ALBERT

Description: Previous formalisms for determining the static perturbation of spherically symmetric self-gravitating elastic Earth models due to displacement dislocations deal with each infinitesimal element of the fault system in its epicentral reference frame. In this work, we overcome this restriction and present novel and compact formulas for obtaining the perturbation due to the whole fault system in an arbitrary and common reference frame. Furthermore, we show that, even in an arbitrary reference frame, it is still possible to discriminate the contributions associated with the polar, bipolar and quadrupolar patterns of the seismic source response, as well as their relation with the along strike, along dip and tensile components of the displacement dislocation. These results allow a better understanding of the relation between the static perturbation and the whole fault system, and find direct applications in geodetic problems, like the modelling of long-wavelength geoid or gravity data from GRACE and GOCE space missions and of the perturbation of the deviatoric inertia tensor of the Earth.

Description: Sensitive instruments like strainmeters and tiltmeters are necessary for measuring slowly varying low amplitude Earth deformations. Nonetheless, laser and fibre interferometers are particularly suitable for interrogating such instruments due to their extreme precision and accuracy. In this paper, a practical design of a simple pendulum borehole tiltmeter based on laser fibre interferometric displacement sensors is presented. A prototype instrument has been constructed using welded borosilicate with a pendulum length of 0.85 m resulting in a main resonance frequency of 0.6 Hz. By implementing three coplanar extrinsic fibre Fabry-Perot interferometric probes and appropriate signal filtering, our instrument provides tilt measurements that are insensitive to parasitic deformations caused by temperature and pressure variations. This prototype has been installed in an underground facility (Rustrel, France) where results show accurate measurements of Earth strains derived from Earth and ocean tides, local hydrologic effects, as well as local and remote earthquakes. The large dynamic range and the high sensitivity of this tiltmeter render it an invaluable tool for numerous geophysical applications such as transient fault motion, volcanic strain and reservoir monitoring.

Description: The geocentre motion is the motion of the centre of mass of the entire Earth, considered an isolated system, in a terrestrial system of reference. We first derive a formula relating the harmonic degree-1 Lagrangian variation of the gravity at a station to both the harmonic degree-1 vertical displacement of the station and the displacement of the whole Earth's centre of mass. The relationship is independent of the nature of the Earth deformation and is valid for any source of deformation. We impose no constraint on the system of reference, except that its origin must initially coincide with the centre of mass of the spherically symmetric Earth model. Next, we consider the geocentre motion caused by surface loading. In a system of reference whose origin is the centre of mass of the solid Earth, we obtain a specific relationship between the gravity variation at the surface, the geocentre displacement and the load Love number $h^{\prime }_1$ , which demands the Earth's structure and rheological behaviour be known. For various networks of real or fictitious stations, we invert synthetic signals of surface gravity variations caused by atmospheric loading to retrieve the degree-1 variation of gravity. We then select six well-distributed stations of the Global Geodynamics Project, which is a world network of superconducting gravimeters, to invert actual gravity data for the degree-1 variations and determine the geocentre displacement between the end of 2004 and the beginning of 2012, assuming it to be due to surface loading. We find annual and semi-annual displacements with amplitude 0.5–2.3 mm.

Description: Defining chromatin interaction frequencies and topological domains is a great challenge for the annotations of genome structures. Although the chromosome conformation capture (3C) and its derivative methods have been developed for exploring the global interactome, they are limited by high experimental complexity and costs. Here we describe a novel computational method, called CITD, for de novo prediction of the chromatin interaction map by integrating histone modification data. We used the public epigenomic data from human fibroblast IMR90 cell and embryonic stem cell (H1) to develop and test CITD, which can not only successfully reconstruct the chromatin interaction frequencies discovered by the Hi-C technology, but also provide additional novel details of chromosomal organizations. We predicted the chromatin interaction frequencies, topological domains and their states (e.g. active or repressive) for 98 additional cell types from Roadmap Epigenomics and ENCODE projects. A total of 131 protein-coding genes located near 78 preserved boundaries among 100 cell types are found to be significantly enriched in functional categories of the nucleosome organization and chromatin assembly. CITD and its predicted results can be used for complementing the topological domains derived from limited Hi-C data and facilitating the understanding of spatial principles underlying the chromosomal organization.

Description: We review the theory of the Earth's elastic and gravitational response to a surface disk load. The solutions for displacement of the surface and the geoid are developed using expansions of Legendre polynomials, their derivatives and the load Love numbers. We provide a matlab  function called diskload that computes the solutions for both uncompensated and compensated disk loads. In order to numerically implement the Legendre expansions, it is necessary to choose a harmonic degree, n max , at which to truncate the series used to construct the solutions. We present a rule of thumb (ROT) for choosing an appropriate value of n max , describe the consequences of truncating the expansions prematurely and provide a means to judiciously violate the ROT when that becomes a practical necessity.

Description: Two types of signals are clearly visible in continuous GPS (cGPS) time-series in Iceland, in particular in the vertical component. The first one is a yearly seasonal cycle, usually sinusoid-like with a minimum in the spring and a maximum in the fall. The second one is a trend of uplift, with higher values the closer the cGPS stations are to the centre of Iceland and ice caps. Here, we study the seasonal cycle signal by deriving its average at 71 GPS sites in Iceland. We estimate the annual and semi-annual components of the cycle in their horizontal and vertical components using a least-squares adjustment. The peak-to-peak amplitude of the cycle of the vertical component at the studied sites ranges from 4 mm near the coastline up to 27 mm at the centre of the Vatnajökull, the largest ice cap in Iceland. The minimum of the seasonal cycle occurs earlier in low lying areas than in the central part of Iceland, consistent with snow load having a large influence on seasonal deformation. Modelling shows that the seasonal cycle is well explained by accounting for elastically induced surface displacements due to snow, atmosphere, reservoir lake and ocean variations. Model displacement fields are derived considering surface loads on a multilayered isotropic spherical Earth. Through forward and inverse modelling, we were able to reproduce a priori information on the average seasonal cycle of known loads (atmosphere, snow in non-glaciated areas and lake reservoir) and get an estimation of other loads (glacier mass balance and ocean). The seasonal glacier mass balance cycle in glaciated areas and snow load in non-glaciated areas are the main contributions to the seasonal deformation. For these loads, induced seasonal vertical displacements range from a few millimetres far from the loads in Iceland, to more than 20 mm at their centres. Lake reservoir load also has to be taken into account on local scale as it can generate up to 20 mm of vertical deformation. Atmosphere load and ocean load are observable and generate vertical displacements in the order of a few millimetres. Inversion results also shows that the Iceland crust is less rigid than the world average. Interannual deviation from the GPS seasonal cycle can occur and are caused by unusual weather conditions over extended period of time.

Description: Dam identification (DamID) is a powerful technique to generate genome-wide maps of chromatin protein binding. Due to its high sensitivity, it is particularly suited to study the genome interactions of chromatin proteins in small tissue samples in model organisms such as Drosophila . Here, we report an intein-based approach to tune the expression level of Dam and Dam-fusion proteins in Drosophila by addition of a ligand to fly food. This helps to suppress possible toxic effects of Dam. In addition, we describe a strategy for genetically controlled expression of Dam in a specific cell type in complex tissues. We demonstrate the utility of the latter by generating a glia-specific map of Polycomb in small samples of brain tissue. These new DamID tools will be valuable for the mapping of binding patterns of chromatin proteins in Drosophila tissues and especially in cell lineages.

Description: DNA methylation is one of the most important epigenetic alterations involved in the control of gene expression. Bisulfite sequencing of genomic DNA is currently the only method to study DNA methylation patterns at single-nucleotide resolution. Hence, next-generation sequencing of bisulfite-converted DNA is the method of choice to investigate DNA methylation profiles at the genome-wide scale. Nevertheless, whole genome sequencing for analysis of human methylomes is expensive, and a method for targeted gene analysis would provide a good alternative in many cases where the primary interest is restricted to a set of genes. Here, we report the successful use of a custom Agilent SureSelect Target Enrichment system for the hybrid capture of bisulfite-converted DNA. We prepared bisulfite-converted next-generation sequencing libraries, which are enriched for the coding and regulatory regions of 174 ADME genes (i.e. genes involved in the metabolism and distribution of drugs). Sequencing of these libraries on Illumina’s HiSeq2000 revealed that the method allows a reliable quantification of methylation levels of CpG sites in the selected genes, and validation of the method using pyrosequencing and the Illumina 450K methylation BeadChips revealed good concordance.

Description: Data from the Gravity Recovery and Climate Experiment (GRACE) satellite mission can be used to estimate the mass change rate for separate drainage systems (DSs) of the Greenland Ice Sheet (GrIS). One approach to do so is by inversion of the level-2 spherical harmonic data to surface mass changes in predefined regions, or mascons. However, the inversion can be numerically unstable for some individual DSs. This occurs mainly for DSs with a small mass change signal that are located in the interior region of Greenland. In this study, we present a modified mascon inversion approach with an improved implementation of the constraint equations to obtain better estimates for individual DSs. We use separate constraints for mass change variability in the coastal zone, where run-off takes place, and for the ice sheet interior above 2000 m, where mass changes are smaller. A multi-objective optimization approach is used to find optimal prior variances for these two areas based on a simulation model. Correlations between adjacent DSs are suppressed when our optimized prior variances are used, while the mass balance estimates for the combination of the DSs that make up the GrIS above 2000 m are not affected significantly. The resulting mass balance estimates for some DSs in the interior are significantly improved compared to an inversion with a single constraint, as determined by a comparison with mass balance estimates from surface mass balance modelling and discharge measurements. The rate of mass change of the GrIS for the period of January 2003 to December 2012 is found to be –266.1 ± 17.2 Gt yr –1 in the coastal zone and areas below 2000 m, and +8.2 ± 8.6 Gt yr –1 in the interior region.

Description: Measurements of ground deformation can be used to identify and interpret geophysical processes occurring at volcanoes. Most studies rely on a single geodetic technique, or fit a geophysical model to the results of multiple geodetic techniques. Here we present a methodology that combines GPS, Total Station measurements and InSAR into a single reference frame to produce an integrated 3-D geodetic velocity surface without any prior geophysical assumptions. The methodology consists of five steps: design of the network, acquisition and processing of the data, spatial integration of the measurements, time series computation and finally the integration of spatial and temporal measurements. The most significant improvements of this method are (1) the reduction of the required field time, (2) the unambiguous detection of outliers, (3) an increased measurement accuracy and (4) the construction of a 3-D geodetic velocity field. We apply this methodology to ongoing motion on Arenal's western flank. Integration of multiple measurement techniques at Arenal volcano revealed a deformation field that is more complex than that described by individual geodetic techniques, yet remains consistent with previous studies. This approach can be applied to volcano monitoring worldwide and has the potential to be extended to incorporate other geodetic techniques and to study transient deformation.

Description: In autumn 2012, the new release 05 (RL05) of monthly geopotencial spherical harmonics Stokes coefficients (SC) from Gravity Recovery and Climate Experiment (GRACE) mission was published. This release reduces the noise in high degree and order SC, but they still need to be filtered. One of the most common filtering processing is the combination of decorrelation and Gaussian filters. Both of them are parameters dependent and must be tuned by the users. Previous studies have analyzed the parameters choice for the RL05 GRACE data for oceanic applications, and for RL04 data for global application. This study updates the latter for RL05 data extending the statistics analysis. The choice of the parameters of the decorrelation filter has been optimized to: (1) balance the noise reduction and the geophysical signal attenuation produced by the filtering process; (2) minimize the differences between GRACE and model-based data and (3) maximize the ratio of variability between continents and oceans. The Gaussian filter has been optimized following the latter criteria. Besides, an anisotropic filter, the fan filter, has been analyzed as an alternative to the Gauss filter, producing better statistics.

Description: The static and transient deformations produced by earthquakes cause density perturbations which, in turn, generate immediate, long-range perturbations of the Earth's gravity field. Here, an analytical solution is derived for gravity perturbations produced by a point double-couple source in homogeneous, infinite, non-self-gravitating elastic media. The solution features transient gravity perturbations that occur at any distance from the source between the rupture onset time and the arrival time of seismic P waves, which are of potential interest for real-time earthquake source studies and early warning. An analytical solution for such prompt gravity perturbations is presented in compact form. We show that it approximates adequately the prompt gravity perturbations generated by strike-slip and dip-slip finite fault ruptures in a half-space obtained by numerical simulations based on the spectral element method. Based on the analytical solution, we estimate that the observability of prompt gravity perturbations within 10 s after rupture onset by current instruments is severely challenged by the background microseism noise but may be achieved by high-precision gravity strainmeters currently under development. Our analytical results facilitate parametric studies of the expected prompt gravity signals that could be recorded by gravity strainmeters.

Description: Seismic waves produced by fault ruptures give rise to gravity perturbations. So far, these perturbations have either been modelled as permanent coseismic gravity change in a half-space or spherical Earth model, or as full time-domain model in infinite space. In this paper, we present the explicit solution of gravity perturbations in time domain produced by a double-couple buried in a homogeneous half-space. This result is especially suited to study gravity perturbations up to a few hundreds of kilometres from the epicentre. It facilitates detailed parametric studies of gravity perturbations from fault rupture, and predicts gravity perturbations of real earthquakes with greatly improved accuracy. The results may serve to develop first designs of gravity-assisted earthquake early-warning systems, made possible by a new generation of ultrasensitive gravity gradiometers, which is currently under development.

Description: Continuous gravimetric observations have been made with three successive generations of superconducting gravimeter over 20 yr at Syowa Station ( $39.6\deg$ E, $69.0\deg$ S), East Antarctica. The third-generation instrument, OSG#058, was installed in January 2010 and was calibrated by an absolute gravimeter during January and February, 2010. The estimated scale factor was –73.823 ± 0.053 μGal V –1 (1 μGal = 10 –8 m s –2 ). The first 5 yr of OSG#058 data from 2010 January 7 to 2015 January 10 were decomposed into tidal waves (M3 to Ssa) and other non-tidal components by applying the Bayesian tidal analysis program BAYTAP. Long-term non-tidal gravity residuals, which were obtained by subtracting annual and 18.6 year tidal waves and the predicted gravity response to the Earth's variable rotation, showed significant correlation with the accumulated snow depth measured at Syowa Station. The greatest correlation occurred when the gravity variations lagged the accumulated snow depth by 21 d. To estimate the gravitational effect of the accumulated snow mass, we inferred a conversion factor of 3.13 ± 0.08 μGal m –1 from this relation. The accumulated snow depth at Syowa Station was found to represent an extensive terrestrial water storage (the snow accumulation) around Syowa Station, which was estimated from the Gravity Recovery and Climate Experiment satellite gravity data. The snow accumulation around Syowa Station was detectable by the superconducting gravimeter.

