ALBERT

Description: We study a model of lava flow to determine its thermal and dynamic characteristics from thermal measurements of the lava at its surface. Mathematically this problem is reduced to solving an inverse boundary problem. Namely, using known conditions at one part of the model boundary we determine the missing condition at the remaining part of the boundary. We develop a numerical approach to the mathematical problem in the case of steady-state flow. Assuming that the temperature and the heat flow are prescribed at the upper surface of the model domain, we determine the flow characteristics in the entire model domain using a variational (adjoint) method. We have performed computations of model examples and showed that in the case of smooth input data the lava temperature and the flow velocity can be reconstructed with a high accuracy. As expected, a noise imposed on the smooth input data results in a less accurate solution, but still acceptable below some noise level. Also we analyse the influence of optimization methods on the solution convergence rate. The proposed method for reconstruction of physical parameters of lava flows can also be applied to other problems in geophysical fluid flows.

Description: Studies of discrete volcanic explosions, that usually last less than 2 or 3 min, have suggested that the partitioning of seismic-acoustic energy is likely related to a range of physical mechanisms that depend on magma properties and other physical constraints such as the location of the fragmentation surface. In this paper, we explore the energy partition of a paroxysmal eruptive phase of Tungurahua volcano that lasted for over 4 hr, on 2006 July 14–15, using seismic-acoustic information recorded by stations on its flanks (near field). We find evidence of a linear scaling between seismic and acoustic energies, with time-dependent intensities, during the sustained explosive phase of the eruption. Furthermore, we argue that this scaling can be explained by two different processes: (1) the fragmentation region ultimately acts as the common source of energy producing both direct seismic waves, that travel through the volcanic edifice, and direct acoustic waves coming from a disturbed atmosphere above the summit; (2) the coupling of acoustic waves with the ground to cause seismic waves. Both processes are concurrent, however we have found that the first one is dominant for seismic records below 4 Hz. Here we use the linear scaling of intensities to construct seismic and acoustic indices, which, we argue, could be used to track an ongoing eruption. Thus, especially in strong paroxysms that can produce pyroclastic flows, the index correlation and their levels can be used as quantitative monitoring parameters to assess the volcanic hazard in real time. Additionally, we suggest from the linear scaling that the source type for both cases, seismic and acoustic, is dipolar and dominant in the near field.

Description: Chromosome-long haplotyping of human genomes is important to identify genetic variants with differing gene expression, in human evolution studies, clinical diagnosis, and other biological and medical fields. Although several methods have realized haplotyping based on sequencing technologies or population statistics, accuracy and cost are factors that prohibit their wide use. Borrowing ideas from group testing theories, we proposed a clone-based haplotyping method by overlapping pool sequencing. The clones from a single individual were pooled combinatorially and then sequenced. According to the distinct pooling pattern for each clone in the overlapping pool sequencing, alleles for the recovered variants could be assigned to their original clones precisely. Subsequently, the clone sequences could be reconstructed by linking these alleles accordingly and assembling them into haplotypes with high accuracy. To verify the utility of our method, we constructed 130 110 clones in silico for the individual NA12878 and simulated the pooling and sequencing process. Ultimately, 99.9% of variants on chromosome 1 that were covered by clones from both parental chromosomes were recovered correctly, and 112 haplotype contigs were assembled with an N50 length of 3.4 Mb and no switch errors. A comparison with current clone-based haplotyping methods indicated our method was more accurate.

Description: Sexual differentiation of malaria parasites into gametocytes in the vertebrate host and subsequent gamete fertilization in mosquitoes is essential for the spreading of the disease. The molecular processes orchestrating these transitions are far from fully understood. Here, we report the first transcriptome analysis of male and female Plasmodium falciparum gametocytes coupled with a comprehensive proteome analysis. In male gametocytes there is an enrichment of proteins involved in the formation of flagellated gametes; proteins involved in DNA replication, chromatin organization and axoneme formation. On the other hand, female gametocytes are enriched in proteins required for zygote formation and functions after fertilization; protein-, lipid- and energy-metabolism. Integration of transcriptome and proteome data revealed 512 highly expressed maternal transcripts without corresponding protein expression indicating large scale translational repression in P. falciparum female gametocytes for the first time. Despite a high degree of conservation between Plasmodium species, 260 of these ‘repressed transcripts’ have not been previously described. Moreover, for some of these genes, protein expression is only reported in oocysts and sporozoites indicating that repressed transcripts can be partitioned into short- and long-term storage. Finally, these data sets provide an essential resource for identification of vaccine/drug targets and for further mechanistic studies.

Description: Identifying large-scale structural variation in cancer genomes continues to be a challenge to researchers. Current methods rely on genome alignments based on a reference that can be a poor fit to highly variant and complex tumor genomes. To address this challenge we developed a method that uses available breakpoint information to generate models of structural variations. We use these models as references to align previously unmapped and discordant reads from a genome. By using these models to align unmapped reads, we show that our method can help to identify large-scale variations that have been previously missed.

Description: Advanced sequencing technologies have generated a plethora of data for many chromatin marks in multiple tissues and cell types, yet there is lack of a generalized tool for optimal utility of those data. A major challenge is to quantitatively model the epigenetic dynamics across both the genome and many cell types for understanding their impacts on differential gene regulation and disease. We introduce IDEAS, an i ntegrative and d iscriminative e pigenome a nnotation s ystem, for jointly characterizing epigenetic landscapes in many cell types and detecting differential regulatory regions. A key distinction between our method and existing state-of-the-art algorithms is that IDEAS integrates epigenomes of many cell types simultaneously in a way that preserves the position-dependent and cell type-specific information at fine scales, thereby greatly improving segmentation accuracy and producing comparable annotations across cell types.

Description: The expansion of offshore renewable energy infrastructure and the need for trans-continental shelf power transmission require the use of submarine high-voltage (HV) cables. These cables have maximum operating surface temperatures of up to 70 °C and are typically buried 1–2 m beneath the seabed, within the wide range of substrates found on the continental shelf. However, the heat flow pattern and potential effects on the sedimentary environments around such anomalously high heat sources in the near-surface sediments are poorly understood. We present temperature measurements from a 2-D laboratory experiment representing a buried submarine HV cable, and identify the thermal regimes generated within typical unconsolidated shelf sediments—coarse silt, fine sand and very coarse sand. We used a large (2 x 2.5 m 2 ) tank filled with water-saturated spherical glass beads (ballotini) and instrumented with a buried heat source and 120 thermocouples to measure the time-dependent 2-D temperature distributions. The observed and corresponding Finite Element Method simulations of the steady state heat flow regimes and normalized radial temperature distributions were assessed. Our results show that the heat transfer and thus temperature fields generated from submarine HV cables buried within a range of sediments are highly variable. Coarse silts are shown to be purely conductive, producing temperature increases of 〉10 °C up to 40 cm from the source of 60 °C above ambient; fine sands demonstrate a transition from conductive to convective heat transfer between cf. 20 and 36 °C above ambient, with 〉10 °C heat increases occurring over a metre from the source of 55 °C above ambient; and very coarse sands exhibit dominantly convective heat transfer even at very low ( cf. 7 °C) operating temperatures and reaching temperatures of up to 18 °C above ambient at a metre from the source at surface temperatures of only 18 °C. These findings are important for the surrounding near-surface environments experiencing such high temperatures and may have significant implications for chemical and physical processes operating at the grain and subgrain scale; biological activity at both microfaunal and macrofaunal levels; and indeed the operational performance of the cables themselves, as convective heat transport would increase cable current ratings, something neglected in existing standards.

Description: A majority of large-scale bacterial genome rearrangements involve mobile genetic elements such as insertion sequence (IS) elements. Here we report novel insertions and excisions of IS elements and recombination between homologous IS elements identified in a large collection of Escherichia coli mutation accumulation lines by analysis of whole genome shotgun sequencing data. Based on 857 identified events (758 IS insertions, 98 recombinations and 1 excision), we estimate that the rate of IS insertion is 3.5 x 10 –4 insertions per genome per generation and the rate of IS homologous recombination is 4.5 x 10 –5 recombinations per genome per generation. These events are mostly contributed by the IS elements IS 1 , IS 2 , IS 5 and IS 186 . Spatial analysis of new insertions suggest that transposition is biased to proximal insertions, and the length spectrum of IS-caused deletions is largely explained by local hopping. For any of the ISs studied there is no region of the circular genome that is favored or disfavored for new insertions but there are notable hotspots for deletions. Some elements have preferences for non-coding sequence or for the beginning and end of coding regions, largely explained by target site motifs. Interestingly, transposition and deletion rates remain constant across the wild-type and 12 mutant E. coli lines, each deficient in a distinct DNA repair pathway. Finally, we characterized the target sites of four IS families, confirming previous results and characterizing a highly specific pattern at IS 186 target-sites, 5'-GGGG(N6/N7)CCCC-3'. We also detected 48 long deletions not involving IS elements.

