ALBERT

Description: Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma ( P = 6.3 x 10 –15 ), even after exclusion of a SNP residing in a known lung cancer susceptibility region ( TERT-CLPTM1L ) P = 6.6 x 10 –6 ). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.

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 dengue and yellow fever mosquito, Aedes aegypti , contributes significantly to global disease burden. Genetic study of Aedes aegypti is essential to understanding its evolutionary history, competence as a disease vector, and the effects and efficacy of vector control methods. The prevalence of repeats and transposable elements in the Aedes aegypti genome complicates marker development and makes genome-wide genetic study challenging. To overcome these challenges, we developed a high-throughput genotyping chip, Axiom_aegypti1. This chip screens for 50,000 single-nucleotide polymorphisms present in Aedes aegypti populations from around the world. The array currently used genotypes 96 samples simultaneously. To ensure that these markers satisfy assumptions commonly made in many genetic analyses, we tested for Mendelian inheritance and linkage disequilibrium in laboratory crosses and a wild population, respectively. We have validated more than 25,000 of these markers to date, and expect this number to increase with more sampling. We also present evidence of the chip’s efficacy in distinguishing populations throughout the world. The markers on this chip are ideal for applications ranging from population genetics to genome-wide association studies. This tool makes rapid, cost-effective, and comparable genotype data attainable to diverse sets of Aedes aegypti researchers, from those interested in potential range shifts due to climate change to those characterizing the genetic underpinnings of its competence to transmit disease.

Description: Previous studies on volcanic rock reservoirs were focused on lithology, lithofacies and fractures. Primary processes may lead to high porosity and permeability, and secondary processes tend to decrease primary porosity. However, this is not the case in northern Xinjiang, where Carboniferous volcanic rocks covered an area of 378 x 10 3 km 2 dominated by intermediate-basic rocks of low porosity. At the end of the Carboniferous, these rocks were uplifted, underwent denudation and weathering, and then formed a weathered crust. All types of volcanic rocks might form favorable reservoirs after long-term weathering. The reservoir properties of the crust were controlled by weathering degree and fault development. Four types of reservoir porosity developed: dissolutional pore, pore-fracture, fracture and fracture-cave. Dissolutional pores and fractures are the main reservoir spaces. Under the influence of fractures and an enhanced fracture dissolution environment, the volcanic reservoirs have improved physical properties in deeper burial settings. The depth range of effective reservoirs under the unconformity, either close to, or far from fracture zones, is between 1100 m and 550 m, with maximum porosities of 32% and 24%, respectively. Hydrocarbons have accumulated close to the effective source rock zone due to strong heterogeneities of the volcanic reservoir. The overlying Carboniferous mudstone formed effective caprock. The current structural highs and slope zone coincided well with the paleogeomorphology and form traps for hydrocarbons. Faults and fractures control hydrocarbon enrichment. This is contrary to the view that the Carboniferous is simply impermeable basement in this region, and not capable of hydrocarbon generation.

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: Most isolates of human rhinovirus, the common cold virus, replicate more robustly at the cool temperatures found in the nasal cavity (33–35 °C) than at core body temperature (37 °C). To gain insight into the mechanism of temperature-dependent growth, we compared the transcriptional response of primary mouse airway epithelial cells...

Description: Author(s): B. P. Hou, L. F. Wei, and S. J. Wang We present the normal-mode splitting and optomechanically induced transparency or absorption phenomena in the strongly tunnel-coupled optomechanical cavities. In the probe output spectrum, there appear central transparency windows or absorption peaks around which two broad sidebands are symmetricall… [Phys. Rev. A 92, 033829] Published Wed Sep 16, 2015

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.