ALBERT

Description: O -GlcNAcylation is an inducible, highly dynamic and reversible post-translational modification, mediated by a unique enzyme named O -linked N -acetyl- d -glucosamine ( O -GlcNAc) transferase (OGT). In response to nutrients, O -GlcNAc levels are differentially regulated on many cellular proteins involved in gene expression, translation, immune reactions, protein degradation, protein–protein interaction, apoptosis and signal transduction. In contrast to eukaryotic cells, little is known about the role of O -GlcNAcylation in the viral life cycle. Here, we show that the overexpression of the OGT reduces the replication efficiency of Kaposi's sarcoma-associated herpesvirus (KSHV) in a dose-dependent manner. In order to investigate the global impact of O -GlcNAcylation in the KSHV life cycle, we systematically analyzed the 85 annotated KSHV-encoded open reading frames for O -GlcNAc modification. For this purpose, an immunoprecipitation (IP) strategy with three different approaches was carried out and the O -GlcNAc signal of the identified proteins was properly controlled for specificity. Out of the 85 KSHV-encoded proteins, 18 proteins were found to be direct targets for O -GlcNAcylation. Selected proteins were further confirmed by mass spectrometry for O -GlcNAc modification. Correlation of the functional annotation and the O -GlcNAc status of KSHV proteins showed that the predominant targets were proteins involved in viral DNA synthesis and replication. These results indicate that O -GlcNAcylation plays a major role in the regulation of KSHV propagation.

Description: Galectins are potent adhesion/growth-regulatory effectors with characteristic expression profiles. Understanding the molecular basis of gene regulation in each case requires detailed information on copy number of genes and sequence(s) of their promoter(s). Our report reveals plasticity in this respect between galectins and species. We here describe occurrence of a two-gene constellation for human galectin (Gal)-7 and define current extent of promoter-sequence divergence. Interestingly, cross-species genome analyses also detected single-copy display. Because the regulatory potential will then be different, extrapolations of expression profiles are precluded between respective species pairs. Gal-4 coding in chromosomal vicinity was found to be confined to one gene, whereas copy-number variation also applied to Gal-9. The example of rat Gal-9 teaches the lesson that the presence of multiple bands in Southern blotting despite a single-copy gene constellation is attributable to two pseudogenes. The documented copy-number variability should thus be taken into consideration when studying regulation of galectin genes, in a species and in comparison between species.

Description: In studying the molecular basis for the potent immune activity of previously described gamma and delta inulin particles and to assist in production of inulin adjuvants under Good Manufacturing Practice, we identified five new inulin isoforms, bringing the total to seven plus the amorphous form. These isoforms comprise the step-wise inulin developmental series amorphous -〉 alpha-1 (AI-1) -〉 alpha-2 (AI-2) -〉 gamma (GI) -〉 delta (DI) -〉 zeta (ZI) -〉 epsilon (EI) -〉 omega (OI) in which each higher isoform can be made either by precipitating dissolved inulin or by direct conversion from its precursor, both cases using regularly increasing temperatures. At higher temperatures, the shorter inulin polymer chains are released from the particle and so the key difference between isoforms is that each higher isoform comprises longer polymer chains than its precursor. An increasing trend of degree of polymerization is confirmed by end-group analysis using 1 H nuclear magnetic resonance spectroscopy. Inulin isoforms were characterized by the critical temperatures of abrupt phase-shifts (solubilizations or precipitations) in water suspensions. Such (aqueous) "melting" or "freezing" points are diagnostic and occur in strikingly periodic steps reflecting quantal increases in noncovalent bonding strength and increments in average polymer lengths. The (dry) melting points as measured by modulated differential scanning calorimetry similarly increase in regular steps. We conclude that the isoforms differ in repeated increments of a precisely repeating structural element. Each isoform has a different spectrum of biological activities and we show the higher inulin isoforms to be more potent alternative complement pathway activators.

Description: The methylotrophic yeast, Pichia pastoris , is an important organism used for the production of therapeutic proteins. Previously, we have reported the glycoengineering of this organism to produce human-like N -linked glycans but up to now no one has addressed engineering the O -linked glycosylation pathway. Typically, O -linked glycans produced by wild-type P. pastoris are linear chains of four to five α-linked mannose residues, which may be capped with β- or phospho-mannose. Previous genetic engineering of the N-linked glycosylation pathway of P. pastoris has eliminated both of these two latter modifications, resulting in O -linked glycans which are linear α-linked mannose structures. Here, we describe a method for the co-expression of an α-1,2-mannosidase, which reduces these glycans to primarily a single O -linked mannose residue. In doing so, we have reduced the potential of these glycans to interact with carbohydrate-binding proteins, such as dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin. Furthermore, the introduction of the enzyme protein- O -linked-mannose β-1,2- N -acetylglucosaminyltransferase 1, resulted in the capping of the single O -linked mannose residues with N -acetylglucosamine. Subsequently, this glycoform was extended into human-like sialylated glycans, similar in structure to α-dystroglycan-type glycoforms. As such, this represents the first example of sialylated O -linked glycans being produced in yeast and extends the utility of the P. pastoris production platform beyond N -linked glycosylated biotherapeutics to include molecules possessing O -linked glycans.

Description: Neurons and other cells require intracellular transport of essential components for viability and function. Previous work has shown that while net amyloid precursor protein (APP) transport is generally anterograde, individual vesicles containing APP move bi-directionally. This discrepancy highlights our poor understanding of the in vivo regulation of APP-vesicle transport. Here, we show that reduction of presenilin (PS) or suppression of gamma-secretase activity substantially increases anterograde and retrograde velocities for APP vesicles. Strikingly, PS deficiency has no effect on an unrelated cargo vesicle class containing synaptotagmin, which is powered by a different kinesin motor. Increased velocities caused by PS or gamma-secretase reduction require functional kinesin-1 and dynein motors. Together, our findings suggest that a normal function of PS is to repress kinesin-1 and dynein motor activity during axonal transport of APP vesicles. Furthermore, our data suggest that axonal transport defects induced by loss of PS-mediated regulatory effects on APP-vesicle motility could be a major cause of neuronal and synaptic defects observed in Alzheimer's Disease (AD) pathogenesis. Thus, perturbations of APP/PS transport could contribute to early neuropathology observed in AD, and highlight a potential novel therapeutic pathway for early intervention, prior to neuronal loss and clinical manifestation of disease.

Description: With age, muscle mass and integrity are progressively lost leaving the elderly frail, weak and unable to independently care for themselves. Defined as sarcopenia, this age-related muscle atrophy appears to be multifactorial but its definite cause is still unknown. Mitochondrial dysfunction has been implicated in this process. Using a novel transgenic mouse model of mitochondrial DNA (mtDNA) double-strand breaks (DSBs) that presents a premature aging-like phenotype, we studied the role of mtDNA damage in muscle wasting. We caused DSBs in mtDNA of adult mice using a ubiquitously expressed mitochondrial-targeted endonuclease, mito- Pst I. We found that a short, transient systemic mtDNA damage led to muscle wasting and a decline in locomotor activity later in life. We found a significant decline in muscle satellite cells, which decreases the muscle's capacity to regenerate and repair during aging. This phenotype was associated with impairment in acetylcholinesterase (AChE) activity and assembly at the neuromuscular junction (NMJ), also associated with muscle aging. Our data suggests that systemic mitochondrial dysfunction plays important roles in age-related muscle wasting by preferentially affecting the myosatellite cell pool.

Description: We present a methodology for infrasonic remote sensing of winds in the stratosphere that does not require discrete ground-truth events. Our method uses measured time delays between arrays of sensors to provide group velocities (referred to here as celerities) and then minimizes the difference between observed and predicted celerities by perturbing an initial atmospheric specification. Because we focus on interarray propagation effects, it is not necessary to simulate the full propagation path from source to receiver. This feature allows us to use a relatively simple forward model that is applicable over short-regional distances. By focusing on stratospheric returns, we show that our non-linear inversion scheme converges much better if the starting model contains a strong stratospheric duct. Using the Horizontal Wind Model (HWM)/Mass Spectrometer Incoherent Scatter (MSISE) empirical climatology as a starting model, we demonstrate that the inversion scheme is robust to large uncertainties in backazimuth, but that uncertainties in the measured trace velocity and celerity require the use of prior constraints to ensure suitable convergence. The inversion of synthetic data, using realistic estimates of measurement error, shows that our scheme will nevertheless improve upon a starting model under most scenarios. The inversion scheme is applied to infrasound data recorded from a large event on 2010 December 25, which is presumed to be a bolide, using data from a nine-element infrasound network in Utah. We show that our recorded data require a stronger zonal wind speed in the stratosphere than is present in the HWM profile, and are more consistent with the Ground-to-Space (G2S) profile.

Description: Coda- Q is a stochastic parameter reflecting the heterogeneities of medium that seismic waves travel through. We confirmed that coda- Q would vary with the stress loaded to an elastic medium using numerical simulations of seismic wave propagation. When the stress is loaded, cracks in the crust could either close or newly open. The closure and opening of the cracks are not random but depending on the magnitude and the direction of the stress and the crack aspect ratio. The cracks in the medium after loading stress could be aligned in a specific orientation, and elastic wave velocity field would become anisotropic due to the alignment of specific crack orientations. Elastic wave velocity is in general faster along the direction corresponding with the crack orientation while slower along the perpendicular direction. In the numerical simulation, the effect of anisotropy in elastic wave velocity field due to the selective closure and opening of the cracks is calculated using a 2-D finite difference method assuming elastic wave velocity to be a function of the magnitude of loaded stress. The coda- Q calculated from seismic waves simulated for a model varies when the averaged normal stress changes. Our simulation indicated that the sensitivity of coda- Q –1 , that is the reciprocal of the coda- Q , would be 1.0 10 –2 (1.0 MPa –1 ) against the magnitude of the confining pressure and 1.0 10 –3 (1.0 deg –1 ) against the direction of principal stress. We would like to conclude that coda- Q , a stochastic parameter reflecting heterogeneities of subsurface medium, could become a quantitative state indicator of the stress field of the medium where seismic waves propagate through. Spatiotemporal variation of coda- Q reflects change in the stress field in the crust.

Description: How do body-wave traveltimes constrain the Earth's radial (1-D) seismic structure? Existing 1-D seismological models underpin 3-D seismic tomography and earthquake location algorithms. It is therefore crucial to assess the quality of such 1-D models, yet quantifying uncertainties in seismological models is challenging and thus often ignored. Ideally, quality assessment should be an integral part of the inverse method. Our aim in this study is twofold: (i) we show how to solve a general Bayesian non-linear inverse problem and quantify model uncertainties, and (ii) we investigate the constraint on spherically symmetric P -wave velocity ( V P ) structure provided by body-wave traveltimes from the EHB bulletin (phases Pn , P , PP and PKP ). Our approach is based on artificial neural networks, which are very common in pattern recognition problems and can be used to approximate an arbitrary function. We use a Mixture Density Network to obtain 1-D marginal posterior probability density functions (pdfs), which provide a quantitative description of our knowledge on the individual Earth parameters. No linearization or model damping is required, which allows us to infer a model which is constrained purely by the data. We present 1-D marginal posterior pdfs for the 22 V P parameters and seven discontinuity depths in our model. P -wave velocities in the inner core, outer core and lower mantle are resolved well, with standard deviations of ~0.2 to 1 per cent with respect to the mean of the posterior pdfs. The maximum likelihoods of V P are in general similar to the corresponding ak135 values, which lie within one or two standard deviations from the posterior means, thus providing an independent validation of ak135 in this part of the radial model. Conversely, the data contain little or no information on P -wave velocity in the D '' layer, the upper mantle and the homogeneous crustal layers. Further, the data do not constrain the depth of the discontinuities in our model. Using additional phases available in the ISC bulletin, such as PcP , PKKP and the converted phases SP and ScP , may enhance the resolvability of these parameters. Finally, we show how the method can be extended to obtain a posterior pdf for a multidimensional model space. This enables us to investigate correlations between model parameters.

Description: We have developed a network optimization method for regional-scale microseismic monitoring networks and applied it to optimize the densification of the existing seismic network in northeastern Switzerland. The new network will build the backbone of a 10-yr study on the neotectonic activity of this area that will help to better constrain the seismic hazard imposed on nuclear power plants and waste repository sites. This task defined the requirements regarding location precision (0.5 km in epicentre and 2 km in source depth) and detection capability [magnitude of completeness M c  = 1.0 ( M L )]. The goal of the optimization was to find the geometry and size of the network that met these requirements. Existing stations in Switzerland, Germany and Austria were considered in the optimization procedure. We based the optimization on the simulated annealing approach proposed by Hardt & Scherbaum, which aims to minimize the volume of the error ellipsoid of the linearized earthquake location problem ( D -criterion). We have extended their algorithm to: calculate traveltimes of seismic body waves using a finite difference ray tracer and the 3-D velocity model of Switzerland, calculate seismic body-wave amplitudes at arbitrary stations assuming the Brune source model and using scaling and attenuation relations recently derived for Switzerland, and estimate the noise level at arbitrary locations within Switzerland using a first-order ambient seismic noise model based on 14 land-use classes defined by the EU-project CORINE and open GIS data. We calculated optimized geometries for networks with 10–35 added stations and tested the stability of the optimization result by repeated runs with changing initial conditions. Further, we estimated the attainable magnitude of completeness ( M c ) for the different sized optimal networks using the Bayesian Magnitude of Completeness (BMC) method introduced by Mignan et al. The algorithm developed in this study is also applicable to smaller optimization problems, for example, small local monitoring networks. Possible applications are volcano monitoring, the surveillance of induced seismicity associated with geotechnical operations and many more. Our algorithm is especially useful to optimize networks in populated areas with heterogeneous noise conditions and if complex velocity structures or existing stations have to be considered.

Description: Fluid injection in and withdrawal from wells are basic procedures in mining activities and deep resources exploitation, such as oil and gas extraction, permeability enhancement for geothermal exploitation and waste fluid disposal. All of these activities have the potential to induce seismicity, as exemplified by the 2006 Basel earthquake ( M L 3.4). Despite several decades of experience, the mechanisms of induced seismicity are not known in detail, which prevents effective risk assessment and/or mitigation. In this study, we provide an interpretation of induced seismicity based on computation of Coulomb stress changes that result from fluid injection/withdrawal at depth, mainly focused on the interpretation of induced seismicity due to stimulation of a geothermal reservoir. Seismicity is, theoretically, more likely where Coulomb stress changes are larger. For modeling purposes, we simulate the thermodynamic evolution of a system after fluid injection/withdrawal. The associated changes in pressure and temperature are subsequently considered as sources of incremental stress changes, which are then converted to Coulomb stress changes on favourably oriented faults, taking into account the background regional stress. Numerical results are applied to the water injection that was performed to create the fractured reservoir at the enhanced-geothermal-system site, Soultz-sous-Forets (France). Our approach describes well the observed seismicity, and provides an explanation for the different behaviors of a system when fluids are injected or withdrawn.