Description: Genetic variants in or near miRNA genes can have profound effects on miRNA expression and targeting. As user-friendly software for the impact prediction of miRNA variants on a large scale is still lacking, we created a tool called miRVaS. miRVaS automates this prediction by annotating the location of the variant relative to functional regions within the miRNA hairpin (seed, mature, loop, hairpin arm, flanks) and by annotating all predicted structural changes within the miRNA due to the variant. In addition, the tool defines the most important region that is predicted to have structural changes and calculates a conservation score that is indicative of the reliability of the structure prediction. The output is presented in a tab-separated file, which enables fast screening, and in an html file, which allows visual comparison between wild-type and variant structures. All separate images are provided for downstream use. Finally, we tested two different approaches on a small test set of published functionally validated genetic variants for their capacity to predict the impact of variants on miRNA expression.

Description: Analysis of RNA-seq data often detects numerous ‘non-co-linear’ (NCL) transcripts, which comprised sequence segments that are topologically inconsistent with their corresponding DNA sequences in the reference genome. However, detection of NCL transcripts involves two major challenges: removal of false positives arising from alignment artifacts and discrimination between different types of NCL transcripts ( trans -spliced, circular or fusion transcripts). Here, we developed a new NCL-transcript-detecting method (‘NCLscan’), which utilized a stepwise alignment strategy to almost completely eliminate false calls (〉98% precision) without sacrificing true positives, enabling NCLscan outperform 18 other publicly-available tools (including fusion- and circular-RNA-detecting tools) in terms of sensitivity and precision, regardless of the generation strategy of simulated dataset, type of intragenic or intergenic NCL event, read depth of coverage, read length or expression level of NCL transcript. With the high accuracy, NCLscan was applied to distinguishing between trans -spliced, circular and fusion transcripts on the basis of poly(A)- and nonpoly(A)-selected RNA-seq data. We showed that circular RNAs were expressed more ubiquitously, more abundantly and less cell type-specifically than trans -spliced and fusion transcripts. Our study thus describes a robust pipeline for the discovery of NCL transcripts, and sheds light on the fundamental biology of these non-canonical RNA events in human transcriptome.

Description: The presence of calcite in and near faults, as the dominant material, cement, or vein fill, indicates that the mechanical behaviour of carbonate-dominated material likely plays an important role in shallow- and mid-crustal faulting. To better understand the behaviour of calcite, under loading conditions relevant to earthquake nucleation, we sheared powdered gouge of Carrara Marble, 〉98 per cent CaCO 3 , at constant normal stresses between 1 and 100 MPa under water-saturated conditions at room temperature. We performed slide-hold-slide tests, 1–3000 s, to measure the amount of static frictional strengthening and creep relaxation, and velocity-stepping tests, 0.1–1000 μm s –1 , to evaluate frictional stability. We observe that the rates of frictional strengthening and creep relaxation decrease with increasing normal stress and diverge as shear velocity is increased from 1 to 3000 μm s –1 during slide-hold-slide experiments. We also observe complex frictional stability behaviour that depends on both normal stress and shearing velocity. At normal stresses less than 20 MPa, we observe predominantly velocity-neutral friction behaviour. Above 20 MPa, we observe strong velocity-strengthening frictional behaviour at low velocities, which then evolves towards velocity-weakening friction behaviour at high velocities. Microstructural analyses of recovered samples highlight a variety of deformation mechanisms including grain size reduction and localization, folding of calcite grains and fluid-assisted diffusion mass transfer processes promoting the development of calcite nanograins in the highly deformed portions of the experimental fault. Our combined analyses indicate that calcite fault gouge transitions from brittle to semi-brittle behaviour at high normal stress and slow sliding velocities. This transition has important implications for earthquake nucleation and propagation on faults in carbonate-dominated lithologies.

Description: The elastic properties of homogeneous, isotropic materials are well constrained. However, in heterogeneous and evolving materials, these essential properties are less well-explored. During sintering of volcanic ash particles by viscous processes as well as during compaction and cementation of sediments, microstructure and porosity undergo changes that affect bulk dynamic elastic properties. Here using a model system of glass particles as an analogue for initially granular rock-forming materials, we have determined porosity and P -wave velocity during densification. Using these results, we test models for the kinetics of densification and the resultant evolution of the elastic properties to derive a quantitative description of the coupling between the kinetics of isotropic densification and the evolving dynamic elastic moduli. We demonstrate the power of the resultant model on a wide range of data for non-coherent sediments as well as sedimentary and volcanic rocks. We propose that such constraints be viewed as an essential ingredient of time-dependent models for the deformation of evolving materials in volcanoes and sedimentary basins.

Description: We present a study of the seismic velocity variations that occurred in the structure before the large 2010 eruption of Merapi volcano. For the first time to our knowledge, the technique of coda wave interferometry is applied to both families of similar events (multiplets) and to correlation functions of seismic noise. About half of the seismic events recorded at the summit stations belong to one of the ten multiplets identified, including 120 similar events that occurred in the last 20 hr preceding the eruption onset. Daily noise cross-correlation functions (NCF) were calculated for the six pairs of short-period stations available. Using the stretching method, we estimate time-series of apparent velocity variation (AVV) for each multiplet and each pair of stations. No significant velocity change is detected until September 2010. From 10 October to the beginning of the eruption on 26 October, a complex pattern of AVV is observed with amplitude of up to ±1.5 per cent. Velocity decrease is first observed from families of deep events and then from shallow earthquakes. In the same period, AVV with different signs and chronologies are estimated from NCF calculated for various station pairs. The location in the horizontal plane of the velocity perturbations related with the AVV obtained from NCF is estimated by using an approach based on the radiative transfer approximation. Although their spatial resolution is limited, the resulting maps display velocity decrease in the upper part of the edifice in the period 12–25 October. After the eruption onset, the pattern of velocity perturbations is significantly modified with respect to the previous one. We interpret these velocity variations in the framework of a scenario of magmatic intrusion that integrates most observations. The perturbation of the stress field associated with the magma migration can induce both decrease and increase of the seismic velocity of rocks. Thus the detected AVVs can be considered as precursors of volcanic eruptions in andesitic volcanoes, without taking their sign into account.

Description: Visualization of chromosomal dynamics is important for understanding many fundamental intra-nuclear processes. Efficient and reliable live-cell multicolor labeling of chromosomal loci can realize this goal. However, the current methods are constrained mainly by insufficient labeling throughput, efficiency, flexibility as well as photostability. Here we have developed a new approach to realize dual-color chromosomal loci imaging based on a modified single-guide RNA (sgRNA) of the CRISPR/Cas9 system. The modification of sgRNA was optimized by structure-guided engineering of the original sgRNA, consisting of RNA aptamer insertions that bind fluorescent protein-tagged effectors. By labeling and tracking telomeres, centromeres and genomic loci, we demonstrate that the new approach is easy to implement and enables robust dual-color imaging of genomic elements. Importantly, our data also indicate that the fast exchange rate of RNA aptamer binding effectors makes our sgRNA-based labeling method much more tolerant to photobleaching than the Cas9-based labeling method. This is crucial for continuous, long-term tracking of chromosomal dynamics. Lastly, as our method is complementary to other live-cell genomic labeling systems, it is therefore possible to combine them into a plentiful palette for the study of native chromatin organization and genome ultrastructure dynamics in living cells.

