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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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    Gemcitabine/Dexamethasone/Cisplatin vs Cytarabine/Dexamethasone/Cisplatin for Relapsed or Refractory Aggressive-Histology Lymphoma: Cost-Utility Analysis of NCIC CTG LY.12 (2015)
    Oxford University Press
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    Publication Date: 2015-04-14
    Description: Background: The NCIC CTG LY.12 study showed that gemcitabine, dexamethasone, and cisplatin (GDP) were noninferior to dexamethasone, cytarabine, and cisplatin (DHAP) in patients with relapsed or refractory aggressive histology lymphoma prior to autologous stem cell transplantation. We conducted an economic evaluation from the perspective of the Canadian public healthcare system based on trial data. Methods: The primary outcome was an incremental cost utility analysis comparing costs and benefits associated with GDP vs DHAP. Resource utilization data were collected from 519 Canadian patients in the trial. Costs were presented in 2012 Canadian dollars and disaggregated to highlight the major cost drivers of care. Benefit was measured as quality-adjusted life-years (QALYs) based on utilities translated from prospectively collected quality-of-life data. All statistical tests were two-sided. Results: The mean overall costs of treatment per patient in the GDP and DHAP arms were $19 961 (95% confidence interval (CI) = $17 286 to $24 565) and $34 425 (95% CI = $31 901 to $39 520), respectively, with an incremental difference in direct medical costs of $14 464 per patient in favor of GDP ( P 〈 .001). The predominant cost driver for both treatment arms was related to hospitalizations. The mean discounted quality-adjusted overall survival with GDP was 0.161 QALYs and 0.152 QALYs for DHAP (difference = 0.01 QALYs, P = .146). In probabilistic sensitivity analysis, GDP was associated with both cost savings and improved quality-adjusted outcomes compared with DHAP in 92.6% of cost-pair simulations. Conclusions: GDP was associated with both lower costs and similar quality-adjusted outcomes compared with DHAP in patients with relapsed or refractory lymphoma. Considering both costs and outcomes, GDP was the dominant therapy.
    Electronic ISSN: 1460-2105
    Topics: Medicine
    Published by Oxford University Press
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  • 3
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    Relative flux calibration for the LAMOST Spectroscopic Survey of the Galactic anticentre (2015)
    Oxford University Press
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    Publication Date: 2015-02-05
    Description: We have developed and implemented an iterative algorithm of flux calibration for the LAMOST Spectroscopic Survey of the Galactic anticentre (LSS-GAC). For a given LSS-GAC plate, the spectra are first processed with a set of nominal spectral response curves (SRCs) and used to derive initial stellar atmospheric parameters (effective temperature T eff , surface gravity log  g and metallicity [Fe/H]) as well as dust reddening E ( B  –  V ) of all targeted stars. For each of the 16 spectrographs, several F-type stars with good signal-to-noise ratios are selected as flux standard stars for further, iterative spectral flux calibration. Comparison of spectrophotometric colours, deduced from the flux-calibrated spectra, with the photometric measurements yield average differences of 0.02 ± 0.07 and –0.04 ± 0.09 mag for ( g  –  r ) and ( g  –  i ), respectively. The relatively large negative offset in ( g  –  i ) is because we have opted not to correct for the telluric bands, most notably the atmospheric A band in the wavelength range of the i band. Comparison of LSS-GAC multi-epoch observations of duplicate targets indicates that the algorithm has achieved an accuracy of about 10 per cent in relative flux calibration for the wavelength range 4000–9000 Å. The shapes of SRCs deduced for individual LAMOST spectrographs vary by up to 30 per cent for a given night, and larger for different nights, indicating that the derivation of SRCs for the individual plates is essential to achieve accurate flux calibration for the LAMOST spectra.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 4
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    Patterns of thermal limits of phytoplankton (2015)
    Oxford University Press
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    Publication Date: 2015-03-25
    Description: The latitudinal patterns of the optimal, minimal and maximal growth temperatures of phytoplankton are analyzed using linear mixed-effect models, and whether environmental temperature plays a role in affecting these thermal traits is tested. The optimal, minimal and maximal growth temperatures of phytoplankton decrease with latitude for marine taxa; whereas the minimal and maximal growth temperatures are relatively invariant with latitude for freshwater phytoplankton. The thermal breadth, defined as the range between the maximal and minimal growth temperature, is larger for freshwater than marine phytoplankton. In contrast to Jenzen's rule, there is no increasing trend of thermal breadth with increasing latitude. For most phytoplankton, the minimal growth temperatures are lower than the lowest environmental temperatures and the maximal growth temperatures are higher than the highest environmental temperatures. In marine phytoplankton, there is a strong phylogenetic signal in the minimal growth temperature and hence the thermal breadth. After controlling other variables (i.e. latitude and maximal growth rate) constant, the minimal growth temperatures of cyanobacteria and dinoflagellates are significantly higher than that of diatoms. The thermal breadths of cyanobacteria and dinoflagellates are narrower than of diatoms. The maximal growth rate is positively correlated with thermal breadth for marine but not freshwater phytoplankton.
