the tangentially geostrophic constraint is imposed on the flow to be estimated. The radial component of the geomagnetic field just within the core is calculated from the radial component and its partial derivatives with respect to the radius, first, derived from continuity of the solenoidal field across the finite jump in electrical conductivity and, second, the geomagnetic diffusion. Below the boundary layer, fluid motions thus derived show some features common to those estimated on the basis of the frozen-flux approximation, and their accompanying vortices at mid and high latitudes are well correlated with upwellings or downwellings inside the boundary layer. The positional relation of upwellings and downwellings in equatorial regions inside and below the boundary layer suggests existence of columnar convective cells there. Intense magnetic flux spots seen in equatorial regions are likely to be produced not by downwellings at tops of cyclonic columns but by flux expulsion due to upwellings between adjacent columnar flows. The present new method leads to a new insight on core surface flows that have not been noted so far.

Description: In most numerical simulations of the Earth's core the dynamo resides outside the tangent cylinder and may be crudely classified as being of the α 2 type. In this region the flow comprises a sea of thin columnar vortices aligned with the rotation axis, taking the form of alternating cyclones and anticyclones. The dynamo is thought to be driven by these columnar vortices within which the flow is observed to be highly helical, helicity being a crucial ingredient of planetary dynamos. As noted in Davidson, one of the mysteries of this dynamo cartoon is the origin of the helicity, which is observed to be positive in the south and negative in the north. While Ekman pumping at the mantle can induce helicity in some of the overly viscous numerical simulations, it is extremely unlikely to be a significant source within planets. In this paper we return to the suggestion of Davidson that the helicity observed in the less viscous simulations owes its existence to helical wave packets, launched in and around the equatorial plane where the buoyancy flux is observed to be strong. Here we show that such wave packets act as a potent source of planetary helicity, constituting a simple, robust mechanism that yields the correct sign for h north and south of the equator. Since such a mechanism does not rely on the presence of a mantle, it can operate within both the Earth and the gas giants. Moreover, our numerical simulations show that helical wave packets dispersing from the equator produce a random sea of thin, columnar cyclone/anticyclone pairs, very like those observed in the more strongly forced dynamo simulations. We examine the local dynamics of helical wave packets dispersing from the equatorial regions, as well as the overall nature of an α 2 -dynamo driven by such wave packets. Our local analysis predicts the mean emf induced by helical waves, an analysis that rests on a number of simple approximations which are consistent with our numerical experiments, while our global analysis yields exact integral relationships between the mean emf induced by the wave packets and the large-scale dipole and azimuthal field. Combining these local and integral equations yields a kinematic model for an α 2 -dynamo driven by helical waves. Order-of-magnitude estimates based on these equations suggest that such a dynamo is indeed feasible.

Description: The Lower Danube Basin is one of the most important loess regions from Europe, which have provided excellent archives for long-term high-resolution palaeoclimate studies. The aim of this paper is to derive new information on the Middle–Late Pleistocene palaeoenvironment from a high resolution multiproxy assessment of the iron mineralogical composition at the Costinesti loess-palaeosol sequence located on the western Black Sea shore. It is the easternmost loess section in the Romanian loess region studied and its distinct pattern of the proxy records can be used to correlate the lower Danube loess to other key sites of the Moldavia and Ukraine loess regions. To investigate the climatic control on soft and hard ferromagnetic minerals we used several types of rock magnetic properties: magnetic susceptibility and its frequency dependence, anhysteretic remanent magnetization, isothermal remanent magnetization, hysteresis properties and FORC distributions, an unmixing model for isothermal remanent magnetization curves and high field (up to 8 T) isothermal remanence measurements. Our results show that the palaeosol horizons, formed during interglacials and climatically more favored periods of the Pleistocene, experienced pedogenic alteration, resulting in high amounts of superparamagnetic, single domain and pseudosingle domain magnetite/maghemite grains and hematite. The loess layers, formed during glacial periods, are mainly dominated by multidomain and/or pseudosingle domain oxidized magnetite and some hematite, all probably of aeolian origin. Goethite contribution is probably minor and constant both in loess and palaeosol horizons. We review the correlation of the loess sections from the lower Danube basin concluding that the new results can be interpreted as a support for the transition of a Mediterranean type climate to a steppe type climate in the last two interglacial periods in the western Black Sea. Because the pattern of magnetic susceptibility data from the lower Danube basin is changing relative fast with distance from the Black Sea shore, it probably reflects the local influence of the Black Sea on continental scale climatic oscillations during the last 600 ka. The values of background magnetic susceptibility of the Romanian loess-palaeosol sections indicate that the main source area of the dust changed during this climatic transition. Our analysis also shows that the age of the loess-palaeosol sections from the Eastern European low lands (Moldavia and Ukraine) must be revised to be in agreement with the chronostratigraphy of the sections from the Lower Danube Basin loess area.