Description: The influx of groundwater into hot kimberlite deposits results in the reaction of water with olivine-rich rocks. The products of the reaction are serpentine and release of latent heat. The rise of temperature due to the heat release increases the rate of the reaction. Under certain conditions, this self-speeding up of the reaction can result in instabilities associated with a significantly higher final serpentinization in slightly warmer regions of the kimberlite deposit. We conduct linear stability analysis of serpentinization in an isolated volume of porous kimberlitic rocks saturated with water and an inert gas. There is a counteracting interplay between the heat release tending to destabilize the uniform distribution of parameters and the heat conduction tending to stabilize it by smoothing out temperature perturbations. We determine the critical spatial scale separating the parameters where one phenomenon dominates over another. The perturbations of longer-than-critical length grow, whereas the perturbations of shorter-than-critical length fade. The analytical results of the linear stability analysis are supported by direct numerical simulations using a full nonlinear model.

Description: Inelastic deformation can either occur with dilatancy or compaction, implying differences in porosity changes, failure and petrophysical properties. In this study, the roles of water as a pore fluid, and of temperature, on the deformation and failure of a micritic limestone (white Tavel limestone, porosity 14.7 per cent) were investigated under triaxial stresses. For each sample, a hydrostatic load was applied up to the desired confining pressure (from 0 up to 85 MPa) at either room temperature or at 70 °C. Two pore fluid conditions were investigated at room temperature: dry and water saturated. The samples were deformed up to failure at a constant strain rate of ~10 –5 s –1 . The experiments were coupled with ultrasonic wave velocity surveys to monitor crack densities. The linear trend between the axial crack density and the relative volumetric strain beyond the onset of dilatancy suggests that cracks propagate at constant aspect ratio. The decrease of ultrasonic wave velocities beyond the onset of inelastic compaction in the semi-brittle regime indicates the ongoing interplay of shear-enhanced compaction and crack development. Water has a weakening effect on the onset of dilatancy in the brittle regime, but no measurable influence on the peak strength. Temperature lowers the confining pressure at which the brittle–semi-brittle transition is observed but does not change the stress states at the onset of inelastic compaction and at the post-yield onset of dilatancy.

Description: Remote sensing thermal data of active lava flows allow the evaluation of effusion rates. This is made possible by a simple formula relating the lava effusion rate to the heat flux radiated per unit time from the surface of the flow. Due to the assumptions of the model, this formula implies that heat flux, surface temperature and lava temperature vary as a function of the flow thickness. These relationships, never verified or validated before, have been used by several authors as a proof of the weakness of the model. Here, multispectral infrared and visible imaging spectrometer (MIVIS) high spatial resolution (5–10 m) thermal data acquired during Etna's 2001 eruption were used to investigate downflow heat flux variations in the lava flow emitted from a vent located at 2100 m a.s.l. A high correlation between the downflow heat flux and the lava flow thickness (measured from a pre-existing digital elevation model) was found. Topography beneath the flow appears to play an important role both in lava emplacement mechanisms and flow dynamics. MIVIS-derived downflow effusion rates are consistent with the law of conservation of mass assessing the reliability of remote sensing techniques.

Description: Presence of excess unaltered, wild-type (WT) DNA providing no information of biological or clinical value often masks rare alterations containing diagnostic or therapeutic clues in cancer, prenatal diagnosis, infectious diseases or organ transplantation. With the surge of high-throughput technologies there is a growing demand for removing unaltered DNA over large pools-of-sequences. Here we present nuclease-assisted minor-allele enrichment with probe-overlap (NaME-PrO), a single-step approach with broad genome coverage that can remove WT-DNA from numerous sequences simultaneously, prior to genomic analysis. NaME-PrO employs a double-strand-DNA-specific nuclease and overlapping oligonucleotide-probes interrogating WT-DNA targets and guiding nuclease digestion to these sites. Mutation-containing DNA creates probe-DNA mismatches that inhibit digestion, thus subsequent DNA-amplification magnifies DNA-alterations at all selected targets. We demonstrate several-hundred-fold mutation enrichment in diverse human samples on multiple clinically relevant targets including tumor samples and circulating DNA in 50-plex reactions. Enrichment enables routine mutation detection at 0.01% abundance while by adjusting conditions it is possible to sequence mutations down to 0.00003% abundance, or to scan tumor-suppressor genes for rare mutations. NaME-PrO introduces a simple and highly parallel process to remove un-informative DNA sequences and unmask clinically and biologically useful alterations.

Description: We performed complex conductivity measurements on 28 core samples from the hole drilled for the Humu'ula Groundwater Research Project (Hawai'i Island, HI, USA). The complex conductivity measurements were performed at 4 different pore water conductivities (0.07, 0.5, 1.0 or 2.0, and 10 S m –1 prepared with NaCl) over the frequency range 1 mHz to 45 kHz at 22 ± 1 °C. The in-phase conductivity data are plotted against the pore water conductivity to determine, sample by sample, the intrinsic formation factor and the surface conductivity. The intrinsic formation factor is related to porosity by Archie's law with an average value of the cementation exponent m of 2.45, indicating that only a small fraction of the connected pore space controls the transport properties. Both the surface and quadrature conductivities are found to be linearly related to the cation exchange capacity of the material, which was measured with the cobalt hexamine chloride method. Surface and quadrature conductivities are found to be proportional to each other like for sedimentary siliclastic rocks. A Stern layer polarization model is used to explain these experimental results. Despite the fact that the samples contain some magnetite (up to 5 per cent wt.), we were not able to identify the effect of this mineral on the complex conductivity spectra. These results are very encouraging in showing that galvanometric induced polarization measurements can be used in volcanic areas to separate the bulk from the surface conductivity and therefore to define some alteration attributes. Such a goal cannot be achieved with resistivity alone.

Description: We investigate the relationship between complex conductivity spectra and both permeability and pore mean size and distribution of 22 core samples (21 volcanic rocks and 1 clayey sandstone). The volcanic core samples were extracted from a wellbore drilled for the Humu‘ula Groundwater Research Project in the Humu‘ula saddle region between Mauna Kea and Mauna Loa volcanoes (Hawaii). The quadrature conductivity spectra of volcanic rocks exhibit a subtle, but generally detectable, relaxation frequency in the range 0.3 Hz to 45 kHz similar to the relaxation frequency observed for clayey sandstones. We find a fair relationship between this relaxation frequency and the pore size determined by mercury porosimetry. Combined with the intrinsic formation factor of the core samples, the relaxation frequency can be used as an indicator of the permeability of the material. The predicted values of the permeability are grossly consistent with the permeability values to air (in the range 0.001–100 mD) within two orders of magnitude. The measured permeability values are highly correlated to the peak of the pore size distribution determined from mercury porosimetry divided by the intrinsic formation factor. By fitting the complex conductivity spectra with the pore size distribution, we obtain the normalized chargeability of the core samples, which is, in turn, highly correlated to the measured cation exchange capacity.

Description: The Puyehue-Cordón Caulle Volcanic Complex (PCCVC) is one of the best examples of tectonic control on volcanism at the Southern Volcanic Zone of the Andes (southern Chile). The PCCVC comprises several volcanic centres that erupted dominantly SiO 2 -rich magmas at the intersection of the trench-parallel Liquiñe-Ofqui Fault Zone (LOFZ) and an inherited NW–SE basement structure. The PCCVC began an explosive and later effusive eruption on 2011 June 4 causing decimetre- to metre-scale surface deformation that was observed by a series of Envisat ASAR satellite scenes. We modelled this data and complemented it with time-series of two continuous GPS stations and seismicity recorded by a local network. Deformation during the first 3 days of the eruption can be modelled either by two point sources aligned with the NW–SE Cordón Caulle graben or by a closing dyke with a significant component of left-lateral motion along the graben. These models are discussed with respect to their implications on the estimated rheology and the eruption mechanism. GPS observations near the volcanic complex reveal an additional, more localised effect related to the LOFZ in the south of the complex. Coeruptive deformation at the main geological structures of the PCCVC is further supported by relocated seismicity, which is concentrated along the Cordón Caulle graben and to the western side of the LOFZ.