Description: We report on a broad-band high-resolution attenuation model for the North China Craton and surrounding regions based on regional Lg -wave data. Vertical broad-band waveforms recorded at 39 stations from 176 crustal earthquakes are collected to extract the Lg -wave amplitude spectra between 0.05 and 10.0 Hz. We use the dual-station method to generate a preliminary Q Lg model and use it as the initial model. Then, we combine the dual- and single-station data together to jointly invert the Q Lg distribution and Lg source excitation functions. These inversions are conducted independently at individual frequencies without using any a priori assumption about the frequency dependences in Q Lg and source terms. The maximum spatial resolution is approximately 1° x 1° in well-covered areas for frequencies between 0.05 and 2.0 Hz. The Q Lg image is then used to determine the relationship between the attenuation and different geological structures. Results show an average Q 0 (1 Hz Q Lg ) of 374 for the entire North China Craton with an increasing trend from east to west. Average Q 0 values are 337, 361 and 421 for the east, central and west blocks, respectively. For the surrounding regions, the Eastern Tibetan plateau has a very low Q 0 of 188, while the Northeast China Plate and the Tianshan–Xingmeng fold belts are characterized by high Q 0 values of 506 and 424, respectively. We also investigate regional variations of the Lg attenuation in low-frequency band between 0.2 and 1.0 Hz.

Description: We present a systematic study on the influence of pressure (0.1–600 MPa), temperature (750–1200 °C), carbon dioxide fugacity (log f CO 2  = –4.41 to 3.60) and time (2–12 hr) on the chemical and physical properties of carbonate rock. Our experiments aim to reproduce the conditions at the periphery of magma chamber where carbonate host rock is influenced by, but not readily assimilated by, magma. This permits the investigation of the natural conditions at which circulating fluids/gases promote infiltration reactions typical of metasomatic skarns that can involve large volumes of subvolcanic carbonate basements. Results show that, providing that carbon dioxide is retained in the pore space, decarbonation does not proceed at any magmatic pressure and temperature. However, when the carbon dioxide is free to escape, decarbonation can occur rapidly and is not hindered by a low initial porosity or permeability. Together with carbon dioxide and lime, portlandite, a mineral commonly found in voluminous metasomatic skarns, readily forms during carbonate decomposition. Post-experimental analyses highlight that thermal microcracking, a result of the highly anisotropic thermal expansion of calcite, exerts a greater influence on rock physical properties (porosity, ultrasonic wave velocities and elastic moduli) than decarbonation. Our data suggest that this will be especially true at the margins of dykes or magma bodies, where temperatures can reach up to 1200 °C. However, rock compressive strength is significantly reduced by both thermal cracking and decarbonation, explained by the relative weakness of lime + portlandite compared to calcite, and an increase in grain size with increasing temperature. Metasomatic skarns, whose petrogenetic reactions may involve a few tens of cubic kilometres, could therefore represent an important source of volcanic instability.

Description: The scattering of plane SH waves incident on a circular sectorial canyon is considered. An accurate region-matching technique is applied to derive a rigorous series solution. Appropriate wavefunctions are employed to describe antiplane motions. Judicious basis functions, involving Gegenbauer polynomials, are well utilized to correctly capture the singular behaviour in stress fields near the canyon bottom. The enforcement of matching conditions on the auxiliary boundary leads to the determination of unknown coefficients. Plotted results demonstrate the influence of pertinent parameters on surface and subsurface motions. Both steady-state and transient results are included. The solution technique proposed achieves a considerable reduction in the computational effort, facilitating benchmark computations. The derived series solution enriches the limited list of series solutions presently known for canyon problems related to SH -wave scattering.

Description: We present 3-D models of the P- and S -wave velocity distributions in the crust and uppermost mantle beneath Sicily, Calabria (Southern Italy), and surrounding submerged areas, obtained by tomographic inversion of traveltimes of regional body waves phases. Our method combines double-difference tomographic inversion with a post-processing procedure [Weighted Average Model method (WAM)]. This procedure was applied to a set of models consistent with the experimental data. We tested the ability of the WAM procedure to mitigate the uncertainty associated with the arbitrary nature of the many input parameters required for each inversion. The local reliability and resolution of the obtained models have been assessed through: synthetic tests, experimental tests carried out with independent data sets and unconventional tests based on the analysis of the internal consistency of the P - and S -velocity models. The tomographic images provide a detailed sketch of P- and S- wave velocity anomalies. These clearly show the shape of the Sicilian-Maghrebian belt beneath Sicily and Calabrian Arc at different depths. Low V P and Vs bodies are imaged beneath Stromboli and Marsili volcanoes in the southern Tyrrhenian, whereas high and low seismic velocities alternate beneath the Etna giving inferences on the possible depth of the mantle melting feeding the volcano. In the upper crust, the main sedimentary basins and tectonic features are also well imaged. Finally, tomographic cross sections show the trend of the Moho in the study area, where its depth ranges between 35 and 40 km beneath the Sicilian belt and between 15 and 22 km in the southern Tyrrhenian basin and Ionian Sea.

Description: We used two tracks of ALOS PALSAR images to investigate the focal mechanism and slip distribution of the 2011 March 24, M W 6.8 Burma strike-slip earthquake. Three different SAR techniques, namely conventional interferometry, SAR pixel offsets (SPO) and multiple-aperture InSAR (MAI), were employed to obtain the coseismic surface deformation fields along the ~30 km length of the fault rupture. Along-track measurements from SPO and MAI techniques show a high correlation, and were subsequently used to precisely determine the location and extent of the surface fault trace. The best-fitting fault model geometry derived from an iterative inversion technique suggests that the rupture occurred on a near-vertical sinistral strike-slip fault west of the Nam Ma fault with a strike of 70°. A maximum slip of 4.2 m occurs at a depth of 2.5 km, with significant slip constrained only to the upper 10 km of the crust.

Description: Knowledge of the mantle reflectivity structure is highly dependent on our ability to efficiently extract, and properly interpret, small seismic arrivals. Among the various data types and techniques, long-period SS/PP precursors and high-frequency receiver functions are routinely utilized to increase the confidence of the recovered mantle stratifications at distinct spatial scales. However, low resolution and a complex Fresnel zone are glaring weaknesses of SS precursors, while over-reliance on receiver distribution is a formidable challenge for the analysis of converted waves from oceanic regions. A promising high frequency alternative to receiver functions is P ' P ' precursors, which are capable of resolving mantle structures at vertical and lateral resolution of ~5 and ~200 km, respectively, owing to their spectral content, shallow angle of incidence and near-symmetric Fresnel zones. This study presents a novel processing method for both SS (or PP) and P ' P ' precursors based on deconvolution, stacking, Radon transform and depth migration. A suite of synthetic tests is performed to quantify the fidelity and stability of this method under different data conditions. Our multiresolution survey of the mantle at targeted areas near Nazca-South America subduction zone reveal both olivine and garnet related transitions at depths below 400 km. We attribute a depressed 660 to thermal variations, whereas compositional variations atop the upper-mantle transition zone are needed to explain the diminished or highly complex reflected/scattered signals from the 410 km discontinuity. We also observe prominent P ' P ' reflections within the transition zone, and the anomalous amplitudes near the plate boundary zone indicate a sharp (~10 km thick) transition that likely resonates with the frequency content of P ' P ' precursors. The migration of SS precursors in this study shows no evidence of split 660 reflections, but potential majorite–ilmenite (590–640 km) and ilmenite–perovskite transitions (740–750 km) are identified based on similarly processed high-frequency P ' P ' precursors. Additional findings of severely scattered energy in the lithosphere and distinct lower mantle reflections at ~800 km could be potentially important but require further verifications. Overall, our improved imaging methods and the strong sensitivity of P ' P ' precursors to the existence, depth, sharpness and strength of reflective structures offer significant future promise for the understanding of mantle mineralogy and dynamics.

Description: Time-dependent probabilistic seismic hazard assessment requires a stochastic description of earthquake occurrences. While short-term seismicity models are well-constrained by observations, the recurrences of characteristic on-fault earthquakes are only derived from theoretical considerations, uncertain palaeo-events or proxy data. Despite the involved uncertainties and complexity, simple statistical models for a quasi-period recurrence of on-fault events are implemented in seismic hazard assessments. To test the applicability of statistical models, such as the Brownian relaxation oscillator or the stress release model, we perform a systematic comparison with deterministic simulations based on rate- and state-dependent friction, high-resolution representations of fault systems and quasi-dynamic rupture propagation. For the specific fault network of the Lower Rhine Embayment, Germany, we run both stochastic and deterministic model simulations based on the same fault geometries and stress interactions. Our results indicate that the stochastic simulators are able to reproduce the first-order characteristics of the major earthquakes on isolated faults as well as for coupled faults with moderate stress interactions. However, we find that all tested statistical models fail to reproduce the characteristics of strongly coupled faults, because multisegment rupturing resulting from a spatiotemporally correlated stress field is underestimated in the stochastic simulators. Our results suggest that stochastic models have to be extended by multirupture probability distributions to provide more reliable results.

Description: Stress waves, known as acoustic emissions (AEs), are released by localized inelastic deformation events during the progressive failure of brittle rocks. Although several numerical models have been developed to simulate the deformation and damage processes of rocks, such as non-linear stress–strain behaviour and localization of failure, only a limited number have been capable of providing quantitative information regarding the associated seismicity. Moreover, the majority of these studies have adopted a pseudo-static approach based on elastic strain energy dissipation that completely disregards elastodynamic effects. This paper describes a new AE modelling technique based on the combined finite-discrete element method (FEM/DEM), a numerical tool that simulates material failure by explicitly considering fracture nucleation and propagation in the modelling domain. Given the explicit time integration scheme of the solver, stress wave propagation and the effect of radiated seismic energy can be directly captured. Quasi-dynamic seismic information is extracted from a FEM/DEM model with a newly developed algorithm based on the monitoring of internal variables (e.g. relative displacements and kinetic energy) in proximity to propagating cracks. The AE of a wing crack propagation model based on this algorithm are cross-analysed by traveltime inversion and energy estimation from seismic recordings. Results indicate a good correlation of AE initiation times and locations, and scaling of energies, independently calculated with the two methods. Finally, the modelling technique is validated by simulating a laboratory compression test on a granite sample. The micromechanical parameters of the heterogeneous model are first calibrated to reproduce the macroscopic stress–strain response measured during standard laboratory tests. Subsequently, AE frequency–magnitude statistics, spatial clustering of source locations and the evolution of AE rate are investigated. The distribution of event magnitude tends to decay as power law while the spatial distribution of sources exhibits a fractal character, in agreement with experimental observations. Moreover, the model can capture the decrease of seismic b value associated with the macrorupture of the rock sample and the transition of AE spatial distribution from diffuse, in the pre-peak stage, to strongly localized at the peak and post-peak stages, as reported in a number of published laboratory studies. In future studies, the validated FEM/DEM-AE modelling technique will be used to obtain further insights into the micromechanics of rock failure with potential applications ranging from laboratory-scale microcracking to engineering-scale processes (e.g. excavations within mines, tunnels and caverns, petroleum and geothermal reservoirs) to tectonic earthquakes triggering.

Description: We used strong-motion records from the 2012 May 20 and 29 Emilia-Romagna earthquakes ( M w 6.1 and 5.9, respectively) and four aftershocks with magnitudes ranging between 4.9 and 5.5 to analyse the S -wave spectral amplitude decay with distance and estimate acceleration source functions and site effects. The data set consists of six earthquakes, 44 stations and 248 records with hypocentral distances in the range 10 〈 r  〈 100 km. We rotated the accelerograms to calculate transverse and radial components of the acceleration spectrum. We found non-parametric attenuation functions that describe the spectral amplitude decay of SH and SV waves with distance at 60 different frequencies between 0.1 and 40 Hz. These attenuation functions provide an estimate of the quality factor Q at each frequency analysed. Assuming that geometrical spreading is 1/ r for r  ≤ r x and 1/( r x r ) 0.5 for r  〉 r x with r x  = 60 km and normalizing at 15 km (the recording distance where the attenuation functions start to decay), we find that the average Q for SH waves can be approximated by Q SH  = 82 ± 1 f  1.2±0.02 and by Q SV  = 79 ± 1 f  1.24±0.03 for SV waves in the frequency range 0.10 ≤ f  ≤ 10.7 Hz. At higher frequencies, 11.8 ≤ f  ≤ 40 Hz, the frequency dependence of Q weakens and is approximated by Q SH  = 301 ± 1 f   0.36±0.04 and Q SV  = 384 ± 1 f  0.28±0.04 . These results indicate that the S -wave attenuation is radially isotropic at local distances in the epicentral area. Nevertheless, we used these attenuation parameters separately to correct the radial (with Q SV ) and transverse (with Q SH ) components of the acceleration spectra and to separate source and site effects using a non-parametric spectral inversion scheme. We found that the source function of the main event and the bigger aftershocks show enhanced low frequency radiation between 0.4 and 3.0 Hz. We converted the source functions into far-field source acceleration spectra and interpreted the resulting source spectra in terms of Brune's model. The stress drops obtained range between approximately 0.9 and 2.9 MPa. Although all the recording stations used are located in the Po Plain, the site functions obtained from the spectral inversion show important amplification variability between the sites. We compared these site functions with the average horizontal to vertical spectral ratios calculated for each station, and we found consistent results for most stations.

Description: The dihedral angle formed at junctions between two plagioclase grains and a grain of augite is only very rarely in textural equilibrium in gabbros from kilometre-scale crustal layered intrusions. The median of a population of these disequilibrium angles, cpp , varies systematically within a single layered intrusion, remaining constant over large stretches of stratigraphy with significant increases and decreases associated with the addition or reduction respectively of the number of phases on the liquidus of the bulk magma. The stepwise changes in cpp are present in the Upper Zone of the Bushveld Complex, the Megacyclic Unit I of the Sept Iles Intrusion, and the Layered Series of the Skaergaard intrusion. The plagioclase-bearing cumulates of Rum have a bimodal distribution of cpp , dependent on whether the cumulus assemblage includes clinopyroxene. The presence of the stepwise changes is independent of the order of arrival of cumulus phases and of the composition of either the cumulus phases or the inferred composition of the interstitial liquid. The only parameter that behaves in an exactly analogous manner to cpp is the rate of change in enthalpy with temperature ( H / T ) during crystallization. Both H / T and cpp increase with the addition of a liquidus phase, and decrease with the removal of a liquidus phase. The replacement of one phase by another has little effect on H / T and no discernible effect on cpp . An increase of H / T results in an increase in the fraction of the total enthalpy budget that is the latent heat of crystallization (the fractional latent heat). It also increases the mass crystallized in each incremental temperature drop (the crystal productivity). These increases of both fractional latent heat and crystal productivity are likely to cause an increase in the time taken to form three-grain junctions in the mush via thermal buffering of a thickened mushy layer. We suggest these are the underlying causes of stepwise increases in cpp . Stepwise changes in the geometry of three-grain junctions in fully solidified gabbros thus provide a clear microstructural marker for the progress of fractionation down the liquid line of descent in layered intrusions.