Description: Statistical models of geomagnetic secular variations in terms of a Giant Gaussian Process (GGP) are compared with palaeontensity databases (Brunhes epoch, effusive rocks). We tested two GGP models TK and QC (suggested by Tauxe-Kent and Quidelleur-Courtillot) against 392 volcanic palaeointensity data, and found both models to be incompatible with the data. Even though at present there is no accepted GGP model of the Brunhes chron, we found interesting to clarify the details of this negative test. While such an incompatibility is clear enough for the TK model, because of its too small dipole coefficient, the incompatibility of the QC model was due the 12 per cent of the data with very small intensities; remaining 88 per cent of data is fully compatible with QC model QC. The troublesome, low-palaeointensity records belong to different sites and ages so their excess presence is not an effect of particular location or time. We found no evidence that the marked discrepancy between the empirical data and theoretical calculations on the QC model can be explained by the possibility that the low-intensity values belong to known excursions of the geomagnetic field. As an alternative, we conjecture that selected low-intensity values can possibly stem from acquisition of chemical remanent magnetization instead of the thermoremanence.

Description: A new method of estimating fluid flows near the core–mantle boundary is presented. Both the geomagnetic diffusion and dynamics in a boundary layer are taken into account under the no-slip condition at the core–mantle boundary. Below the boundary layer, the tangentially geostrophic constraint is imposed on the flow to be estimated. The radial component of the geomagnetic field just within the core is calculated from the radial component and its partial derivatives with respect to the radius, first, derived from continuity of the solenoidal field across the finite jump in electrical conductivity and, second, the geomagnetic diffusion. Below the boundary layer, fluid motions thus derived show some features common to those estimated on the basis of the frozen-flux approximation, and their accompanying vortices at mid and high latitudes are well correlated with upwellings or downwellings inside the boundary layer. The positional relation of upwellings and downwellings in equatorial regions inside and below the boundary layer suggests existence of columnar convective cells there. Intense magnetic flux spots seen in equatorial regions are likely to be produced not by downwellings at tops of cyclonic columns but by flux expulsion due to upwellings between adjacent columnar flows. The present new method leads to a new insight on core surface flows that have not been noted so far.

Description: Practical applications of controlled-source electromagnetic (EM) modelling require solutions for multiple sources at several frequencies, thus leading to a dramatic increase of the computational cost. In this paper, we present an approach using block Krylov subspace solvers that are iterative methods especially designed for problems with multiple right-hand sides (RHS). Their main advantage is the shared subspace for approximate solutions, hence, these methods are expected to converge in less iterations than the corresponding standard solver applied to each linear system. Block solvers also share the same preconditioner, which is constructed only once. Simultaneously computed block operations have better utilization of cache due to the less frequent access to the system matrix. In this paper, we implement two different block solvers for sparse matrices resulting from the finite-difference and the finite-element discretizations, discuss the computational cost of the algorithms and study their dependence on the number of RHS given at once. The effectiveness of the proposed methods is demonstrated on two EM survey scenarios, including a large marine model. As the results of the simulations show, when a powerful preconditioning is employed, block methods are faster than standard iterative techniques in terms of both iterations and time.