Description: Coal fires are severe hazards to environment, health and safety throughout the world. Efficient and economical extinguishing of these fires requires that the extent of the subsurface coal fires should be delineated. Electrical and electromagnetic methods have been used to detect coal fires in recent years. However, the resistivity change of coal-bearing rocks at high temperature is rarely investigated. The resistivity characteristics of coal fires at different temperatures and depths are seldomly researched as well. In this paper, we present the results of measurements of several coal-bearing rocks’ resistivity and permeability under high temperature. Two major causes for the change in resistivity with increasing temperature are recognized, there are the increase of charge carriers and thermal fracturing, of which the first one is probably the dominant cause. A set of 2-D simulations is carried out to compare the relation of resolution and efficiency of coal fires detection to temperature and depth when adopting the electrical resistance tomography. The simulation results show that the resolution and efficiency decrease with the decrease of temperature and the increase of depth. Finally, the electrical resistance tomography is used to delineate coal fires in the Anjialing Open Pit Mine. Most low-resistivity regions are verified as coal-fire areas according to the long-term monitoring of borehole temperature. The results indicate that the electrical resistance tomography can be used as a tool for the detection of coal fires.

Description: The RAG1/RAG2 endonuclease initiates V(D)J recombination at antigen receptor loci but also binds to thousands of places outside of these loci. RAG2 localizes directly to lysine 4 trimethylated histone 3 (H3K4me3) through a plant homeodomain (PHD) finger. The relative contribution of RAG2-dependent and RAG1-intrinsic mechanisms in determining RAG1 binding patterns is not known. Through analysis of deep RAG1 ChIP-seq data, we provide a quantitative description of the forces underlying genome-wide targeting of RAG1. Surprisingly, sequence-specific DNA binding contributes minimally to RAG1 targeting outside of antigen receptor loci. Instead, RAG1 binding is driven by two distinct modes of interaction with chromatin: the first is driven by H3K4me3, promoter-focused and dependent on the RAG2 PHD, and the second is defined by H3K27Ac, enhancer-focused and dependent on ‘non-core’ portions of RAG1. Based on this and additional chromatin and genomic features, we formulated a predictive model of RAG1 targeting to the genome. RAG1 binding sites predicted by our model correlate well with observed patterns of RAG1-mediated breaks in human pro-B acute lymphoblastic leukemia. Overall, this study provides an integrative model for RAG1 genome-wide binding and off-target activity and reveals a novel role for the RAG1 non-core region in RAG1 targeting.

Description: Accurate information on thermal conductivity and thermal diffusivity of materials is of central importance in relation to geoscience and engineering problems involving the transfer of heat. Several methods, including the classical divided bar technique, are available for laboratory measurements of thermal conductivity, but much fewer for thermal diffusivity. We have generalized the divided bar technique to the transient case in which thermal conductivity, volumetric heat capacity and thereby also thermal diffusivity are measured simultaneously. As the density of samples is easily determined independently, specific heat capacity can also be determined. The finite element formulation provides a flexible forward solution for heat transfer across the bar, and thermal properties are estimated by inverse Monte Carlo modelling. This methodology enables a proper quantification of experimental uncertainties on measured thermal properties and information on their origin. The developed methodology was applied to various materials, including a standard ceramic material and different rock samples, and measuring results were compared with results applying traditional steady-state divided bar and an independent line-source method. All measurements show highly consistent results and with excellent reproducibility and high accuracy. For conductivity the obtained uncertainty is typically 1–3 per cent, and for diffusivity uncertainty may be reduced to about 3–5 per cent. The main uncertainty originates from the presence of thermal contact resistance associated with the internal interfaces in the bar. These are not resolved during inversion and it is imperative that they are minimized. The proposed procedure is simple and may quite easily be implemented to the many steady-state divided bar systems in operation. A thermally controlled bath, as applied here, may not be needed. Simpler systems, such as applying temperature-controlled water directly from a tap, may also be applied.

Description: Clonal populations accumulate mutations over time, resulting in different haplotypes. Deep sequencing of such a population in principle provides information to reconstruct these haplotypes and the frequency at which the haplotypes occur. However, this reconstruction is technically not trivial, especially not in clonal systems with a relatively low mutation frequency. The low number of segregating sites in those systems adds ambiguity to the haplotype phasing and thus obviates the reconstruction of genome-wide haplotypes based on sequence overlap information. Therefore, we present EVORhA, a haplotype reconstruction method that complements phasing information in the non-empty read overlap with the frequency estimations of inferred local haplotypes. As was shown with simulated data, as soon as read lengths and/or mutation rates become restrictive for state-of-the-art methods, the use of this additional frequency information allows EVORhA to still reliably reconstruct genome-wide haplotypes. On real data, we show the applicability of the method in reconstructing the population composition of evolved bacterial populations and in decomposing mixed bacterial infections from clinical samples.

Description: Data on biological mechanisms of aging are mostly obtained from cross-sectional study designs. An inherent disadvantage of this design is that inter-individual differences can mask small but biologically significant age-dependent changes. A serially sampled design (same individual at different time points) would overcome this problem but is often limited by the relatively small numbers of available paired samples and the statistics being used. To overcome these limitations, we have developed a new vector-based approach, termed three-component analysis, which incorporates temporal distance, signal intensity and variance into one single score for gene ranking and is combined with gene set enrichment analysis. We tested our method on a unique age-based sample set of human skin fibroblasts and combined genome-wide transcription, DNA methylation and histone methylation (H3K4me3 and H3K27me3) data. Importantly, our method can now for the first time demonstrate a clear age-dependent decrease in expression of genes coding for proteins involved in translation and ribosome function. Using analogies with data from lower organisms, we propose a model where age-dependent down-regulation of protein translation-related components contributes to extend human lifespan.

Description: A major challenge in the field of shotgun metagenomics is the accurate identification of organisms present within a microbial community, based on classification of short sequence reads. Though existing microbial community profiling methods have attempted to rapidly classify the millions of reads output from modern sequencers, the combination of incomplete databases, similarity among otherwise divergent genomes, errors and biases in sequencing technologies, and the large volumes of sequencing data required for metagenome sequencing has led to unacceptably high false discovery rates (FDR). Here, we present the application of a novel, gene-independent and signature-based metagenomic taxonomic profiling method with significantly and consistently smaller FDR than any other available method. Our algorithm circumvents false positives using a series of non-redundant signature databases and examines G enomic O rigins T hrough T axonomic CHA llenge (GOTTCHA). GOTTCHA was tested and validated on 20 synthetic and mock datasets ranging in community composition and complexity, was applied successfully to data generated from spiked environmental and clinical samples, and robustly demonstrates superior performance compared with other available tools.

Description: Lying below Vatnajökull ice cap in Iceland, Bárðarbunga stratovolcano began experiencing wholesale caldera collapse in 2014 August 16, one of the largest such events recorded in the modern instrumental era. Simultaneous with this collapse is the initiation of a plate boundary rifting episode north of the caldera. Observations using the international constellation of radar satellites indicate rapid 50 cm d –1 subsidence of the glacier surface overlying the collapsing caldera and metre-scale crustal deformation in the active rift zone. Anomalous earthquakes around the rim of the caldera with highly nondouble-couple focal mechanisms provide a mechanical link to the dynamics of the collapsing magma chamber. A model of the collapse consistent with available geodetic and seismic observations suggests that the majority of the observed subsidence occurs aseismically via a deflating sill-like magma chamber.

Description: With read lengths of currently up to 2 x 300 bp, high throughput and low sequencing costs Illumina's MiSeq is becoming one of the most utilized sequencing platforms worldwide. The platform is manageable and affordable even for smaller labs. This enables quick turnaround on a broad range of applications such as targeted gene sequencing, metagenomics, small genome sequencing and clinical molecular diagnostics. However, Illumina error profiles are still poorly understood and programs are therefore not designed for the idiosyncrasies of Illumina data. A better knowledge of the error patterns is essential for sequence analysis and vital if we are to draw valid conclusions. Studying true genetic variation in a population sample is fundamental for understanding diseases, evolution and origin. We conducted a large study on the error patterns for the MiSeq based on 16S rRNA amplicon sequencing data. We tested state-of-the-art library preparation methods for amplicon sequencing and showed that the library preparation method and the choice of primers are the most significant sources of bias and cause distinct error patterns. Furthermore we tested the efficiency of various error correction strategies and identified quality trimming (Sickle) combined with error correction (BayesHammer) followed by read overlapping (PANDAseq) as the most successful approach, reducing substitution error rates on average by 93%.