Description: High-resolution sampling in monogenetic fields has the potential to reveal fine-scale heterogeneity of the mantle, a feature that may be overwhelmed by larger fluxes of magma, or missed by under-sampling. The Quaternary Auckland Volcanic Field (AVF) in northern New Zealand is a basaltic field of 51 small-volume volcanic centres, and is one of the best-sampled examples of a monogenetic volcanic field. We present data for 12 centres in the volcanic field. These show the large compositional variations between volcanoes as well as through single eruptive sequences. Whole-rock compositions range from subalkaline basalt in the larger centres, through alkali basalt to nephelinite in the smallest centres. Fractional crystallization has had a limited effect in many of the centres, but high-pressure clinopyroxene crystallization may have occurred in others. Three end-members are observed in Pb isotope space, indicating that distinct mantle source components are involved in the petrogenesis of the magmas. Whole-rock multi-element patterns show that the larger centres have prominent positive Sr anomalies and lack K anomalies, whereas the smaller centres have prominent negative K anomalies and lack Sr anomalies. The melting parameters and compositions of the sources involved are modelled using trace element ratios and multi-element patterns, and three components are characterized: (1) fertile peridotite with a Pb-isotope composition similar to Pacific mid-ocean ridge basalt; (2) eclogite domains with a HIMU-like isotope composition dispersed within the fertile peridotite; (3) slightly depleted subduction-metasomatized peridotitic lithospheric mantle (containing c . 3% subduction fluids). Modelling shows that melting in the AVF begins in garnet-bearing fertile asthenosphere (with preferential melting of eclogite domains) and that melts are variably diluted by melts of the lithospheric source. The U–Th isotope compositions of the end-members in the AVF show 230 Th excess [( 230 Th/ 232 Th) ratios of 1·11–1·38], with the samples of lower ( 230 Th/ 232 Th) exhibiting higher ( 238 U/ 232 Th), which we attribute to the dilution effect of the melts from the lithospheric mantle source. Modelling reveals a correlation between melting in the asthenosphere, the degree of melting and incorporation of the metasomatized lithospheric mantle source, and the resultant size of the volcanic centre. This suggests that the scale of the eruption may essentially be controlled by asthenospheric mantle dynamics.

Description: The origin of mafic and ultramafic sills exhibiting different whole-rock compositional profiles (e.g. I-, C-, D-, M- and S-shaped profiles) remains controversial. We have addressed this issue by revisiting three ~100 m thick Siberian dolerite sills (Vavukansky, Kuz’movsky and Vilyuysky) that display remarkable internal differentiation. The Vavukansky sill has an M-shaped profile with prominent basal and top reversals showing inward increases in whole-rock MgO, Mg-number [100Mg/(Mg + Fe)] and normative An content [100An/(An + Ab)], followed by the Layered and Upper Border Series with inward decreases in these indices. The Kuz’movsky and Vilyuysky sills both show S-shaped profiles similar to the Vavukansky sill, but lack a top reversal. These whole-rock M- and S-shaped profiles are accompanied by similar profiles in mineral compositions. Plagioclase and, to a lesser extent, olivine show systematic inward increases in An content and Mg-number, respectively, across basal and top reversals. These compositional trends are followed by inward decreases in these ratios in the interiors of the Vavukansky and Kuz’movsky sills. Currently accepted models attribute whole-rock M- and S-shaped compositional profiles to crystal settling, compositional convection or compaction operating in closed systems. Our observations challenge these traditional interpretations because variations in mineral compositions observed in marginal reversals cannot result from closed-system fractionation. We suggest instead that initially the sills evolved as open systems that were slowly inflated by magmas that became gradually more primitive with time. The inflation was accompanied by in situ crystallization that preserved the preceding fractionation history of the injected magmas by forming basal and top reversals with minerals becoming more primitive inwards. This process culminated with rapid inflation of the sills to their current size owing to a major influx of primitive magma. Subsequently, magma flow through the sills ceased and they evolved as closed systems by fractional crystallization. This resulted in the Layered and Upper Border Series with minerals becoming more evolved inwards. This model can be extended to explain other compositional profiles and petrological features in mafic and ultramafic sills.

Description: Motivation: Pyrosequencing technology provides an important new approach to more extensively characterize diverse sequence populations and detect low frequency variants. However, the promise of this technology has been difficult to realize, as careful correction of sequencing errors is crucial to distinguish rare variants (~1%) in an infected host with high sensitivity and specificity. Results: We developed a new approach, referred to as Indel and Carryforward Correction (ICC), to cluster sequences without substitutions and locally correct only indel and carryforward sequencing errors within clusters to ensure that no rare variants are lost. ICC performs sequence clustering in the order of (i) homopolymer indel patterns only, (ii) indel patterns only and (iii) carryforward errors only, without the requirement of a distance cutoff value. Overall, ICC removed 93–95% of sequencing errors found in control datasets. On pyrosequencing data from a PCR fragment derived from 15 HIV-1 plasmid clones mixed at various frequencies as low as 0.1%, ICC achieved the highest sensitivity and similar specificity compared with other commonly used error correction and variant calling algorithms. Availability and implementation: Source code is freely available for download at http://indra.mullins.microbiol.washington.edu/ICC . It is implemented in Perl and supported on Linux, Mac OS X and MS Windows. Contact: jmullins@uw.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : Tiki proteins appear to antagonize Wnt signalling pathway by acting as Wnt proteases, thereby affecting Wnt solubility by its amino-terminal cleavage. Tiki1 protease activity was shown to be metal ion-dependent and was inhibited by chelating agents and thus was tentatively proposed to be a metalloprotease. Nevertheless, Tiki proteins exhibit no detectable sequence similarity to previously described metalloproteases, but instead have been reported as being homologues of TraB proteins (Pfam ID: PF01963), a widely distributed family of unknown function and structure. Here, we show that Tiki proteins are members of a new superfamily of domains contained not just in TraB proteins, but also in erythromycin esterase (Pfam ID: PF05139), DUF399 (domain of unknown function 399; Pfam ID: PF04187) and MARTX toxins that contribute to host invasion and pathogenesis by bacteria. We establish the core fold of this enzymatic domain and its catalytic residues. Contact: luis.sanchezpulido@dpag.ox.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: The research area metabolomics achieved tremendous popularity and development in the last couple of years. Owing to its unique interdisciplinarity, it requires to combine knowledge from various scientific disciplines. Advances in the high-throughput technology and the consequently growing quality and quantity of data put new demands on applied analytical and computational methods. Exploration of finally generated and analyzed datasets furthermore relies on powerful tools for data mining and visualization. Results: To cover and keep up with these requirements, we have created MeltDB 2.0, a next-generation web application addressing storage, sharing, standardization, integration and analysis of metabolomics experiments. New features improve both efficiency and effectivity of the entire processing pipeline of chromatographic raw data from pre-processing to the derivation of new biological knowledge. First, the generation of high-quality metabolic datasets has been vastly simplified. Second, the new statistics tool box allows to investigate these datasets according to a wide spectrum of scientific and explorative questions. Availability: The system is publicly available at https://meltdb.cebitec.uni-bielefeld.de . A login is required but freely available. Contact: nkessler@cebitec.uni-bielefeld.de

Description: Motivation: High - throughput next - generation sequencing technologies enable increasingly fast and affordable sequencing of genomes and transcriptomes, with a broad range of applications. The quality of the sequencing data is crucial for all applications. A significant portion of the data produced contains errors, and ever more efficient error correction programs are needed. Results: We propose RACER (Rapid and Accurate Correction of Errors in Reads), a new software program for correcting errors in sequencing data. RACER has better error-correcting performance than existing programs, is faster and requires less memory. To support our claims, we performed extensive comparison with the existing leading programs on a variety of real datasets. Availability: RACER is freely available for non-commercial use at www.csd.uwo.ca/~ilie/RACER/ . Contact: ilie@csd.uwo.ca Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : Interactions between various types of molecules that regulate crucial cellular processes are extensively investigated by high-throughput experiments and require dedicated computational methods for the analysis of the resulting data. In many cases, these data can be represented as a bipartite graph because it describes interactions between elements of two different types such as the influence of different experimental conditions on cellular variables or the direct interaction between receptors and their activators/inhibitors. One of the major challenges in the analysis of such noisy datasets is the statistical evaluation of the relationship between any two elements of the same type. Here, we present SICOP (significant co-interaction patterns), an implementation of a method that provides such an evaluation based on the number of their common interaction partners, their so-called co-interaction. This general network analytic method, proved successful in diverse fields, provides a framework for assessing the significance of this relationship by comparison with the expected co-interaction in a suitable null model of the same bipartite graph. SICOP takes into consideration up to two distinct types of interactions such as up- or downregulation. The tool is written in Java and accepts several common input formats and supports different output formats, facilitating further analysis and visualization. Its key features include a user-friendly interface, easy installation and platform independence. Availability: The software is open source and available at cna.cs.uni-kl.de/SICOP under the terms of the GNU General Public Licence (version 3 or later). Contact: agnes.horvat@iwr.uni-heidelberg.de or zweig@cs.uni-kl.de

Description: : Molecular recognition features (MoRFs) are small, intrinsically disordered regions in proteins that undergo a disorder-to-order transition on binding to their partners. MoRFs are involved in protein–protein interactions and may function as the initial step in molecular recognition. The aim of this work was to collect, organize and store all membrane proteins that contain MoRFs. Membrane proteins constitute ~30% of fully sequenced proteomes and are responsible for a wide variety of cellular functions. MoRFs were classified according to their secondary structure, after interacting with their partners. We identified MoRFs in transmembrane and peripheral membrane proteins. The position of transmembrane protein MoRFs was determined in relation to a protein’s topology. All information was stored in a publicly available mySQL database with a user-friendly web interface. A Jmol applet is integrated for visualization of the structures. mpMoRFsDB provides valuable information related to disorder-based protein–protein interactions in membrane proteins. Availability: http://bioinformatics.biol.uoa.gr/mpMoRFsDB Contact: shamodr@biol.uoa.gr

Description: : The signaling Petri net (SPN) simulator, designed to provide insights into the trends of molecules’ activity levels in response to an external stimulus, contributes to the systems biology necessity of analyzing the dynamics of large-scale cellular networks. Implemented into the freely available software, BioLayout Express 3D , the simulator is publicly available and easy to use, provided the input files are prepared in the GraphML format, typically using the network editing software, yEd, and standards specific to the software. However, analysis of complex networks represented using other systems biology formatting languages (on which popular software, such as CellDesigner and Cytoscape, are based) requires manual manipulation, a step that is prone to error and limits the use of the SPN simulator in BioLayout Express 3D . To overcome this, we present a Cytoscape plug-in that enables users to automatically convert networks for analysis with the SPN simulator from the standard systems biology markup language. The automation of this step opens the SPN simulator to a far larger user group than has previously been possible. Availability and implementation: Distributed under the GNU General Public License Version 3 at http://apps.cytoscape.org/apps/spnconverter . Contact: christine@picb.ac.cn

Description: Motivation: Conformational diversity is a key concept in the understanding of different issues related with protein function such as the study of catalytic processes in enzymes, protein-protein recognition, protein evolution and the origins of new biological functions. Here, we present a database of proteins with different degrees of conformational diversity. Conformational Diversity of Native State (CoDNaS) is a redundant collection of three-dimensional structures for the same protein derived from protein data bank. Structures for the same protein obtained under different crystallographic conditions have been associated with snapshots of protein dynamism and consequently could characterize protein conformers. CoDNaS allows the user to explore global and local structural differences among conformers as a function of different parameters such as presence of ligand, post-translational modifications, changes in oligomeric states and differences in pH and temperature. Additionally, CoDNaS contains information about protein taxonomy and function, disorder level and structural classification offering useful information to explore the underlying mechanism of conformational diversity and its close relationship with protein function. Currently, CoDNaS has 122 122 structures integrating 12 684 entries, with an average of 9.63 conformers per protein. Availability: The database is freely available at http://www.codnas.com.ar/ . Contact: gusparisi@gmail.com