Description: The new release AIUB-RL02 of monthly gravity models from GRACE GPS and K-Band range-rate data is based on reprocessed satellite orbits referring to the reference frame IGb08. The release is consistent with the IERS2010 conventions. Improvements with respect to its predecessor AIUB-RL01 include the use of reprocessed (RL02) GRACE observations, new atmosphere and ocean dealiasing products (RL05), an upgraded ocean tide model (EOT11A), and the interpolation of shallow ocean tides (admittances). The stochastic parametrization of AIUB-RL02 was adapted to include daily accelerometer scale factors, which drastically reduces spurious signal at the 161 d period in C 20 and at other low degree and order gravity field coefficients. Moreover, the correlation between the noise in the monthly gravity models and solar activity is considerably reduced in the new release. The signal and the noise content of the new AIUB-RL02 monthly gravity fields are studied and calibrated errors are derived from their non-secular and non-seasonal variability. The short-period time-variable signal over the oceans, mostly representing noise, is reduced by 50 per cent with respect to AIUB-RL01. Compared to the official GFZ-RL05a and CSR-RL05 monthly models, the AIUB-RL02 stands out by its low noise at high degrees, a fact emerging from the estimation of seasonal variations for selected river basins and of mass trends in polar regions. Two versions of the monthly AIUB-RL02 gravity models, with spherical harmonics resolution of degree and order 60 and 90, respectively, are available for the time period from March 2003 to March 2014 at the International Center for Global Earth Models or from ftp://ftp.unibe.ch/aiub/GRAVITY/GRACE (last accessed 22 March 2016).

Description: The relative gravimeter is the primary terrestrial instrument for measuring spatially and temporally varying gravitational fields. The background noise of the instrument—that is, non-linear drift and random tares—typically requires some form of least-squares network adjustment to integrate data collected during a campaign that may take several days to weeks. Here, we present an approach to remove the change in the observed relative-gravity differences caused by hydrologic or other transient processes during a single campaign, so that the adjusted gravity values can be referenced to a single epoch. The conceptual approach is an example of coupled hydrogeophysical inversion, by which a hydrologic model is used to inform and constrain the geophysical forward model. The hydrologic model simulates the spatial variation of the rate of change of gravity as either a linear function of distance from an infiltration source, or using a 3-D numerical groundwater model. The linear function can be included in and solved for as part of the network adjustment. Alternatively, the groundwater model is used to predict the change of gravity at each station through time, from which the accumulated gravity change is calculated and removed from the data prior to the network adjustment. Data from a field experiment conducted at an artificial-recharge facility are used to verify our approach. Maximum gravity change due to hydrology (observed using a superconducting gravimeter) during the relative-gravity field campaigns was up to 2.6 μGal d –1 , each campaign was between 4 and 6 d and one month elapsed between campaigns. The maximum absolute difference in the estimated gravity change between two campaigns, two months apart, using the standard network adjustment method and the new approach, was 5.5 μGal. The maximum gravity change between the same two campaigns was 148 μGal, and spatial variation in gravity change revealed zones of preferential infiltration and areas of relatively high groundwater storage. The accommodation for spatially varying gravity change would be most important for long-duration campaigns, campaigns with very rapid changes in gravity and (or) campaigns where especially precise observed relative-gravity differences are used in the network adjustment.

Description: We document two kinds of traveling ionospheric disturbances, namely, CTIDs (Co-tsunami-Traveling-Ionospheric-disturbances) and ATIDs (Ahead-of-Tsunami-Traveling-Ionospheric-disturbances) related to the Tohoku-Oki tsunami of 2011 March 11. They are referred to the disturbances that remain behind and ahead of the principal tsunami wave front, respectively. We first note their presence in a numerical experiment performed using a simulation code coupling the tsunami, atmosphere and ionosphere. This code uses the tsunami wavefield as an input and simulates acoustic-gravity waves (AGWs) in the atmosphere and TIDs, in the form of total electron content (TEC) disturbance, in the ionosphere. The simulated TEC reveals the excitation of CTIDs (at about 2 TECU) and ATIDs (at about 1 TECU), representing up to 5 per cent disturbance over the ambient electron density, and they arise from the dissipation of AGWs in the thermosphere. A novel outcome is that during the tsunami passage between ~6° and 12° of epicentral distance, strong ATIDs arrive ~20–60 min ahead of the tsunami wave front covering ~3°–10° of distance from the tsunami location. Simulation results are compared with the far-field observations using GNSS satellites and confirm that ATIDs are the first detected TEC maximum, occurring 20–60 min ahead of the tsunami arrival. Our simulation also confirms the presence of largest TEC maximum representing CTIDs, 10–20 min after the first tsunami wave. ATIDs reported in this study have characteristics that can be potentially used for the early warning of the tsunami.

Description: In the present work we illustrate a new local inversion algorithm to retrieve the Moho depth from GOCE (Gravity field and steady-state Ocean Circulation Explorer) gravity field. In details the proposed procedure can be divided into two main steps: the first one consists in recognizing and isolating the different geological provinces in the study area by exploiting information coming from the GOCE global gravity field model. Once the main geological provinces are defined, a function relating the crust density of each province with depth is built and used to reduce the data. The gravitational effects of sediments, topography, bathymetry and upper mantle are also removed. In the second step the residual gravitational field is inverted to retrieve the Moho depth and some information on the crustal density. In particular, the clustering of geological province is performed by means of an automatic Bayesian classification algorithm while the inversion of GOCE residual field is performed by adapting the global algorithm developed in the framework of the GEMMA project to the local scale. The procedure, based on an iterative Wiener filter, allows to compute the Moho depth considering lateral as well as radial variations of crustal density. The algorithm has been applied to the fifth release of GOCE time-wise global gravity field model to infer information on the crustal structure in the Western Balkan area, that is, the region laying between Bulgaria and the Adriatic Sea. This region is one of the most complex and active, from the tectonic point of view, in the whole Europe and it is characterized by the presence of the Alpine-Himalayan orogenic belt, formed by the collision between the African and Eurasian plates, and by the opening of the Pannonian Basin. Results show a good agreement between the obtained geological provinces with the actual knowledge on the region. The resulting Moho depth ranges between about 20 km beneath the Adriatic Sea and 45 km in the Dinarides. Comparisons with available seismic data show differences smaller than 1 km (standard deviation).

Description: Gravity variations associated with Earth's oblateness ( J 2 ) have been observed by satellite laser ranging (SLR) since 1976. The J 2 time-series has been used to measure and help understand many geophysical processes within the Earth system ranging from the mantle to the atmosphere. While post glacial rebound and the Earth climate system are believed to be the primary driving forces of long-term and seasonal J 2 variations, the physical cause of decadal and longer timescale J 2 variations has remained uncertain, although recent evidence indicates that polar ice mass changes are important. In this study, we estimate a variety of climate contributions to J 2 over the period 1979–2010, and find that ice mass variations in Greenland and Antarctica are the dominant cause of observed decadal and longer J 2 variations. Residual variations at periods near 10–11 years may reflect limitations of numerical climate models in estimating mass change variability at long periods, but are also suggestive of potential contribution related to variable solar activity.

Description: Interferometric synthetic aperture radar (InSAR) technology provides a valuable tool for obtaining Earth surface deformation and topography at high spatial resolution for crustal deformation studies. Similar to global positioning system (GPS), InSAR measurements are affected by the Earth's ionospheric and tropospheric layers as the electromagnetic signals significantly refract while propagating through the different layers. While GPS signals propagating through the neutral atmosphere are affected primarily by the distribution, pressure and temperature of atmospheric gases, including water vapour, the propagation through the ionosphere is mainly affected by the number of free electrons along the signal path. Here, we present the use of dense regional GPS networks for extracting tropospheric zenith delays and ionospheric total electron content (TEC) maps in order to reduce the noise levels in InSAR images. The results show significant reduction in the root mean square (RMS) values when simultaneously combining the two corrections, both at short time periods where no surface deformation is expected, and at longer periods, where imaging of localized subsidence and fault creep is enhanced.

Description: The main objective of the Gravity Recovery and Climate Experiment (GRACE) Atmospheric and Oceanic De-Aliasing Level-1B product (AOD1B) is the removal of high-frequency non-tidal mass variations due to sub-monthly mass transport in the atmosphere and oceans. Application of AOD1B shall avoid aliasing of these high-frequency signals into monthly gravity models derived from modern gravity missions and shall help to derive consistent orbit solutions for altimetry and Satellite Laser Ranging missions. The AOD1B 6-h series of spherical harmonic coefficients up to degree and order 100 are routinely generated at the German Research Centre for Geoscience and distributed to the GRACE Science Data System and the user community. Inputs for this product are acquired from numerical weather prediction models which are regularly revised and consequently not stable in time. The latest AOD1B release 5 (RL05) is based, as all other releases, on input from ECMWF and does not resolve this problem of discontinuities present in the surface pressure and surface geopotential input data. This might contaminate the gravity field variations derived from atmospheric mass variations. In this paper we present a method to overcome this problem during future AOD1B product generation, as well as two new Level-2 products (GAE and GAF) that, over land, fix a posteriori the two jumps present in the already distributed Level-2 RL05 monthly gravity models which were based on AOD1B RL05. The impact of the proposed correction on the variations and long-term trend of the total mass of the atmosphere and on the ice mass balance over Antarctica and over Greenland is also illustrated. We found that the GAE/GAF-corrected trend of the global atmospheric mass over the GRACE mission lifetime significantly decreased from –0.05 to –0.02 mm yr –1 in terms of geoid height. A considerable effect (33 per cent) was also found in the quadratic term of ice mass loss over Antarctica which results in an acceleration of 3.2 Gt yr –1  yr –1 smaller than without applying this correction.

Description: Previous studies of Earth rotation perturbations due to ice-age loading have predicted a slow secular drift of the rotation axis relative to the surface geography (i.e. true polar wander, TPW) of order of several degrees over the Plio-Pleistocene. It has been argued that this drift and the change in the geographic distribution of solar insolation that it implies may have been responsible for important transitions in ice-age climate, including the termination of ice-age cycles.We use a revised rotational stability theory that incorporates a more accurate treatment of the Earth's background ellipticity to reconsider this issue, and demonstrate that the net displacement of the pole predicted in earlier studies disappears. This more muted polar motion is due to two factors: first, the revised theory no longer predicts the permanent shift in the rotation axis, or the so-called ‘unidirectional TPW’, that appears in the traditional stability theory; and, second, the increased background ellipticity incorporated in the revised predictions acts to reduce the normal mode amplitudes governing the motion of the pole. We conclude that ice-age-induced TPW was not responsible for the termination of the ice age. This does not preclude the possibility that TPW induced by mantle convective flow may have played a role in major Plio-Pleistocene climate transitions, including the onset of Northern Hemisphere glaciation.

Description: Apparent acceleration in Gravity Recovery and Climate Experiment (GRACE) Antarctic ice mass time-series may reflect both ice discharge and surface mass balance contributions. However, a recent study suggests there is also contamination from errors in atmospheric pressure de-aliasing fields [European Center for Medium-Range Weather Forecast (ECMWF) operational products] used during GRACE data processing. To further examine this question, we compare GRACE atmospheric pressure de-aliasing (GAA) fields with in situ surface pressure data from coastal and inland stations. Differences between the two are likely due to GAA errors, and provide a measure of error in GRACE solutions. Time-series of differences at individual weather stations are fit to four presumed error components: annual sinusoids, a linear trend, an acceleration term and jumps at times of known ECMWF model changes. Using data from inland stations, we estimate that atmospheric pressure error causes an acceleration error of about +7.0 Gt yr –2 , which is large relative to prior GRACE estimates of Antarctic ice mass acceleration in the range of –12 to –14 Gt yr –2 . We also estimate apparent acceleration rates from other barometric pressure (reanalysis) fields, including ERA-Interim, MERRA and NCEP/DOE. When integrated over East Antarctica, the four mass acceleration estimates (from GAA and the three reanalysis fields) vary considerably (by ~2–16 Gt yr –2 ). This shows the need for further effort to improve atmospheric mass estimates in this region of sparse in situ observations, in order to use GRACE observations to measure ice mass acceleration and related sea level change.

Description: The long-wavelength gravity field contains information about processes in the sublithospheric mantle. As satellite-derived gravity models now provide the long to medium-wavelength gravity field at unprecedented accuracy, techniques used to process gravity data need to be updated. We show that when determining these long-wavelengths, the treatment of topographic-isostatic effect (TIE) and isostatic effects (IE) is a likely source of error. We constructed a global isostatic model and calculated global TIE and IE. These calculations were done for ground stations as well as stations at satellite height. We considered both gravity and gravity gradients. Using these results, we determined how much of the gravity signal comes from distant sources. We find that a significant long-wavelength bias is introduced if far-field effects on the topographic effect are neglected. However, due to isostatic compensation far-field effects of the topographic effect are to a large degree compensated by the far-field IE. This means that far-field effects can be reduced effectively by always considering topographic masses together with their compensating isostatic masses. We show that to correctly represent the ultra-long wavelengths, a global background model should be used. This is demonstrated both globally and for a continental-scale case area in North America. In the case of regional modelling, where the ultra-long wavelengths are not of prime importance, gravity gradients can be used to help minimize correction errors caused by far-field effects.

Description: Constraining laterally varying structures in planetary interiors is important for understanding both the composition and the internal dynamics of a planet. Recognizing that seismic imaging technique is currently only viable for studying the Earth's interior structures, methods that can be supported by advanced space geodetic techniques may become alternatives to ‘image’ the interiors of other planets. The method of tidal tomography is one possibility, and it relies on high precision measurement of the response of a planet to its body tide. However, it is essential to develop an efficient analytical tool that computes the dependence of tidal response to 3-D interior structures. In this paper, we present a complete formulation of such an analytical tool, which calculates to high accuracy the tidal response of a terrestrial planet with lateral heterogeneities in its elastic and density structures. We treat the lateral heterogeneities as small perturbations and derive the governing equations based on the perturbation theory. In a spherical harmonic representation, equations at each order of perturbation are reduced into multiple matrix equations at harmonics that are allowed by mode couplings, and the total response equals the sum of all those single-harmonic responses, which can be solved semi-analytically. We test our perturbation method by applying it to the Moon with a harmonic degree-1 mantle structure for which the perturbation solutions of the tidal response are compared with those from a fully numerical method. The remarkable agreement between results from these two methods validates the perturbation method. As an example, we then use the perturbation method to evaluate the impact of lunar crustal thickness variations on tidal response of the Moon. We find that lunar crust produces much smaller degree-3 tidal responses than a relatively weak degree-1 structure in the deep lunar mantle. Our calculations show that degree-3 tidal response measurements may hold key constraints on possible degree-1 mantle structure of the Moon, as suggested from previous modelling results.