Description: While it has been long recognized that genes are not randomly positioned along the genome, the degree to which its 3D structure influences the arrangement of genes has remained elusive. In particular, several lines of evidence suggest that actively transcribed genes are spatially co-localized, forming transcription factories; however, a generalized systematic test has hitherto not been described. Here we reveal transcription factories using a rigorous definition of genomic structure based on Saccharomyces cerevisiae chromosome conformation capture data, coupled with an experimental design controlling for the primary gene order. We develop a data-driven method for the interpolation and the embedding of such datasets and introduce statistics that enable the comparison of the spatial and genomic densities of genes. Combining these, we report evidence that co-regulated genes are clustered in space, beyond their observed clustering in the context of gene order along the genome and show this phenomenon is significant for 64 out of 117 transcription factors. Furthermore, we show that those transcription factors with high spatially co-localized targets are expressed higher than those whose targets are not spatially clustered. Collectively, our results support the notion that, at a given time, the physical density of genes is intimately related to regulatory activity.

Description: Pan-genome ortholog clustering tool ( PanOCT ) is a tool for pan-genomic analysis of closely related prokaryotic species or strains. PanOCT uses conserved gene neighborhood information to separate recently diverged paralogs into orthologous clusters where homology-only clustering methods cannot. The results from PanOCT and three commonly used graph-based ortholog-finding programs were compared using a set of four publicly available strains of the same bacterial species. All four methods agreed on ~70% of the clusters and ~86% of the proteins. The clusters that did not agree were inspected for evidence of correctness resulting in 85 high-confidence manually curated clusters that were used to compare all four methods.

Description: A novel ab initio parameter-tuning-free system to identify transcriptional factor (TF) binding motifs (TFBMs) in genome DNA sequences was developed. It is based on the comparison of two types of frequency distributions with respect to the TFBM candidates in the target DNA sequences and the non-candidates in the background sequence, with the latter generated by utilizing the intergenic sequences. For benchmark tests, we used DNA sequence datasets extracted by ChIP-on-chip and ChIP-seq techniques and identified 65 yeast and four mammalian TFBMs, with the latter including gaps. The accuracy of our system was compared with those of other available programs (i.e. MEME, Weeder, BioProspector, MDscan and DME) and was the best among them, even without tuning of the parameter set for each TFBM and pre-treatment/editing of the target DNA sequences. Moreover, with respect to some TFs for which the identified motifs are inconsistent with those in the references, our results were revealed to be correct, by comparing them with other existing experimental data. Thus, our identification system does not need any other biological information except for gene positions, and is also expected to be applicable to genome DNA sequences to identify unknown TFBMs as well as known ones.

Description: MicroRNAs (miRNAs) are major regulators of gene expression in multicellular organisms. They recognize their targets by sequence complementarity and guide them to cleavage or translational arrest. It is generally accepted that plant miRNAs have extensive complementarity to their targets and their prediction usually relies on the use of empirical parameters deduced from known miRNA–target interactions. Here, we developed a strategy to identify miRNA targets which is mainly based on the conservation of the potential regulation in different species. We applied the approach to expressed sequence tags datasets from angiosperms. Using this strategy, we predicted many new interactions and experimentally validated previously unknown miRNA targets in Arabidopsis thaliana . Newly identified targets that are broadly conserved include auxin regulators, transcription factors and transporters. Some of them might participate in the same pathways as the targets known before, suggesting that some miRNAs might control different aspects of a biological process. Furthermore, this approach can be used to identify targets present in a specific group of species, and, as a proof of principle, we analyzed Solanaceae -specific targets. The presented strategy can be used alone or in combination with other approaches to find miRNA targets in plants.

Description: We address the challenge of regulatory sequence alignment with a new method, Pro-Coffee, a multiple aligner specifically designed for homologous promoter regions. Pro-Coffee uses a dinucleotide substitution matrix estimated on alignments of functional binding sites from TRANSFAC. We designed a validation framework using several thousand families of orthologous promoters. This dataset was used to evaluate the accuracy for predicting true human orthologs among their paralogs. We found that whereas other methods achieve on average 73.5% accuracy, and 77.6% when trained on that same dataset, the figure goes up to 80.4% for Pro-Coffee. We then applied a novel validation procedure based on multi-species ChIP-seq data. Trained and untrained methods were tested for their capacity to correctly align experimentally detected binding sites. Whereas the average number of correctly aligned sites for two transcription factors is 284 for default methods and 316 for trained methods, Pro-Coffee achieves 331, 16.5% above the default average. We find a high correlation between a method's performance when classifying orthologs and its ability to correctly align proven binding sites. Not only has this interesting biological consequences, it also allows us to conclude that any method that is trained on the ortholog data set will result in functionally more informative alignments.