Description: Motivation: Recent experimental advancements allow determining positions of nucleosomes for complete genomes. However, the resulting nucleosome occupancy maps are averages of heterogeneous cell populations. Accordingly, they represent a snapshot of a dynamic ensemble at a single time point with an overlay of many configurations from different cells. To study the organization of nucleosomes along the genome and to understand the mechanisms of nucleosome translocation, it is necessary to retrieve features of specific conformations from the population average. Results: Here, we present a method for identifying non-overlapping nucleosome configurations that combines binary-variable analysis and a Monte Carlo approach with a simulated annealing scheme. In this manner, we obtain specific nucleosome configurations and optimized solutions for the complex positioning patterns from experimental data. We apply the method to compare nucleosome positioning at transcription factor binding sites in different mouse cell types. Our method can model nucleosome translocations at regulatory genomic elements and generate configurations for simulations of the spatial folding of the nucleosome chain. Availability: Source code, precompiled binaries, test data and a web-based test installation are freely available at http://bioinformatics.fh-stralsund.de/nucpos/ Contact: gero.wedemann@fh-stralsund.de Supplementary Information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Residue–residue contacts across the transmembrane helices dictate the three-dimensional topology of alpha-helical membrane proteins. However, contact determination through experiments is difficult because most transmembrane proteins are hard to crystallize. Results: We present a novel method (MemBrain) to derive transmembrane inter-helix contacts from amino acid sequences by combining correlated mutations and multiple machine learning classifiers. Tested on 60 non-redundant polytopic proteins using a strict leave-one-out cross-validation protocol, MemBrain achieves an average accuracy of 62%, which is 12.5% higher than the current best method from the literature. When applied to 13 recently solved G protein-coupled receptors, the MemBrain contact predictions helped increase the TM-score of the I-TASSER models by 37% in the transmembrane region. The number of foldable cases (TM-score 〉0.5) increased by 100%, where all G protein-coupled receptor templates and homologous templates with sequence identity 〉30% were excluded. These results demonstrate significant progress in contact prediction and a potential for contact-driven structure modeling of transmembrane proteins. Availability: www.csbio.sjtu.edu.cn/bioinf/MemBrain/ Contact: hbshen@sjtu.edu.cn or zhng@umich.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Identification of protein–ligand binding sites is critical to protein function annotation and drug discovery. However, there is no method that could generate optimal binding site prediction for different protein types. Combination of complementary predictions is probably the most reliable solution to the problem. Results: We develop two new methods, one based on binding-specific substructure comparison (TM-SITE) and another on sequence profile alignment (S-SITE), for complementary binding site predictions. The methods are tested on a set of 500 non-redundant proteins harboring 814 natural, drug-like and metal ion molecules. Starting from low-resolution protein structure predictions, the methods successfully recognize 〉51% of binding residues with average Matthews correlation coefficient (MCC) significantly higher (with P -value 〈10 –9 in student t -test) than other state-of-the-art methods, including COFACTOR, FINDSITE and ConCavity. When combining TM-SITE and S-SITE with other structure-based programs, a consensus approach (COACH) can increase MCC by 15% over the best individual predictions. COACH was examined in the recent community-wide COMEO experiment and consistently ranked as the best method in last 22 individual datasets with the Area Under the Curve score 22.5% higher than the second best method. These data demonstrate a new robust approach to protein–ligand binding site recognition, which is ready for genome-wide structure-based function annotations. Availability: http://zhanglab.ccmb.med.umich.edu/COACH/ Contact: zhng@umich.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: The nucleosome is the basic repeating unit of chromatin. It contains two copies each of the four core histones H2A, H2B, H3 and H4 and about 147 bp of DNA. The residues of the histone proteins are subject to numerous post-translational modifications, such as methylation or acetylation. Chromatin immunoprecipitiation followed by sequencing (ChIP-seq) is a technique that provides genome-wide occupancy data of these modified histone proteins, and it requires appropriate computational methods. Results: We present NucHunter, an algorithm that uses the data from ChIP-seq experiments directed against many histone modifications to infer positioned nucleosomes. NucHunter annotates each of these nucleosomes with the intensities of the histone modifications. We demonstrate that these annotations can be used to infer nucleosomal states with distinct correlations to underlying genomic features and chromatin-related processes, such as transcriptional start sites, enhancers, elongation by RNA polymerase II and chromatin-mediated repression. Thus, NucHunter is a versatile tool that can be used to predict positioned nucleosomes from a panel of histone modification ChIP-seq experiments and infer distinct histone modification patterns associated to different chromatin states. Availability: The software is available at http://epigen.molgen.mpg.de/nuchunter/ . Contact: chung@molgen.mpg.de Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: In biomedical research a growing number of platforms and technologies are used to measure diverse but related information, and the task of clustering a set of objects based on multiple sources of data arises in several applications. Most current approaches to multisource clustering either independently determine a separate clustering for each data source or determine a single ‘joint’ clustering for all data sources. There is a need for more flexible approaches that simultaneously model the dependence and the heterogeneity of the data sources. Results: We propose an integrative statistical model that permits a separate clustering of the objects for each data source. These separate clusterings adhere loosely to an overall consensus clustering, and hence they are not independent. We describe a computationally scalable Bayesian framework for simultaneous estimation of both the consensus clustering and the source-specific clusterings. We demonstrate that this flexible approach is more robust than joint clustering of all data sources, and is more powerful than clustering each data source independently. We present an application to subtype identification of breast cancer tumor samples using publicly available data from The Cancer Genome Atlas. Availability: R code with instructions and examples is available at http://people.duke.edu/%7Eel113/software.html . Contact: Eric.Lock@duke.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: More and more evidences have indicated that long–non-coding RNAs (lncRNAs) play critical roles in many important biological processes. Therefore, mutations and dysregulations of these lncRNAs would contribute to the development of various complex diseases. Developing powerful computational models for potential disease-related lncRNAs identification would benefit biomarker identification and drug discovery for human disease diagnosis, treatment, prognosis and prevention. Results : In this article, we proposed the assumption that similar diseases tend to be associated with functionally similar lncRNAs. Then, we further developed the method of Laplacian Regularized Least Squares for LncRNA–Disease Association (LRLSLDA) in the semisupervised learning framework. Although known disease–lncRNA associations in the database are rare, LRLSLDA still obtained an AUC of 0.7760 in the leave-one-out cross validation, significantly improving the performance of previous methods. We also illustrated the performance of LRLSLDA is not sensitive (even robust) to the parameters selection and it can obtain a reliable performance in all the test classes. Plenty of potential disease–lncRNA associations were publicly released and some of them have been confirmed by recent results in biological experiments. It is anticipated that LRLSLDA could be an effective and important biological tool for biomedical research. Availability: The code of LRLSLDA is freely available at http://asdcd.amss.ac.cn/Software/Details/2 . Contact: xingchen@amss.ac.cn or yangy@amt.ac.cn Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Genomic repositories are rapidly growing, as witnessed by the 1000 Genomes or the UK10K projects. Hence, compression of multiple genomes of the same species has become an active research area in the past years. The well-known large redundancy in human sequences is not easy to exploit because of huge memory requirements from traditional compression algorithms. Results: We show how to obtain several times higher compression ratio than of the best reported results, on two large genome collections (1092 human and 775 plant genomes). Our inputs are variant call format files restricted to their essential fields. More precisely, our novel Ziv-Lempel-style compression algorithm squeezes a single human genome to ~400 KB. The key to high compression is to look for similarities across the whole collection, not just against one reference sequence, what is typical for existing solutions. Availability: http://sun.aei.polsl.pl/tgc (also as Supplementary Material) under a free license. Supplementary data: Supplementary data are available at Bioinformatics online. Contact: sebastian.deorowicz@polsl.pl

Description: Motivation:  Biological systems are understood through iterations of modeling and experimentation. Not all experiments, however, are equally valuable for predictive modeling. This study introduces an efficient method for experimental design aimed at selecting dynamical models from data. Motivated by biological applications, the method enables the design of crucial experiments: it determines a highly informative selection of measurement readouts and time points. Results:  We demonstrate formal guarantees of design efficiency on the basis of previous results. By reducing our task to the setting of graphical models, we prove that the method finds a near-optimal design selection with a polynomial number of evaluations. Moreover, the method exhibits the best polynomial-complexity constant approximation factor, unless P = NP. We measure the performance of the method in comparison with established alternatives, such as ensemble non-centrality, on example models of different complexity. Efficient design accelerates the loop between modeling and experimentation: it enables the inference of complex mechanisms, such as those controlling central metabolic operation. Availability:  Toolbox ‘NearOED’ available with source code under GPL on the Machine Learning Open Source Software Web site (mloss.org). Contact:   busettoa@inf.ethz.ch Supplementary information:   Supplementary data are available at Bioinformatics online.

Description: : Small RNA deep sequencing is widely used to characterize non-coding RNAs (ncRNAs) differentially expressed between two conditions, e.g. healthy and diseased individuals and to reveal insights into molecular mechanisms underlying condition-specific phenotypic traits. The ncRNAome is composed of a multitude of RNAs, such as transfer RNA, small nucleolar RNA and microRNA (miRNA), to name few. Here we present omiRas, a Web server for the annotation, comparison and visualization of interaction networks of ncRNAs derived from next-generation sequencing experiments of two different conditions. The Web tool allows the user to submit raw sequencing data and results are presented as: (i) static annotation results including length distribution, mapping statistics, alignments and quantification tables for each library as well as lists of differentially expressed ncRNAs between conditions and (ii) an interactive network visualization of user-selected miRNAs and their target genes based on the combination of several miRNA–mRNA interaction databases. Availability and Implementation: The omiRas Web server is implemented in Python, PostgreSQL, R and can be accessed at: http://tools.genxpro.net/omiras/ . Contact: rotter@genxpro.de Supplementary Information: Supplementary data are available at Bioinformatics online.

Description: : We present PARSEC (PAtteRn Search and Contextualization), a new open source platform for guided discovery, allowing localization and biological characterization of short genomic sites in entire eukaryotic genomes. PARSEC can search for a sequence or a degenerated pattern. The retrieved set of genomic sites can be characterized in terms of (i) conservation in model organisms, (ii) genomic context (proximity to genes) and (iii) function of neighboring genes. These modules allow the user to explore, visualize, filter and extract biological knowledge from a set of short genomic regions such as transcription factor binding sites. Availability: Web site implemented in Java, JavaScript and C++, with all major browsers supported. Freely available at lbgi.fr/parsec. Source code is freely available at sourceforge.net/projects/genomicparsec. Contact: odile.lecompte@unistra.fr Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : At the rate that prokaryotic genomes can now be generated, comparative genomics studies require a flexible method for quickly and accurately predicting orthologs among the rapidly changing set of genomes available. SPOCS implements a graph-based ortholog prediction method to generate a simple tab-delimited table of orthologs and in addition, html files that provide a visualization of the predicted ortholog/paralog relationships to which gene/protein expression metadata may be overlaid. Availability and Implementation: A SPOCS web application is freely available at http://cbb.pnnl.gov/portal/tools/spocs.html . Source code for Linux systems is also freely available under an open source license at http://cbb.pnnl.gov/portal/software/spocs.html ; the Boost C++ libraries and BLAST are required. Contact: leeann.mccue@pnnl.gov

Description: : Automated image processing has allowed cell migration research to evolve to a high-throughput research field. As a consequence, there is now an unmet need for data management in this domain. The absence of a generic management system for the quantitative data generated in cell migration assays results in each dataset being treated in isolation, making data comparison across experiments difficult. Moreover, by integrating quality control and analysis capabilities into such a data management system, the common practice of having to manually transfer data across different downstream analysis tools will be markedly sped up and made more robust. In addition, access to a data management solution creates gateways for data standardization, meta-analysis and structured public data dissemination. We here present CellMissy, a cross-platform data management system for cell migration data with a focus on wound healing data. CellMissy simplifies and automates data management, storage and analysis from the initial experimental set-up to data exploration. Availability and implementation: CellMissy is a cross-platform open-source software developed in Java. Source code and cross-platform binaries are freely available under the Apache2 open source license at http://cellmissy.googlecode.com . Contact: lennart.martens@ugent.be Supplementary Information: Supplementary data are available at Bioinformatics online.

Description: Motivation: With the expansion of high-throughput technologies, understanding different kinds of genome-level data is a common task. MicroRNA (miRNA) is increasingly profiled using high-throughput technologies (microarrays or next-generation sequencing). The downstream analysis of miRNA targets can be difficult. Although there are many databases and algorithms to predict miRNA targets, there are few tools to integrate miRNA–gene interaction data into high-throughput genomic analyses. Results: We present targetHub, a CouchDB database of miRNA–gene interactions. TargetHub provides a programmer-friendly interface to access miRNA targets. The Web site provides RESTful access to miRNA–gene interactions with an assortment of gene and miRNA identifiers. It can be a useful tool to integrate miRNA target interaction data directly into high-throughput bioinformatics analyses. Availability: TargetHub is available on the web at http://app1.bioinformatics.mdanderson.org/tarhub/_design/basic/index.html . Contact: coombes.3@osu.edu

Description: Resistive forces along convergent plate boundaries have a major impact on surface deformation, most visibly at collisional plate boundaries. Although quantification of these forces is key to understanding the evolution and present state of mountain belts, they remain highly uncertain due to the complexity of plate boundary structures and rheologies. In previous studies of the Eurasian Plate, we have analysed the balance of plate boundary forces, tractions resulting from lithosphere–mantle coupling, and intraplate variations in topography and density structure. This yielded a range of acceptable force distributions. In this study, we investigate to which extent the observed present-day stress field provides further constraints on the distribution of forces. We address the dynamics of the Eurasian Plate as a whole. This enables us to base our analysis on mechanical equilibrium of a tectonic plate and to evaluate all forces as part of an internally consistent set of forces driving and deforming Eurasia. We incorporate tractions from convective mantle flow modelling in a lithospheric model in which edge and lithospheric body forces are modelled explicitly and compute resulting stresses in a homogeneous elastic thin shell. Intraplate stress observations used are from the World Stress Map project. Eurasia's stress field turns out to be particularly sensitive to the distribution of collision forces on the plate's southern margin and, to a much lesser extent, to lithospheric density structure and tractions from mantle flow. Stress observations require collision forces on the India–Eurasia boundary of 7.0–10.5 TN m –1 and on the Arabia–Eurasia boundary of 1.3–2.7 TN m –1 . Implication of mechanical equilibrium of the plate is that forces on the contacts with the African and Australian plates amount to 1.0–2.5 and 0–1.3 TN m –1 , respectively. We use our results to assess the validity of the classical view that the mean elevation of an orogenic plateau can be taken as a measure of the magnitude of the compressive (in this case: collision-related) forces involved. For both the Tibetan and the Iranian plateaus, two plateaus with significantly different average elevations, we find that the horizontal force derived from the excess gravitational potential energy (collapse force) is in balance with the collision force.

Description: Magma movement and fault slip alter the magnitude and orientation of the stress in the surrounding crust. Observations of a sequence of events clustered in space and time provide information about the triggering mechanism and stress interactions between magma intrusion, earthquakes and eruptions. We investigate the syn- and post-intrusion stress changes associated with the 2007 Gelei dyke intrusion episode and subsequent eruption of nearby Oldonyo Lengai. Previous studies produced a kinematic model of the 2007 June–August sequence involving ~1 m slip on a normal fault followed by the intrusion of the 7–10-km long Gelei dyke, collapse of a shallow graben and the deflation of the Gelei magma chamber. Immediately following this, the volcano Oldoinyo Lengai (〈10 km away) experienced a new phase of explosive activity lasting for several months. Here, we present new geodetic observations covering Gelei and Oldoinyo Lengai in 2008 September–2010. We show continued slip on graben-bounding faults above the Gelei dyke. The eruption of Oldoinyo Lengai was accompanied by the intrusion of a 4 km-long E–W-trending dyke followed by deflation of a shallow source directly below the summit of the volcano. Next, we use stress calculations to investigate a number of hypotheses linking these events. (1) Before the onset of surface deformation, a dyke sufficiently deep and narrow to be geodetically undetectable could still have produced sufficient stress changes to trigger slip on the normal fault (i.e. the sequence could have been magmatically driven). (2) Stresses at the dyke tip would have been sufficient to overcome the effect of continued slip on the normal fault, allowing the dyke to propagate upwards into a region of clamping. (3) The Gelei sequence would have produced a significant stress change on the chamber beneath Oldoinyo Lengai. These static stress calculations allow us to discuss the roles played by dynamic stress, deeper magmatic changes and background stresses throughout the sequence with implications for the stress triggering of both seismic and volcanic hazards.