Description: Seismic data are primarily used in studies of the Earth's lithospheric structure including the Moho geometry. In regions, where seismic data are sparse or completely absent, gravimetric or combined gravimetric-seismic methods could be applied to determine the Moho depth. In this study, we derive and present generalized expressions for solving the Vening Meinesz–Moritz's (VMM) inverse problem of isostasy for a Moho depth determination from gravity and vertical gravity-gradient data. By solving the (non-linear) Fredholm's integral equation of the first kind, the linearized observation equations, which functionally relate the (given) gravity/gravity-gradient data to the (unknown) Moho depth, are derived in the spectral domain. The VMM gravimetric results are validated by using available seismic and gravimetric Moho models. Our results show that the VMM Moho solutions obtained by solving the VMM problem for gravity and gravity-gradient data are almost the same. This finding indicates that in global applications, using the global gravity/gravity-gradient data coverage, the spherical harmonic expressions for the gravimetric forward and inverse modelling yield (theoretically) the same results. Globally, these gravimetric solutions have also a relatively good agreement with the CRUST1.0 and GEMMA GOCE models in terms of their rms Moho differences (4.7 km and 4.1 km, respectively).

Description: Geophysical techniques are widely used to monitor volcanic unrest. A number of studies have also demonstrated that hydrological processes can produce or trigger geophysical signals. Hydrologically induced gravity signals have previously been recorded by specifically designed gravity surveys as well as, inadvertently, by volcano monitoring studies. Water table corrections of microgravity surveys are commonplace. However, the fluctuations of the water table beneath survey locations are often poorly known, and such a correction fails to account for changes in water-mass storage in the unsaturated zone. Here, we combine 2-D axis-symmetrical numerical fluid-flow models with an axis-symmetric, distributed-mass, gravity calculation to model gravity changes in response to fluctuating hydrological recharge. Flow simulations are based on tropical volcanic settings where high surface permeabilities promote thick unsaturated zones. Our study highlights that mass storage (saturation) changes within the unsaturated zone beneath a survey point can generate recordable gravity changes. We show that for a tropical climate, recharge variations can generate gravity variations of over 150 μGal; although, we demonstrate that for the scenarios investigated here, the probability of recording such large signals is low. Our modelling results indicate that microgravity survey corrections based on water table elevation may result in errors of up to 100 μGal. The effect of inter-annual recharge fluctuations dominate over seasonal cycles which makes prediction and correction of the hydrological contribution more difficult. Spatial hydrogeological heterogeneity can also impact on the accuracy of relative gravity surveys, and can even result in the introduction of additional survey errors. The loading fluctuations associated with saturation variations in the unsaturated zone may also have implications for other geophysical monitoring techniques, such as geodetic monitoring of ground deformation.

Description: A new approach based on energy conservation principle for satellite gravimetry mission has been developed and yields more accurate estimation of in situ geopotential difference observables using K-band ranging (KBR) measurements from the Gravity Recovery and Climate Experiment (GRACE) twin-satellite mission. This new approach preserves more gravity information sensed by KBR range-rate measurements and reduces orbit error as compared to previous energy balance methods. Results from analysis of 11 yr of GRACE data indicated that the resulting geopotential difference estimates agree well with predicted values from official Level 2 solutions: with much higher correlation at 0.9, as compared to 0.5–0.8 reported by previous published energy balance studies. We demonstrate that our approach produced a comparable time-variable gravity solution with the Level 2 solutions. The regional GRACE temporal gravity solutions over Greenland reveals that a substantially higher temporal resolution is achievable at 10-d sampling as compared to the official monthly solutions, but without the compromise of spatial resolution, nor the need to use regularization or post-processing.

Description: Many cancers comprise heterogeneous populations of cells at primary and metastatic sites throughout the body. The presence or emergence of distinct subclones with drug-resistant genetic and epigenetic phenotypes within these populations can greatly complicate therapeutic intervention. Liquid biopsies of peripheral blood from cancer patients have been suggested as an ideal means of sampling intratumor genetic and epigenetic heterogeneity for diagnostics, monitoring and therapeutic guidance. However, current molecular diagnostic and sequencing methods are not well suited to the routine assessment of epigenetic heterogeneity in difficult samples such as liquid biopsies that contain intrinsically low fractional concentrations of circulating tumor DNA (ctDNA) and rare epigenetic subclonal populations. Here we report an alternative approach, deemed DREAMing (Discrimination of Rare EpiAlleles by Melt), which uses semi-limiting dilution and precise melt curve analysis to distinguish and enumerate individual copies of epiallelic species at single-CpG-site resolution in fractions as low as 0.005%, providing facile and inexpensive ultrasensitive assessment of locus-specific epigenetic heterogeneity directly from liquid biopsies. The technique is demonstrated here for the evaluation of epigenetic heterogeneity at p14 ARF and BRCA1 gene-promoter loci in liquid biopsies obtained from patients in association with non-small cell lung cancer (NSCLC) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), respectively.

Description: Bisulfite sequencing is a key methodology in epigenetics. However, the standard workflow of bisulfite sequencing involves heat and strongly basic conditions to convert the intermediary product 5,6-dihydrouridine-6-sulfonate (dhU6S) (generated by reaction of bisulfite with deoxycytidine (dC)) to uracil (dU). These harsh conditions generally lead to sample loss and DNA damage while milder conditions may result in incomplete conversion of intermediates to uracil. Both can lead to poor recovery of bisulfite-treated DNA by the polymerase chain reaction (PCR) as either damaged DNA and/or intermediates of bisulfite treatment are poor substrate for standard DNA polymerases. Here we describe an engineered DNA polymerase (5D4) with an enhanced ability to replicate and PCR amplify bisulfite-treated DNA due to an ability to bypass both DNA lesions and bisulfite intermediates, allowing significantly milder conversion conditions and increased sensitivity in the PCR amplification of bisulfite-treated DNA. Incorporation of the 5D4 DNA polymerase into the bisulfite sequencing workflow thus promises significant sensitivity and efficiency gains.

Description: Several attempts have been made to obtain a radiographic image inside volcanoes using cosmic-ray muons (muography). Muography is expected to resolve highly heterogeneous density profiles near the surface of volcanoes. However, several prior works have failed to make clear observations due to contamination by background noise. The background contamination leads to an overestimation of the muon flux and consequently a significant underestimation of the density in the target mountains. To investigate the origin of the background noise, we performed a Monte Carlo simulation. The main components of the background noise in muography are found to be low-energy protons, electrons and muons in case of detectors without particle identification and with energy thresholds below 1 GeV. This result was confirmed by comparisons with actual observations of nuclear emulsions. This result will be useful for detector design in future works, and in addition some previous works of muography should be reviewed from the view point of background contamination.

Description: Essential to understanding sea level change and its causes during the last interglacial (LIG) is the quantification of uncertainties. In order to estimate the uncertainties, we develop a statistical framework for the comparison of palaeoclimatic sea level index points and GIA model predictions. For the investigation of uncertainties, as well as to generate better model predictions, we implement a massive ensemble approach by applying a data assimilation scheme based on particle filter methods. The different runs are distinguished through varying ice sheet reconstructions based on oxygen-isotope curves and different parameter selections within the GIA model. This framework has several advantages over earlier work, such as the ability to examine either the contribution of individual observations to the results or the probability of specific input parameters. This exploration of input parameters and data leads to a larger range of estimates than previously published work. We illustrate how the assumptions that enter into the statistical analysis, such as the existence of outliers in the observational database or the initial ice volume history, can introduce large variations to the estimate of the maximum highstand. Thus, caution is required to avoid overinterpreting results. We conclude that there are reasonable doubts whether the data sets previously used in statistical analyses are able to tightly constrain the value of maximum highstand during the LIG.

Description: A 3-D density model of the crust and upper mantle beneath the Karoo basin is presented here. The model is constrained using potential field, borehole and seismic data. Uplift of the basin by the end of the Cretaceous has resulted in an unusually high plateau (〉1000 m) covering a large portion of South Africa. Isostatic studies show the topography is largely compensated by changes in Moho depths (~35 km on-craton and 〉45 km off-craton) and changes in lithospheric mantle densities between the Kaapvaal Craton and surrounding regions (~50 kg m –3 increase from on- to off-craton). This density contrast is determined by inverted satellite gravity and gravity gradient data. The highest topography along the edge of the plateau (〉1200 m) and a strong Bouguer gravity low over Lesotho, however, can only be explained by a buoyant asthenosphere with a density decrease of around 40 kg m –3 .

Description: A method to estimate the rotation change in the orientation of the centre-of-figure (CF) frame caused by earthquakes is proposed for the first time. This method involves using the point dislocation theory based on a spherical, non-rotating, perfectly elastic and isotropic (SNREI) Earth. The rotation change in the orientation is related solely to the toroidal displacements of degree one induced by the vertical dip slip dislocation, and the spheroidal displacements induced by an earthquake have no contribution. The effects of two recent large earthquakes, the 2004 Sumatra and the 2011 Tohoku-Oki, are studied. Results showed that the Sumatra and Tohoku-Oki earthquakes both caused the CF frame to rotate by at least tens of μas (micro-arc-second). Although the visible co-seismic displacements are identified and removed from the coordinate time-series, the rotation change due to the unidentified ones and errors in removal is non-negligible. Therefore, the rotation change in the orientation of the CF frame due to seismic deformation should be taken into account in the future in reference frame and geodesy applications.

Description: Nucleosomes, the fundamental subunits of eukaryotic chromatin, are organized with respect to transcriptional start sites. A major challenge to the persistence of this organization is the disassembly of nucleosomes during DNA replication. Here, we use complimentary approaches to map the locations of nucleosomes on recently replicated DNA. We find that nucleosomes are substantially realigned with promoters during the minutes following DNA replication. As a result, the nucleosomal landscape is largely re-established before newly replicated chromosomes are partitioned into daughter cells and can serve as a platform for the re-establishment of gene expression programmes. When the supply of histones is disrupted through mutation of the chaperone Caf1, a promoter-based architecture is generated, but with increased inter-nucleosomal spacing. This indicates that the chromatin remodelling enzymes responsible for spacing nucleosomes are capable of organizing nucleosomes with a range of different linker DNA lengths.

Description: DNA methylation plays an important role in many biological processes. Existing epigenome-wide association studies (EWAS) have successfully identified aberrantly methylated genes in many diseases and disorders with most studies focusing on analysing methylation sites one at a time. Incorporating prior biological information such as biological networks has been proven to be powerful in identifying disease-associated genes in both gene expression studies and genome-wide association studies (GWAS) but has been under studied in EWAS. Although recent studies have noticed that there are differences in methylation variation in different groups, only a few existing methods consider variance signals in DNA methylation studies. Here, we present a network-assisted algorithm, NEpiC, that combines both mean and variance signals in searching for differentially methylated sub-networks using the protein–protein interaction (PPI) network. In simulation studies, we demonstrate the power gain from using both the prior biological information and variance signals compared to using either of the two or neither information. Applications to several DNA methylation datasets from the Cancer Genome Atlas (TCGA) project and DNA methylation data on hepatocellular carcinoma (HCC) from the Columbia University Medical Center (CUMC) suggest that the proposed NEpiC algorithm identifies more cancer-related genes and generates better replication results.

Description: To improve the epigenomic analysis of tissues rich in 5-hydroxymethylcytosine (hmC), we developed a novel protocol called TAB-Methyl-SEQ, which allows for single base resolution profiling of both hmC and 5-methylcytosine by targeted next-generation sequencing. TAB-Methyl-SEQ data were extensively validated by a set of five methodologically different protocols. Importantly, these extensive cross-comparisons revealed that protocols based on Tet1-assisted bisulfite conversion provided more precise hmC values than TrueMethyl-based methods. A total of 109 454 CpG sites were analyzed by TAB-Methyl-SEQ for mC and hmC in 188 genes from 20 different adult human livers. We describe three types of variability of hepatic hmC profiles: (i) sample-specific variability at 40.8% of CpG sites analyzed, where the local hmC values correlate to the global hmC content of livers (measured by LC-MS), (ii) gene-specific variability, where hmC levels in the coding regions positively correlate to expression of the respective gene and (iii) site-specific variability, where prominent hmC peaks span only 1 to 3 neighboring CpG sites. Our data suggest that both the gene- and site-specific components of hmC variability might contribute to the epigenetic control of hepatic genes. The protocol described here should be useful for targeted DNA analysis in a variety of applications.

Description: In this study, we propose an approach for determining the geopotential difference using high-frequency-stability microwave links between satellite and ground station based on Doppler cancellation system. Suppose a satellite and a ground station are equipped with precise optical-atomic clocks (OACs) and oscillators. The ground oscillator emits a signal with frequency f a towards the satellite and the satellite receiver (connected with the satellite oscillator) receives this signal with frequency f b which contains the gravitational frequency shift effect and other signals and noises. After receiving this signal, the satellite oscillator transmits and emits, respectively, two signals with frequencies f b and f c towards the ground station. Via Doppler cancellation technique, the geopotential difference between the satellite and the ground station can be determined based on gravitational frequency shift equation by a combination of these three frequencies. For arbitrary two stations on ground, based on similar procedures as described above, we may determine the geopotential difference between these two stations via a satellite. Our analysis shows that the accuracy can reach 1 m 2 s – 2 based on the clocks’ inaccuracy of about 10 –17 (s s –1 ) level. Since OACs with instability around 10 –18 in several hours and inaccuracy around 10 –18 level have been generated in laboratory, the proposed approach may have prospective applications in geoscience, and especially, based on this approach a unified world height system could be realized with one-centimetre level accuracy in the near future.

Description: We interpreted the TRIDENT satellite derived gravity field to provide detailed insights into the spatial distribution of the crustal density structures in the area of the Yellow Sea. We used 3-D forward density modelling for the interpretation that incorporated constraints from existing geological and geophysical information. A gravity stripping method is used to separate out the gravity effects of different geological crustal structures. From this analysis we see that (1) the Gunsan sedimentary basin is isostatically compensated. (2) The satellite-derived Bouguer anomalies ranging from 15 to –30 x 10 –5 m s –2 are linked to basin thicknesses in the Yellow Sea. (3) The calculated Moho depth in the Yellow Sea varies from 27 km beneath the deep sedimentary basin to 34 km in the uplifted zones. (4) Moho depth calculations show two distinct areas, characterized by the deepest Moho depths and the largest crustal thicknesses in the Yellow Sea. The one region extends along the Qianliyan Uplift Zone from Jiaodong to Hongsung while the other area extends from southeastern China to Hongsung in the Korean peninsula. Compared to previous works we suggest that they are the part of the collisions zone between North and South China Blocks extending from China to the Korean peninsula via the Yellow Sea.