Description: MCScan is an algorithm able to scan multiple genomes or subgenomes in order to identify putative homologous chromosomal regions, and align these regions using genes as anchors. The MCScanX toolkit implements an adjusted MCScan algorithm for detection of synteny and collinearity that extends the original software by incorporating 14 utility programs for visualization of results and additional downstream analyses. Applications of MCScanX to several sequenced plant genomes and gene families are shown as examples. MCScanX can be used to effectively analyze chromosome structural changes, and reveal the history of gene family expansions that might contribute to the adaptation of lineages and taxa. An integrated view of various modes of gene duplication can supplement the traditional gene tree analysis in specific families. The source code and documentation of MCScanX are freely available at http://chibba.pgml.uga.edu/mcscan2/ .

Description: Loess deposits in the arid Central Asia contain valuable information on the evolution of local aridification and dust sources in the Northern Hemisphere. Xinjiang is located in the eastern part of Central Asia and previous researches have revealed the complex enhancement of magnetic susceptibility in loess–paleosol sequences. However, systematic magnetic archives of loess deposit in this arid Asian interior are still far from adequate. In this study, magnetic parameters combined with nonmagnetic properties (granulometry and chromaticity) were analysed on a loess section in Shawan (SW), northwestern China. The section shares a similar magnetic composition with those in the Chinese Loess Plateau (CLP) as well as other sites in Xinjiang. Ferrimagnetic components (magnetite and maghemite) dominate the magnetic signal while the contribution of antiferromagnetic phases (like hematite and goethite) and paramagnetic portions are relatively low. There is no specific correlation between magnetic concentration and pedogenic intensity in the SW section. In general, magnetic enhancement was largely influenced by the paleowind intensity. However, a positive correlation between magnetic susceptibility and pedogenesis is observed in the upper part (0–3.5 m depths), which is characterized by a moderate wind intensity. Moreover, pedogenesis might be responsible for the enhancement of fine magnetic particles in paleosols. Magnetic properties are controlled by coarse magnetic particles in the pseudo-single domain state, but a coarse stable single domain phase was found in certain paleosol samples. The input of detrital fractions from a nearby dust source probably controlled the magnetic properties while a superparamagnetic fraction, which has been deemed as a product of pedogenesis in the CLP, is limited in the SW section. Caution is needed to employ magnetic susceptibility directly for paleoclimatic assessment because of its uncertainty in the Xinjiang loess. However, the ARM /SIRM ratio enhanced in paleosols and has more potential as an alternative index for the weakly pedogenic degree in this area.

Description: Mantle control on the geodynamo is often simulated using numerical dynamos with imposed outer boundary heat flux inferred from lower mantle tomography, assuming that seismic and thermal anomalies in the lowermost mantle are highly correlated. However, non-thermal effects might perturb this idealized linear seismic–thermal mapping. Here we use a probabilistic tomography model to isolate the thermal part of the seismic anomaly in order to impose a more realistic core–mantle boundary heat flux pattern on the outer boundary of numerical dynamo simulations. We demonstrate that on time average these dynamo models have more low-latitude convective and magnetic activity than corresponding models with conventional tomographic heat flux. In addition, the low-latitude magnetic flux and kinetic energy contributions are more time-dependent in the dynamo models with a probabilistic tomography heat flux, and thus may recover the observed latitudinal distribution of geomagnetic flux on the core–mantle boundary, which we propose as a morphological criterion for Earth-like dynamo models.

Description: The statistics of directional data on a sphere can be modelled either using the Fisher distribution that is conditioned on the magnitude being unity, in which case the sample space is confined to the unit sphere, or using the latitude–longitude marginal distribution derived from a trivariate Gaussian model that places no constraint on the magnitude. These two distributions are derived from first principles and compared. The Fisher distribution more closely approximates the uniform distribution on a sphere for a given small value of the concentration parameter, while the latitude–longitude marginal distribution is always slightly larger than the Fisher distribution at small off-axis angles for large values of the concentration parameter. Asymptotic analysis shows that the two distributions only become equivalent in the limit of large concentration parameter and very small off-axis angle.

