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  • 1
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    DNA-PKcs phosphorylates hnRNP-A1 to facilitate the RPA-to-POT1 switch and telomere capping after replication (2015)
    Oxford University Press
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    Publication Date: 2015-07-12
    Description: The heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) has been implicated in telomere protection and telomerase activation. Recent evidence has further demonstrated that hnRNP-A1 plays a crucial role in maintaining newly replicated telomeric 3' overhangs and facilitating the switch from replication protein A (RPA) to protection of telomeres 1 (POT1). The role of hnRNP-A1 in telomere protection also involves DNA-dependent protein kinase catalytic subunit (DNA-PKcs), although the detailed regulation mechanism has not been clear. Here we report that hnRNP-A1 is phosphorylated by DNA-PKcs during the G2 and M phases and that DNA-PK-dependent hnRNP-A1 phosphorylation promotes the RPA-to-POT1 switch on telomeric single-stranded 3' overhangs. Consequently, in cells lacking hnRNP-A1 or DNA-PKcs-dependent hnRNP-A1 phosphorylation, impairment of the RPA-to-POT1 switch results in DNA damage response at telomeres during mitosis as well as induction of fragile telomeres. Taken together, our results indicate that DNA-PKcs-dependent hnRNP-A1 phosphorylation is critical for capping of the newly replicated telomeres and prevention of telomeric aberrations.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Empirical metallicity-dependent calibrations of effective temperature against colours for dwarfs and giants based on interferometric data (2015)
    Oxford University Press
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    Publication Date: 2015-10-19
    Description: We present empirical metallicity-dependent calibrations of effective temperature against colours for dwarfs of luminosity classes IV and V and for giants of luminosity classes II and III, based on a collection from the literature of about two hundred nearby stars with direct effective temperature measurements of better than 2.5 per cent. The calibrations are valid for an effective temperature range 3100–10 000 K for dwarfs of spectral types M5 to A0 and 3100–5700 K for giants of spectral types K5 to G5. A total of 21 colours for dwarfs and 18 colours for giants of bands of four photometric systems, i.e. the Johnson ( UBVR J I J JHK ), the Cousins ( R C I C ), the Sloan Digital Sky Survey ( gr ) and the Two Micron All Sky Survey ( JHK s ), have been calibrated. Restricted by the metallicity range of the current sample, the calibrations are mainly applicable for disc stars ([Fe/H] – 1.0). The normalized percentage residuals of the calibrations are typically 2.0 and 1.5 per cent for dwarfs and giants, respectively. Some systematic discrepancies at various levels are found between the current scales and those available in the literature (e.g. those based on the infrared flux method or spectroscopy). Based on the current calibrations, we have re-determined the colours of the Sun. We have also investigated the systematic errors in effective temperatures yielded by the current on-going large-scale low- to intermediate-resolution stellar spectroscopic surveys. We show that the calibration of colour ( g – K s ) presented in this work provides an invaluable tool for the estimation of stellar effective temperature for those on-going or upcoming surveys.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 3
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    An integrative somatic mutation analysis to identify pathways linked with survival outcomes across 19 cancer types (2016)
    Oxford University Press
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    Publication Date: 2016-06-01
    Description: Motivation: Identification of altered pathways that are clinically relevant across human cancers is a key challenge in cancer genomics. Precise identification and understanding of these altered pathways may provide novel insights into patient stratification, therapeutic strategies and the development of new drugs. However, a challenge remains in accurately identifying pathways altered by somatic mutations across human cancers, due to the diverse mutation spectrum. We developed an innovative approach to integrate somatic mutation data with gene networks and pathways, in order to identify pathways altered by somatic mutations across cancers. Results: We applied our approach to The Cancer Genome Atlas (TCGA) dataset of somatic mutations in 4790 cancer patients with 19 different types of tumors. Our analysis identified cancer-type-specific altered pathways enriched with known cancer-relevant genes and targets of currently available drugs. To investigate the clinical significance of these altered pathways, we performed consensus clustering for patient stratification using member genes in the altered pathways coupled with gene expression datasets from 4870 patients from TCGA, and multiple independent cohorts confirmed that the altered pathways could be used to stratify patients into subgroups with significantly different clinical outcomes. Of particular significance, certain patient subpopulations with poor prognosis were identified because they had specific altered pathways for which there are available targeted therapies. These findings could be used to tailor and intensify therapy in these patients, for whom current therapy is suboptimal. Availability and implementation: The code is available at: http://www.taehyunlab.org . Contact: jhcheong@yuhs.ac or taehyun.hwang@utsouthwestern.edu or taehyun.cs@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 4
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    Genomic Basis of Adaptive Evolution: The Survival of Amur Ide (Leuciscus waleckii) in an Extremely Alkaline Environment (2017)
    Oxford University Press