Description: Regional refinement of the gravity field models from satellite data using spherical radial base functions (SRBF) is an ill-posed problem. This is mainly due to the regional confinement of the data and the base functions, which leads to severe instabilities in the solutions. Here, this ill-posedness as well as the related regularization process are investigated. We compare three methods for the choice of the regularization parameter, which have been frequently used in gravity modelling. These methods are (1) the variance component estimation (VCE), (2) the generalized cross validation (GCV) and (3) the L-curve criterion. A particular emphasis is put on the impact of the SRBF type on the regularization parameter. To do this, we include two types of SRBF which are often used for regional gravity field modelling. These are the Shannon SRBF or the reproducing kernel and the Spline SRBF. The investigations are performed on two months of the real GOCE ultrasensitive gravity gradients over Central Africa and Amazon. The solutions are validated against a state-of-the-art global gravity solution. We conclude that if a proper regularization method is applied, both SRBF deliver more or less the same accuracy. We show that when the Shannon wavelet is used, the L-curve method gives the best results, while with the Spline kernel, the GCV outperforms the other two methods. Moreover, we observe that the estimated coefficients for the Spline kernel cannot be spatially interpreted. In contrast, the coefficients obtained for the Shannon wavelet reflect the energy of the recovered gravity field with a correlation factor of above 95 per cent. Therefore, when combined with the L-curve method, the Shannon SRBF is advantageous for regional gravity field estimation, since it is one of the simplest band-limited SRBF. In addition, it delivers promising solutions and the estimated coefficients represent the characteristics of the gravity field within the target region.

Description: This paper describes an alternative acceleration approach for determining GRACE monthly gravity field models. The main differences compared to the traditional acceleration approach can be summarized as: (1) The position errors of GRACE orbits in the functional model are taken into account; (2) The range ambiguity is eliminated via the difference of the range measurements and (3) The mean acceleration equation is formed based on Cowell integration. Using this developed approach, a new time-series of GRACE monthly solution spanning the period January 2003 to December 2010, called Tongji_Acc RL01, has been derived. The annual signals from the Tongji_Acc RL01 time-series agree well with those from the GLDAS model. The performance of Tongji_Acc RL01 shows that this new model is comparable with the RL05 models released by CSR and JPL as well as with the RL05a model released by GFZ.

Description: In this paper, we present a method for incorporating prior geological information into potential field data inversion problem. As opposed to the traditional inverse algorithm, our proposed method takes full advantage of prior geological information as a constraint and thus obtains a new objective function for inversion by adding Lagrangian multipliers and slack variables to the traditional inversion method. These additional parameters can be easily solved during iterations. We used both synthetic and observed data sets to test the stability and validity of the proposed method. Our results using synthetic gravity data show that our new method predicts depth and density anomalies more efficiently and accurately than the traditional inversion method that does not include prior geological constraints. Then using observed gravity data in the Three Gorges area and geological constraint information, we obtained the density distribution of the upper and middle crust in this area thus revealing its geological structure. These results confirm the proposed method's validity and indicate its potential application for magnetism data inversion and exploration of geological structures.

Description: The large number of chemical modifications that are found on the histone proteins of eukaryotic cells form multiple complex combinations, which can act as recognition signals for reader proteins. We have used peptide capture in conjunction with super-SILAC quantification to carry out an unbiased high-throughput analysis of the composition of protein complexes that bind to histone H3K9/S10 and H3K27/S28 methyl-phospho modifications. The accurate quantification allowed us to perform Weighted correlation network analysis (WGCNA) to obtain a systems-level view of the histone H3 histone tail interactome. The analysis reveals the underlying modularity of the histone reader network with members of nuclear complexes exhibiting very similar binding signatures, which suggests that many proteins bind to histones as part of pre-organized complexes. Our results identify a novel complex that binds to the double H3K9me3/S10ph modification, which includes Atrx, Daxx and members of the FACT complex. The super-SILAC approach allows comparison of binding to multiple peptides with different combinations of modifications and the resolution of the WGCNA analysis is enhanced by maximizing the number of combinations that are compared. This makes it a useful approach for assessing the effects of changes in histone modification combinations on the composition and function of bound complexes.

Description: Genome-wide assessment of protein–DNA interaction by chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) is a key technology for studying transcription factor (TF) localization and regulation of gene expression. Signal-to-noise-ratio and signal specificity in ChIP-seq studies depend on many variables, including antibody affinity and specificity. Thus far, efforts to improve antibody reagents for ChIP-seq experiments have focused mainly on generating higher quality antibodies. Here we introduce KOIN (knockout implemented normalization) as a novel strategy to increase signal specificity and reduce noise by using TF knockout mice as a critical control for ChIP-seq data experiments. Additionally, KOIN can identify ‘hyper ChIPable regions’ as another source of false-positive signals. As the use of the KOIN algorithm reduces false-positive results and thereby prevents misinterpretation of ChIP-seq data, it should be considered as the gold standard for future ChIP-seq analyses, particularly when developing ChIP-assays with novel antibody reagents.

Description: It remains enigmatic how slow slip events (SSEs) interact with other slow seismic events and large distant earthquakes at many subduction zones. Here we model the spatiotemporal slip evolution of the most recent long-term SSE in 2009–2011 in the Bungo Channel region, southwest Japan using GEONET GPS position time-series and a Kalman filter-based, time-dependent slip inversion method. We examine the space-time relationship between the geodetically determined slow slip transient and seismically observed low frequency earthquakes (LFEs) and very-low frequency earthquakes (V-LFEs) near the Nankai trough. We find a strong but distinct temporal correlation between transient slip and LFEs and V-LFEs, suggesting a different relationship to the SSE. We also find the great Tohoku-Oki earthquake appears to disrupt the normal source process of the SSE, probably reflecting large-scale stress redistribution caused by the earthquake. Comparison of the 2009–2011 SSE with others in the same region shows much similarity in slip and moment release, confirming its recurrent nature. Comparison of transient slip with plate coupling shows that slip transients mainly concentrate on the transition zone from strong coupling region to downdip LFEs with transient slip relieving elastic strain accumulation at transitional depth. The less consistent spatial correlation between the long-term SSE and seismic slow earthquakes, and susceptibility of these slow earthquakes to various triggering sources including long-term slow slip, suggests caution in using the seismically determined slow earthquakes as a proxy for slow slip.

Description: Normal mode treatments of the Earth's body tide response were developed in the 1980s to account for the effects of Earth rotation, ellipticity, anelasticity and resonant excitation within the diurnal band. Recent space-geodetic measurements of the Earth's crustal displacement in response to luni-solar tidal forcings have revealed geographical variations that are indicative of aspherical deep mantle structure, thus providing a novel data set for constraining deep mantle elastic and density structure. In light of this, we make use of advances in seismic free oscillation literature to develop a new, generalized normal mode theory for the tidal response within the semi-diurnal and long-period tidal band. Our theory involves a perturbation method that permits an efficient calculation of the impact of aspherical structure on the tidal response. In addition, we introduce a normal mode treatment of anelasticity that is distinct from both earlier work in body tides and the approach adopted in free oscillation seismology. We present several simple numerical applications of the new theory. First, we compute the tidal response of a spherically symmetric, non-rotating, elastic and isotropic Earth model and demonstrate that our predictions match those based on standard Love number theory. Second, we compute perturbations to this response associated with mantle anelasticity and demonstrate that the usual set of seismic modes adopted for this purpose must be augmented by a family of relaxation modes to accurately capture the full effect of anelasticity on the body tide response. Finally, we explore aspherical effects including rotation and we benchmark results from several illustrative case studies of aspherical Earth structure against independent finite-volume numerical calculations of the semi-diurnal body tide response. These tests confirm the accuracy of the normal mode methodology to at least the level of numerical error in the finite-volume predictions. They also demonstrate that full coupling of normal modes, rather than group coupling, is necessary for accurate predictions of the body tide response.

Description: We present a capture-based approach for bisulfite-converted DNA that allows interrogation of pre-defined genomic locations, allowing quantitative and qualitative assessments of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) at CG dinucleotides and in non-CG contexts (CHG, CHH) in mammalian and plant genomes. We show the technique works robustly and reproducibly using as little as 500 ng of starting DNA, with results correlating well with whole genome bisulfite sequencing data, and demonstrate that human DNA can be tested in samples contaminated with microbial DNA. This targeting approach will allow cell type-specific designs to maximize the value of 5mC and 5hmC sequencing.

Description: Androgen receptor (AR) variants (AR-Vs) expressed in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo . Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chromatin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa.

Description: A sequence of large earthquakes occurred along the North Anatolian fault in the 20th century. These earthquakes, including the 1999 Izmit/Düzce earthquakes, generally propagated westward towards the Marmara Sea, defining the Main Marmara fault as a potential seismic gap. It is important to conduct a detailed assessment of the seismic hazards along the main Marmara fault because the megacity Istanbul lies only approximately 10 km north of the eastern segment of the Main Marmara fault, which is referred to as the Princes’ Islands Fault segment (PIF). Here, we study the locking status of this fault segment to evaluate the seismic hazard potential. For the first time, combined ascending and descending Interferometric Synthetic Aperture Radar and Global Positioning System observations were used to investigate the crustal deformation associated with the PIF. After careful corrections of the estimated ground velocity, a deformation pattern relating to fault locking near the Princes’ Islands was identified. The modeling results revealed that the slip rate and locking depth of the fault segment show a clear trade-off, which were estimated as 18.9 ± 7.2 mm yr –1 and 12.1 ± 7.0 km, respectively. With a moment accumulation rate of 1.7 ± 0.4  x  10 17 Nm yr –1 (proportional to the product of slip rate and locking depth), our results imply a build-up of a geodetic moment on the PIF and therefore a potential for earthquake hazards in the vicinity of the Istanbul megacity.

Description: Nucleosomal DNA is thought to be generally inaccessible to DNA-binding factors, such as micrococcal nuclease (MNase). Here, we digest Drosophila chromatin with high and low concentrations of MNase to reveal two distinct nucleosome types: MNase-sensitive and MNase-resistant. MNase-resistant nucleosomes assemble on sequences depleted of A/T and enriched in G/C-containing dinucleotides, whereas MNase-sensitive nucleosomes form on A/T-rich sequences found at transcription start and termination sites, enhancers and DNase I hypersensitive sites. Estimates of nucleosome formation energies indicate that MNase-sensitive nucleosomes tend to be less stable than MNase-resistant ones. Strikingly, a decrease in cell growth temperature of about 10°C makes MNase-sensitive nucleosomes less accessible, suggesting that observed variations in MNase sensitivity are related to either thermal fluctuations of chromatin fibers or the activity of enzymatic machinery. In the vicinity of active genes and DNase I hypersensitive sites nucleosomes are organized into periodic arrays, likely due to ‘phasing’ off potential barriers formed by DNA-bound factors or by nucleosomes anchored to their positions through external interactions. The latter idea is substantiated by our biophysical model of nucleosome positioning and energetics, which predicts that nucleosomes immediately downstream of transcription start sites are anchored and recapitulates nucleosome phasing at active genes significantly better than sequence-dependent models.

Description: We present a distributed slip model for the 1999 M w 6.3 Chamoli earthquake of north India using interferometric synthetic aperture radar (InSAR) data from both ascending and descending orbits and Bayesian estimation of confidence levels and trade-offs of the model geometry parameters. The results of fault-slip inversion in an elastic half-space show that the earthquake ruptured a $9 _{ - 2.2}^{\circ + 3.4}$ northeast-dipping plane with a maximum slip of ~1 m. The fault plane is located at a depth of ~ $15.9_{ - 3.0}^{ + 1.1}$ km and is ~120 km north of the Main Frontal Thrust, implying that the rupture plane was on the northernmost detachment near the mid-crustal ramp of the Main Himalayan Thrust. The InSAR-determined moment is 3.35 x 10 18 Nm with a shear modulus of 30 GPa, equivalent to M w 6.3, which is smaller than the seismic moment estimates of M w 6.4–6.6. Possible reasons for this discrepancy include the trade-off between moment and depth, uncertainties in seismic moment tensor components for shallow dip-slip earthquakes and the role of earth structure models in the inversions. The released seismic energy from recent earthquakes in the Garhwal region is far less than the accumulated strain energy since the 1803 M s 7.5 earthquake, implying substantial hazard of future great earthquakes.

Description: We use a Bayesian formalism combined with a grid node discretization for the linear inversion of gravimetric data in terms of 3-D density distribution. The forward modelling and the inversion method are derived from seismological inversion techniques in order to facilitate joint inversion or interpretation of density and seismic velocity models. The Bayesian formulation introduces covariance matrices on model parameters to regularize the ill-posed problem and reduce the non-uniqueness of the solution. This formalism favours smooth solutions and allows us to specify a spatial correlation length and to perform inversions at multiple scales. We also extract resolution parameters from the resolution matrix to discuss how well our density models are resolved. This method is applied to the inversion of data from the volcanic island of Basse-Terre in Guadeloupe, Lesser Antilles. A series of synthetic tests are performed to investigate advantages and limitations of the methodology in this context. This study results in the first 3-D density models of the island of Basse-Terre for which we identify: (i) a southward decrease of densities parallel to the migration of volcanic activity within the island, (ii) three dense anomalies beneath Petite Plaine Valley, Beaugendre Valley and the Grande-Découverte-Carmichaël-Soufrière Complex that may reflect the trace of former major volcanic feeding systems, (iii) shallow low-density anomalies in the southern part of Basse-Terre, especially around La Soufrière active volcano, Piton de Bouillante edifice and along the western coast, reflecting the presence of hydrothermal systems and fractured and altered rocks.

Description: The Illumina HumanMethylation450 BeadChip is increasingly utilized in epigenome-wide association studies, however, this array-based measurement of DNA methylation is subject to measurement variation. Appropriate data preprocessing to remove background noise is important for detecting the small changes that may be associated with disease. We developed a novel background correction method, ENmix, that uses a mixture of exponential and truncated normal distributions to flexibly model signal intensity and uses a truncated normal distribution to model background noise. Depending on data availability, we employ three approaches to estimate background normal distribution parameters using (i) internal chip negative controls, (ii) out-of-band Infinium I probe intensities or (iii) combined methylated and unmethylated intensities. We evaluate ENmix against other available methods for both reproducibility among duplicate samples and accuracy of methylation measurement among laboratory control samples. ENmix out-performed other background correction methods for both these measures and substantially reduced the probe-design type bias between Infinium I and II probes. In reanalysis of existing EWAS data we show that ENmix can identify additional CpGs, and results in smaller P -value estimates for previously-validated CpGs. We incorporated the method into R package ENmix , which is freely available from Bioconductor website.