Description: The relationships between magnetic susceptibility and pedogenic development are different in various regions of the world. For example, loess magnetic susceptibility shows a positive correlation with pedogenic development in Chinese Loess Plateau (CLP), while it displays a negative correlation with pedogenesis in Alaska and Siberia. To better understand the relationship between magnetic properties and pedogenic development, detailed sampling of Dashing Rocks loess section at Timaru, South Island, New Zealand, was carried out. Multiproxy magnetic parameters such as magnetic susceptibility, anhysteretic remanent magnetization, magnetic hysteresis loops, M s – T curves and – T curves were measured. The results show that the types of magnetic minerals are similar to CLP: magnetite, maghemite, goethite and hematite. However, great differences are found in their concentration: most minerals in the Dashing Rocks section are hard magnetic, such as goethite, the content of paramagnetic minerals is rather high, while the soft-magnetic mineral content is very low. Hard-magnetic and paramagnetic minerals increase with depth, but soft-magnetic minerals decrease with depth, and are absent in the lower part of the profile. Gammate soil structures and Fe/Mn nodules (or pans) are commonly observed in the section, indicating that high susceptibility magnetite and maghemite have been converted to goethite and migrated downward to enrich certain horizons during chemical weathering. This process leads to lower magnetic susceptibility values, possibly related to the source and the transformation of soft-magnetic minerals in a high soil moisture environment. The relationship between magnetic susceptibility and pedogenic development in Dashing Rocks loess section is therefore different from the simple positive and negative relationships in CLP and Siberia, respectively. The more complex relationships between magnetic properties and pedogenic development in New Zealand loess may be related to differing degrees of magnetic mineral transformation at different depths and at different times.

Description: Vehicle traffic is at present one of the major sources of environmental pollution in urban areas. Magnetic parameters are successfully applied in environmental studies to obtain detailed information about concentrations and quality of iron-bearing minerals. A general aim of this research was to investigate the magnetic, microstructural and mineralogical properties of dust extracted from the roadside snowpack accumulated on the side of an urban highway, northern Helsinki. Vertical snow profiles were taken at different distances (5, 10 and 15 m) from the road edge, during winter season 2010–2011. The temporal distribution of mass magnetic susceptibility () of the road dust shows that the concentration of magnetic particles increases in the snowpack during winter. Roadside snowpack preserves a large fraction of the magnetic particulate until the late stages of melting and this could be considered as one of the main factors responsible for the resuspension phenomenon observed in Nordic countries. The vertical distribution of and SIRM (saturation isothermal remanent magnetization)/ ratio may indicate the migration of magnetic particles down in the snowpack during melting conditions. Ultrafine to coarse-grained (superparamagnetic to multidomain) magnetite was identified as the primary magnetic mineral in all the studied road dust samples. The examined road dust contains significant amount of dia/paramagnetic minerals (e.g. quartz, albite, biotite) and the content of magnetite is relatively low (below 1 weight percent, wt%). The roadside snowpack is enriched in anthropogenic particles such as angular and spherical iron-oxides, tungsten-rich particles and sodium chloride. This study demonstrates the suitability of snow as an efficient collecting medium of magnetic particulates generated by anthropogenic activities.

Description: We explore the use of on-land GPS observations to detect deformation due to tsunami propagation near source regions of large interplate earthquakes. Here, we focus on the M w 9 Tohoku-oki earthquake, which occurred around 14:46 (JST) on 2011 March 11. We consider GPS data in the time span 14:54–15:22 (JST) along the Sanriku coast, where the tsunami had the largest amplitude. The displacement data shows the signatures of large aftershocks as well as post-seismic fault slip (afterslip). These effects are particularly evident in the east component. From the horizontal displacement vectors, we construct a simple fault model for the early phase of the afterslip. Mean slip velocity of the early afterslip reaches 0.1 mm s –1 . By compiling the early afterslip velocity of recent interplate earthquakes around that region, we find its increasing trend with the main shock magnitude. This scaling relation may reflect higher stressing rates at edges of larger main shock faults. Separately, we forward calculate land deformation due to tsunami height changes based on a tsunami simulation. Tsunami-induced deformation is only evident in the vertical direction at coastal GPS stations. The predicted subsidence amounts at some coastal stations can account for a large portion of the residuals between the observation and the modelled deformation due to the fault slip.

Description: Observations of the Earth's nutations provide constraints on the mechanical coupling at the core–mantle and inner core boundaries. An important physical mechanism that could be responsible for the observed dissipation is the electromagnetic (EM) coupling, to which this paper is devoted. Previous studies assumed that the main feature of the magnetic field that affects the EM coupling is its overall strength, its morphology being considered unimportant. In particular, these studies rely on the hypothesis that the contribution to the torque from all the non-dipolar components of the field can be approximated by the contribution that a uniform radial field with the same strength would have. In this study, we compute the EM torque for more realistic configurations of the magnetic field at the core boundaries and thereby assess the role of its spatial distribution on the strength of the EM torque. For field strengths typical of the core–mantle boundary (CMB), we show that the spatial distribution affects weakly the strength of the torque, with the approximation by a uniform field leading to an overestimation of the torque magnitude by ~15–20 per cent. However, for field strengths typical of the inner core boundary (ICB), the morphology of the field has a more significant influence on the EM torque and the approximation by a uniform field overestimates the torque by ~30–40 per cent. Assuming that EM coupling is responsible for the observed dissipation, we infer constraints on the strength of the radial magnetic field at both the CMB and ICB. We show how the unknown morphology of the magnetic field induces uncertainties on the estimated field strength at the ICB, which can take values anywhere in the range of ~9–16 mT. These very large values suggest that EM coupling at the ICB cannot be the only mechanism responsible for the observed dissipation.

Description: Variations in the degree-2 Stokes coefficients C 20 , C 21 and S 21 can be used to understand long- and short-term climate forcing. Here we derive changes in these coefficients for the period 2003 January–2012 April using Earth rotation data. Earth rotation data contain contributions from motion terms (the effects of winds and currents) and contributions from the effects of mass redistribution. We remove the effects of tides, atmospheric winds and oceanic currents from our data. We compare two different models of atmospheric and oceanic angular momentum for removing the effects of winds and currents: (1) using products from the National Centers for Environmental Prediction and (2) using data from the European Centre for Medium-range Weather Forecasts (ECMWF). We assess the quality of these motion models by comparing the two resulting sets of degree-2 Stokes coefficients to independent degree-2 estimates from satellite laser ranging (SLR), GRACE and a geophysical loading model. We find a good agreement between the coefficients from Earth rotation and the coefficients from other sources. In general, the agreement is better for the coefficients we obtain by removing winds and currents effects using the ECMWF model. In this case, we find higher correlations with the independent models and smaller scatters in differences. This fact holds in particular for C 20 and C 21 , whereas we cannot observe a significant difference for S 21 . At the annual and semiannual periods, our Earth rotation derived coefficients agree well with the estimates from the other sources, particularly for C 21 and S 21 . The slight discrepancies we obtain for C 20 can probably be explained by errors in the atmospheric models and are most likely the result of an over-/underestimation of the annual and semiannual contributions of atmospheric winds to the length-of-day excitation.

Description: Subduction zones are complex 3-D features in which one tectonic plate sinks underneath another into the deep mantle. During subduction the overriding plate (OP) remains in physical contact with the subducting plate and stresses generated at the subduction zone interface and by mantle flow force the OP to deform. We present results of 3-D dynamic laboratory models of subduction that include an OP. We introduce new interplate materials comprising homogeneous mixtures of petrolatum and paraffin oil to achieve progressive subduction. The rheology of these mixtures is characterized by measurements using a strain rate controlled rheometer. The results show that the strength of the mixture increases with petrolatum content, which can be used as a proxy for the degree of mechanical coupling along the subduction interface. Results of subduction experiments are presented with different degrees of mechanical coupling and the influence this has on the dynamics and kinematics of subduction. The modelling results show that variations in the degree of mechanical coupling between the plates have a major impact on subduction velocities, slab geometry and the rate of OP deformation. In all experiments the OP is displaced following trench migration and experiences overall extension localized in the plate interior. This suggests that OP deformation is driven primarily by the toroidal component of subduction-related mantle return flow. The subduction rate is always very slow in experiments with medium mechanical coupling, and subduction stops prematurely in experiments with very high coupling. This implies that the shear forces along the plate interface in natural subduction zone systems must be relatively low and do not vary significantly. Otherwise a higher variability in natural subduction velocities should be observed for mature, non-perturbed subduction zones. The required low shear force is likely controlled by the rheology of highly hydrated sedimentary and basaltic rocks.

Description: The Frank-Kamenetskii (FK) approximation is a common method to represent the Arrhenius-type viscosity of planetary mantles because it reduces the viscosity contrast in the lithosphere to save computational resources and prevent numerical errors. In some cases, this approximation does not lead to satisfying results; for example, it can lead to a mobile-lid regime, whereas use of the Arrhenius law shows a thin stagnant lid. We therefore derive a new, more accurate approximation called ‘damped FK approximation’ for a temperature- and pressure-dependent viscosity. This damped FK approximation is a mixture between the standard first-order FK approximation and an approximation of second-order accuracy controlled by a damping parameter. Furthermore, the FK parameters are determined self-consistently at every time step. This study shows that the damped FK approximation represents the mantle flow of an Arrhenius-type viscosity for a much larger parameter space than for the standard first-order approximation. It can also be used to simulate terrestrial planets, such as super-Earths, with high pressure dependence of the viscosity, if the surface temperature does not exceed a specific threshold value and if a high enough damping parameter is used. We also test the FK approximation for plate tectonics simulations. The second-order FK approximation best represents the Arrhenius flow in the investigated parameter range. In particular, the dependence of the critical yield stress, at which the transition from the plate tectonics regime to the stagnant-lid regime can be observed, on the Rayleigh number can differ from the Arrhenius case (and the second-order FK approximation) when using a first-order FK approximation or rheology parameters in the Arrhenius law that differ from laboratory values to yield small viscosity contrasts. This finding may have strong implications for the prediction of plate tectonics on terrestrial planets.

Description: We propose new scaling laws for the properties of planetary dynamos. In particular, the Rossby number, the magnetic Reynolds number, the ratio of magnetic to kinetic energy, the Ohmic dissipation timescale and the characteristic aspect ratio of the columnar convection cells are all predicted to be power-law functions of two observable quantities: the magnetic dipole moment and the planetary rotation rate. The resulting scaling laws constitute a somewhat modified version of the scalings proposed by Christensen and Aubert. The main difference is that, in view of the small value of the Rossby number in planetary cores, we insist that the non-linear inertial term, ${\boldsymbol u} \cdot \nabla {\boldsymbol u}$ , is negligible. This changes the exponents in the power-laws which relate the various properties of the fluid dynamo to the planetary dipole moment and rotation rate. Our scaling laws are consistent with the available numerical evidence.

Description: Earlier studies at the large Vredefort impact structure since 1960 have shown that values of natural remanent magnetizations (NRMs) and, hence, Koenigsberger's Q values (ratio of remanent over induced magnetization), for different rock lithologies are elevated compared to the values for similar rock types around the world. Three origins for the high Q values have been suggested, namely shock by meteorite impact, enhanced plasma field and lightning strikes. We have studied whether laboratory lightning experiments can produce enhanced NRMs in the Vredefort target rocks. For comparison, we also included rocks from the Johannesburg dome, which is not a meteorite impact site. The results revealed increased NRMs, susceptibility and Q values of the rocks from both Vredefort and Johannesburg domes. Rock magnetic measurements and scanning electron microscope analyses of lightning pulsed and unpulsed samples showed that the lightning included changes in magnetic properties of the rocks. We suggest that in some samples lightning have changed magnetic mineralogy by oxidizing magnetite to maghemite. Indication of this oxidation came from the low-temperature variation of the remanent magnetization where we observed several hallmarks of maghemitization in samples treated by lightning strikes. Further indications of mineralogical changes include increased Curie points above the magnetite's Curie point (580 °C) and appearance of pronounced lower temperature (200–400 °C) phases in susceptibility versus temperature curves. These changes are interpreted to indicate partially oxidized magnetite (maghemitization) coupled with grain fragmentations and by this way grain size reduction. High-temperature hysteresis and REM (= NRM/saturation isothermal remanent magnetization) studies support these conclusions. Our results were analogous with the ones for lodestones and protolodestones where partially oxidized magnetite is thought to make magnetization more intense.

Description: Regeneration of the Earth's magnetic field by convection in the liquid core produces a broad spectrum of time variation. Relative palaeointensity measurements in marine sediments provide a detailed record over the past 2 Myr, but an explicit reconstruction of the underlying dynamics is not feasible. A more practical alternative is to construct a stochastic model from estimates of the virtual axial dipole moment. The deterministic part of the model (drift term) describes time-averaged behaviour, whereas the random part (diffusion term) characterizes complex interactions over convective timescales. We recover estimates of the drift and diffusion terms from the SINT2000 model of Valet et al. and the PADM2M model of Ziegler et al. The results are used in numerical solutions of the Fokker–Planck equation to predict statistical properties of the palaeomagnetic field, including the average rates of magnetic reversals and excursions. A physical interpretation of the stochastic model suggests that the timescale for adjustments in the axial dipole moment is set by the dipole decay time d . We obtain d = 29 kyr from the stochastic models, which falls within the expected range for the Earth's core. We also predict the amplitude of convective fluctuations in the core, and establish a physical connection to the rates of magnetic reversals and excursions. Chrons lasting longer than 10 Myr are unlikely under present-day conditions. However, long chrons become more likely if the diffusion term is reduced by a factor of 2. Such a change is accomplished by reducing the velocity fluctuations in the core by a factor of 2, which could be attributed to a shift in the spatial pattern of heat flux from the core or a reduction in the total core heat flow.