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    Publication Date: 2017-01-05
    Description: The Amur ide ( Leuciscus waleckii ) is a cyprinid fish that is widely distributed in Northeast Asia. The Lake Dali Nur population inhabits one of the most extreme aquatic environments on Earth, with an alkalinity up to 50 mmol/L (pH 9.6), thus providing an exceptional model with which to characterize the mechanisms of genomic evolution underlying adaptation to extreme environments. Here, we developed the reference genome assembly for L. waleckii from Lake Dali Nur. Intriguingly, we identified unusual expanded long terminal repeats (LTRs) with higher nucleotide substitution rates than in many other teleosts, suggesting their more recent insertion into the L. waleckii genome. We also identified expansions in genes encoding egg coat proteins and natriuretic peptide receptors, possibly underlying the adaptation to extreme environmental stress. We further sequenced the genomes of 10 additional individuals from freshwater and 18 from Lake Dali Nur populations, and we detected a total of 7.6 million SNPs from both populations. In a genome scan and comparison of these two populations, we identified a set of genomic regions under selective sweeps that harbor genes involved in ion homoeostasis, acid-base regulation, unfolded protein response, reactive oxygen species elimination, and urea excretion. Our findings provide comprehensive insight into the genomic mechanisms of teleost fish that underlie their adaptation to extreme alkaline environments.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    The Milky Way's rotation curve out to 100 kpc and its constraint on the Galactic mass distribution (2016)
    Oxford University Press
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    Publication Date: 2016-10-08
    Description: The rotation curve (RC) of the Milky Way out to ~100 kpc has been constructed using ~16 000 primary red clump giants (PRCGs) in the outer disc selected from the LAMOST Spectroscopic Survey of the Galactic Anti-centre (LSS-GAC) and the Sloan Digital Sky Survey (SDSS)-III/APOGEE survey, combined with ~5700 halo K giants (HKGs) selected from the SDSS/SEGUE survey. To derive the RC, the PRCG sample of the warm disc population and the HKG sample of halo stellar population are, respectively, analysed using a kinematical model allowing for the asymmetric drift corrections and re-analysed using the spherical Jeans equation along with measurements of the anisotropic parameter β currently available. The typical uncertainties of RC derived from the PRCG and HKG samples are, respectively, 5–7 km s –1 and several tens km s –1 . We determine a circular velocity at the solar position, V c ( R 0 ) = 240 ± 6 km s –1 and an azimuthal peculiar speed of the Sun, V = 12.1 ± 7.6 km s –1 , both in good agreement with the previous determinations. The newly constructed RC has a generally flat value of 240 km s –1 within a Galactocentric distance r of 25 kpc and then decreases steadily to 150 km s –1 at r  ~ 100 kpc. On top of this overall trend, the RC exhibits two prominent localized dips, one at r  ~ 11 kpc and another at r  ~ 19 kpc. From the newly constructed RC, combined with other constraints, we have built a parametrized mass model for the Galaxy, yielding a virial mass of the Milky Way's dark matter halo of $0.90^{+0.07}_{-0.08} \times 10^{12}$  M and a local dark matter density, $\rho _{\rm {\odot }, dm} = 0.32^{+0.02}_{-0.02}$  GeV cm –3 .
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 6
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    Conpair: concordance and contamination estimator for matched tumor-normal pairs (2016)
    Oxford University Press
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    Publication Date: 2016-10-08
    Description: Motivation: Sequencing of matched tumor and normal samples is the standard study design for reliable detection of somatic alterations. However, even very low levels of cross-sample contamination significantly impact calling of somatic mutations, because contaminant germline variants can be incorrectly interpreted as somatic. There are currently no sequence-only based methods that reliably estimate contamination levels in tumor samples, which frequently display copy number changes. As a solution, we developed Conpair, a tool for detection of sample swaps and cross-individual contamination in whole-genome and whole-exome tumor–normal sequencing experiments. Results: On a ladder of in silico contaminated samples, we demonstrated that Conpair reliably measures contamination levels as low as 0.1%, even in presence of copy number changes. We also estimated contamination levels in glioblastoma WGS and WXS tumor–normal datasets from TCGA and showed that they strongly correlate with tumor–normal concordance, as well as with the number of germline variants called as somatic by several widely-used somatic callers. Availability and Implementation: The method is available at: https://github.com/nygenome/conpair . Contact: egrabowska@gmail.com or mczody@nygenome.org Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 7
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    Tumor suppressor protein DAB2IP participates in chromosomal stability maintenance through activating spindle assembly checkpoint and stabilizing kinetochore-microtubule attachments (2016)
    Oxford University Press
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    Publication Date: 2016-10-14