Description: We compute the gravimetric factor at the Chandler wobble (CW) frequency using time-series from superconducting gravimeters (SG) longer than a decade. We first individually process the polar motion and data at each individual gravity station to estimate the gravimetric factor amplitude and phase, then we make a global analysis by applying a stacking method to different subsets of up to seven SG stations. The stacking is an efficient way of getting rid of local effects and improving the signal-to-noise ratio of the combined data sets. Using the stacking method, we find a gravimetric factor amplitude and phase of 1.118 ± 0.016 and –0.45 ± 0.66 deg, respectively, which is smaller in amplitude than expected. The sources of error are then carefully considered. For both local and global analyses, the uncertainties on our results are reliably constrained by computing the standard deviation of the estimates of the gravimetric factor amplitude and phase for increasing length of the time-series. Constraints on the CW anelastic dissipation can be set since any departure of the gravimetric factor from its elastic value may provide some insights into the dissipative processes that occur at the CW period. In particular, assuming given rheological models for the Earth's mantle enables us to make the link between the gravimetric factor phase and the CW quality factor.

Description: Analysing independent 1-yr data sets of 10 European superconducting gravimeters (SG) reveals statistically significant temporal variations of M2 tidal parameters. Both common short-term (〈2 yr) and long-term (〉2 yr) features are identified in all SG time-series but one. The averaged variations of the amplitude factor are about 0.2. The path of load vector variations equivalent to the temporal changes of tidal parameters suggests the presence of an 8.85 yr modulation (lunar perigee). The tidal waves having the potential to modulate M2 with this period belong to the 3rd degree constituents. Their amplitude factors turn out to be much closer to body tide model predictions than that of the main 2nd degree M2, which indicates ocean loading for 3rd degree waves to be less prominent than for 2nd degree waves within the M2 group. These two different responses to the loading suggest that the observed modulation is more due to insufficient frequency resolution of limited time-series rather than to time variable loading. Presently, SG gravity time-series are still too short to prove if time variable loading processes are involved too as in case of the annual M2 modulation known to appear for analysis intervals of less than 1 yr. Whatever the variations are caused by, they provide the upper accuracy limit for earth model validation and permit estimating the temporal stability of SG scale factors and assessing the quality of gravity time-series.

Description: A sequence of large earthquakes occurred along the North Anatolian fault in the 20th century. These earthquakes, including the 1999 Izmit/Düzce earthquakes, generally propagated westward towards the Marmara Sea, defining the Main Marmara fault as a potential seismic gap. It is important to conduct a detailed assessment of the seismic hazards along the main Marmara fault because the megacity Istanbul lies only approximately 10 km north of the eastern segment of the Main Marmara fault, which is referred to as the Princes’ Islands Fault segment (PIF). Here, we study the locking status of this fault segment to evaluate the seismic hazard potential. For the first time, combined ascending and descending Interferometric Synthetic Aperture Radar and Global Positioning System observations were used to investigate the crustal deformation associated with the PIF. After careful corrections of the estimated ground velocity, a deformation pattern relating to fault locking near the Princes’ Islands was identified. The modeling results revealed that the slip rate and locking depth of the fault segment show a clear trade-off, which were estimated as 18.9 ± 7.2 mm yr –1 and 12.1 ± 7.0 km, respectively. With a moment accumulation rate of 1.7 ± 0.4  x  10 17 Nm yr –1 (proportional to the product of slip rate and locking depth), our results imply a build-up of a geodetic moment on the PIF and therefore a potential for earthquake hazards in the vicinity of the Istanbul megacity.

Description: Deformation analysis in general and strain analysis in particular using permanent GPS networks require proper analysis of time-series in which all functional effects are taken into consideration and all stochastic effects are captured using an appropriate noise model. This contribution addresses both issues when considering the strain parameters of a GPS network. Estimates of spatial correlation, time correlated noise, and multivariate power spectrum for daily position time-series of the Southern California Integrated GPS Network (SCIGN) stations collected between 1996 and 2011 are obtained. Significant signals with periods of 13.63 d and those related to the GPS draconitic year are identified in these time-series. We aim to assess the effect of a realistic noise model of the series on the uncertainties of the strain parameters including displacements, normal and shear strains, and rotations. For the SCIGN network considered, the following results are highlighted. Contrary to the common belief, the uncertainties of the displacements parameters become smaller when taking a realistic noise model into account. This however was not the case when assessing the noise characteristics of the normal and shear strain, and rotation parameters. The uncertainties increase nearly by a factor of two, in agreement to what is expected. Some of the significant deformation parameters of the white noise model become less significant in case of the realistic noise model.

Description: Crustal vertical deformation (CVD) observed by continuous GPS height time-series can be explained largely by surface loading effects recovered from both Gravity Recover and Climate Experiment (GRACE) and General Circulation Models (GCMs) data. We first show that lower degree CVD spatial spectrum due to the Earth's elastic response to a uniform surface loading plays more important roles than that of high-degree case. We then demonstrate that GRACE data with 300–400 km spatial resolution have the ability to detect 99 per cent power of global and regional CVD in spatial spectrum domain using a global frequency–wavenumber spectrum method. We can just use either GRACE or GCMs 36 degree/order (d/o) spherical harmonic coefficients (SHCs) which correspond to 500 km spatial resolution to acquire more than 90 per cent variance of total CVD modeled by up to 180 d/o SHCs at 98 per cent global gridpoints. Globally, CVD modeled by GRACE loading can explain 72 per cent annual amplitude and 69 per cent variance of GPS observed height time-series, which is better than the GCMs results of 64 per cent for annual amplitude and 41 per cent for variance. Using a three cornered hat method, we also show that the noise level of monthly averaged CVD is about 3 mm for both GPS height time-series and GRACE loading result, while that of GCMs result is only 1.3 mm.

Description: We present a new method to derive 3-D surface deformation from an integration of interferometric synthetic aperture radar (InSAR) images and Global Navigation Satellite System (GNSS) observations based on Akaike's Bayesian Information Criterion (ABIC), considering relationship between deformations of neighbouring locations. This method avoids interpolated errors by excluding the interpolation of GNSS into the same spatial resolution as InSAR images and harnesses the data sets and the prior smooth constraints of surface deformation objectively and simultaneously by using ABIC, which were inherently unresolved in previous studies. In particular, we define surface roughness measuring smoothing degree to evaluate the performance of the prior constraints and deduce the formula of the covariance for the estimation errors to estimate the uncertainty of modelled solution. We validate this method using synthetic tests and the 2008 M w 7.9 Wenchuan earthquake. We find that the optimal weights associated with ABIC minimum are generally at trade-off locations that balance contributions from InSAR, GNSS data sets and the prior constraints. We use this method to evaluate the influence of the interpolated errors from the Ordinary Kriging algorithm on the derivation of surface deformation. Tests show that the interpolated errors may contribute to biasing very large weights imposed on Kriged GNSS data, suggesting that fixing the relative weights is required in this case. We also make a comparison with SISTEM method, indicating that our method allows obtaining better estimations even with sparse GNSS observations. In addition, this method can be generalized to provide a solution for situations where some types of data sets are lacking and can be exploited further to account for data sets such as the integration of displacements along radar lines and offsets along satellite tracks.

Description: While it has been known for some time that offsets in the time-series of Global Navigation Satellite System (GNSS) position estimates degrade station velocity determinations, the magnitude of the effect has not been clear. Using products of the International GNSS Service (IGS), we assess the impact empirically by injecting progressively larger numbers of artificial offsets and solving for a series of long-term secular GNSS frames. Our results show that the stability of the IGS global frame datum is fairly robust, with significant effects at the formal error level only for the R x (and Y-pole) and R z rotational orientations. On the other hand, station velocity estimates are more seriously affected, especially the vertical component. For the typical IGS station, the mean vertical rate uncertainty is already limited to 0.34 mm yr –1 for the current set of position discontinuities. If the number of breaks doubles, which might occur using newer detection schemes, then that uncertainty will worsen by ~40 per cent to 0.48 mm yr –1 . This error source is generally a more important component of realistic velocity uncertainties than any other, including accounting for temporal correlations in the GNSS data. The only way to improve future GNSS velocity estimates is to severely limit manmade displacements at the tracking stations.

Description: DNA methylation is an important epigenetic modification involved in many biological processes and diseases. Recent developments in whole genome bisulfite sequencing (WGBS) technology have enabled genome-wide measurements of DNA methylation at single base pair resolution. Many experiments have been conducted to compare DNA methylation profiles under different biological contexts, with the goal of identifying differentially methylated regions (DMRs). Due to the high cost of WGBS experiments, many studies are still conducted without biological replicates. Methods and tools available for analyzing such data are very limited. We develop a statistical method, DSS-single, for detecting DMRs from WGBS data without replicates. We characterize the count data using a rigorous model that accounts for the spatial correlation of methylation levels, sequence depth and biological variation. We demonstrate that using information from neighboring CG sites, biological variation can be estimated accurately even without replicates. DMR detection is then carried out via a Wald test procedure. Simulations demonstrate that DSS-single has greater sensitivity and accuracy than existing methods, and an analysis of H1 versus IMR90 cell lines suggests that it also yields the most biologically meaningful results. DSS-single is implemented in the Bioconductor package DSS.

Description: We have extended backwards from 2001 to 1979 the current release 05 (RL05) of the Gravity Recovery and Climate Experiment (GRACE) Atmospheric and Oceanic De-aliasing Level-1B (AOD1B) product and studied the impact of this and a previous release 04 (RL04) of the AOD1B product on precise orbits of five altimetry satellites (ERS-1, ERS-2, TOPEX/Poseidon, Envisat and Jason-1) for the time span 1991–2012, as compared to the case when no AOD1B product is used. We have found that using AOD1B RL05 product reduces root mean square (RMS) fits of satellite laser ranging (SLR) observations by about 1.0–6.4 per cent, 2-d arc overlaps in radial, cross-track and along-track directions by about 1.3–12.0, 0.3–10.0 and 2.0–10.0 per cent, respectively, for various satellites tested, as compared to the case without AOD1B product. Using AOD1B RL05 product instead of RL04 one reduces SLR RMS fits by 0.1–0.7 per cent, 2-d arc overlaps in radial, cross-track and along-track directions by 0.1–0.6, 0.1–1.3 and 0.2–1.2 per cent, respectively, for the satellite orbits tested. The multi-mission crossover analysis shows that the application of an AOD1B product reduces the scatter of radial errors by 0.4–2.8 per cent for the satellite missions studied. At the regions with the most pronounced changes the use of the AOD1B products improves the consistency between the sea level as measured by the TOPEX and ERS-2 missions and by the Jason-1 and Envisat missions by 5 to 10 per cent (globally by about 2 per cent). The results of our study show that extended AOD1B RL05 product performs better than the AOD1B RL04 and improves orbits of altimetry satellites and consistency of sea level products.

Description: The epigenetic modification of 5-hydroxymethylcytosine (5hmC) is receiving great attention due to its potential role in DNA methylation reprogramming and as a cell state identifier. Given this interest, it is important to identify reliable and cost-effective methods for the enrichment of 5hmC marked DNA for downstream analysis. We tested three commonly used affinity-based enrichment techniques; (i) antibody, (ii) chemical capture and (iii) protein affinity enrichment and assessed their ability to accurately and reproducibly report 5hmC profiles in mouse tissues containing high (brain) and lower (liver) levels of 5hmC. The protein-affinity technique is a poor reporter of 5hmC profiles, delivering 5hmC patterns that are incompatible with other methods. Both antibody and chemical capture-based techniques generate highly similar genome-wide patterns for 5hmC, which are independently validated by standard quantitative PCR (qPCR) and glucosyl-sensitive restriction enzyme digestion (gRES-qPCR). Both antibody and chemical capture generated profiles reproducibly link to unique chromatin modification profiles associated with 5hmC. However, there appears to be a slight bias of the antibody to bind to regions of DNA rich in simple repeats. Ultimately, the increased specificity observed with chemical capture-based approaches makes this an attractive method for the analysis of locus-specific or genome-wide patterns of 5hmC.

Description: Methylation-specific fluorescence in situ hybridization (MeFISH) was developed for microscopic visualization of DNA methylation status at specific repeat sequences in individual cells. MeFISH is based on the differential reactivity of 5-methylcytosine and cytosine in target DNA for interstrand complex formation with osmium and bipyridine-containing nucleic acids (ICON). Cell nuclei and chromosomes hybridized with fluorescence-labeled ICON probes for mouse major and minor satellite repeats were treated with osmium for crosslinking. After denaturation, fluorescent signals were retained specifically at satellite repeats in wild-type, but not in DNA methyltransferase triple-knockout (negative control) mouse embryonic stem cells. Moreover, using MeFISH, we successfully detected hypomethylated satellite repeats in cells from patients with immunodeficiency, centromeric instability and facial anomalies syndrome and 5-hydroxymethylated satellite repeats in male germ cells, the latter of which had been considered to be unmethylated based on anti-5-methylcytosine antibody staining. MeFISH will be suitable for a wide range of applications in epigenetics research and medical diagnosis.

Description: DNA methylation is an important epigenetic modification that has essential roles in cellular processes including gene regulation, development and disease and is widely dysregulated in most types of cancer. Recent advances in sequencing technology have enabled the measurement of DNA methylation at single nucleotide resolution through methods such as whole-genome bisulfite sequencing and reduced representation bisulfite sequencing. In DNA methylation studies, a key task is to identify differences under distinct biological contexts, for example, between tumor and normal tissue. A challenge in sequencing studies is that the number of biological replicates is often limited by the costs of sequencing. The small number of replicates leads to unstable variance estimation, which can reduce accuracy to detect differentially methylated loci (DML). Here we propose a novel statistical method to detect DML when comparing two treatment groups. The sequencing counts are described by a lognormal-beta-binomial hierarchical model, which provides a basis for information sharing across different CpG sites. A Wald test is developed for hypothesis testing at each CpG site. Simulation results show that the proposed method yields improved DML detection compared to existing methods, particularly when the number of replicates is low. The proposed method is implemented in the Bioconductor package DSS.