Description: RNA-seq is a sensitive and accurate technique to compare steady-state levels of RNA between different cellular states. However, as it does not provide an account of transcriptional activity per se , other technologies are needed to more precisely determine acute transcriptional responses. Here, we have developed an easy, sensitive and accurate novel computational method, iRNA-seq , for genome-wide assessment of transcriptional activity based on analysis of intron coverage from total RNA-seq data. Comparison of the results derived from iRNA-seq analyses with parallel results derived using current methods for genome-wide determination of transcriptional activity, i.e. global run-on (GRO)-seq and RNA polymerase II (RNAPII) ChIP-seq, demonstrate that iRNA-seq provides similar results in terms of number of regulated genes and their fold change. However, unlike the current methods that are all very labor-intensive and demanding in terms of sample material and technologies, iRNA-seq is cheap and easy and requires very little sample material. In conclusion, iRNA-seq offers an attractive novel alternative to current methods for determination of changes in transcriptional activity at a genome-wide level.

Description: Deformation experiments on partially molten rocks in simple shear form melt bands at 20° to the shear plane instead of at the expected 45° principal compressive stress direction. These melt bands may play an important role in melt focusing in mid-ocean ridges. Such shallow bands are known to form for two-phase media under shear if strongly non-Newtonian power-law creep is employed for the solid phase, or anisotropy imposed. However laboratory experiments show that shallow bands occur regardless of creep mechanism, even in diffusion creep, which is nominally Newtonian. Here we propose that a couple of forms of two-phase damage allow for shallow melt bands even in diffusion creep.

Description: Progressive deformation of upper mantle rocks via dislocation creep causes their constituent crystals to take on a non-random orientation distribution (crystallographic preferred orientation or CPO) whose observable signatures include shear-wave splitting and azimuthal dependence of surface wave speeds. Comparison of these signatures with mantle flow models thus allows mantle dynamics to be unraveled on global and regional scales. However, existing self-consistent models of CPO evolution are computationally expensive when used with 3-D and/or time-dependent convection models. Here we propose a new method, called ANPAR, which is based on an analytical parametrization of the crystallographic spin predicted by the second-order (SO) self-consistent theory. Our parametrization runs 2–6  x  10 4 times faster than the SO model and fits its predictions for CPO and crystallographic spin with a variance reduction 〉99 per cent. We illustrate the ANPAR model predictions for the deformation of olivine with three dominant slip systems, (010)[100], (001)[100] and (010)[001], for three uniform deformations (uniaxial compression, pure shear and simple shear) and for a corner-flow model of a spreading mid-ocean ridge.

Description: Any given human individual carries multiple genetic variants that disrupt protein-coding genes, through structural variation, as well as nucleotide variants and indels. Predicting the phenotypic consequences of a gene disruption remains a significant challenge. Current approaches employ information from a range of biological networks to predict which human genes are haploinsufficient (meaning two copies are required for normal function) or essential (meaning at least one copy is required for viability). Using recently available study gene sets, we show that these approaches are strongly biased towards providing accurate predictions for well-studied genes. By contrast, we derive a haploinsufficiency score from a combination of unbiased large-scale high-throughput datasets, including gene co-expression and genetic variation in over 6000 human exomes. Our approach provides a haploinsufficiency prediction for over twice as many genes currently unassociated with papers listed in Pubmed as three commonly-used approaches, and outperforms these approaches for predicting haploinsufficiency for less-studied genes. We also show that fine-tuning the predictor on a set of well-studied ‘gold standard’ haploinsufficient genes does not improve the prediction for less-studied genes. This new score can readily be used to prioritize gene disruptions resulting from any genetic variant, including copy number variants, indels and single-nucleotide variants.

Description: We investigate the capability of Time Reversal Mirror (TRM) algorithm to image local acoustic sources (〈3.5 km) associated with complex, sustained volcanic eruptions. Accurate source localization for volcano infrasound (low-frequency acoustic waves) is often challenging due to pronounced volcanic topography and emergent arrivals of infrasound signals. While the accuracy of the conventional approaches (e.g. triangulation and semblance method) can be severely compromised by the complex volcanic settings, a TRM-based method may have the potential to properly image acoustic sources by the use of full waveform information and numerical modelling of the time-reversed wavefield. We apply the TRM algorithm to a pyroclastic-laden eruption (sustained for ~60 s) at Santiaguito Volcano, Guatemala, and show that an ordinary TRM operation can undergo significant reduction of its focusing power due to strong topographic propagation effects (e.g. reflection and diffraction). We propose a weighted imaging condition to compensate for complicated transmission loss of the time-reversed wavefield and demonstrate that the presented condition significantly improves the focusing quality of TRM in the presence of complex topography. The consequent TRM source images exhibit remarkable agreement with the visual observation of the eruption implying that the TRM method with a proper imaging condition can be used to localize and track acoustic sources associated with complex volcanic eruptions.

Description: Meta-analysis of gene expression has enabled numerous insights into biological systems, but current methods have several limitations. We developed a method to perform a meta-analysis using the elastic net, a powerful and versatile approach for classification and regression. To demonstrate the utility of our method, we conducted a meta-analysis of lung cancer gene expression based on publicly available data. Using 629 samples from five data sets, we trained a multinomial classifier to distinguish between four lung cancer subtypes. Our meta-analysis-derived classifier included 58 genes and achieved 91% accuracy on leave-one-study-out cross-validation and on three independent data sets. Our method makes meta-analysis of gene expression more systematic and expands the range of questions that a meta-analysis can be used to address. As the amount of publicly available gene expression data continues to grow, our method will be an effective tool to help distill these data into knowledge.

Description: Extensive and multi-dimensional data sets generated from recent cancer omics profiling projects have presented new challenges and opportunities for unraveling the complexity of cancer genome landscapes. In particular, distinguishing the unique complement of genes that drive tumorigenesis in each patient from a sea of passenger mutations is necessary for translating the full benefit of cancer genome sequencing into the clinic. We address this need by presenting a data integration framework (OncoIMPACT) to nominate patient-specific driver genes based on their phenotypic impact. Extensive in silico and in vitro validation helped establish OncoIMPACT's robustness, improved precision over competing approaches and verifiable patient and cell line specific predictions (2/2 and 6/7 true positives and negatives, respectively). In particular, we computationally predicted and experimentally validated the gene TRIM24 as a putative novel amplified driver in a melanoma patient. Applying OncoIMPACT to more than 1000 tumor samples, we generated patient-specific driver gene lists in five different cancer types to identify modes of synergistic action. We also provide the first demonstration that computationally derived driver mutation signatures can be overall superior to single gene and gene expression based signatures in enabling patient stratification and prognostication. Source code and executables for OncoIMPACT are freely available from http://sourceforge.net/projects/oncoimpact .

Description: Analysis of rewired upstream subnetworks impacting downstream differential gene expression aids the delineation of evolving molecular mechanisms. Cumulative statistics based on conventional differential correlation are limited for subnetwork rewiring analysis since rewiring is not necessarily equivalent to change in correlation coefficients. Here we present a computational method ChiNet to quantify subnetwork rewiring by statistical heterogeneity that enables detection of potential genotype changes causing altered transcription regulation in evolving organisms. Given a differentially expressed downstream gene set, ChiNet backtracks a rewired upstream subnetwork from a super-network including gene interactions known to occur under various molecular contexts. We benchmarked ChiNet for its high accuracy in distinguishing rewired artificial subnetworks, in silico yeast transcription-metabolic subnetworks, and rewired transcription subnetworks for Candida albicans versus Saccharomyces cerevisiae , against two differential-correlation based subnetwork rewiring approaches. Then, using transcriptome data from tolerant S. cerevisiae strain NRRL Y-50049 and a wild-type intolerant strain, ChiNet identified 44 metabolic pathways affected by rewired transcription subnetworks anchored to major adaptively activated transcription factor genes YAP1 , RPN4 , SFP1 and ROX1 , in response to toxic chemical challenges involved in lignocellulose-to-biofuels conversion. These findings support the use of ChiNet in rewiring analysis of subnetworks where differential interaction patterns resulting from divergent nonlinear dynamics abound.

Description: We present a strategy to thoroughly investigate the effects of prominent topography on the surface tilt due to a spherical pressure source. We use Etna's topography as a case of study and, for different source positions, we compare the tilt fields calculated through (i) a 3-D boundary element method and (ii) analytical half-space solutions. We systematically determine (i) the source positions leading to the strongest tilt misfits when numerical and analytical results are compared and (ii) the surface areas where the strongest distortions in the tilt field are most likely to be observed. We also demonstrate that, under critical circumstances, in terms of respective positions of pressure source and observation points, results of inversion procedures aimed at retrieving the source parameters can be misleading, if tilt data are analysed using models that do not account for topography.