Description: Since King presented the ‘plates and spheres’ model in an attempt to investigate the origin of the inclination error in sediments, no one to date has conducted specific experiments designed to separate the individual contribution of platy and spherical particles to depositional remanent magnetizations (DRMs). It is commonly accepted that it is the flattening of plates, rather than the rolling of spheres that is the main source of inclination error in sediments. Recently, however, Bilardello et al. have shown that spheres alone may lead to significant amounts of shallowing. A comparison of experiments run in parallel using synthetic platy and spherical particles is presented. Experiments of the duration of 24 hr were run in 100 μT field intensity ( μ 0 H ) and varying field inclinations ( I F ) from vertical to horizontal. A systematic dependence of the magnetization on field inclination is apparent. Results indicate that magnetic moment measurements are more repeatable for spherical particles than for plates, yielding smaller uncertainties. Inclination measurements, however, are more repeatable for platy particles, with a more linear relationship of inclination error to applied field inclination. Moreover, plates yield smaller inclination error than spheres. A clear field inclination dependency of the inclination error also exists, with the error decreasing through field inclinations of 30°, 60° and 90°. A continuous acquisition experiment involving plates was also run up to 10 d of deposition in μ 0 H = 100 μT and I F = 60°. The acquisition curves for moment, inclination and thickness of depositing sediment are compared to the mean curves measured for spheres by Bilardello et al. under the same field conditions. No unequivocal evidence of compaction of the platy particles is observed, while the inclination error is acquired virtually instantaneously for all particles. These preliminary results contradict the widespread understanding that inclination shallowing is more prominent for platy particles (e.g. hematite) than it is for more spherical particles (e.g. magnetite). It is true that larger amounts of shallowing have been commonly observed in natural hematite-bearing rocks, but the overall ranges of shallowing are also larger. The particles used in these experiments may not be a reliable proxy for natural crystals and one must exercise caution when extrapolating to the natural scenarios; however, the results provide insight into the behaviour of differently shaped particles.

Description: Monoclinic 4C pyrrhotite (Fe 7 S 8 ) is ferrimagnetic due to an ordered defect structure with alternating vacancy and vacancy-free sublattices. Its low-temperature magnetic transition near 35 K is characterized by the distinct increase in coercivity and remanent magnetization. The increase of these parameters has been attributed to changes in the domain wall structure. We present static and dynamic magnetization data of a powder sample to study the domain-wall dynamics across the low-temperature transition. The amplitude-dependent ac susceptibility and the ferromagnetic resonance spectroscopy indicate that the hardening of the domain-wall pinning at the transition occurs simultaneously with the decrease in initial saturation remanent magnetization. These two effects are explained by the enhanced inhomogeneity of the bulk material caused by the persistency of the ordered vacancies and by newly formed defects due to localized distortion of Fe(II) sites in the vacancy-free sublattice. The generated localized defects are the link between the domain wall dynamics and the low-temperature transition in 4C pyrrhotite.

Description: Thermal anomalies associated with ore-mineralization (Pb–Cu–Zn and Fe) were studied using thermal infrared data collected over Mamandur polymetal prospect, India, with the aid of satellite, field, and laboratory measurements. Day and night ASTER data were analysed in conjunction with field measurements to estimate thermal inertia of the ore body, altered zones and country rocks. Representative samples collected from field were also analysed for thermal conductivity, diffusivity, and inertia using a self-fabricated setup. Spatial changes in thermal inertia were mapped by look up table (LUT) and advanced thermal inertia mapping (ATIM) approaches. Mineralized zones show very high thermal contrast ( T ) both in field (15–25°C) and satellite data (14.9–16.9 o C). They also exhibit the lowest thermal inertia in field-(2118–5474 J m –2 K –1 s –1/2 ) and satellite-based (3783–4037 J m –2 K –1 s –1/2 ) measurements. In non-mineralized areas, acidic rocks (granite, migmatite and granite gneiss) have lower inertia than basic rocks (basic granulite, dolerite and charnockite). Results estimated by LUT and ATIM approaches correlate very well at satellite ( R 2  = 0.97) and field ( R 2  = 0.89) scales. Similarly, field- and satellite-based results also have good correlation ( R 2  = 0.69–0.72). This study illustrates the potential of thermal inertia mapping in delineating ore bodies and deciphering the lithological changes even under veneer of soil.

Description: We present a novel global 3-D electromagnetic (EM) inverse solution that allows to work in a unified and consistent manner with frequency-domain data that originate from ionospheric and magnetospheric sources irrespective of their spatial complexity. The main idea behind the approach is simultaneous determination of the source and conductivity distribution in the Earth. Such a determination is implemented in our solution as a looped sequential procedure that involves two steps: (1) determination of the source using a fixed 3-D conductivity model and (2) recovery of a 3-D conductivity model using a fixed source. We focus in this paper on analysis of Sq data and numerically verify each step separately and combined using data synthesized from 3-D models of the Earth induced by a realistic Sq source. To determine the source we implement an approach that makes use of a known conductivity structure of the Earth with non-uniform oceans. Based on model studies we show that this approach outperforms the conventional potential method. As for recovery of 3-D conductivity in the mantle, our inverse scheme relies on a regularized least-square formulation, exploits a limited-memory quasi-Newton optimization method and makes use of the adjoint source approach to calculate efficiently the misfit gradient. We perform resolution studies with checkerboard conductivity structures at depths between 10 and 1600 km for different inverse setups and conclude from these studies that: (1) inverting Z component gives much better results than inverting all ( X , Y and Z ) components; (2) data from the Sq source allows for resolving 3-D structures in depth range between 100 and 520 km; (3) the best resolution is achieved in the depth range of 100–250 km.

Description: The discontinuity surface between Earth crust and mantle, the so-called Moho, is commonly estimated by means of seismic or gravimetric methods. Usually these methods do not yield the same result since they are based on different geological and geophysical hypotheses, as well as different data types, also in terms of quality and spatial distribution. In particular, global crust models based only on seismic data (e.g. the CRUST2.0 model) can be locally very accurate since seismic profiles give an almost direct observation of the actual crust structure, but can be quite uninformative in large regions where no data are available or they are too inhomogeneous. On the contrary, when using satellite gravity observations like those provided by the ESA mission GOCE, information on the Moho can be inferred from a uniform and global data set. However, Moho models estimated by gravity data are in general characterized by simplified hypotheses to guarantee the uniqueness of the solution of the inverse gravitational problem. The aim of this work is to attenuate these drawbacks by combining the seismic global model CRUST2.0 with gravity observations from the GOCE satellite mission. More specifically, the used GOCE data are grid values at mean satellite altitude estimated by the so-called space-wise approach. After reducing the data to a two-layer model by removing the effect of topography, bathymetry and sediments, a combined inversion driven by a priori information on the CRUST2.0 accuracy and by the error covariance structure of the GOCE grids is performed. In addition, the observation errors as well as the error due to the data reduction are tentatively taken into account to estimate the accuracy of the final Moho model. The result is an update of the CRUST2.0 Moho model with a 0.5°  x 0.5° resolution, which at the same time contains seismic and geological information and it is consistent, at 20 mE level, to the actually observed gravity field. A first comparison with the CRUST2.0 Moho shows that in the continental crust the mean difference between the two models is of the order of 1.5 km with standard deviations depending on the considered region. As expected, the main variations (standard deviation of the order of 7 km) are located in South America, Africa and Antarctica where very few data in the CRUST2.0 were originally used. In the rest of the world, differences have a standard deviation of about 4 km. As for the oceanic crust, it can be noted that the corrections to the CRUST2.0 model are of the order of 3 km (mean value) with a standard deviation of 6 km. Finally, the solution computed in this paper has been compared with a set of Moho models at different scales from global to local ones showing that it is reasonably consistent (differences of about 5 km standard deviation) also with seismic observations.

Description: Gravity gradiometry, whether from ground or airborne surveys, for geodesy and geophysics typically requires that the gravitational effect of the visible terrain is removed from the measured values. A systematic, algorithmic approach is developed to determine the extent of terrain data needed to maintain a truncation error below a desired level. The algorithm is based on a geostatistical analysis of the topography and applies to gradient differences over a particular size of survey area. It was found that a suitable modification of the kernel of the integral for the terrain effect can reduce the needed extent significantly in some cases. The determination of the needed extent for a given truncation error (standard deviation) and survey area size requires knowing a reasonable amplitude of the power spectral density (PSD) of the local topography, but otherwise is based on the fractal nature of topography, which also assumes that it is stationary. The algorithm is illustrated for ground and airborne cases in both moderate and rough terrain. For example, for an airborne gradiometer survey at 5 km altitude over 50 km of moderate terrain, the algorithm predicts requiring a topographic data extent of about 48 km for 1 Eötvös error (standard deviation) in the terrain effect. This extent can be reduced to 35 km with the kernel modification. In addition, the developed PSD models may be extended to determine the data resolution required for the terrain effect using a simple analytic formula.

Description: The commonest technique for determination of the continental-oceanic crustal boundary or transition (COB) zone is based on locating and visually correlating bathymetric and potential field anomalies and constructing crustal models constrained by seismic data. In this paper, we present a simple method for spatial correlation of bathymetric and potential field geophysical anomalies. Angular differences between gradient directions are used to determine different types of correlation between gravity and bathymetric or magnetic data. It is found that the relationship between bathymetry and gravity anomalies can be correctly identified using this method. It is demonstrated, by comparison with previously published models for the southwest African margin, that this method enables the demarcation of the zone of transition from oceanic to continental crust assuming that this it is associated with geophysical anomalies, which can be correlated using gradient directions rather than magnitudes. We also applied this method, supported by 2-D gravity modelling, to the more complex Liberia and Cote d'Ivoire-Ghana sectors of the West African transform margin and obtained results that are in remarkable agreement with past predictions of the COB in that region. We suggest the use of this method for a first-pass interpretation as a prelude to rigorous modelling of the COB in frontier areas.

Description: Gravity inversion allows us to constrain the interior mass distribution of a planetary body using the observed shape, rotation and gravity. Traditionally, techniques developed for gravity inversion can be divided into Monte Carlo methods, matrix inversion methods and spectral methods. Here we employ both matrix inversion and Monte Carlo in order to explore the space of exact solutions, in a method which is particularly suited for arbitrary shape bodies. We expand the mass density function using orthogonal polynomials, and map the contribution of each term to the global gravitational field generated. This map is linear in the density terms, and can be pseudo-inverted in the underdetermined regime using QR decomposition, to obtain a basis of the affine space of exact interior structure solutions. As the interior structure solutions are degenerate, assumptions have to be made in order to control their properties, and these assumptions can be transformed into scalar functions and used to explore the solutions space using Monte Carlo techniques. Sample applications show that the range of solutions tend to converge towards the nominal one as long as the generic assumptions made are correct, even in the presence of moderate noise. We present the underlying mathematical formalism and an analysis of how to impose specific features on the global solution, including uniform solutions, gradients and layered models. Analytical formulas for the computation of the relevant quantities when the shape is represented using several common methods are included in the Appendix.

Description: Tortuosity is a key parameter for investigating the pore structure of sedimentary rock. The conventional model for calculating the tortuosity is derived from Archie's law which is only valid for one conductive phase contained in a porous rock. However, there have been increasingly cases to show the non-Archie phenomenon in instances where the rock matrix has extra conductive phases such as surface conductivity caused by the electrical double layer. Therefore, such model may be inapplicable in these cases and in calculations involving partial melting. We investigated the relation between formation factor and porosity ( F– ) over a wide range of porosities by the lattice-gas automata method (LGA) with the electrical double layer. The digital rock samples were constructed by packing up solid grains with different shapes and size distribution, as previously measured in the laboratory on real rock specimens. Our purpose was to identify the origin of non-Archie behaviour of the F– relation sometimes observed. The simulations show that Archie's law may only be an approximation of the F– relation in a high porosity range. Based on our LGA simulations and additional laboratory experimental data, we developed new equations for non-Archie F– relation and tortuosity potentially useful for improving the evaluation of pore structure.

Description: In this study, we investigate the seismic wave attenuation beneath Sikkim Himalaya using P , S and coda waves from 68 local earthquakes registered by eight broad-band stations of the SIKKIM network. The attenuation quality factor ( Q ) depends on frequency as well as lapse time and depth. The value of Q varies from (i) 141 to 639 for P waves, (ii) 143 to 1108 for S waves and (iii) 274 to 1678 for coda waves, at central frequencies of 1.5 Hz and 9 Hz, respectively. The relations that govern the attenuation versus frequency dependence are Q α  = (96 ± 0.9) f (0.94 ± 0.01) , Q β  = (100 ± 1.4) f (1.16 ± 0.01) and Q c  = (189 ± 1.5) f (1.2 ± 0.01) for P , S and coda waves, respectively. The ratio between Q β and Q α is larger than unity, implying larger attenuation of P compared to S waves. Also, the values of Q c are higher than Q β . Estimation of the relative contribution of intrinsic ( Q i ) and scattering ( Q s ) attenuation reveals that the former mechanism is dominant in Sikkim Himalaya. We note that the estimates of Q c lie in between Q i and Q s and are very close to Q i at lower frequencies. This is in agreement with the theoretical and laboratory experiments. The strong frequency and depth dependence of the attenuation quality factor suggests a highly heterogeneous crust in the Sikkim Himalaya. Also, the high Q values estimated for this region compared to the other segments of Himalaya can be reconciled in terms of moderate seismic activity, unlike rest of the Himalaya, which is seismically more active.

Description: The seismic wavefield mainly contains reflected, refracted and direct waves but energy related to elastic scattering can also be identified at frequencies of 1 Hz and higher. The scattered, high-frequency seismic wavefield contains information on the small-scale structure of the Earth's crust, mantle and core. Due to the high thermal conductivity of mantle materials causing rapid dissipation of thermal anomalies, the Earth's small-scale structure most likely reveals details of the composition of the interior, and, is therefore essential for our understanding of the dynamics and evolution of the Earth. Using specific ray configurations we can identify scattered energy originating in the lower mantle and under certain circumstances locate its point of origin in the Earth allowing further insight into the structure of the lowermost mantle. Here we present evidence, from scattered PKP waves, for a heterogeneous structure at the core–mantle boundary (CMB) beneath southern Africa. The structure rises approximately 80 km above the CMB and is located at the eastern edge of the African LLSVP. Mining-related and tectonic seismic events in South Africa, with m b from 3.2 to 6.0 recorded at epicentral distances of 119.3° to 138.8° from Yellowknife Array (YKA) (Canada), show large amplitude precursors to PKP df arriving 3–15 s prior to the main phase. We use array processing to measure slowness and backazimuth of the scattered energy and determine the scatterer location in the deep Earth. To improve the resolution of the slowness vector at the medium aperture YKA we present a new application of the F -statistic. The high-resolution slowness and backazimuth measurements indicate scattering from a structure up to 80 km tall at the CMB with lateral dimensions of at least 1200 km by 300 km, at the edge of the African Large Low Shear Velocity Province. The forward scattering nature of the PKP probe indicates that this is velocity-type scattering resulting primarily from changes in elastic parameters. The PKP scattering data are in agreement with dynamically supported dense material related to the Large Low Shear Velocity Province.

