ALBERT

Description: Dynamic epigenetic reprogramming occurs during normal embryonic development at the preimplantation stage. Erroneous epigenetic modifications due to environmental perturbations such as manipulation and culture of embryos during in vitro fertilization (IVF) are linked to various short- or long-term consequences. Among these, the skewed sex ratio, an indicator of reproductive hazards,...

Description: Cocaine abuse is a world-wide public health and social problem without a US Food and Drug Administration-approved medication. An ideal anticocaine medication would accelerate cocaine metabolism, producing biologically inactive metabolites by administration of an efficient cocaine-specific exogenous enzyme. Our recent studies have led to the discovery of the desirable, highly...

Description: Whole-genome sequencing of wild-derived rat species can provide novel genomic resources, which may help decipher the genetics underlying complex phenotypes. As a notorious pest, reservoir of human pathogens, and colonizer, the Asian house rat, Rattus tanezumi , is successfully adapted to its habitat. However, little is known regarding genetic variation in this species. In this study, we identified over 41,000,000 single-nucleotide polymorphisms, plus insertions and deletions, through whole-genome sequencing and bioinformatics analyses. Moreover, we identified over 12,000 structural variants, including 143 chromosomal inversions. Further functional analyses revealed several fixed nonsense mutations associated with infection and immunity-related adaptations, and a number of fixed missense mutations that may be related to anticoagulant resistance. A genome-wide scan for loci under selection identified various genes related to neural activity. Our whole-genome sequencing data provide a genomic resource for future genetic studies of the Asian house rat species and have the potential to facilitate understanding of the molecular adaptations of rats to their ecological niches.

Description: The transcription factor (TF) SOX18 drives lymphatic vessel development in both embryogenesis and tumour-induced neo-lymphangiogenesis. Genetic disruption of Sox18 in a mouse model protects from tumour metastasis and established the SOX18 protein as a molecular target. Here, we report the crystal structure of the SOX18 DNA binding high-mobility group (HMG) box bound to a DNA element regulating Prox1 transcription. The crystals diffracted to 1.75Å presenting the highest resolution structure of a SOX/DNA complex presently available revealing water structure, structural adjustments at the DNA contact interface and non-canonical conformations of the DNA backbone. To explore alternatives to challenging small molecule approaches for targeting the DNA-binding activity of SOX18, we designed a set of five decoys based on modified Prox1 -DNA. Four decoys potently inhibited DNA binding of SOX18 in vitro and did not interact with non-SOX TFs. Serum stability, nuclease resistance and thermal denaturation assays demonstrated that a decoy circularized with a hexaethylene glycol linker and terminal phosphorothioate modifications is most stable. This SOX decoy also interfered with the expression of a luciferase reporter under control of a SOX18-dependent VCAM1 promoter in COS7 cells. Collectively, we propose SOX decoys as potential strategy for inhibiting SOX18 activity to disrupt tumour-induced neo-lymphangiogenesis.