Description: The agreement between shear wave velocities for the Earth's inner core observed from seismology with those derived from mineral physics is considerably worse than for any other region of the Earth. Furthermore, there is still debate as to the phase of iron present in the inner core, particularly when alloying with nickel and light elements is taken into account. To investigate the extent to which the mismatch between seismology and mineral physics is a function of either crystal structure and/or the amount of nickel present, we have used ab initio molecular dynamics simulations to calculate the elastic constants and seismic velocities ( V p and V s ) of face centred cubic (fcc) iron at Earth's inner core pressures (360 GPa) and at temperatures up to ~7000 K. We find that V p for fcc iron (fcc-Fe) is very similar to that for hexagonal close packed (hcp) iron at all temperatures. In contrast, V s for fcc-Fe is significantly higher than in hcp-Fe, with the difference increasing with increasing temperature; the difference between V s for the core (from seismology) and V s for fcc-Fe exceeds 40 per cent. These results are consistent with previous work at lower temperatures. We have also investigated the effect of 6.5 and 13 atm% Ni in fcc-Fe. We find that Ni only slightly reduces V p and V s (e.g. by 2 per cent in V s for 13 atm% Ni at 5500 K), and cannot account for the difference between the velocities observed in the core and those of pure fcc-Fe. We also tried to examine pre-melting behaviour in fcc-Fe, as reported in hcp-Fe by extending the study to very high temperatures (at which superheating may occur). However, we find that fcc-Fe spontaneously transforms to other hcp-like structures before melting; two hcp-like structures were found, both of hexagonal symmetry, which may most easily be regarded as being derived from an hcp crystal with stacking faults. That the structure did not transform to a true hcp phase is likely as a consequence of the limited size of the simulation box (108 atoms). At 360 GPa, in pure fcc-Fe, we find that the transition from fcc to the hcp-like structure occurs at 7000 K, whereas in the Ni bearing system, the transition occurs at higher temperature (7250 K). This reinforces previous work showing that fcc-Fe might transform to hcp-Fe just before melting, and that Ni tends to stabilize the fcc structure with respect to hcp.

Description: Viscoelastic behaviour of materials in nature is observed in post-event deformations due to seismic or volcanic activities. In this paper, by adopting the correspondence principle, we propose an inelastic model to predict first the Laplace-domain response of a transversely isotropic viscoelastic half-space due to a shear or tensile fault of polygonal shape. The displacement and stress fields in the time domain are then obtained using an efficient and accurate algorithm for the inverse Laplace transform. Numerical examples are presented to validate the proposed solution and to show the viscoelastic displacement and stress fields due to a strike-slip, dip-slip and tensile fault of rectangular shape. The obtained results indicate that both viscoelasticity and transverse isotropy play significant roles in the viscoelastic response of the half-space due to faults, which could be used as benchmarks for the future numerical analysis of realistic post-seismic or volcanic event.

Description: One of the unresolved questions concerning fault deformation is the degree and cause of localization of shear at depth beneath a fault. Geologic observations of exhumed shear zones indicate that while the motion is no longer planar, it can still be localized near the down-dip extension of the fault; however, the degree of localization is uncertain. We employ simple analytic and numerical models to investigate the structural form of distributed shear beneath a strike-slip fault, and the relative importance of the physical mechanisms that have the potential to localize a shear zone. For a purely depth dependent viscosity, = 0 exp (– z / z 0 ), we find that a shear zone develops with a half-width $\delta _w\sim \sqrt{z_0}$ for small z 0 at the base of the layer, where lengths are non-dimensionalized by the layer thickness ( d km). Including a non-linear stress–strain-rate relation ( $\dot{\epsilon }\propto \sigma ^n$ ) scales w by $1/\sqrt{n}$ , comparable to deformation length scales in thin viscous sheet calculations. We find that the primary control on the shear-zone width is the depth dependence of viscosity that arises from the temperature dependence of viscosity and the increase in temperature with depth. As this relationship is exponential, scaling relations give a dimensional half-width that scales approximately as $$ \tilde{\delta }_w\approx T_{\frac{1}{2}}\sqrt{\frac{Rd}{nQ\beta }}\text{ km}, $$ where $T_{\frac{1}{2}}$ (K) is the temperature at the midpoint of the layer, R (J mol –1 K –1 ) the gas constant, Q (J mol –1 ) the activation energy and β (K km –1 ) the geothermal gradient. This relation predicts the numerical results for the parameter range consistent with continental rheologies to within 2–5 per cent and shear-zone half-widths from 2 to 6 km. The inclusion of shear-stress heating reduces w by only an additional 5–25 per cent, depending on the initial width of the shear zone. While the width of the shear zone may not decrease significantly, local temperature increases from shear-stress heating range from 50 to 300 °C resulting in a reduction in viscosities beneath the fault of several orders of magnitude and a concomitant reduction in the stresses needed to drive the motion.

Description: Ribosome biogenesis, a central and essential cellular process, occurs through sequential association and mutual co-folding of protein–RNA constituents in a well-defined assembly pathway. Here, we construct a network of co-evolving nucleotide/amino acid residues within the ribosome and demonstrate that assembly constraints are strong predictors of co-evolutionary patterns. Predictors of co-evolution include a wide spectrum of structural reconstitution events, such as cooperativity phenomenon, protein-induced rRNA reconstitutions, molecular packing of different rRNA domains, protein–rRNA recognition, etc. A correlation between folding rate of small globular proteins and their topological features is known. We have introduced an analogous topological characteristic for co-evolutionary network of ribosome, which allows us to differentiate between rRNA regions subjected to rapid reconstitutions from those hindered by kinetic traps. Furthermore, co-evolutionary patterns provide a biological basis for deleterious mutation sites and further allow prediction of potential antibiotic targeting sites. Understanding assembly pathways of multicomponent macromolecules remains a key challenge in biophysics. Our study provides a ‘proof of concept’ that directly relates co-evolution to biophysical interactions during multicomponent assembly and suggests predictive power to identify candidates for critical functional interactions as well as for assembly-blocking antibiotic target sites.

Description: The emergence of new sequencing technologies has facilitated the use of bacterial whole genome alignments for evolutionary studies and outbreak analyses. These datasets, of increasing size, often include examples of multiple different mechanisms of horizontal sequence transfer resulting in substantial alterations to prokaryotic chromosomes. The impact of these processes demands rapid and flexible approaches able to account for recombination when reconstructing isolates’ recent diversification. Gubbins is an iterative algorithm that uses spatial scanning statistics to identify loci containing elevated densities of base substitutions suggestive of horizontal sequence transfer while concurrently constructing a maximum likelihood phylogeny based on the putative point mutations outside these regions of high sequence diversity. Simulations demonstrate the algorithm generates highly accurate reconstructions under realistically parameterized models of bacterial evolution, and achieves convergence in only a few hours on alignments of hundreds of bacterial genome sequences. Gubbins is appropriate for reconstructing the recent evolutionary history of a variety of haploid genotype alignments, as it makes no assumptions about the underlying mechanism of recombination. The software is freely available for download at github.com/sanger-pathogens/Gubbins , implemented in Python and C and supported on Linux and Mac OS X.

Description: Genomic structural variation (SV), a common hallmark of cancer, has important predictive and therapeutic implications. However, accurately detecting SV using high-throughput sequencing data remains challenging, especially for ‘targeted’ resequencing efforts. This is critically important in the clinical setting where targeted resequencing is frequently being applied to rapidly assess clinically actionable mutations in tumor biopsies in a cost-effective manner. We present BreaKmer, a novel approach that uses a ‘kmer’ strategy to assemble misaligned sequence reads for predicting insertions, deletions, inversions, tandem duplications and translocations at base-pair resolution in targeted resequencing data. Variants are predicted by realigning an assembled consensus sequence created from sequence reads that were abnormally aligned to the reference genome. Using targeted resequencing data from tumor specimens with orthogonally validated SV, non-tumor samples and whole-genome sequencing data, BreaKmer had a 97.4% overall sensitivity for known events and predicted 17 positively validated, novel variants. Relative to four publically available algorithms, BreaKmer detected SV with increased sensitivity and limited calls in non-tumor samples, key features for variant analysis of tumor specimens in both the clinical and research settings.