Description: In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource ( larva.gersteinlab.org ).

Description: With advancing computational resources, 3-D inversion techniques have become feasible in recent years and are now a more widely used tool for magnetotelluric (MT) data interpretation. Galvanic distortion caused by small-scale near-surface inhomogeneities remains an obstacle for 3-D MT inversion which so far has experienced little attention. If not considered properly, the effect on 3-D inversion can be immense and result in erroneous subsurface models and interpretations. To tackle the problem we implemented inversion of the distortion-free phase tensor into the ModEM inversion package. The dimensionless phase tensor components describe only variations of the conductivity structure. When inverting these data, particular care has to be taken of the conductivity structure in the a priori model, which provides the reference frame when transferring the information from phase tensors into absolute conductivity values. Our results obtained with synthetic data show that phase tensor inversion can recover the regional conductivity structure in presence of galvanic distortion if the a priori model provides a reasonable assumption for the regional resistivity average. Joint inversion of phase tensor data and vertical magnetic transfer functions improves recovery of the absolute resistivity structure and is less dependent on the prior model. We also used phase tensor inversion for a data set of more than 250 MT sites from the central San Andreas fault, California, where a number of sites showed significant galvanic distortion. We find the regional structure of the phase tensor inversion results compatible with previously obtained models from impedance inversion. In the vicinity of distorted sites, phase tensor inversion models exhibit more homogeneous/smoother conductivity structures.

Description: Earth's liquid core hosts a diverse set of waves with periods ranging from days to thousands of years. One class of waves with periods of several decades is known to arise from an interplay between magnetic, Archimedes and Coriolis forces. These so-called MAC waves are thought to be relevant for interpreting historical fluctuations in the geomagnetic field. In this study, we show that MAC waves provide a good description of time-dependent zonal flow at the top of the core. The same collection of waves also offers a simple explanation for observed fluctuations in the dipole field. Both of these predictions require a stratified layer at the top of the core with a thickness of 130–140 km and a buoyancy frequency comparable to Earth's rotation rate. We extend these predictions to include changes in the length of day (LOD) and find that MAC waves can account for about half of the observed fluctuation at decadal periods. Larger fluctuations are possible when electromagnetic stresses couple MAC waves to flow in the interior of the core. In fact, an idealized model for the coupled motion overestimates the LOD fluctuations, probably reflecting limitations in this idealized model. Our results offer support for stable stratification at the top of the core and suggest a common origin for decadal fluctuations in the geomagnetic field and the LOD.

Description: A detailed magnetic analysis has been conducted on the borehole CJ-1 (172.3 m in length) from the Changjiang (Yangtze) River delta. Results show that the dominant magnetic carriers are magnetite and hematite. Palaeomagnetic results reveal that high-frequency changes in palaeomagnetic inclinations are tied significantly to abnormal anisotropy of magnetic susceptibility (AMS) patterns due to effects of the high-energy depositional environment in this region. On the basis of AMS patterns, doubtful palaeomagnetic directional anomalies can be distinguished from authentic palaeomagnetic excursions. Magnetostratigraphic results indicate that the Matuyama–Brunhes boundary (MBB) was recorded at a depth of ~152.5 m. The presence of several short-lived inclination anomalies implied that the sedimentation could be continuous even at the millennial timescale at certain depth intervals bracketing these fast geomagnetic events. In summary, our study provides new insights into constructing reliable magnetostratigraphy in the delta region. Moreover, our new magnetostratigraphy of the Changjiang River delta deposits will facilitate studies on the relevant long-term palaeoenvironmental evolution of the delta.