Description: In this paper, some methods for scoring the performances of an earthquake forecasting probability model are applied retrospectively for different goals. The time-dependent occurrence probabilities of a renewal process are tested against earthquakes of M w ≥ 5.3 recorded in Italy according to decades of the past century. An aim was to check the capability of the model to reproduce the data by which the model was calibrated. The scoring procedures used can be distinguished on the basis of the requirement (or absence) of a reference model and of probability thresholds. Overall, a rank-based score, information gain, gambling scores, indices used in binary predictions and their loss functions are considered. The definition of various probability thresholds as percentages of the hazard functions allows proposals of the values associated with the best forecasting performance as alarm level in procedures for seismic risk mitigation. Some improvements are then made to the input data concerning the completeness of the historical catalogue and the consistency of the composite seismogenic sources with the hypotheses of the probability model. Another purpose of this study was thus to obtain hints on what is the most influential factor and on the suitability of adopting the consequent changes of the data sets. This is achieved by repeating the estimation procedure of the occurrence probabilities and the retrospective validation of the forecasts obtained under the new assumptions. According to the rank-based score, the completeness appears to be the most influential factor, while there are no clear indications of the usefulness of the decomposition of some composite sources, although in some cases, it has led to improvements of the forecast.

Description: We propose a numerical algorithm for solving first arrival transmission traveltime tomography problems where the underlying slowness is piecewise continuous. The idea is based upon our previously efficient approach for smooth slowness inversion (Leung & Qian) using the fast sweeping method and the adjoint state method. In this work, we further incorporate the level set method to implicitly represent the discontinuity in the velocity. One main advantage of such implicit representation is that there is no assumption on the number of disjoint components in the inverted structure. The evolution of the level set function will naturally take care of the change in the topology. Like in the previous work, the gradient of the mismatch functional is derived using the adjoint state method. The forward problem and the adjoint equation are efficiently solved by the fast sweeping method. To further improve the computational efficiency, we also propose a local level set method so that most computer power of updating the level set evolution is spent near the discontinuity in the slowness. Numerical results will be given to demonstrate the robustness of the algorithm.

Description: We present a 1-D velocity model of the Earth's crust in Campania–Lucania region obtained by solving the coupled hypocentre–velocity inverse problem for 1312 local earthquakes recorded at a dense regional network. The model is constructed using the VELEST program, which calculates 1-D ‘minimum’ velocity model from body wave traveltimes, together with station corrections, which account for deviations from the simple 1-D structure. The spatial distribution of station corrections correlates with the P -wave velocity variations of a preliminary 3-D crustal velocity model that has been obtained from the tomographic inversion of the same data set of P traveltimes. We found that station corrections reflect not only inhomogeneous near-surface structures, but also larger-scale geological features associated to the transition between carbonate platform outcrops at Southwest and Miocene sedimentary basins at Northeast. We observe a significant trade-off between epicentral locations and station corrections, related to the existence of a thick low-velocity layer to the NE. This effect is taken into account and minimized by re-computing station corrections, fixing the position of a subset of well-determined hypocentres, located in the 3-D tomographic model.

Description: High-rate GPS and seismic sensors are mutually contributing to seismological applications for capturing earthquake-induced coseismic displacements. In this study, we propose an approach for tightly integrating GPS and strong motion data on raw observation level to increase the quality of the derived displacements. The performance of the proposed approach is demonstrated using 5 Hz high-rate GPS and 200 Hz strong motion data collected during the El Mayor–Cucapah earthquake ( M w 7.2, 2010 April 4) in Baja California, Mexico. The new approach not only takes advantages of both GPS and strong motion sensors, but also improves the reliability of the displacement by enhancing GPS integer-cycle phase ambiguity resolution, which is very critical for deriving displacements with highest quality.

Description: The Pegasus Bay aftershock sequence is the most recent aftershock sequence of the 2010 September 3 UTC moment magnitude ( M w ) 7.1 Darfield earthquake in the Canterbury region of New Zealand. The Pegasus Bay aftershock sequence began on 2011 December 23 UTC with three events of M w 5.4–5.9 located in the offshore region of Pegasus Bay, east of Christchurch city. We present a summary of key aspects of the sequence derived using various geophysical methods. Relocations carried out using double-difference tomography show a well-defined NNE–SSW to NE–SW series of aftershocks with most of the activity occurring at depths 〉5 km and an average depth of ~10 km. Regional moment tensor solutions calculated for the Pegasus Bay sequence indicate that the vast majority (45 of 53 events) are reverse-faulting events with an average P -axis azimuth of 125°. Strong-motion data inversion favours a SE-dipping fault plane for the largest event ( M w 5.9) with a slip patch of 18 km  x 15 km and a maximum slip of 0.8 m at 3.5 km depth. Peak ground accelerations ranging up to 0.98 g on the vertical component were recorded during the sequence, and the largest event produced horizontal accelerations of 0.2–0.4 g in the Christchurch central business district. Apparent stress estimates for the two largest events are 1.1 MPa ( M w 5.9) and 0.2 MPa ( M w 5.8), which are compatible with global averages, although lower than other large events in the Canterbury aftershock sequence. Coulomb stress analysis indicates that previous large earthquakes in the Canterbury sequence generate Coulomb stress increases for the two events only at relatively shallow depths (3–5 km). At greater depths, Coulomb stress decreases are predicted at the locations of the two events. The trend of the aftershocks is similar to mapped reverse faults north of Christchurch, and the high number of reverse-faulting mechanisms suggests that similar reverse-faulting structures are present in the offshore region east of Christchurch.

Description: Magma dynamics and time scales during the VEI 5, 2000 bp eruption of El Misti volcano, southern Peru (EM2000BP) are investigated to address cyclic explosive activity at this hazardous volcano. The 1·4 km 3 of pumice falls and flows have abundant mingled pumice of high-K, calc-alkaline rhyolite and andesite composition. Phenocryst zoning and compositions reveal mutual exchange of plagioclase between the two magmas; amphibole in the rhyolite was derived from the andesite. Amphiboles in the andesite are predominantly unrimmed crystals whereas those in the rhyolite mostly exhibit reaction rims. Phase equilibria indicate that the andesite formed at ~900–950°C and 2–3 kbar pressure and was water-saturated with 5·1–6·0 wt % H 2 O, broadly similar to El Misti magmas overall. Amphibole, plagioclase, Ti-magnetite, and two pyroxenes were the crystallizing phases. A separate rhyolite magma existed higher in the crust at a temperature of 816 ± 30°C and ~5% H 2 O in which only plagioclase and Fe–Ti oxides were stable. The lack of cognate amphibole in the rhyolite despite H 2 O saturation requires that it staged above the stability limit of amphibole (〈100 MPa). Exchange reactions in amphibole (dominantly pargasitic) and trace element partitioning in plagioclase indicate that both andesite and rhyolite magmas were broadly constant in temperature and H 2 O content. These constraints suggest that the initially separate rhyolite and deeper andesite magmas interacted by an initial andesite recharge event that resulted in mingling and crystal exchange. A period of 50–60 days is required for amphibole introduced into the rhyolite to develop reaction rims owing to decompression. These rims are dominated by plagioclase, a consequence of the Al-rich nature of the amphibole. The lack of reaction rims on amphibole in the andesite implicates a second, more-forceful and voluminous eruption-triggering recharge event during which andesite rose rapidly from source to surface in ≤5 days at ascent rates of at least 0·023 m s –1 . Further decompression-driven crystallization is recorded in plagioclase rims and microlite growth that may have contributed to a rapid increase in viscosity leading to explosive eruption. This VEI 5 plinian eruption shares characteristics with other explosive events at El Misti on a time scale of 2000–4000 years, suggesting periodic recharge-driven explosive activity.

Description: We report structural evidence of ductile strain localization in mantle pyroxenite from the spinel to plagioclase websterite transition in the Ronda Peridotite (southern Spain). Mapping shows that, in this domain, small-scale shear zones occurring at the base of the lithospheric section are systematically located within thin pyroxenite layers, suggesting that the pyroxenite was locally weaker than the host peridotite. Strain localization is associated with a sudden decrease of grain size and increasing volume fractions of plagioclase and amphibole as a result of a spinel to plagioclase phase transformation reaction during decompression. This reaction also fostered hydrogen extraction (‘dehydroxylation’) from clinopyroxene producing effective fluid saturation that catalyzed the synkinematic net-transfer reaction. This reaction produced fine-grained olivine and plagioclase, allowing the onset of grain-size sensitive creep and further strain localization in these pyroxenite bands. The strain localization in the pyroxenites is thus explained by their more fertile composition, which allowed earlier onset of the phase transition reactions. Geothermobarometry undertaken on compositionally zoned constituent minerals suggests that this positive feedback between reactions and deformation is associated with cooling from at least 1000°C to 700°C and decompression from 1·0 to 0·5 GPa.

Description: Motivation: Human miRNAs have recently been found to have important roles in viral replication. Understanding the patterns and details of human miRNA interactions during virus–host interactions may help uncover novel antiviral therapies. Based on the abundance of knowledge available regarding protein–protein interactions (PPI), virus–host protein interactions, experimentally validated human miRNA-target pairs and transcriptional regulation of human miRNAs, it is possible to explore the complex regulatory network that exists between viral proteins and human miRNAs at the system level. Results: By integrating current data regarding the virus–human interactome and human miRNA-target pairs, the overlap between targets of viral proteins and human miRNAs was identified and found to represent topologically important proteins (e.g. hubs or bottlenecks) at the global center of the human PPI network. Viral proteins and human miRNAs were also found to significantly target human PPI pairs. Furthermore, an overlap analysis of virus targets and transcription factors (TFs) of human miRNAs revealed that viral proteins preferentially target human miRNA TFs, representing a new pattern of virus–host interactions. Potential feedback loops formed by viruses, human miRNAs and miRNA TFs were also identified, and these may be exploited by viruses resulting in greater virulence and more effective replication strategies. Contact: boxc@bmi.ac.cn or ni.ming@163.com or sqwang@bmi.ac.cn Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: In sequencing studies of common diseases and quantitative traits, power to test rare and low frequency variants individually is weak. To improve power, a common approach is to combine statistical evidence from several genetic variants in a region. Major challenges are how to do the combining and which statistical framework to use. General approaches for testing association between rare variants and quantitative traits include aggregating genotypes and trait values, referred to as ‘collapsing’, or using a score-based variance component test. However, little attention has been paid to alternative models tailored for protein truncating variants. Recent studies have highlighted the important role that protein truncating variants, commonly referred to as ‘loss of function’ variants, may have on disease susceptibility and quantitative levels of biomarkers. We propose a Bayesian modelling framework for the analysis of protein truncating variants and quantitative traits. Results: Our simulation results show that our models have an advantage over the commonly used methods. We apply our models to sequence and exome-array data and discover strong evidence of association between low plasma triglyceride levels and protein truncating variants at APOC3 (Apolipoprotein C3). Availability: Software is available from http://www.well.ox.ac.uk/~rivas/mamba Contact: donnelly@well.ox.ac.uk

Description: Motivation: Structural information of macromolecular complexes provides key insights into the way they carry out their biological functions. Achieving high-resolution structural details with electron microscopy requires the identification of a large number (up to hundreds of thousands) of single particles from electron micrographs, which is a laborious task if it has to be manually done and constitutes a hurdle towards high-throughput. Automatic particle selection in micrographs is far from being settled and new and more robust algorithms are required to reduce the number of false positives and false negatives. Results: In this article, we introduce an automatic particle picker that learns from the user the kind of particles he is interested in. Particle candidates are quickly and robustly classified as particles or non-particles. A number of new discriminative shape-related features as well as some statistical description of the image grey intensities are used to train two support vector machine classifiers. Experimental results demonstrate that the proposed method: (i) has a considerably low computational complexity and (ii) provides results better or comparable with previously reported methods at a fraction of their computing time. Availability: The algorithm is fully implemented in the open-source Xmipp package and downloadable from http://xmipp.cnb.csic.es . Contact: vabrishami@cnb.csic.es or coss@cnb.csic.es Supplementary Information: Supplementary data are available at Bioinformatics online.

Description: : Recent major cancer genome sequencing studies have used whole-genome sequencing to detect various types of genomic variation. However, a number of these studies have continued to rely on SNP array information to provide additional results for copy number and loss-of-heterozygosity estimation and assessing tumour purity. OncoSNP-SEQ is a statistical model-based approach for inferring copy number profiles directly from high-coverage whole genome sequencing data that is able to account for unknown tumour purity and ploidy. Availability: MATLAB code is available at the following URL: https://sites.google.com/site/oncosnpseq/ . Contact : c.yau@imperial.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : Multi-Image Genome (MIG) viewer is a web-based application for visualizing, querying and filtering many thousands of genome browser regions as well as for exporting the data in a variety of formats. This methodology has been used successfully to analyze ChIP-Seq data and RNA-Seq data and to detect somatic mutations in genome resequencing projects. Availability: MIG is available at https://mig.molbiol.ox.ac.uk/mig/ Contact: simon.mcgowan@imm.ox.ac.uk

Description: : Unlike DNA, RNA abundances can vary over several orders of magnitude. Thus, identification of RNA–protein binding sites from high-throughput sequencing data presents unique challenges. Although peak identification in ChIP-Seq data has been extensively explored, there are few bioinformatics tools tailored for peak calling on analogous datasets for RNA-binding proteins. Here we describe ASPeak (abundance sensitive peak detection algorithm), an implementation of an algorithm that we previously applied to detect peaks in exon junction complex RNA immunoprecipitation in tandem experiments. Our peak detection algorithm yields stringent and robust target sets enabling sensitive motif finding and downstream functional analyses. Availability: ASPeak is implemented in Perl as a complete pipeline that takes bedGraph files as input. ASPeak implementation is freely available at https://sourceforge.net/projects/as-peak under the GNU General Public License. ASPeak can be run on a personal computer, yet is designed to be easily parallelizable. ASPeak can also run on high performance computing clusters providing efficient speedup. The documentation and user manual can be obtained from http://master.dl.sourceforge.net/project/as-peak/manual.pdf . Contact: alper.kucukural@umassmed.edu or ccenik@stanford.edu