Description: Epigenetic regulation of gene expression involves, besides DNA and histone modifications, the relative positioning of DNA sequences within the nucleus. To trace specific DNA sequences in living cells, we used programmable sequence-specific DNA binding of designer transcription activator-like effectors (dTALEs). We designed a recombinant dTALE (msTALE) with variable repeat domains to specifically bind a 19-bp target sequence of major satellite DNA. The msTALE was fused with green fluorescent protein (GFP) and stably expressed in mouse embryonic stem cells. Hybridization with a major satellite probe (3D-fluorescent in situ hybridization) and co-staining for known cellular structures confirmed in vivo binding of the GFP-msTALE to major satellite DNA present at nuclear chromocenters. Dual tracing of major satellite DNA and the replication machinery throughout S-phase showed co-localization during mid to late S-phase, directly demonstrating the late replication timing of major satellite DNA. Fluorescence bleaching experiments indicated a relatively stable but still dynamic binding, with mean residence times in the range of minutes. Fluorescently labeled dTALEs open new perspectives to target and trace DNA sequences and to monitor dynamic changes in subnuclear positioning as well as interactions with functional nuclear structures during cell cycle progression and cellular differentiation.

Description: Coupling bisulfite conversion with next-generation sequencing (Bisulfite-seq) enables genome-wide measurement of DNA methylation, but poses unique challenges for mapping. However, despite a proliferation of Bisulfite-seq mapping tools, no systematic comparison of their genomic coverage and quantitative accuracy has been reported. We sequenced bisulfite-converted DNA from two tissues from each of two healthy human adults and systematically compared five widely used Bisulfite-seq mapping algorithms: Bismark, BSMAP, Pash, BatMeth and BS Seeker. We evaluated their computational speed and genomic coverage and verified their percentage methylation estimates. With the exception of BatMeth, all mappers covered 〉70% of CpG sites genome-wide and yielded highly concordant estimates of percentage methylation ( r 2 ≥ 0.95). Fourfold variation in mapping time was found between BSMAP (fastest) and Pash (slowest). In each library, 8–12% of genomic regions covered by Bismark and Pash were not covered by BSMAP. An experiment using simulated reads confirmed that Pash has an exceptional ability to uniquely map reads in genomic regions of structural variation. Independent verification by bisulfite pyrosequencing generally confirmed the percentage methylation estimates by the mappers. Of these algorithms, Bismark provides an attractive combination of processing speed, genomic coverage and quantitative accuracy, whereas Pash offers considerably higher genomic coverage.

Description: Three-dimensional organization of chromatin is fundamental for transcriptional regulation. Tissue-specific transcriptional programs are orchestrated by transcription factors and epigenetic regulators. The RUNX2 transcription factor is required for differentiation of precursor cells into mature osteoblasts. Although organization and control of the bone-specific Runx2-P1 promoter have been studied extensively, long-range regulation has not been explored. In this study, we investigated higher-order organization of the Runx2-P1 promoter during osteoblast differentiation. Mining the ENCODE database revealed interactions between Runx2-P1 and  Supt3h promoters in several non-mesenchymal human cell lines. Supt3h is a ubiquitously expressed gene located within the first intron of Runx2 . These two genes show shared synteny across species from humans to sponges. Chromosome conformation capture analysis in the murine pre-osteoblastic MC3T3-E1 cell line revealed increased contact frequency between Runx2-P1 and Supt3h promoters during differentiation. This increase was accompanied by enhanced DNaseI hypersensitivity along with RUNX2 and CTCF binding at the Supt3h promoter. Furthermore, interplasmid-3C and luciferase reporter assays showed that the Supt3h promoter can modulate Runx2-P1 activity via direct association. Taken together, our data demonstrate physical proximity between Runx2-P1 and Supt3h promoters, consistent with their syntenic nature. Importantly, we identify the Supt3h promoter as a potential regulator of the bone-specific Runx2-P1 promoter .

Description: The paper in question by Van Camp and co-authors [MVC] challenges previous work showing that ground gravity data arising from hydrology can provide a consistent signal for the comparison with satellite gravity data. The data sets used are similar to those used previously, that is, the gravity field as measured by the GRACE satellites versus ground-based data from superconducting gravimeters (SGs) over the same continental area, in this case Central Europe. One of the main impediments in this paper is the presentation that is frequently confusing and misleading as to what the data analysis really shows, for example, the irregular treatment of annual components that are first subtracted then reappear in the analysis. More importantly, we disagree on specific points. Two calculations are included in our comment to illustrate where we believe that the processing in [MVC] paper is deficient. The first deals with their erroneous treatment of the global hydrology using a truncated spherical harmonic approach which explains almost a factor 2 error in their computation of the loading. The second shows the effect of making the wrong assumption in the GRACE/hydrology/surface gravity comparison by inverting the whole of the hydrology loading for underground stations. We also challenge their claims that empirical orthogonal function techniques cannot be done in the presence of periodic components, and that SG data cannot be corrected for comparisons with GRACE data. The main conclusion of their paper, that there is little coherence between ground gravity stations and this invalidates GRACE comparisons, is therefore questionable. There is nothing in [MVC] that contradicts any of the previous papers that have shown clearly a strong relation between seasonal signals obtained from both ground gravity and GRACE satellite data.

Description: The influence of changes in surface ice-mass redistribution and associated viscoelastic response of the Earth, known as glacial isostatic adjustment (GIA), on the Earth's rotational dynamics has long been known. Equally important is the effect of the changes in the rotational dynamics on the viscoelastic deformation of the Earth. This signal, known as the rotational feedback, or more precisely, the rotational feedback on the sea level equation, has been mathematically described by the sea level equation extended for the term that is proportional to perturbation in the centrifugal potential and the second-degree tidal Love number. The perturbation in the centrifugal force due to changes in the Earth's rotational dynamics enters not only into the sea level equation, but also into the conservation law of linear momentum such that the internal viscoelastic force, the perturbation in the gravitational force and the perturbation in the centrifugal force are in balance. Adding the centrifugal-force perturbation to the linear-momentum balance creates an additional rotational feedback on the viscoelastic deformations of the Earth. We term this feedback mechanism, which is studied in this paper, as the rotational feedback on the linear-momentum balance. We extend both the time-domain method for modelling the GIA response of laterally heterogeneous earth models developed by Martinec and the traditional Laplace-domain method for modelling the GIA-induced rotational response to surface loading by considering the rotational feedback on linear-momentum balance. The correctness of the mathematical extensions of the methods is validated numerically by comparing the polar-motion response to the GIA process and the rotationally induced degree 2 and order 1 spherical harmonic component of the surface vertical displacement and gravity field. We present the difference between the case where the rotational feedback on linear-momentum balance is considered against that where it is not. Numerical simulations show that the resulting difference in radial displacement and sea level change between these situations since the Last Glacial Maximum reaches values of ±25 and ±1.8 m, respectively. Furthermore, the surface deformation pattern is modified by up to 10 per cent in areas of former or ongoing glaciation, but by up to 50 per cent at the bottom of the southern Indian ocean. This also results in the movement of coastlines during the last deglaciation to differ between the two cases due to the difference in the ocean loading, which is seen for instance in the area around Hudson Bay, Canada and along the Chinese, Australian or Argentinian coastlines.

Description: During megathrust earthquakes, great ruptures are accompanied by large scale mass redistribution inside the solid Earth and by ocean mass redistribution due to bathymetry changes. These large scale mass displacements can be detected using the monthly gravity maps of the GRACE satellite mission. In recent years it has become increasingly common to use the long wavelength changes in the Earth's gravity field observed by GRACE to infer seismic source properties for large megathrust earthquakes. An important advantage of space gravimetry is that it is independent from the availability of land for its measurements. This is relevant for observation of megathrust earthquakes, which occur mostly offshore, such as the $M_{\text{w}} \sim 9$ 2004 Sumatra–Andaman, 2010 Maule (Chile) and 2011 Tohoku-Oki (Japan) events. In Broerse et al. , we examined the effect of the presence of an ocean above the rupture on long wavelength gravity changes and showed it to be of the first order. Here we revisit the implementation of an ocean layer through the sea level equation and compare the results with approximated methods that have been used in the literature. One of the simplifications usually lies in the assumption of a globally uniform ocean layer. We show that especially in the case of the 2010 Maule earthquake, due to the closeness of the South American continent, the uniform ocean assumption is not valid and causes errors up to 57 per cent for modelled peak geoid height changes (expressed at a spherical harmonic truncation degree of 40). In addition, we show that when a large amount of slip occurs close to the trench, horizontal motions of the ocean floor play a mayor role in the ocean contribution to gravity changes. Using a slip model of the 2011 Tohoku-Oki earthquake that places the majority of slip close to the surface, the peak value in geoid height change increases by 50 per cent due to horizontal ocean floor motion. Furthermore, we test the influence of the maximum spherical harmonic degree at which the sea level equation is performed for sea level changes occurring along coastlines, which shows to be important for relative sea level changes occurring along the shore. Finally, we demonstrate that ocean floor loading, self-gravitation of water and conservation of water mass are of second order importance for coseismic gravity changes. When GRACE observations are used to determine earthquake parameters such as seismic moment or source depth, the uniform ocean layer method introduces large biases, depending on the location of the rupture with respect to the continent. The same holds for interpreting shallow slip when horizontal motions are not properly accounted for in the ocean contribution. In both cases the depth at which slip occurs will be underestimated.

Description: Long-term volcanic subsidence provides insight into intereruptive processes, which comprise the longest portion of the eruptive cycle. Ground-based geodetic surveys of Medicine Lake Volcano (MLV), northern CA, document subsidence at rates of ~–10 mm yr –1 between 1954 and 2004. The long observation period plus the duration and stable magnitude of this signal presents an ideal opportunity to study long-term volcanic deformation, but this first requires accurate knowledge of the geometry and magnitude of the source. Best-fitting analytical source models to past levelling and GPS data sets show conflicting source parameters—primarily the model depth. To overcome this, we combine multiple tracks of InSAR data, each with a different look angle, to improve upon the spatial resolution of ground-based measurements. We compare the results from InSAR to those of past geodetic studies, extending the geodetic record to 2011 and demonstrating that subsidence at MLV continues at ~–10 mm yr –1 . Using geophysical inversions, we obtain the best-fitting analytical source model—a sill located at 9–10 km depth beneath the caldera. This model geometry is similar to those of past studies, providing a good fit to the high spatial density of InSAR measurements, while accounting for the high ratio of vertical to horizontal deformation derived from InSAR and recorded by existing levelling and GPS data sets. We discuss possible causes of subsidence and show that this model supports the hypothesis that deformation at MLV is driven by tectonic extension, gravitational loading, plus a component of volume loss at depth, most likely due to cooling and crystallization within the intrusive complex that underlies the edifice. Past InSAR surveys at MLV, and throughout the Cascades, are of variable success due to dense vegetation, snow cover and atmospheric artefacts. In this study, we demonstrate how InSAR may be successfully used in this setting by applying a suite of multitemporal analysis methods that account for atmospheric and orbital noise sources. These methods include: a stacking strategy based upon the noise characteristics of each data set; pixelwise rate-map formation (-RATE) and persistent scatterer InSAR (StaMPS).

Description: In the literature, the inverted coseismic slip models from seismological and geodetic data for the 2011 Tohoku-Oki earthquake portray significant discrepancies, in particular regarding the intensity and the distribution of the rupture near the trench. For a megathrust earthquake, it is difficult to discern the slip along the shallow part of the fault from the geodetic data, which are often acquired on land. In this paper, we discuss the uncertainties in the slip distribution inversion using the geodetic data for the 2011 Tohoku earthquake and the Fully Bayesian Inversion method. These uncertainties are due to the prior information regarding the boundary conditions at the edges of the fault, the dip subduction angle and the smoothing operator. Using continuous GPS data from the Japan Island, the results for the rigid and free boundary conditions show that they produce remarkably different slip distributions at shallow depths, with the latter producing a large slip exceeding 30 m near the surface. These results indicate that the smoothing operator (gradient or Laplacian schemes) does not severely affect the slip pattern. To better invert the coseismic slip, we then introduce the ocean bottom GPS (OB-GPS) data, which improve the resolution of the shallow part of the fault. We obtain a near-trench slip greater than 40 m that reaches the Earth's surface, regardless of which boundary condition is used. Additionally, we show that using a mean dip angle for the fault as derived from subduction models is adequate if the goal is to invert for the general features of the slip pattern of this megathrust event.

Description: In general, observations are normally considered to refer to an epoch in time, however, observations take time. During this time span temporal variations of the observable alias the measurement. Similar phenomenon can be defined in the space domain as well: data treated to refer to a geographical location often contains integrated information of the surroundings. In each case the appropriate signal content can partially be recovered by desmoothing the averaged data. The present study delivers the theoretical foundation of a desmoothing method, and suggests its use on different applications in geodesy. The theoretical formulation of the desmoothing has been derived for 1-D and 2-D signals, the latter is interpreted on a plain and also on a sphere. The presented case studies are less elaborated, but intended to demonstrate the need and usefulness of the desmoothing tool.

Description: Extracting geophysical signals from Global Positioning System (GPS) coordinate time-series is a well-established practice that has led to great insights into how the Earth deforms. Often small discontinuities are found in such time-series and are traceable to either broad-scale deformation (i.e. earthquakes) or discontinuities due to equipment changes and/or failures. Estimating these offsets accurately enables the identification of coseismic deformation estimates in the former case, and the removal of unwanted signals in the latter case which then allows tectonic rates to be estimated more accurately. We develop a method to estimate accurately discontinuities in time series of GPS positions at specified epochs, based on a so-called ‘offset series’. The offset series are obtained by varying the amount of GPS data before and after an event while estimating the offset. Two methods, a mean and a weighted mean method, are then investigated to produce the estimated discontinuity from the offset series. The mean method estimates coseismic offsets without making assumptions about geophysical processes that may be present in the data (i.e. tectonic rate, seasonal variations), whereas the weighted mean method includes estimating coseismic offsets with a model of these processes. We investigate which approach is the most appropriate given certain lengths of available data and noise within the time-series themselves. For the Sumatra–Andaman event, with 4.5 yr of pre-event data, we show that between 2 and 3 yr of post-event data are required to produce accurate offset estimates with the weighted mean method. With less data, the mean method should be used, but the uncertainties of the estimated discontinuity are larger.