Description: Non-stoichiometric monoclinic 4C pyrrhotite (Fe 7 S 8 ) is a major magnetic remanence carrier in the Earth's crust and in extraterrestrial materials. Because of its low-temperature magnetic transition around 30 K also known as Besnus transition, which is considered to be an intrinsic property, this mineral phase is easily detectable in natural samples. Although the physical properties of pyrrhotite have intensively been studied, the mechanism behind the pronounced change in magnetization at the low-temperature transition is still debated. Here we report magnetization experiments on a pyrrhotite crystal (Fe 6.6 S 8 ) that consists of a 4C and an incommensurate 5C* superstructure that are different in their defect structure. The occurrence of two superstructures is magnetically confirmed by symmetric inflection points in hysteresis measurements above the transition at about 30 K. The disappearance of the inflection points and the associated change of the hysteresis parameters indicate that the two superstructures become strongly coupled to form a unitary magnetic anisotropy system at the transition. From this it follows that the Besnus transition in monoclinic pyrrhotite is an extrinsic magnetic phenomenon with respect to the 4C superstructure and therefore the physics behind it is in fact different from that of the well-known Verwey transition.

Description: Disease-gene identification is a challenging process that has multiple applications within functional genomics and personalized medicine. Typically, this process involves both finding genes known to be associated with the disease (through literature search) and carrying out preliminary experiments or screens (e.g. linkage or association studies, copy number analyses, expression profiling) to determine a set of promising candidates for experimental validation. This requires extensive time and monetary resources. We describe Beegle , an online search and discovery engine that attempts to simplify this process by automating the typical approaches. It starts by mining the literature to quickly extract a set of genes known to be linked with a given query, then it integrates the learning methodology of Endeavour (a gene prioritization tool) to train a genomic model and rank a set of candidate genes to generate novel hypotheses. In a realistic evaluation setup, Beegle has an average recall of 84% in the top 100 returned genes as a search engine, which improves the discovery engine by 12.6% in the top 5% prioritized genes. Beegle is publicly available at http://beegle.esat.kuleuven.be/ .

Description: Alternative splicing is an important mechanism in eukaryotes that expands the transcriptome and proteome significantly. It plays an important role in a number of biological processes. Understanding its regulation is hence an important challenge. Recently, increasing evidence has been collected that supports an involvement of intragenic DNA methylation in the regulation of alternative splicing. The exact mechanisms of regulation, however, are largely unknown, and speculated to be complex: different methylation profiles might exist, each of which could be associated with a different regulation mechanism. We present a computational technique that is able to determine such stable methylation patterns and allows to correlate these patterns with inclusion propensity of exons. Pattern detection is based on dynamic time warping (DTW) of methylation profiles, a sophisticated similarity measure for signals that can be non-trivially transformed. We design a flexible self-organizing map approach to pattern grouping. Exemplary application on available data sets indicates that stable patterns which correlate non-trivially with exon inclusion do indeed exist. To improve the reliability of these predictions, further studies on larger data sets will be required. We have thus taken great care that our software runs efficiently on modern hardware, so that it can support future studies on large-scale data sets.

Description: Tumors are characterized by properties of genetic instability, heterogeneity, and significant oligoclonality. Elucidating this intratumoral heterogeneity is challenging but important. In this study, we propose a framework, BubbleTree, to characterize the tumor clonality using next generation sequencing (NGS) data. BubbleTree simultaneously elucidates the complexity of a tumor biopsy, estimating cancerous cell purity, tumor ploidy, allele-specific copy number, and clonality and represents this in an intuitive graph. We further developed a three-step heuristic method to automate the interpretation of the BubbleTree graph, using a divide-and-conquer strategy. In this study, we demonstrated the performance of BubbleTree with comparisons to similar commonly used tools such as THetA2, ABSOLUTE, AbsCN-seq and ASCAT, using both simulated and patient-derived data. BubbleTree outperformed these tools, particularly in identifying tumor subclonal populations and polyploidy. We further demonstrated BubbleTree's utility in tracking clonality changes from patients’ primary to metastatic tumor and dating somatic single nucleotide and copy number variants along the tumor clonal evolution. Overall, the BubbleTree graph and corresponding model is a powerful approach to provide a comprehensive spectrum of the heterogeneous tumor karyotype in human tumors. BubbleTree is R-based and freely available to the research community ( https://www.bioconductor.org/packages/release/bioc/html/BubbleTree.html ).