ALBERT

Description: The Antarctic Peninsula (AP) consists of a long lived and uniquely well preserved magmatic arc system. The broad tectonic structure of the AP arc is well understood. However, magmatic processes occurring along the arc are only constrained by regional geophysical and relatively sparse geological data. Key questions remain about the timing, volume, and structural controls on magma emplacement. We present new high resolution aeromagnetic data across Adelaide Island, on the western margin of the AP revealing the complex structure of the AP arc/forearc boundary. Using digital enhancement, 2-D modelling and 3-D inversion we constrain the form of the magnetic sources at the arc/forearc boundary. Our interpretation of these magnetic data, guided by geological evidence and new zircon U-Pb dating, suggests significant Palaeogene to Neogene magmatism formed ~25 per cent of the upper crust in this region (~7500 km 3 ). Significant structural control on Neogene magma emplacement along the arc/forearc boundary is also revealed. We hypothesize that this Neogene magmatism reflects mantle return flow through a slab window generated by Late Palaeogene cessation of subduction south of Adelaide Island. This mantle process may have affected the final stages of arc magmatism along the AP margin.

Description: The Scythian Platform (ScP) with a heterogeneous basement of Baikalian–Variscan–Cimmerian age is located between the East European Craton (EEC) on the north and the Crimean–Caucasus orogenic belt and the Black Sea (BS) Basin on the south. In order to get new constrains on the basin architecture and crustal structure of the ScP and a better understanding of the tectonic processes and evolution of the southern margin of the EEC during Mesozoic and Cenozoic time, a 630-km-long seismic wide-angle refraction and reflection (WARR) profile DOBRE-5 was acquired in 2011 October. It crosses in a W–E direction the Fore-Dobrudja Trough, the Odessa Shelf of the BS and the Crimean Plain. The field acquisition included eight chemical shot points located every 50 km and recorded by 215 stations placed every ~2.0 km on the land. In addition, the offshore data from existing profile 26, placed in the Odessa Shelf, were used. The obtained seismic model shows clear lateral segmentation of the crust within the study region on four domains: the Fore-Dobrudja Domain (km 20–160), an offshore domain of the Karkinit Trough at the Odessa Shelf of the BS (km 160–360), an onshore domain of the Central Crimean Uplift (Crimean Plain, km 360–520) and the Indolo-Kuban Trough at the Kerch Peninsula (km 520–620) that is the easternmost part of the Crimea. Two contrasting domains of the ScP within the central part of the DOBRE-5 profile, the Karkinit Trough and the Central Crimean Uplift, may represent different stages of the ScP formation. A deep Karkinit Trough with an underlying high-velocity (〉7.16 km s –1 ) lower crust body suggests its rifting-related origin during Early Cretaceous time. The Central Crimean Uplift represents a thick (up to 47 km) crustal domain consisting of three layers with velocities 5.8–6.4, 6.5–6.6 and 6.7–7.0 km s –1 , which could be evidence of this part of the ScP originating on the crust of Precambrian craton (EEC). The thick heterogeneous basement of the Central Crimean Uplift shows inclusions of granitic bodies associated with magmatic activity related with Variscan orogeny within the ScP. General bending and crustal scale buckling of the Central Crimean Uplift with a wavelength of 230 km could be an effect of the Alpine compressional tectonics in the adjacent Crimean Mountains. The extended/rifted continental margin of the ScP (EEC) at the Odessa Shelf and buckling/uplifted domain of the Central Crimean Uplift affected by compressional tectonics, are separated by the N–S oriented Western Crimean Fault. The crust of the southern margin of the EEC is separated from the ScP, which originated on the EEC crust tectonised and reworked during the Palaeozoic–Mesozoic, by the crustal fault of ~W–E orientation, which corresponds with the Golitsyn Fault observed at the surface between the EEC and the ScP. The Fore-Dobrudja Domain with a thick (〉10 km) heterogeneous basement and two subhorizontal layers in the crystalline crust (with velocities 6.2–6.3 and 6.4–6.65 km s –1 ) differs from the ScP crust and its origin could be very similar to that of the Trans-European Suture Zone and Palaeozoic West European Platform.

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: 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: 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: 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: Post-seismic deformation is commonly attributed to viscoelastic relaxation and/or afterslip, although discerning between the two driving mechanisms can be difficult. A major complication in modeling post-seismic deformation is that forward models can be computationally expensive, making it difficult to adequately search model space to find the optimal fault slip distribution and lithospheric viscosity structure that can explain observable post-seismic deformation. We propose an inverse method which uses coseismic and early post-seismic deformation to rapidly and simultaneously estimate a fault slip history and an arbitrarily discretized viscosity structure of the lithosphere. Our method is based on an approximation which is applicable to the early post-seismic period and expresses surface deformation resulting from viscoelastic relaxation as a linearized function with respect to lithospheric fluidity. We demonstrate this approximation using two-dimensional earthquake models. We validate the approximation and our inverse method using two three-dimensional synthetic tests. The success of our synthetic tests suggests that our method is capable of distinguishing the mechanisms driving early post-seismic deformation and recovering an effective viscosity structure of the lithosphere.