    Description: Defects in kinetochore-microtubule (KT-MT) attachment and the spindle assembly checkpoint (SAC) during cell division are strongly associated with chromosomal instability (CIN). CIN has been linked to carcinogenesis, metastasis, poor prognosis and resistance to cancer therapy. We previously reported that the DAB2IP is a tumor suppressor, and that loss of DAB2IP is often detected in advanced prostate cancer (PCa) and is indicative of poor prognosis. Here, we report that the loss of DAB2IP results in impaired KT-MT attachment, compromised SAC and aberrant chromosomal segregation. We discovered that DAB2IP directly interacts with Plk1 and its loss inhibits Plk1 kinase activity, thereby impairing Plk1-mediated BubR1 phosphorylation. Loss of DAB2IP decreases the localization of BubR1 at the kinetochore during mitosis progression. In addition, the reconstitution of DAB2IP enhances the sensitivity of PCa cells to microtubule stabilizing drugs (paclitaxel, docetaxel) and Plk1 inhibitor (BI2536). Our findings demonstrate a novel function of DAB2IP in the maintenance of KT-MT structure and SAC regulation during mitosis which is essential for chromosomal stability.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 8
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    Constraining the Galactic structure parameters with the XSTPS-GAC and SDSS photometric surveys (2016)
    Oxford University Press
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    Publication Date: 2016-11-05
    Description: Photometric data from the Xuyi Schmidt Telescope Photometric Survey of the Galactic Anticentre (XSTPS-GAC) and the Sloan Digital Sky Survey (SDSS) are used to derive the global structure parameters of the smooth components of the Milky Way. The data, which cover nearly 11 000 deg 2 sky area and the full range of Galactic latitude, allow us to construct a globally representative Galactic model. The number density distribution of Galactic halo stars is fitted with an oblate spheroid that decays by power law. The best fitting yields an axis ratio and a power-law index = 0.65 and p = 2.79, respectively. The r -band differential star counts of three dwarf samples are then fitted with a Galactic model. The best-fitting model yielded by a Markov Chain Monte Carlo analysis has thin and thick disc scale heights and lengths of H 1 = 322 pc and L 1 = 2343 pc, H 2 = 794 pc and L 2 = 3638 pc, a local thick-to-thin disc density ratio of f 2 = 11 per cent, and a local density ratio of the oblate halo to the thin disc of f h = 0.16 per cent. The measured star count distribution, which is in good agreement with the above model for most of the sky area, shows a number of statistically significant large-scale overdensities, including some of the previously known substructures, such as the Virgo overdensity and the so-called ‘north near structure’, and a new feature between $150^\circ 〈 l 〈 240^\circ$ and $-1^\circ 〈 b 〈 -5^\circ$ , at an estimated distance between 1.0 and 1.5 kpc. The Galactic North–South asymmetry in the anticentre is even stronger than previously thought.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 9
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    Estimating stellar atmospheric parameters, absolute magnitudes and elemental abundances from the LAMOST spectra with Kernel-based principal component analysis (2016)
    Oxford University Press
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    Publication Date: 2016-11-16
    Description: Accurate determination of stellar atmospheric parameters and elemental abundances is crucial for Galactic archaeology via large-scale spectroscopic surveys. In this paper, we estimate stellar atmospheric parameters – effective temperature T eff , surface gravity log  g and metallicity [Fe/H], absolute magnitudes M V and M K s , α-element to metal (and iron) abundance ratio [α/M] (and [α/Fe]), as well as carbon and nitrogen abundances [C/H] and [N/H] from the Large Sky Area Multi-Object Fibre Spectroscopic Telescope (LAMOST) spectra with a multivariate regression method based on kernel-based principal component analysis, using stars in common with other surveys ( Hipparcos, Kepler , Apache Point Observatory Galactic Evolution Experiment) as training data sets. Both internal and external examinations indicate that given a spectral signal-to-noise ratio (SNR) better than 50, our method is capable of delivering stellar parameters with a precision of ~100 K for T eff , ~0.1 dex for log  g , 0.3–0.4 mag for M V and M K s , 0.1 dex for [Fe/H], [C/H] and [N/H], and better than 0.05 dex for [α/M] ([α/Fe]). The results are satisfactory even for a spectral SNR of 20. The work presents first determinations of [C/H] and [N/H] abundances from a vast data set of LAMOST, and, to our knowledge, the first reported implementation of absolute magnitude estimation directly based on a vast data set of observed spectra. The derived stellar parameters for millions of stars from the LAMOST surveys will be publicly available in the form of value-added catalogues.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 10
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    Expanding the CRISPR imaging toolset with Staphylococcus aureus Cas9 for simultaneous imaging of multiple genomic loci (2016)
    Oxford University Press
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    Publication Date: 2016-05-06
    Description: In order to elucidate the functional organization of the genome, it is vital to directly visualize the interactions between genomic elements in living cells. For this purpose, we engineered the Cas9 protein from Staphylococcus aureus (SaCas9) for the imaging of endogenous genomic loci, which showed a similar robustness and efficiency as previously reported for Streptococcus pyogenes Cas9 (SpCas9). Imaging readouts allowed us to characterize the DNA-binding activity of SaCas9 and to optimize its sgRNA scaffold. Combining SaCas9 and SpCas9, we demonstrated two-color CRISPR imaging with the capability to resolve genomic loci spaced by 〈300 kb. Combinatorial color-mixing further enabled us to code multiple genomic elements in the same cell. Our results highlight the potential of combining SpCas9 and SaCas9 for multiplexed CRISPR-Cas9 applications, such as imaging and genome engineering.
    Keywords: Recombination, Cell biology, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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