Description: The Hongniu-Hongshan Cu skarn deposit (77.8 Mt at 1.8% Cu) is located in the central part of the Zhongdian porphyry and skarn Cu belt in southwestern China. Skarn and orebodies occur mainly between the different units of the Upper Triassic Qugasi Formation or within altered limestone adjacent to Late Cretaceous intrusions (78–76 Ma). Three main paragenetic stages of skarn formation and ore deposition have been recognized on the basis of petrographic observations: (1) pre-ore-stage hornfels with diopside (Di 87–72 Hd 12–7 ), small-scale endoskarn with reddish grossular (Adr 22–57 Gr 78–43 ), diopside (Di 83–92 Hd 7–15 ), vesuvianite, and abundant exoskarn with red-brown andradite (Adr 75–98 Gr 2–22 ), sahlite (Di 28–41 Hd 58–71 ), and wollastonite; (2) syn-ore-stage retrograde minerals, sulfides (pyrite, chalcopyrite, pyrrhotite, molybdenite, galena, and sphalerite), quartz, and calcite; and (3) post-ore-stage calcite veins. Sulfur isotope values of sulfides are relatively high, with an average 34 S = 4.9 (n = 40), suggesting that the ore-forming fluid was magmatic and that the sulfides precipitated from a relatively reducing ore fluid. The coexistence of silicate melt and primary fluid inclusions in quartz phenocrysts of the mineralization-related quartz monzonite porphyry indicates the simultaneous entrapment of fluid and melt, and records the process of the aqueous fluid exsolving from the crystallizing melt. The initial single-phase fluid has a salinity of 8.8 to 12.7 wt % NaCl equiv and homogenization temperatures of 566° to 650°C, corresponding to pressures of 680 to 940 bar and lithostatic depth of 2.5 to 3.5 km. The primary fluid inclusions in the pre-ore-stage garnet and pyroxene composed of coeval vapor-rich (V type) and halite-bearing (S-I and S-II types containing sylvite) inclusions (32–〉79 total wt % salts) share similar homogenization temperatures (450°–550°C), indicative of the occurrence of fluid unmixing under lithostatic pressures of ~550 to 780 bar (〉2.0-km depth). Primary fluid inclusions trapped in syn-ore quartz, calcite, and epidote show the common development of S-type inclusions (~37.3 wt % NaCl equiv) with coexisting V-type, liquid-rich (L type), and CO 2 -bearing (C-I type) inclusions, all of which have homogenization temperatures of 300° to 400°C and trapping pressures of 100 to 400 bar (~1.5-km depth). Brine inclusions homogenized by halite dissolution after vapor disappearance in both the pre- and syn-ore stages are interpreted to have been trapped under overpressured conditions (〉1,520 bar). Oxygen isotope analyses were conducted on garnet, wollastonite, epidote, quartz, and calcite. The pre-ore-stage garnet and wollastonite have 18 O fluid values of 5.6 to 8.1, whereas the syn-ore-stage epidote, quartz, and calcite have more variable 18 O fluid values in the range of 3.9 to 17.5. The 18 O fluid values of the post-ore-stage vein calcite (15.2–21.3) are much higher than both the pre- and syn-ore stages. The vapor phase of inclusions contains H 2 S, CH 4 , and C 2 H 6 in the syn-ore stages. All these observations reveal that (1) the formation of the Cu skarn deposit was dominated by a magmatic hydrothermal system, (2) multiple fluid pulses contributed to the formation of the pre- and syn-ore-stage skarn minerals and sulfides, and (3) the increase in pH due to the neutralization of the acidic fluid could be the main factor controlling the large-scale ore deposition in Hongniu-Hongshan.