Description: Combinations of histone modifications have significant biological roles, such as maintenance of pluripotency and cancer development, but cannot be analyzed at the single cell level. Here, we visualized a combination of histone modifications by applying the in situ proximity ligation assay, which detects two proteins in close vicinity (~30 nm). The specificity of the method [designated as imaging of a combination of histone modifications (iChmo)] was confirmed by positive signals from H3K4me3/acetylated H3K9, H3K4me3/RNA polymerase II and H3K9me3/H4K20me3, and negative signals from H3K4me3/H3K9me3. Bivalent modification was clearly visualized by iChmo in wild-type embryonic stem cells (ESCs) known to have it, whereas rarely in Suz12 knockout ESCs and mouse embryonic fibroblasts known to have little of it. iChmo was applied to analysis of epigenetic and phenotypic changes of heterogeneous cell population, namely, ESCs at an early stage of differentiation, and this revealed that the bivalent modification disappeared in a highly concerted manner, whereas phenotypic differentiation proceeded with large variations among cells. Also, using this method, we were able to visualize a combination of repressive histone marks in tissue samples. The application of iChmo to samples with heterogeneous cell population and tissue samples is expected to clarify unknown biological and pathological significance of various combinations of epigenetic modifications.

Description: We explore thermal convection of a fluid with a temperature-dependent viscosity in a basally heated 3-D spherical shell using linear stability analyses and numerical experiments, while considering the application of our results to terrestrial planets. The inner to outer radius ratio of the shell f assumed in the linear stability analyses is in the range of 0.11–0.88. The critical Rayleigh number R c for the onset of thermal convection decreases by two orders of magnitude as f increases from 0.11 to 0.88, when the viscosity depends sensitively on the temperature, as is the case for real mantle materials. Numerical simulations carried out in the range of f  = 0.11–0.55 show that a thermal boundary layer (TBL) develops both along the surface and bottom boundaries to induce cold and hot plumes, respectively, when f is 0.33 or larger. However, for smaller f values, a TBL develops only on the bottom boundary. Convection occurs in the stagnant-lid regime where the root mean square velocity on the surface boundary is less than 1 per cent of its maximum at depth, when the ratio of the viscosity at the surface boundary to that at the bottom boundary exceeds a threshold that depends on f . The threshold decreases from 10 6.5 at f  = 0.11 to 10 4 at f  = 0.55. If the viscosity at the base of the convecting mantle is 10 20 –10 21  Pa s, the Rayleigh number exceeds R c for Mars, Venus and the Earth, but does not for the Moon and Mercury; convection is unlikely to occur in the latter planets unless the mantle viscosity is much lower than 10 20  Pa s and/or the mantle contains a strong internal heat source.

Description: The aftershock distribution of the 1933 Sanriku-oki outer trench earthquake is estimated by using modern relocation methods and a newly developed velocity structure to examine the spatial extent of the source-fault and the possibility of a triggered interplate seismicity. In this study, we first examined the regional data quality of the 1933 earthquake based on smoked-paper records and then relocated the earthquakes by using the 3-D velocity structure and double-difference method. The improvements of hypocentre locations using these methods were confirmed by the examination of recent earthquakes that are accurately located based on ocean bottom seismometer data. The results show that the 1933 aftershocks occurred under both the outer- and inner-trench-slope regions. In the outer-trench-slope region, aftershocks are distributed in a ~280-km-long area and their depths are shallower than 50 km. Although we could not constrain the fault geometry from the hypocentre distribution, the depth distribution suggests the whole lithosphere is probably not under deviatoric tension at the time of the 1933 earthquake. The occurrence of aftershocks under the inner trench slope was also confirmed by an investigation of waveform frequency difference between outer and inner trench earthquakes as recorded at Mizusawa. The earthquakes under the inner trench slope were shallow (depth less double equals30 km) and the waveforms show a low-frequency character similar to the waveforms of recent, precisely located earthquakes in the same area. They are also located where recent activity of interplate thrust earthquakes is high. These suggest that the 1933 outer-trench-slope main shock triggered interplate earthquakes, which is an unusual case in the order of occurrence in contrast with the more common pairing of a large initial interplate shock with subsequent outer-slope earthquakes. The off-trench earthquakes are distributed about 80 km width in the trench perpendicular direction. This wide width cannot be explained from a single high-angle fault confined at a shallow depth (depth less double equals50 km). The upward motion of the 1933 tsunami waveform records observed at Sanriku coast also cannot be explained from a single high-angle west-dipping normal fault. If we consider additional fault, involvement of high-angle, east-dipping normal faults can better explain the tsunami first motion and triggering of the aftershock in a wide area under the outer trench slope. Therefore multiple off-trench normal faults may have activated during the 1933 earthquake. We also relocated recent (2001–2012) seismicity by the same method. The results show that the present seismicity in the outer-trench-slope region can be divided into several groups along the trench. Comparison of the 1933 rupture dimensions based on our aftershock relocations with the morphologies of fault scarps in the outer trench slope suggest that the rupture was limited to the region where fault scarps are largely trench parallel and cross cut the seafloor spreading fabric. These findings imply that bending geometry and structural segmentation of the incoming plate largely controls the spatial extent of the 1933 seismogenic faulting. In this shallow rupture model for this largest outer trench earthquake, triggered seismicity in the forearc and structural control of faulting represent an important deformation styles for off-trench and shallow megathrust zones.