Description: The equation that relates pressure, temperature and volume and is described by parameters that are function of temperature at 1 bar (hereafter called thermal equation of state, TEOS), has practical computational advantages for petrological and geophysical applications over the equation that considers explicitly a thermal pressure. Some considerations that justify the use of the TEOS are discussed here. (1) The assumption that the parameters are function of temperature is perhaps better understood by looking at the Helmholtz energy function that is implicitly assumed in the case of an equation of state (EOS) derived from interatomic potentials. A test case shows that the Helmholtz energy related to the Vinet EOS and the Helmholtz energy from the Debye model are very similar. (2) The TEOS should be able to reproduce thermal expansion (α), isothermal bulk modulus ( K T ) and heat capacity ( C p and C v ) at high P , T computed from a lattice vibration model. The generalized Rydberg EOS applied to MgO is able to fit reasonably well the properties computed using Jacobs’ lattice dynamics formulation ( T range = 300–3000 K, P range = 1 bar–1500 kbar). (3) It is shown that in the case of MgO, the TEOS can be used quite successfully for extrapolation that goes beyond the P , T range of the measured/given data. Some physical constraints need to be applied to the derivation of the volume, bulk modulus and derivative of the bulk modulus with pressure at 1 bar. (4) The pressure dependence of the reference parameters in the TEOS that was inferred several decades ago is only apparent. A numerical computation demonstrates that the combined pressure effect in the terms defining the partial derivative of the reference V and K (and K') over temperature cancels out, making the reference parameters independent of pressure at any condition.

Description: The equation that relates pressure, temperature and volume and is described by parameters that are function of temperature at 1 bar (hereafter called thermal equation of state, TEOS), has practical computational advantages for petrological and geophysical applications over the equation that considers explicitly a thermal pressure. Some considerations that justify the use of the TEOS are discussed here. (1) The assumption that the parameters are function of temperature is perhaps better understood by looking at the Helmholtz energy function that is implicitly assumed in the case of an equation of state (EOS) derived from interatomic potentials. A test case shows that the Helmholtz energy related to the Vinet EOS and the Helmholtz energy from the Debye model are very similar. (2) The TEOS should be able to reproduce thermal expansion (α), isothermal bulk modulus ( K T ) and heat capacity ( C p and C v ) at high P , T computed from a lattice vibration model. The generalized Rydberg EOS applied to MgO is able to fit reasonably well the properties computed using Jacobs’ lattice dynamics formulation ( T range = 300–3000 K, P range = 1 bar–1500 kbar). (3) It is shown that in the case of MgO, the TEOS can be used quite successfully for extrapolation that goes beyond the P , T range of the measured/given data. Some physical constraints need to be applied to the derivation of the volume, bulk modulus and derivative of the bulk modulus with pressure at 1 bar. (4) The pressure dependence of the reference parameters in the TEOS that was inferred several decades ago is only apparent. A numerical computation demonstrates that the combined pressure effect in the terms defining the partial derivative of the reference V and K (and K') over temperature cancels out, making the reference parameters independent of pressure at any condition.

Description: A knowledge of subsurface temperatures in sedimentary basins, fault zones, volcanic environments and polar ice sheets is of interest for a wide variety of geophysical applications. However, the process of drilling deep boreholes in these environments to provide access for temperature and other measurements invariably disturbs the temperature field around a newly created borehole. Although this disturbance dissipates over time, most temperature measurements are made while the temperature field is still disturbed. Thus, the measurements must be ‘corrected’ for the drilling-disturbance effect if the undisturbed temperature field is to be determined. This paper provides compact analytical solutions for the thermal drilling disturbance based on 1-D (radial) and 2-D (radial and depth) Green's functions (GFs) in cylindrical coordinates. Solutions are developed for three types of boundary conditions (BCs) at the borehole wall: (1) prescribed temperature, (2) prescribed heat flux and (3) a prescribed convective condition. The BC at the borehole wall is allowed to vary both with depth and time. Inclusion of the depth dimension in the 2-D solution allows vertical heat-transfer effects to be quantified in situations where they are potentially important, that is, near the earth's surface, at the bottom of a well and when considering finite-drilling rates. The 2-D solution also includes a radial- and time-dependent BC at the earth's surface to assess the impact of drilling-related infrastructure (drilling pads, mud pits, permanent shelters) on the subsurface temperature field. Latent-heat effects due to the melting and subsequent refreezing of interstitial ice while drilling a borehole through ice-rich permafrost can be included in the GF solution as a moving-plane heat source (or sink) located at the solid–liquid interface. Synthetic examples are provided illustrating the 1-D and 2-D GF solutions. The flexibility of the approach allows the investigation of thermal drilling effects in rock or ice for a wide variety of drilling technologies. Numerical values for the required radial GFs G R are available through the Advanced Cooperative Arctic Data and Information Service at doi:10.5065/D64F1NS6.

Description: Detecting allelic biases from high-throughput sequencing data requires an approach that maximises sensitivity while minimizing false positives. Here, we present Allelome.PRO, an automated user-friendly bioinformatics pipeline, which uses high-throughput sequencing data from reciprocal crosses of two genetically distinct mouse strains to detect allele-specific expression and chromatin modifications. Allelome.PRO extends approaches used in previous studies that exclusively analyzed imprinted expression to give a complete picture of the ‘allelome’ by automatically categorising the allelic expression of all genes in a given cell type into imprinted, strain-biased, biallelic or non-informative. Allelome.PRO offers increased sensitivity to analyze lowly expressed transcripts, together with a robust false discovery rate empirically calculated from variation in the sequencing data. We used RNA-seq data from mouse embryonic fibroblasts from F1 reciprocal crosses to determine a biologically relevant allelic ratio cutoff, and define for the first time an entire allelome. Furthermore, we show that Allelome.PRO detects differential enrichment of H3K4me3 over promoters from ChIP-seq data validating the RNA-seq results. This approach can be easily extended to analyze histone marks of active enhancers, or transcription factor binding sites and therefore provides a powerful tool to identify candidate cis regulatory elements genome wide.

Description: Methods to interpret personal genome sequences are increasingly required. Here, we report a novel framework (EvoTol) to identify disease-causing genes using patient sequence data from within protein coding-regions. EvoTol quantifies a gene's intolerance to mutation using evolutionary conservation of protein sequences and can incorporate tissue-specific gene expression data. We apply this framework to the analysis of whole-exome sequence data in epilepsy and congenital heart disease, and demonstrate EvoTol's ability to identify known disease-causing genes is unmatched by competing methods. Application of EvoTol to the human interactome revealed networks enriched for genes intolerant to protein sequence variation, informing novel polygenic contributions to human disease.

Description: Detecting in vivo transcription factor (TF) binding is important for understanding gene regulatory circuitries. ChIP-seq is a powerful technique to empirically define TF binding in vivo . However, the multitude of distinct TFs makes genome-wide profiling for them all labor-intensive and costly. Algorithms for in silico prediction of TF binding have been developed, based mostly on histone modification or DNase I hypersensitivity data in conjunction with DNA motif and other genomic features. However, technical limitations of these methods prevent them from being applied broadly, especially in clinical settings. We conducted a comprehensive survey involving multiple cell lines, TFs, and methylation types and found that there are intimate relationships between TF binding and methylation level changes around the binding sites. Exploiting the connection between DNA methylation and TF binding, we proposed a novel supervised learning approach to predict TF–DNA interaction using data from base-resolution whole-genome methylation sequencing experiments. We devised beta-binomial models to characterize methylation data around TF binding sites and the background. Along with other static genomic features, we adopted a random forest framework to predict TF–DNA interaction. After conducting comprehensive tests, we saw that the proposed method accurately predicts TF binding and performs favorably versus competing methods.