    Print ISSN: 0142-7873
    Electronic ISSN: 1464-3774
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    The LAMOST stellar parameter pipeline at Peking University - LSP3 (2015)
    Oxford University Press
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    Publication Date: 2015-02-12
    Description: We introduce the Large Sky Area Multi-Object Fiber Spectroscopic Telescope (LAMOST) stellar parameter pipeline at Peking University – lsp3 , developed and implemented for the determinations of radial velocity V r and stellar atmospheric parameters (effective temperature T eff , surface gravity log  g , metallicity [Fe/H]) for the LAMOST Spectroscopic Survey of the Galactic Anticentre (LSS-GAC). We describe the algorithms of lsp3 and examine the accuracy of parameters yielded by it. The precision and accuracy of parameters yielded are investigated by comparing results of multi-epoch observations and of candidate members of open and globular clusters, with photometric calibration, as well as with independent determinations available from a number of external data bases, including the PASTEL archive, the APOGEE, SDSS and RAVE surveys, as well as those released in the LAMOST DR1. The uncertainties of lsp3 parameters are characterized and quantified as a function of the spectral signal-to-noise ratio (SNR) and stellar atmospheric parameters. We conclude that the current implementation of lsp3 has achieved an accuracy of 5.0 km s –1 , 150 K, 0.25 dex, 0.15 dex for the radial velocity, effective temperature, surface gravity and metallicity, respectively, for LSS-GAC spectra of FGK stars of SNRs per pixel higher than 10. The lsp3 has been applied to over a million LSS-GAC spectra collected hitherto. Stellar parameters yielded by the lsp3 will be released to the general public following the data policy of LAMOST, together with estimates of the interstellar extinction E ( B – V ) and stellar distances, deduced by combining spectroscopic and multiband photometric measurements using a variety of techniques.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 6
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    LAMOST Spectroscopic Survey of the Galactic Anticentre (LSS-GAC): target selection and the first release of value-added catalogues (2015)
    Oxford University Press
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    Publication Date: 2015-02-12
    Description: As a major component of the LAMOST Galactic surveys, the LAMOST Spectroscopic Survey of the Galactic Anticentre (LSS-GAC) aims to survey a significant volume of the Galactic thin/thick discs and halo for a contiguous sky area of over 3400 deg 2 centred on the Galactic anticentre (| b | ≤ 30°, 150 ≤  l  ≤ 210°), and obtain 3700–9000 low-resolution ( R  ~ 1800) spectra for a statistically complete sample of ~3 M stars of all colours down to a limiting magnitude of r  ~ 17.8 mag (to 18.5 mag for limited fields). Together with Gaia , the LSS-GAC will yield a unique data set to advance our understanding of the structure and assemblage history of the Galaxy, in particular its disc(s). In addition to the main survey, the LSS-GAC will also target hundreds of thousands objects in the vicinity fields of M 31 and M 33 and survey a significant fraction (over a million) of randomly selected very bright stars ( r  ≤ 14 mag) in the Northern hemisphere. During the Pilot and the first year Regular Surveys of LAMOST, a total of 1042 586 [750 867] spectra of a signal-to-noise ratio S/N(7450 Å) ≥ 10 [S/N(4650 Å) ≥ 10] have been collected. In this paper, we present a detailed description of the target selection algorithm, survey design, observations and the first data release of value-added catalogues (including radial velocities, effective temperatures, surface gravities, metallicities, values of interstellar extinction, distances, proper motions and orbital parameters) of the LSS-GAC.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 7
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    Identifying protein complexes and functional modules--from static PPI networks to dynamic PPI networks (2014)