Description: Motivation: Kinases of the eukaryotic protein kinase superfamily are key regulators of most aspects eukaryotic cellular behavior and have provided several drug targets including kinases dysregulated in cancers. The rapid increase in the number of genomic sequences has created an acute need to identify and classify members of this important class of enzymes efficiently and accurately. Results: Kinannote produces a draft kinome and comparative analyses for a predicted proteome using a single line command, and it is currently the only tool that automatically classifies protein kinases using the controlled vocabulary of Hanks and Hunter [Hanks and Hunter (1995)]. A hidden Markov model in combination with a position-specific scoring matrix is used by Kinannote to identify kinases, which are subsequently classified using a BLAST comparison with a local version of KinBase, the curated protein kinase dataset from www.kinase.com . Kinannote was tested on the predicted proteomes from four divergent species. The average sensitivity and precision for kinome retrieval from the test species are 94.4 and 96.8%. The ability of Kinannote to classify identified kinases was also evaluated, and the average sensitivity and precision for full classification of conserved kinases are 71.5 and 82.5%, respectively. Kinannote has had a significant impact on eukaryotic genome annotation, providing protein kinase annotations for 36 genomes made public by the Broad Institute in the period spanning 2009 to the present. Availability: Kinannote is freely available at http://sourceforge.net/projects/kinannote . Contact: jmgold@broadinstitute.org Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Quantification of lipids is a primary goal in lipidomics. In direct infusion/injection (or shotgun) lipidomics, accurate downstream identification and quantitation requires accurate summarization of repetitive peak measurements. Imprecise peak summarization multiplies downstream error by propagating into species identification and intensity estimation. To our knowledge, this is the first analysis of direct infusion peak summarization in the literature. Results: We present two novel peak summarization algorithms for direct infusion samples and compare them with an off-machine ad hoc summarization algorithm as well as with the propriety Xcalibur algorithm. Our statistical agglomeration algorithm reduces peakwise error by 38% mass/charge (m/z) and 44% (intensity) compared with the ad hoc method over three datasets. Pointwise error is reduced by 23% (m/z). Compared with Xcalibur, our statistical agglomeration algorithm produces 68% less m/z error and 51% less intensity error on average on two comparable datasets. Availability: The source code for Statistical Agglomeration and the datasets used are freely available for non-commercial purposes at https://github.com/optimusmoose/statistical_agglomeration . Modified Bin Aggolmeration is freely available in MSpire, an open source mass spectrometry package at https://github.com/princelab/mspire/ . Contact: 2robsmith@gmail.com or jtprince@chem.byu.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Liquid chromatography coupled to mass spectrometry (LC-MS) is the dominant technological platform for proteomics. An LC-MS analysis of a complex biological sample can be visualized as a ‘map’ of which the positional coordinates are the mass-to-charge ratio (m/z) and chromatographic retention time (RT) of the chemical species profiled. Label-free quantitative proteomics requires the alignment and comparison of multiple LC-MS maps to ascertain the reproducibility of experiments or reveal proteome changes under different conditions. The main challenge in this task lies in correcting inevitable RT shifts. Similar, but not identical, LC instruments and settings can cause peptides to elute at very different times and sometimes in a different order, violating the assumptions of many state-of-the-art alignment tools. To meet this challenge, we developed LWBMatch, a new algorithm based on weighted bipartite matching. Unlike existing tools, which search for accurate warping functions to correct RT shifts, we directly seek a peak-to-peak mapping by maximizing a global similarity function between two LC-MS maps. For alignment tasks with large RT shifts (〉500 s), an approximate warping function is determined by locally weighted scatterplot smoothing of potential matched features, detected using a novel voting scheme based on co-elution. For validation, we defined the ground truth for alignment success based on tandem mass spectrometry identifications from sequence searching. We showed that our method outperforms several existing tools in terms of precision and recall, and is capable of aligning maps from different instruments and settings. Availability: Available at https://sourceforge.net/projects/rt-alignment/ . Contact: kehlam@ust.hk Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : We propose SW#, a new CUDA graphical processor unit-enabled and memory-efficient implementation of dynamic programming algorithm, for local alignment. It can be used as either a stand-alone application or a library. Although there are other graphical processor unit implementations of the Smith–Waterman algorithm, SW# is the only one publicly available that can produce sequence alignments on genome-wide scale. For long sequences, it is at least a few hundred times faster than a CPU version of the same algorithm. Availability: Source code and installation instructions freely available for download at http://complex.zesoi.fer.hr/SW.html . Contact: mile.sikic@fer.hr Supplementary information: Supplementary results are available at Bioinformatics online.

Description: Spinal muscular atrophy (SMA) is caused by mutations of the survival motor neuron 1 ( SMN1 ) gene, retention of the survival motor neuron 2 ( SMN2 ) gene and insufficient expression of full-length survival motor neuron (SMN) protein. Quinazolines increase SMN2 promoter activity and inhibit the ribonucleic acid scavenger enzyme DcpS. The quinazoline derivative RG3039 has advanced to early phase clinical trials. In preparation for efficacy studies in SMA patients, we investigated the effects of RG3039 in severe SMA mice. Here, we show that RG3039 distributed to central nervous system tissues where it robustly inhibited DcpS enzyme activity, but minimally activated SMN expression or the assembly of small nuclear ribonucleoproteins. Nonetheless, treated SMA mice showed a dose-dependent increase in survival, weight and motor function. This was associated with improved motor neuron somal and neuromuscular junction synaptic innervation and function and increased muscle size. RG3039 also enhanced survival of conditional SMA mice in which SMN had been genetically restored to motor neurons. As this systemically delivered drug may have therapeutic benefits that extend beyond motor neurons, it could act additively with SMN-restoring therapies delivered directly to the central nervous system such as antisense oligonucleotides or gene therapy.

Description: Coronary heart disease (CHD) is the leading cause of death worldwide. Mitochondrial genetic determinant for the development of CHD remains poorly explored. We report there the clinical, genetic, molecular and biochemical characterization of a four-generation Chinese family with maternally inherited CHD. Thirteen of 32 adult members in this family exhibited variable severity and age-at-onset of CHD. Mutational analysis of their mitochondrial genomes identified the tRNA Thr 15927G〉A mutation belonging to the Eastern Asian haplogroup B5. The anticipated destabilization of a highly conserved base-pairing (28C-42G) by the 15927G〉A mutation affects structure and function of tRNA Thr . Northern analysis revealed 80% decrease in the steady-state level of tRNA Thr in the mutant cell lines carrying the 15927G〉A mutation. The 15927G〉A mutation changed the conformation of tRNA Thr , as suggested by slower electrophoretic mobility of mutated tRNA with respect to the wild-type molecule. In addition, ~39% reduction in aminoacylated efficiency of tRNA Thr was observed in mutant cells derived from this Chinese family. An in vivo mitochondrial protein labeling analysis showed ~53% reduction in the rate of mitochondrial translation in mutant cells. The impaired mitochondrial protein synthesis leads to defects in overall respiratory capacity or malate/glutamate-promoted respiration or succinate/glycerol-3-phosphate-promoted respiration, or N,N,N',N '-tetramethyl-pphenylenediamine/ascorbate-promoted respiration in mutant cells. An increasing production of reactive oxygen species was observed in the mutant cells carrying the 15927G〉A mutation. These results provide the direct evidence that the tRNA Thr 15927G〉A mutation is associated with CHD. Our findings may provide new insights into pathophysiology and intervention targets of this disorder.

Description: Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder that stems from low levels of survival of motor neuron (SMN) protein. The processes that cause motor neurons and muscle cells to become dysfunctional are incompletely understood. We are interested in neuromuscular homeostasis and the stresses put upon that system by loss of SMN. We recently reported that α-COP, a member of the coatomer complex of coat protein I (COPI) vesicles, is an SMN-binding partner, implicating this protein complex in normal SMN function. To investigate the functional significance of the interaction between α-COP and SMN, we constructed an inducible NSC-34 cell culture system to model the consequences of SMN depletion and find that depletion of SMN protein results in shortened neurites. Heterologous expression of human SMN, and interestingly over-expression of α-COP, restores normal neurite length and morphology. Mutagenesis of the canonical COPI dilysine motifs in exon 2b results in failure to bind to α-COP and abrogates the ability of human SMN to restore neurite outgrowth in SMN-depleted motor neuron-like NSC-34 cells. We conclude that the interaction between SMN and α-COP serves an important function in the growth and maintenance of motor neuron processes and may play a significant role in the pathogenesis of SMA.

Description: Human cortical malformations, including lissencephaly, polymicrogyria and other diseases of neurodevelopment, have been associated with mutations in microtubule subunits and microtubule-associated proteins. Here we report our cloning of the brain dimple ( brdp ) mouse mutation, which we recovered from an ENU screen for recessive perinatal phenotypes affecting neurodevelopment. We identify the causal mutation in the tubulin, beta-2b ( Tubb2b) gene as a missense mutation at a highly conserved residue (N247S). Brdp/brdp homozygous mutants have significant thinning of the cortical epithelium, which is markedly more severe in the caudo-lateral portion of the telencephalon, and do not survive past birth. The cortical defects are largely due to a major increase in apoptosis and we note abnormal proliferation of the basal progenitors. Adult brdp/+ mice are viable and fertile but exhibit behavioral phenotypes. This allele of Tubb2b represents the most severely affected mouse tubulin phenotype reported to date and this is the first report of a tubulin mutation affecting neuronal proliferation and survival.

Description: CCDC28B encodes a coiled coil domain-containing protein involved in ciliogenesis that was originally identified as a second site modifier of the ciliopathy Bardet–Biedl syndrome. We have previously shown that the depletion of CCDC28B leads to shortened cilia; however, the mechanism underlying how this protein controls ciliary length is unknown. Here, we show that CCDC28B interacts with SIN1, a component of the mTOR complex 2 (mTORC2), and that this interaction is important both in the context of mTOR signaling and in a hitherto unknown, mTORC-independent role of SIN1 in cilia biology. We show that CCDC28B is a positive regulator of mTORC2, participating in its assembly/stability and modulating its activity, while not affecting mTORC1 function. Further, we show that Ccdc28b regulates cilia length in vivo , at least in part, through its interaction with Sin1. Importantly, depletion of Rictor, another core component of mTORC2, does not result in shortened cilia. Taken together, our findings implicate CCDC28B in the regulation of mTORC2, and uncover a novel function of SIN1 regulating cilia length that is likely independent of mTOR signaling.

Description: Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein due to the functional loss of the SMN1 gene and the inability of its paralog, SMN2 , to fully compensate due to reduced exon 7 splicing efficiency. Since SMA patients have at least one copy of SMN2 , drug discovery campaigns have sought to identify SMN2 inducers. C5-substituted quinazolines increase SMN2 promoter activity in cell-based assays and a derivative, RG3039, has progressed to clinical testing. It is orally bioavailable, brain-penetrant and has been shown to be an inhibitor of the mRNA decapping enzyme, DcpS. Our pharmacological characterization of RG3039, reported here, demonstrates that RG3039 can extend survival and improve function in two SMA mouse models of varying disease severity (Taiwanese 5058 Hemi and 2B/– SMA mice), and positively impacts neuromuscular pathologies. In 2B/– SMA mice, RG3039 provided a 〉600% survival benefit (median 18 days to 〉112 days) when dosing began at P4, highlighting the importance of early intervention. We determined the minimum effective dose and the associated pharmacokinetic (PK) and exposure relationship of RG3039 and DcpS inhibition ex vivo . These data support the long PK half-life with extended pharmacodynamic outcome of RG3039 in 2B/– SMA mice. In motor neurons, RG3039 significantly increased both the average number of cells with gems and average number of gems per cell, which is used as an indirect measure of SMN levels. These studies contribute to dose selection and exposure estimates for the first studies with RG3039 in human subjects.

Description: Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by selective degeneration of upper and lower motoneurons. The primary triggers for motoneuron degeneration are still unknown, but inflammation is considered an important contributing factor. P2X7 receptor is a key player in microglia response to toxic insults and was previously shown to increase pro-inflammatory actions of SOD1-G93A ALS microglia. We therefore hypothesized that lack of P2X7 receptor could modify disease features in the SOD1-G93A mice. Hetero- and homozygous P2X7 receptor knock-out SOD1-G93A mice were thus generated and analysed for body weight, disease onset and progression (by behavioural scores, grip and rotarod tests) and survival. Although the lifespan of P2X7 +/– and P2X7 –/– /SOD1-G93A female mice was extended by 6–7% with respect to SOD1-G93A mice, to our surprise the clinical onset was significantly anticipated and the disease progression worsened in both male and female P2X7 –/– /SOD1-G93A mice. Consistently, we found increased astrogliosis, microgliosis, motoneuron loss, induction of the pro-inflammatory markers NOX2 and iNOS and activation of the MAPKs pathway in the lumbar spinal cord of end-stage P2X7 –/– /SOD1-G93A mice. These results show that the constitutive deletion of P2X7 receptor aggravates the ALS pathogenesis, suggesting that the receptor might have beneficial effects in at least definite stages of the disease. This study unravels a complex dual role of P2X7 receptor in ALS and strengthens the importance of a successful time window of therapeutic intervention in contrasting the pathology.

Description: There are certain de novo germline mutations associated with genetic disorders whose mutation rates per generation are orders of magnitude higher than the genome average. Moreover, these mutations occur exclusively in the male germ line and older men have a higher probability of having an affected child than younger ones, known as the paternal age effect (PAE). The classic example of a genetic disorder exhibiting a PAE is achondroplasia, caused predominantly by a single-nucleotide substitution (c.1138G〉A) in FGFR3 . To elucidate what mechanisms might be driving the high frequency of this mutation in the male germline, we examined the spatial distribution of the c.1138G〉A substitution in a testis from an 80-year-old unaffected man. Using a technology based on bead-emulsion amplification, we were able to measure mutation frequencies in 192 individual pieces of the dissected testis with a false-positive rate lower than 2.7 x 10 –6 . We observed that most mutations are clustered in a few pieces with 95% of all mutations occurring in 27% of the total testis. Using computational simulations, we rejected the model proposing an elevated mutation rate per cell division at this nucleotide site. Instead, we determined that the observed mutation distribution fits a germline selection model, where mutant spermatogonial stem cells have a proliferative advantage over unmutated cells. Combined with data on several other PAE mutations, our results support the idea that the PAE, associated with a number of Mendelian disorders, may be explained primarily by a selective mechanism.

Description: microRNAs (miRNAs) are dysregulated in a variety of disease states, suggesting that this newly discovered class of gene expression repressors may be viable therapeutic targets. A microarray of miRNA changes in ALS-model superoxide dismutase 1 (SOD1) G93A rodents identified 12 miRNAs as significantly changed. Six miRNAs tested in human ALS tissues were confirmed increased. Specifically, miR-155 was increased 5-fold in mice and 2-fold in human spinal cords. To test miRNA inhibition in the central nervous system (CNS) as a potential novel therapeutic, we developed oligonucleotide-based miRNA inhibitors (anti-miRs) that could inhibit miRNAs throughout the CNS and in the periphery. Anti-miR-155 caused global derepression of targets in peritoneal macrophages and, following intraventricular delivery, demonstrated widespread functional distribution in the brain and spinal cord. After treating SOD1 G93A mice with anti-miR-155, we significantly extended survival by 10 days and disease duration by 15 days (38%) while a scrambled control anti-miR did not significantly improve survival or disease duration. Therefore, antisense oligonucleotides may be used to successfully inhibit miRNAs throughout the brain and spinal cord, and miR-155 is a promising new therapeutic target for human ALS.