Description: : The development of the Infinium HumanMethylation450 BeadChip enables epigenome-wide association studies at a reduced cost. One observation of the 450K data is that many CpG sites the beadchip interrogates have very large measurement errors. Including these noisy CpGs will decrease the statistical power of detecting relevant associations due to multiple testing correction. We propose to use intra-class correlation coefficient (ICC), which characterizes the relative contribution of the biological variability to the total variability, to filter CpGs when technical replicates are available. We estimate the ICC based on a linear mixed effects model by pooling all the samples instead of using the technical replicates only. An ultra-fast algorithm has been developed to address the computational complexity and CpG filtering can be completed in minutes on a desktop computer for a 450K data set of over 1000 samples. Our method is very flexible and can accommodate any replicate design. Simulations and a real data application demonstrate that our whole-sample ICC method performs better than replicate-sample ICC or variance-based method. Availability and implementation : CpGFilter is implemented in R and publicly available under CRAN via the R package ‘CpGFilter’. Contact : chen.jun2@mayo.edu or xlin@hsph.harvard.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Many Carlin-like Au deposits occur within the late Paleozoic and Triassic Youjiang basin of southwest China. The Huijiabao trend in Guizhou Province contains over 300 metric tons (t; 10.6 Moz) of Au at an average grade of 7 to 18 g/t in a narrow corridor that is about 20 km long and 5 km wide. Petrographic and SEM studies of pyrite in barren host rocks and high-grade orebodies led to the recognition of four stages of pyrite. Py1 consists of fine-grained framboidal crystals in black mudstone. Py2 is comprised of coarser grained euhedralsubhedral clusters that are spatially related to organic matter. Py3 is coarse grained, euhedral, and occurs as overgrowths on Py1 and Py2. Py3’s porous texture, inclusion of randomly oriented detrital minerals, and association with quartz recrystallization suggest it was deformed during Late Triassic orogenesis with Py1 and Py2. Py4 generally occurs as rims on Py1 to Py3 and is intergrown with arsenopyrite. Sensitive high-resolution ion microprobe (SHRIMP) 34 S analyses of each pyrite type and arsenopyrite show that Py1 is related to Py2 and that Py3 is related to Py4 and arsenopyrite. The S isotope compositions of Py1 (–7.5 to +5.9) and Py2 (–5.3 to +7.9) are bimodal, which suggests that H 2 S was generated by biogenic sulfate reduction in open marine and sulfate limited systems during sedimentation and/or diagenesis. The compositions of Py3 (–2.6 to +1.5), Py4 (–1.2 to +1.5), and arsenopyrite (–0.8 to +0.9) are homogeneous and have an intermediate range of values near 0 that suggest that H 2 S was derived either from average pyrite (0.2) in sedimentary rocks or from a concealed magmatic source. Laser ablation-inductively coupled plasma-mass spectrometer (LA–ICP–MS) trace element analyses (As, Ni, Co, Cu, Ag, Se, V) support different origins and show that Py3 and Py4 are ore related. The lower w (Co)/ w (Ni) and w (S)/ w (Se) ratios of Py1 and Py2 are consistent with formation during sedimentation or diagenesis, whereas the higher ratios of Py3, Py4, and arsenopyrite are consistent with a hydrothermal origin. The lower concentrations of Au in Py1 (0.23–2.5 ppm) and Py2 (0.06–12 ppm) show that little Au was added during sedimentation or diagenesis. The higher concentrations of Au in hydrothermal Py3 (1.1–110 ppm) and Py4 (0.34–810 ppm) indicate that most of the Au was introduced during subsequent hydrothermal fluid flow. The low Au contents of arsenopyrite (0.09–0.52 ppm) suggests they formed from Au-depleted fluids. The Au/As ratios of Py1 and Py2 are typical of diagenetic pyrite whereas Py3 and Py4 have ratios that approach those of ore-stage pyrite in Nevada Carlin-type deposits. The fracturing of Py3 and its cementation by Py4 suggests that ore fluid movement was associated with deformation. Published isochron ages on arsenopyrite (Re-Os ~200 Ma) and late calcite-realgar veinlets (Sm-Nd ~135 Ma) in the Huijiabao trend are older than mafic dikes (84 Ma) exposed ~20 km to the east. If the 200 and 135 Ma ages are valid, H 2 S and Au may be derived from a sedimentary source because igneous intrusions of this age have not been found. If these ages are not valid and the gold deposits are actually Late Cretaceous in age, then H 2 S and Au may be derived from a magmatic source. Additional geochronology and isotopic tracer studies are needed to resolve this uncertainty.

Description: Motivation : High-dimensional DNA methylation markers may mediate pathways linking environmental exposures with health outcomes. However, there is a lack of analytical methods to identify significant mediators for high-dimensional mediation analysis. Results: Based on sure independent screening and minimax concave penalty techniques, we use a joint significance test for mediation effect. We demonstrate its practical performance using Monte Carlo simulation studies and apply this method to investigate the extent to which DNA methylation markers mediate the causal pathway from smoking to reduced lung function in the Normative Aging Study. We identify 2 CpGs with significant mediation effects. Availability and implementation : R package, source code, and simulation study are available at https://github.com/YinanZheng/HIMA . Contact: lei.liu@northwestern.edu

Description: The data of 223 stars within 4 kpc from the Sun and 400 pc from the plane are collected from Melnik et al., who listed photometric distances and velocities of 674 long-period Cepheids in the disc of our Galaxy. Both line-of-sight and transverse along the Galactic longitude velocities of the selected stars are analysed on the assumption that the system is the subject to Lin–Shu-type moderately unstable, low-amplitude, tightly wound and rigidly rotating density waves. Minimization of the least-squares estimator S of measured and modelled velocities of stars was performed in the geometrical parameters of waves. The wave structures defined from the two independent samples of velocities are nearly similar. Different radial scales (wavelengths) of velocity inhomogeneity of about 1, 2 and 4 kpc, which do not depend on the number of spiral arms m , were found. But for now it is unclear if one can identify these scales as fully independent global modes of collective oscillations or they are Fourier harmonics of a single wave, or they just reveal the segments of large-scale Orion, Sagittarius and Perseus arms. The dominant mode is the one-armed wave for the main minimum of all S considered. However, because the S values for fits with m = 1–4 are almost equal the latter conclusion must be regarded as tentative until more extensive data are available. High-precision Gaia observations could reveal in the near future whether the wave-like velocity fluctuations near the Sun reported here do indeed exist.