Description: Complications arise in the interpretation of gravity fields because of interference from systematic degradations, such as boundary blurring and distortion. The major sources of these degradations are the various systematic errors that inevitably occur during gravity field data acquisition, discretization and geophysical forward modelling. To address this problem, we evaluate deconvolution method that aim to detect the clear horizontal boundaries of anomalous sources by the suppression of systematic errors. A convolution-based multilayer projection model, based on the classical 3-D gravity field forward model, is innovatively derived to model the systematic error degradation. Our deconvolution algorithm is specifically designed based on this multilayer projection model, in which three types of systematic error are defined. The degradations of the different systematic errors are considered in the deconvolution algorithm. As the primary source of degradation, the convolution-based systematic error is the main object of the multilayer projection model. Both the random systematic error and the projection systematic error are shown to form an integral part of the multilayer projection model, and the mixed norm regularization method and the primal-dual optimization method are therefore employed to control these errors and stabilize the deconvolution solution. We herein analyse the parameter identification and convergence of the proposed algorithms, and synthetic and field data sets are both used to illustrate their effectiveness. Additional synthetic examples are specifically designed to analyse the effects of the projection systematic error, which is caused by the uncertainty associated with the estimation of the impulse response function.

Description: We propose to test if gravimetry can prove useful in discriminating different models of long-term deep crustal processes in the case of the Taiwan mountain belt. We discuss two existing tectonic models that differ in the deep processes proposed to sustain the long-term growth of the orogen. One model assumes underplating of the uppermost Eurasian crust with subduction of the deeper part of the crust into the mantle. The other one suggests the accretion of the whole Eurasian crust above crustal-scale ramps, the lower crust being accreted into the collisional orogen. We compute the temporal gravity changes caused only by long-term rock mass transfers at depth for each of them. We show that the underplating model implies a rate of gravity change of –6 x 10 –2 μGal yr –1 , a value that increases to 2 x 10 –2 μGal yr –1 if crustal subduction is neglected. If the accretion of the whole Eurasian crust occurs, a rate of 7 x 10 –2 μGal yr –1 is obtained. The two models tested differ both in signal amplitude and spatial distribution. The yearly gravity changes expected by long-term deep crustal mass processes in Taiwan are two orders of magnitude below the present-day uncertainty of land-based gravity measurements. Assuming that these annually averaged long-term gravity changes will linearly accumulate with ongoing mountain building, multidecadal time-series are needed to identify comparable rates of gravity change. However, as gravity is sensitive to any mass redistribution, effects of short-term processes such as seismicity and surface mass transfers (erosion, sedimentation, ground-water) may prevent from detecting any long-term deep signal. This study indicates that temporal gravity is not appropriate for deciphering the long-term deep crustal processes involved in the Taiwan mountain belt.

Description: The computation of quasi-static deformation for axisymmetric viscoelastic structures on a gravitating spherical earth is addressed using the spectral element method (SEM). A 2-D spectral element domain is defined with respect to spherical coordinates of radius and angular distance from a pole of symmetry, and 3-D viscoelastic structure is assumed to be azimuthally symmetric with respect to this pole. A point dislocation source that is periodic in azimuth is implemented with a truncated sequence of azimuthal order numbers. Viscoelasticity is limited to linear rheologies and is implemented with the correspondence principle in the Laplace transform domain. This leads to a series of decoupled 2-D problems which are solved with the SEM. Inverse Laplace transform of the independent 2-D solutions leads to the time-domain solution of the 3-D equations of quasi-static equilibrium imposed on a 2-D structure. The numerical procedure is verified through comparison with analytic solutions for finite faults embedded in a laterally homogeneous viscoelastic structure. This methodology is applicable to situations where the predominant structure varies in one horizontal direction, such as a structural contrast across (or parallel to) a long strike-slip fault.

Description: The geodetic rates for the gravity variation and vertical uplift in polar regions subject to past and present-day ice-mass changes (PDIMCs) provide important insight into the rheological structure of the Earth. We provide an update of the rates observed at Ny-Ålesund, Svalbard. To do so, we extract and remove the significant seasonal content from the observations. The rate of gravity variations, derived from absolute and relative gravity measurements, is –1.39 ± 0.11 μGal yr –1 . The rate of vertical displacements is estimated using GPS and tide gauge measurements. We obtain 7.94 ± 0.21 and 8.29 ± 1.60 mm yr –1 , respectively. We compare the extracted signal with that predicted by GLDAS/Noah and ERA-interim hydrology models. We find that the seasonal gravity variations are well-represented by local hydrology changes contained in the ERA-interim model. The phase of seasonal vertical displacements are due to non-local continental hydrology and non-tidal ocean loading. However, a large part of the amplitude of the seasonal vertical displacements remains unexplained. The geodetic rates are used to investigate the asthenosphere viscosity and lithosphere/asthenosphere thicknesses. We first correct the updated geodetic rates for those induced by PDIMCs in Svalbard, using published results, and the sea level change due to the melting of the major ice reservoirs. We show that the latter are at the level of the geodetic rate uncertainties and are responsible for rates of gravity variations and vertical displacements of –0.29 ± 0.03 μGal yr –1 and 1.11 ± 0.10 mm yr –1 , respectively. To account for the late Pleistocene deglaciation, we use the global ice evolution model ICE-3G. The Little Ice Age (LIA) deglaciation in Svalbard is modelled using a disc load model with a simple linear temporal evolution. The geodetic rates at Ny-Ålesund induced by the past deglaciations depend on the viscosity structure of the Earth. We find that viscous relaxation time due to the LIA deglaciation in Svalbard is more than 60 times shorter than that due to the Pleistocene deglaciation. We also find that the response to past and PDIMCs of an Earth model with asthenosphere viscosities ranging between 1.0 and 5.5 x 10 18 Pa s and lithosphere (resp. asthenosphere) thicknesses ranging between 50 and 100 km (resp. 120 and 170 km) can explain the rates derived from geodetic observations.

Description: Understanding the role of a given transcription factor (TF) in regulating gene expression requires precise mapping of its binding sites in the genome. Chromatin immunoprecipitation-exo, an emerging technique using exonuclease to digest TF unbound DNA after ChIP, is designed to reveal transcription factor binding site (TFBS) boundaries with near-single nucleotide resolution. Although ChIP-exo promises deeper insights into transcription regulation, no dedicated bioinformatics tool exists to leverage its advantages. Most ChIP-seq and ChIP-chip analytic methods are not tailored for ChIP-exo, and thus cannot take full advantage of high-resolution ChIP-exo data. Here we describe a novel analysis framework, termed MACE (model-based analysis of ChIP-exo) dedicated to ChIP-exo data analysis. The MACE workflow consists of four steps: (i) sequencing data normalization and bias correction; (ii) signal consolidation and noise reduction; (iii) single-nucleotide resolution border peak detection using the Chebyshev Inequality and (iv) border matching using the Gale-Shapley stable matching algorithm. When applied to published human CTCF, yeast Reb1 and our own mouse ONECUT1/HNF6 ChIP-exo data, MACE is able to define TFBSs with high sensitivity, specificity and spatial resolution, as evidenced by multiple criteria including motif enrichment, sequence conservation, direct sequence pileup, nucleosome positioning and open chromatin states. In addition, we show that the fundamental advance of MACE is the identification of two boundaries of a TFBS with high resolution, whereas other methods only report a single location of the same event. The two boundaries help elucidate the in vivo binding structure of a given TF, e.g. whether the TF may bind as dimers or in a complex with other co-factors.

Description: The 2 principle and the unbiased predictive risk estimator are used to determine optimal regularization parameters in the context of 3-D focusing gravity inversion with the minimum support stabilizer. At each iteration of the focusing inversion the minimum support stabilizer is determined and then the fidelity term is updated using the standard form transformation. Solution of the resulting Tikhonov functional is found efficiently using the singular value decomposition of the transformed model matrix, which also provides for efficient determination of the updated regularization parameter each step. Experimental 3-D simulations using synthetic data of a dipping dike and a cube anomaly demonstrate that both parameter estimation techniques outperform the Morozov discrepancy principle for determining the regularization parameter. Smaller relative errors of the reconstructed models are obtained with fewer iterations. Data acquired over the Gotvand dam site in the south-west of Iran are used to validate use of the methods for inversion of practical data and provide good estimates of anomalous structures within the subsurface.

Description: Global navigation satellite systems (GNSSs) have revealed that a mega-thrust earthquake that occurs in an island-arc trench system causes post-seismic crustal deformation. Such crustal deformation data have been interpreted by combining three mechanisms: afterslip, poroelastic rebound and viscoelastic relaxation. It is seismologically important to determine the contribution of each mechanism because it provides frictional properties between the plate boundaries and viscosity estimates in the asthenosphere which are necessary to evaluate the stress behaviour during earthquake cycles. However, the observation sites of GNSS are mostly deployed over land and can detect only a small part of the large-scale deformation, which precludes a clear separation of the mechanisms. To extend the spatial coverage of the deformation area, recent studies started to use satellite gravity data that can detect long-wavelength deformations over the ocean. To date, compared with theoretical models for calculating the post-seismic crustal deformation, a few models have been proposed to interpret the corresponding gravity variations. Previous approaches have adopted approximations for the effects of compressibility, sphericity and self-gravitation when computing gravity changes. In this study, a new spectral-finite element approach is presented to consider the effects of material compressibility for Burgers viscoelastic earth model with a laterally heterogeneous viscosity distribution. After the basic principles are explained, it is applied to the 2004 Sumatra–Andaman earthquake. For this event, post-seismic deformation mechanisms are still a controversial topic. Using the developed approach, it is shown that the spatial patterns of gravity change generated by the above three mechanisms clearly differ from one another. A comparison of the theoretical simulation results with the satellite gravity data obtained from the Gravity Recovery and Climate Experiment reveals that both afterslip and viscoelastic relaxation are occurring. Considering the spatial patterns in satellite gravity fields is an effective method for investigating post-seismic deformation mechanisms.

Description: Some of the major geothermal anomalies in central Europe are linked to tectonic structures within the top of crystalline basement, which modify strongly the top of this basement. Their assessment is a major challenge in exploration geophysics. Gravity has been proven to be suitable for the detection of mainly large scale lithological and structural inhomogeneities. Indeed, it is well known and proven by different wells that, for example, in northern Switzerland extended negative anomalies are linked to such structures. Due to depth limitation of wells, there vertical extension is often unknown. In this study, we have investigated the potential of gravity for the geometrical characterization of such basement structures. Our approach consists in the combination of the series of Butterworth filters, geological modelling and best-fitting between observed and computed residual anomalies. In this respect, filters of variable wavelength are applied to observed and computed gravity data. The geological model is discretized into a finite element mesh. Near-surface anomalies and the effect of the sedimentary cover were eliminated using cut-off wavelength of 10 km and geological and seismic information. We analysed the potential of preferential Butterworth filtering in a sensitivity study and applied the above mentioned approach to part of the Swiss molasses basin. Sensitivity analyses reveal that such sets of residual anomalies represents a pseudo-tomography revealing the distribution of different structures with depth. This finding allows for interpreting negative anomalies in terms of 3-D volumes. Best-fitting then permits determination of the most likely 3-D geometries of such basement structures. Our model fits both, geological observations and gravity: among 10 deep boreholes in the studied area, six reach the respective units and confirm our distribution of the negative (and positive) anomalies.

Description: A new analytical method for the computation of a truncated series of solid spherical harmonic coefficients (HCs) from data on a spheroid (i.e. an oblate ellipsoid of revolution) is derived, using a transformation between surface and solid spherical HCs. A two-step procedure is derived to extend this transformation beyond degree and order (d/o) 520. The method is compared to the Hotine–Jekeli transformation in a numerical study based on the EGM2008 global gravity model. Both methods are shown to achieve submicrometre precision in terms of height anomalies for a model to d/o 2239. However, both methods result in spherical harmonic models that are different by up to 7.6 mm in height anomalies and 2.5 mGal in gravity disturbances due to the different coordinate system used. While the Hotine–Jekeli transformation requires the use of an ellipsoidal coordinate system, the new method uses only spherical polar coordinates. The Hotine–Jekeli transformation is numerically more efficient, but the new method can more easily be extended to cases where (a linear combination of) normal derivatives of the function under consideration are given on the surface of the spheroid. It therefore provides a solution to many types of ellipsoidal boundary-value problems in the spectral domain.

Description: Epigenetic modifications of histone tails play an essential role in the regulation of eukaryotic transcription. Writer and eraser enzymes establish and maintain the epigenetic code by creating or removing posttranslational marks. Specific binding proteins, called readers, recognize the modifications and mediate epigenetic signalling. Here, we present a versatile assay platform for the investigation of the interaction between methyl lysine readers and their ligands. This can be utilized for the screening of small-molecule inhibitors of such protein–protein interactions and the detailed characterization of the inhibition. Our platform is constructed in a modular way consisting of orthogonal in vitro binding assays for ligand screening and verification of initial hits and biophysical, label-free techniques for further kinetic characterization of confirmed ligands. A stability assay for the investigation of target engagement in a cellular context complements the platform. We applied the complete evaluation chain to the Tudor domain containing protein Spindlin1 and established the in vitro test systems for the double Tudor domain of the histone demethylase JMJD2C. We finally conducted an exploratory screen for inhibitors of the interaction between Spindlin1 and H3K4me3 and identified A366 as the first nanomolar small-molecule ligand of a Tudor domain containing methyl lysine reader.

Description: We explore Earth's elastic deformation response to ocean tidal loading (OTL) using kinematic Global Positioning System (GPS) observations and forward-modelled predictions across South America. Harmonic coefficients are extracted from up to 14 yr of GPS-inferred receiver locations, which we estimate at 5 min intervals using precise point positioning. We compare the observed OTL-induced surface displacements against predictions derived from spherically symmetric, non-rotating, elastic and isotropic (SNREI) Earth models. We also compare sets of modelled predictions directly for various ocean-tide and Earth-model combinations. The vector differences between predicted displacements computed using separate ocean-tide models reveal uniform-displacement components common to all stations in the South America network. Removal of the network-mean OTL-induced displacements from each site substantially reduces the vector differences between observed and predicted displacements. We focus on the dominant astronomical tidal harmonics from three distinct frequency bands: semidiurnal (M 2 ), diurnal (O 1 ) and fortnightly (M f ). In each band, the observed OTL-induced surface displacements strongly resemble the modelled displacement-response patterns, and the residuals agree to about 0.3 mm or better. Even with the submillimetre correspondence between observations and predictions, we detect regional-scale spatial coherency in the final set of residuals, most notably for the M 2 harmonic. The spatial coherency appears relatively insensitive to the specific choice of ocean-tide or SNREI-Earth model. Varying the load model or 1-D elastic structure yields predicted OTL-induced displacement differences of order 0.1 mm or less for the network. Furthermore, estimates of the observational uncertainty place the noise level below the magnitude of the residual displacements for most stations, supporting our interpretation that random errors cannot account for the entire misfit. Therefore, the spatially coherent residuals may reveal deficiencies in the a priori SNREI Earth models. In particular, the residuals may indicate sensitivity to regional deviations from standard globally averaged Earth structure due to the presence of the South American craton.