Description: Tarim Craton is a Precambrian block situated in northwest China, just north of the Tibetan Plateau, where a large sedimentary basin with abundant hydrocarbon potential has developed. Accurate heat flow data for Tarim is vital for understanding the lithospheric evolution and hydrocarbon generation in this area; however, there were unavailable until now, due to a lack of high quality steady-state temperature logging data. Here, we report 10 new heat flow values derived from steady-state temperature logging and measured thermal conductivity data. New heat flow values range from 40.1 to 49.4 mW m –2 , with a mean of 43.1 ± 3.0 mW m –2 . In addition, radiogenic heat production from the sediments accounts for 20 per cent of the observed surface heat flow, whilst the mantle heat flow is estimated to be as low as 6–15 mW m –2 ; this indicates a dominant contribution from crustal heat, to the observed heat flow. The average heat flow and crustal temperature in the Tarim Craton are markedly lower than those in the Tibetan Plateau, whilst the calculated rheological strength of the lithosphere, beneath Tarim, is sufficiently large to resist the elevation-induced gravitational potential energy difference between Tarim and Tibet. This inherited thermal and rheological contrast, between the craton and Plateau, can be traced back to before the India–Asia collision; this accounts for the differential active deformation pattern in the Tarim Craton and adjacent areas.

Description: Copy-number variants (CNVs) are a major form of genetic variation and a risk factor for various human diseases, so it is crucial to accurately detect and characterize them. It is conceivable that allele-specific reads from high-throughput sequencing data could be leveraged to both enhance CNV detection and produce allele-specific copy number (ASCN) calls. Although statistical methods have been developed to detect CNVs using whole-genome sequence (WGS) and/or whole-exome sequence (WES) data, information from allele-specific read counts has not yet been adequately exploited. In this paper, we develop an integrated method, called AS-GENSENG, which incorporates allele-specific read counts in CNV detection and estimates ASCN using either WGS or WES data. To evaluate the performance of AS-GENSENG, we conducted extensive simulations, generated empirical data using existing WGS and WES data sets and validated predicted CNVs using an independent methodology. We conclude that AS-GENSENG not only predicts accurate ASCN calls but also improves the accuracy of total copy number calls, owing to its unique ability to exploit information from both total and allele-specific read counts while accounting for various experimental biases in sequence data. Our novel, user-friendly and computationally efficient method and a complete analytic protocol is freely available at https://sourceforge.net/projects/asgenseng/ .

Description: Increased sequencing of microbial genomes has revealed that prevailing prokaryotic species assignments can be inconsistent with whole genome information for a significant number of species. The long-standing need for a systematic and scalable species assignment technique can be met by the genome-wide Average Nucleotide Identity (gANI) metric, which is widely acknowledged as a robust measure of genomic relatedness. In this work, we demonstrate that the combination of gANI and the alignment fraction (AF) between two genomes accurately reflects their genomic relatedness. We introduce an efficient implementation of AF,gANI and discuss its successful application to 86.5M genome pairs between 13,151 prokaryotic genomes assigned to 3032 species. Subsequently, by comparing the genome clusters obtained from complete linkage clustering of these pairs to existing taxonomy, we observed that nearly 18% of all prokaryotic species suffer from anomalies in species definition. Our results can be used to explore central questions such as whether microorganisms form a continuum of genetic diversity or distinct species represented by distinct genetic signatures. We propose that this precise and objective AF,gANI-based species definition: the MiSI (Microbial Species Identifier) method, be used to address previous inconsistencies in species classification and as the primary guide for new taxonomic species assignment, supplemented by the traditional polyphasic approach, as required.

Description: Classically or alternatively activated macrophages (M1 and M2, respectively) play distinct and important roles for microbiocidal activity, regulation of inflammation and tissue homeostasis. Despite this, their transcriptional regulatory dynamics are poorly understood. Using promoter-level expression profiling by non-biased deepCAGE we have studied the transcriptional dynamics of classically and alternatively activated macrophages. Transcription factor (TF) binding motif activity analysis revealed four motifs, NFKB1_REL_RELA, IRF1,2, IRF7 and TBP that are commonly activated but have distinct activity dynamics in M1 and M2 activation. We observe matching changes in the expression profiles of the corresponding TFs and show that only a restricted set of TFs change expression. There is an overall drastic and transient up-regulation in M1 and a weaker and more sustainable up-regulation in M2. Novel TFs, such as Thap6, Maff , (M1) and Hivep1, Nfil3, Prdm1 , (M2) among others, were suggested to be involved in the activation processes. Additionally, 52 (M1) and 67 (M2) novel differentially expressed genes and, for the first time, several differentially expressed long non-coding RNA (lncRNA) transcriptome markers were identified. In conclusion, the finding of novel motifs, TFs and protein-coding and lncRNA genes is an important step forward to fully understand the transcriptional machinery of macrophage activation.

Description: In this study, equations are developed that predict for synthetic sedimentary rocks (clastics, carbonates and evapourates) thermal properties comprising thermal conductivity, specific heat capacity and thermal diffusivity. The rock groups are composed of mineral assemblages with variable contents of 15 major rock-forming minerals and porosities of 0–30 per cent. Petrophysical properties and their well-logging-tool-characteristic readings were assigned to these rock-forming minerals and to pore-filling fluids. Relationships are explored between each thermal property and other petrophysical properties (density, sonic interval transit time, hydrogen index, volume fraction of shale and photoelectric absorption index) using multivariate statistics. The application of these relations allows computing continuous borehole profiles for each rock thermal property. The uncertainties in the prediction of each property vary depending on the selected well-log combination. Best prediction is in the range of 2–8 per cent for the specific heat capacity, of 5–10 per cent for the thermal conductivity, and of 8–15 for the thermal diffusivity, respectively. Well-log derived thermal conductivity is validated by laboratory data measured on cores from deep boreholes of the Danish Basin, the North German Basin, and the Molasse Basin. Additional validation of thermal conductivity was performed by comparing predicted and measured temperature logs. The maximum deviation between these logs is 〈3 °C. The thermal-conductivity calculation allowed an evaluation of the depth range in which the palaeoclimatic effect on the subsurface temperature field can be observed in the North German Basin. This effect reduces the surface heat-flow density by 25 mW m –2 .

Description: It is important to know the electrokinetic properties of crustal rocks for interpreting the conductivity mechanisms and seismoelectric phenomena during earthquakes and seismoelectric well logging. In this study, electrokinetic experiments are conducted using a special core-holder by employing an AC lock-in technique. A series of experiments are conducted on 10 sandstone samples to measure the streaming potentials and streaming currents, and the experiments on each sample are done at six different salinities. The streaming potential coefficient and streaming current coefficient are calculated from the measured streaming potentials and streaming currents. The experimental results show that streaming potential coefficient and streaming current coefficient decrease as the salinity increases. The dependence of these two coefficients on permeability and pore radius are analysed and compared with previous works. At low salinities, the streaming potential coefficient and streaming current coefficient increase with the increasing permeability and pore radius. At high salinities, the streaming potential coefficient (streaming current coefficient) almost share a same value for 10 different samples. This conclusion indicates that the differences of rock parameters can only be well recognized at lower salinities, and the electrokinetic signals are invalid at high salinities, which offers a restrictive condition for using the amplitude of electrokinetic signals to estimate rock parameters. The zeta-potential have also been estimated through combined measurements of streaming potential and streaming current. The surface conductivity and its contribution to electrokinetic effects are determined from a comparison of zeta-potentials by two different methods, and then the validation of the Helmholz–Smoluchowski equation for a capillary tube is tested in rocks. We also compare our date with theoretical and experimental works, and set up an expression about the relationship between zeta potential and salinity, which fits the experimental data well.

Description: We used ab initio molecular dynamics to calculate the elastic constants of MgSiO 3 , FeSiO 3 and (Fe 0.5 Mg 0.5 )SiO 3 perovskite under lower-most mantle conditions (136 GPa, 2000–4000 K). At 0 K, V p and V s for FeSiO 3 perovskite are 12 and 18 per cent lower, respectively than those for MgSiO 3 , in agreement with previous work. The difference in velocity, however, increases with temperature for high spin (but not low spin) states and at 4000 K, V p and V s for the end-member FeSiO 3 are, respectively, 19 and 34 per cent lower than those of MgSiO 3 . We find that (dln V s /dln V p ) T,P of Fe x Mg 1- x O 3 remains below 2 for all relevant iron concentrations and lower than the value of 3 seen in most ultralow velocity zones (ULVZ). Moreover, we are unable to match simultaneously the observed density increase and shear wave velocity reduction shown by ULVZs by increasing the ferrous iron content in perovskite except for the largest density increases and the smallest shear wave decreases observed in ULVZs. Assuming that current seismic estimates of ULVZ properties are accurate, our results suggest that ferrous iron enrichment alone cannot explain ULVZs.