Description: Planar faults are widely adopted during inversions to determine slip distributions and fault geometries using geodetic observations; however, little research has been conducted with respect to curved faults. We attribute this to the lack of an appropriate parameterized modelling method. In this paper, we present a curved-fault modelling method (CFMM) that describes a curved fault according to specific parameters, and we also develop a corresponding hybrid iterative inversion algorithm (HIIA) to perform inversions for parametric curved-fault geometries and slips. The results of the strike-component and dip-component synthetic tests show that a complex S-shaped fault surface and a circular slip distribution are successfully recovered, indicating the strong performance of the CFMM and HIIA methods. In addition, we describe and verify a scenario for determining the number of necessary geometrical parameters for the HIIA and examine the case study of the Wenchuan earthquake, which occurred on a complex listric fault surface. During the iteration process of the HIIA, both the fault geometry and slip distribution of the Beichuan and Pengguan faults converge to optimal values, indicating a Beichuan fault (BCF) model with a continuous listric shape and gradual steepening from the southwest to the northeast, which is highly consistent with geological survey results. Both the synthetic and real-world case studies show that the HIIA and the CMFF are superior to the conventional fault modelling method based on rectangular planes and that these models have the potential for use in more integrated research involving inversion studies, such as joint slip/curved-fault-geometry inversions that take into account data resolving power.

Description: Globally gridded estimates of monthly-mean anomalies of terrestrial water storage (TWS) are estimated from the most recent GRACE release 05a of GFZ Potsdam in order to provide non-geodetic users a convenient access to state-of-the-art GRACE monitoring data. We use an ensemble of five global land model simulations with different physics and different atmospheric forcing to obtain reliable gridded scaling factors required to correct for spatial leakage introduced during data processing. To allow for the application of this data-set for large-scale monitoring tasks, model validation efforts, and subsequently also data assimilation experiments, globally gridded estimates of TWS uncertainties that include (i) measurement, (ii) leakage and (iii) re-scaling errors are provided as well. The results are generally consistent with the gridded data provided by Tellus, but deviate in some basins which are largely affected by the uncertainties of the model information required for re-scaling, where the approach based on the median of a small ensemble of global land models introduced in this paper leads to more robust results.

Description: The brain is built from a large number of cell types which have been historically classified using location, morphology and molecular markers. Recent research suggests an important role of epigenetics in shaping and maintaining cell identity in the brain. To elucidate the role of DNA methylation in neuronal differentiation, we developed a new protocol for separation of nuclei from the two major populations of human prefrontal cortex neurons—GABAergic interneurons and glutamatergic (GLU) projection neurons. Major differences between the neuronal subtypes were revealed in CpG, non-CpG and hydroxymethylation (hCpG). A dramatically greater number of undermethylated CpG sites in GLU versus GABA neurons were identified. These differences did not directly translate into differences in gene expression and did not stem from the differences in hCpG methylation, as more hCpG methylation was detected in GLU versus GABA neurons. Notably, a comparable number of undermethylated non-CpG sites were identified in GLU and GABA neurons, and non-CpG methylation was a better predictor of subtype-specific gene expression compared to CpG methylation. Regions that are differentially methylated in GABA and GLU neurons were significantly enriched for schizophrenia risk loci. Collectively, our findings suggest that functional differences between neuronal subtypes are linked to their epigenetic specification.

Description: Chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) is a key technique in chromatin research. Although heavily applied, existing ChIP-seq protocols are often highly fine-tuned workflows, optimized for specific experimental requirements. Especially the initial steps of ChIP-seq, particularly chromatin shearing, are deemed to be exceedingly cell-type-specific, thus impeding any protocol standardization efforts. Here we demonstrate that harmonization of ChIP-seq workflows across cell types and conditions is possible when obtaining chromatin from properly isolated nuclei. We established an ultrasound-based nuclei extraction method (NEXSON: Nuclei EXtraction by SONication) that is highly effective across various organisms, cell types and cell numbers. The described method has the potential to replace complex cell-type-specific, but largely ineffective, nuclei isolation protocols. By including NEXSON in ChIP-seq workflows, we completely eliminate the need for extensive optimization and sample-dependent adjustments. Apart from this significant simplification, our approach also provides the basis for a fully standardized ChIP-seq and yields highly reproducible transcription factor and histone modifications maps for a wide range of different cell types. Even small cell numbers (~10 000 cells per ChIP) can be easily processed without application of modified chromatin or library preparation protocols.

Description: Regional recovery of the disturbing gravitational potential in the area of Central Europe from satellite gravitational gradients data is discussed in this contribution. The disturbing gravitational potential is obtained by inverting surface integral formulas which transform the disturbing gravitational potential onto disturbing gravitational gradients in the spherical local north-oriented frame. Two numerical approaches that solve the inverse problem are considered. In the first approach, the integral formulas are rigorously decomposed into two parts, that is, the effects of the gradient data within near and distant zones. While the effect of the near zone data is sought as an inverse problem, the effect of the distant zone data is synthesized from the global gravitational model GGM05S using spectral weights given by truncation error coefficients up to the degree 150. In the second approach, a reference gravitational field up to the degree 180 is applied to reduce and smooth measured gravitational gradients. In both cases we recovered the disturbing gravitational potential from each of the four well-measured gravitational gradients of the GOCE satellite separately as well as from their combination. Obtained results are compared with the EGM2008, DIR-r2, TIM-r2 and SPW-r2 global gravitational models. The best fit was achieved for EGM2008 and the second approach combining all four well-measured gravitational gradients with rms of 1.231 m 2  s –2 .

Description: We present efficient Fourier-domain algorithms for modelling gravity effects due to topographic masses. The well-known Parker's formula originally based on the standard fast Fourier transform (FFT) algorithm is modified by applying the Gauss–FFT method instead. Numerical precision of the forward and inverse Fourier transforms embedded in Parker's formula and its extended forms are significantly improved by the Gauss–FFT method. The topographic model is composed of two major aspects, the geometry and the density. Versatile geometric representations, including the mass line model, the mass prism model, the polyhedron model and smoother topographic models interpolated from discrete data sets using high-order splines or pre-defined by analytical functions, in combination with density distributions that vary both laterally and vertically in rather arbitrary ways following exponential or general polynomial functions, now can be treated in a consistent framework by applying the Gauss–FFT method. The method presented has been numerically checked by space-domain analytical and hybrid analytical/numerical solutions already established in the literature. Synthetic and real model tests show that both the Gauss–FFT method and the standard FFT method run much faster than space-domain solutions, with the Gauss–FFT method being superior in numerical accuracy. When truncation errors are negligible, the Gauss–FFT method can provide forward results almost identical to space-domain analytical or semi-numerical solutions in much less time.

Description: The gravity gradient tensor (GGT) has been increasingly used in practical applications, but the advantages and the disadvantages of the analysis of GGT components versus the analysis of the vertical component of the gravity field are still debated. We analyse the performance of joint inversion of GGT components versus separate inversion of the gravity field alone, or of one tensor component. We perform our analysis by inspection of the Picard Plot, a Singular Value Decomposition tool, and analyse both synthetic data and gradiometer measurements carried out at the Vredefort structure, South Africa. We show that the main factors controlling the reliability of the inversion are algebraic ambiguity (the difference between the number of unknowns and the number of available data points) and signal-to-noise ratio. Provided that algebraic ambiguity is kept low and the noise level is small enough so that a sufficient number of SVD components can be included in the regularized solution, we find that: (i) the choice of tensor components involved in the inversion is not crucial to the overall reliability of the reconstructions; (ii) GGT inversion can yield the same resolution as inversion with a denser distribution of gravity data points, but with the advantage of using fewer measurement stations.

Description: Bromodeoxyuridine (5-bromo-2'-deoxyuridine, BrdU) is a halogenated nucleotide of low toxicity commonly used to monitor DNA replication. It is considered a valuable tool for in vitro and in vivo studies, including the detection of the small population of neural stem cells (NSC) in the mammalian brain. Here, we show that NSC grown in self-renewing conditions in vitro , when exposed to BrdU, lose the expression of stem cell markers like Nestin, Sox2 and Pax6 and undergo glial differentiation, strongly up-regulating the astrocytic marker GFAP. The onset of GFAP expression in BrdU exposed NSC was paralleled by a reduced expression of key DNA methyltransferases (DNMT) and a rapid loss of global DNA CpG methylation, as we determined by our specially developed analytic assay. Remarkably, a known DNA demethylating compound, 5-aza-2'-deoxycytidine (Decitabine), had similar effect on demethylation and differentiation of NSC. Since our key findings apply also to NSC derived from murine forebrain, our observations strongly suggest more caution in BrdU uses in stem cells research. We also propose that BrdU and its related substances may also open new opportunities for differentiation therapy in oncology.

Description: In Escherichia coli , the SeqA protein binds specifically to GATC sequences which are methylated on the A of the old strand but not on the new strand. Such hemimethylated DNA is produced by progression of the replication forks and lasts until Dam methyltransferase methylates the new strand. It is therefore believed that a region of hemimethylated DNA covered by SeqA follows the replication fork. We show that this is, indeed, the case by using global ChIP on Chip analysis of SeqA in cells synchronized regarding DNA replication. To assess hemimethylation, we developed the first genome-wide method for methylation analysis in bacteria. Since loss of the SeqA protein affects growth rate only during rapid growth when cells contain multiple replication forks, a comparison of rapid and slow growth was performed. In cells with six replication forks per chromosome, the two old forks were found to bind surprisingly little SeqA protein. Cell cycle analysis showed that loss of SeqA from the old forks did not occur at initiation of the new forks, but instead occurs at a time point coinciding with the end of SeqA-dependent origin sequestration. The finding suggests simultaneous origin de-sequestration and loss of SeqA from old replication forks.

Description: Live-cell measurement of protein binding to chromatin allows probing cellular biochemistry in physiological conditions, which are difficult to mimic in vitro . However, different studies have yielded widely discrepant predictions, and so it remains uncertain how to make the measurements accurately. To establish a benchmark we measured binding of the transcription factor p53 to chromatin by three approaches: fluorescence recovery after photobleaching (FRAP), fluorescence correlation spectroscopy (FCS) and single-molecule tracking (SMT). Using new procedures to analyze the SMT data and to guide the FRAP and FCS analysis, we show how all three approaches yield similar estimates for both the fraction of p53 molecules bound to chromatin (only about 20%) and the residence time of these bound molecules (~1.8 s). We also apply these procedures to mutants in p53 chromatin binding. Our results support the model that p53 locates specific sites by first binding at sequence-independent sites.

Description: This paper compares GRACE (Gravity Recovery and Climate Experiment) and ICESat (Ice, Cloud and land Elevation Satellite) observations to confirm whether the observed gravity increase in the Tibetan Plateau (TP) was primarily caused by lake storage gain, and comprehensively analyses the changing pattern of lake level over 2003–2009. An improved automated method was used to obtain lake-level changes and the underestimation of lake water storage was considered due to lake area expansion and lake density. The result demonstrates that GRACE recorded a mass gain (16.43 ± 1.65/11.79 ± 1.25 gt a –1 ) in the total/inner TP, of which lake storage increase accounts for (8.78 ± 0.75/7.53 ± 0.56 gt a –1 ) based on ICESat. The northwestern residual may be stored in new lakes and soil moisture as a result of net precipitation gain. According to the character of the lake-level changes, we divide the TP into four subregions. Generally, the changing pattern of lake level concurs with the distribution of precipitation, which is increasing in the inner TP and decreasing in the upstream area of the Indus and Brahmaputra Rivers. An excess of rainfall in the northeastern TP in the summer of 2005 and 2009 caused a simultaneous large increase in water level in many lakes. The correlation of lake changes with precipitation demonstrates that precipitation rather than glacial melt is the main cause of lake-level change in most places. Nonetheless, the meltwater is a considerable supplement for lakes near glaciers such as Selin Co and Nam Co, which partly explains why GRACE indicates a much weaker signal in this region.

Description: Traditional processing of Global Navigation Satellite System (GNSS) data using dedicated scientific software has provided the highest levels of positional accuracy, and has been used extensively in geophysical deformation studies. To achieve these accuracies a significant level of understanding and training is required, limiting their availability to the general scientific community. Various online GNSS processing services, now freely available, address some of these difficulties and allow users to easily process their own GNSS data and potentially obtain high quality results. Previous research into these services has focused on Continually Operating Reference Station (CORS) GNSS data. Less research exists on the results achievable with these services using large campaign GNSS data sets, which are inherently noisier than CORS data. Even less research exists on the quality of velocity fields derived from campaign GNSS data processed through online precise point positioning services. Particularly, whether they are suitable for geodynamic and deformation studies where precise and reliable velocities are needed. In this research, we process a very large campaign GPS data set (spanning 10 yr) with the online Jet Propulsion Laboratory Automated Precise Positioning Service. This data set is taken from a GNSS network specifically designed and surveyed to measure deformation through the central North Island of New Zealand. This includes regional CORS stations. We then use these coordinates to derive a horizontal and vertical velocity field. This is the first time that a large campaign GPS data set has been processed solely using an online service and the solutions used to determine a horizontal and vertical velocity field. We compared this velocity field to that of another well utilized GNSS scientific software package. The results show a good agreement between the CORS positions and campaign station velocities obtained from the two approaches. We discuss the implications of these results for how future GNSS campaign field surveys might be conducted and how their data might be processed.

Description: The study of changes in protein–DNA interactions measured by ChIP-seq on dynamic systems, such as cell differentiation, response to treatments or the comparison of healthy and diseased individuals, is still an open challenge. There are few computational methods comparing changes in ChIP-seq signals with replicates. Moreover, none of these previous approaches addresses ChIP-seq specific experimental artefacts arising from studies with biological replicates. We propose THOR, a Hidden Markov Model based approach, to detect differential peaks between pairs of biological conditions with replicates. THOR provides all pre- and post-processing steps required in ChIP-seq analyses. Moreover, we propose a novel normalization approach based on housekeeping genes to deal with cases where replicates have distinct signal-to-noise ratios. To evaluate differential peak calling methods, we delineate a methodology using both biological and simulated data. This includes an evaluation procedure that associates differential peaks with changes in gene expression as well as histone modifications close to these peaks. We evaluate THOR and seven competing methods on data sets with distinct characteristics from in vitro studies with technical replicates to clinical studies of cancer patients. Our evaluation analysis comprises of 13 comparisons between pairs of biological conditions. We show that THOR performs best in all scenarios.