    Oxford University Press
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    Publication Date: 2014-03-18
    Description: Cellular processes are typically carried out by protein complexes and functional modules. Identifying them plays an important role for our attempt to reveal principles of cellular organizations and functions. In this article, we review computational algorithms for identifying protein complexes and/or functional modules from protein–protein interaction (PPI) networks. We first describe issues and pitfalls when interpreting PPI networks. Then based on types of data used and main ideas involved, we briefly describe protein complex and/or functional module identification algorithms in four categories: (i) those based on topological structures of unweighted PPI networks; (ii) those based on characters of weighted PPI networks; (iii) those based on multiple data integrations; and (iv) those based on dynamic PPI networks. The PPI networks are modelled increasingly precise when integrating more types of data, and the study of protein complexes would benefit by shifting from static to dynamic PPI networks.
    Print ISSN: 1467-5463
    Electronic ISSN: 1477-4054
    Topics: Biology , Computer Science
    Published by Oxford University Press
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  • 8
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    Genome-wide analysis associates familial colorectal cancer with increases in copy number variations and a rare structural variation at 12p12.3 (2014)
    Oxford University Press
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    Publication Date: 2014-02-01
    Description: Colorectal cancer (CRC) is one of the most common cancer worldwide. However, a large number of genetic risk factors involved in CRC have not been understood. Copy number variations (CNVs) might partly contribute to the ‘missing heritability’ of CRC. An increased overall burden of CNV has been identified in several complex diseases, whereas the association between the overall CNV burden and CRC risk is largely unknown. We performed a genome-wide investigation of CNVs on genomic DNA from 384 familial CRC cases and 1285 healthy controls by the Affymetrix 6.0 array. An increase of overall CNV burden was observed in familial CRC patients compared with healthy controls, especially for CNVs larger than 50kb (case/control ratio = 1.66, P = 0.025). In addition, we discovered for the first time a novel structural variation at 12p12.3 and determined the breakpoints by strategic PCR and sequencing. This 12p12.3 structural variation was found in four of 2862 CRC cases but not in 6243 healthy controls ( P = 0.0098). RERGL gene (RERG/RAS-like), the only gene influenced by the 12p12.3 structural variation, sharing most of the conserved regions with its close family member RERG tumor suppressor gene (RAS-like, estrogen-regulated, growth inhibitor), might be a novel CRC-related gene. In conclusion, this is the first study to reveal the contribution of the overall burden of CNVs to familial CRC risk and identify a novel rare structural variation at 12p12.3 containing RERGL gene to be associated with CRC.
    Print ISSN: 0143-3334
    Electronic ISSN: 1460-2180
    Topics: Medicine
    Published by Oxford University Press
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  • 9
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    miR-200b suppresses invasiveness and modulates the cytoskeletal and adhesive machinery in esophageal squamous cell carcinoma cells via targeting Kindlin-2 (2014)
    Oxford University Press
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    Publication Date: 2014-02-01
    Description: To further our understanding of the pathobiology of esophageal squamous cell carcinoma (ESCC), we previously performed microRNA profiling that revealed downregulation of miR-200b in ESCC. Using quantitative real-time PCR applied to 88 patient samples, we confirmed that ESCC tumors expressed significantly lower levels of miR-200b compared with the respective adjacent benign tissues ( P = 0.003). Importantly, downregulation of miR-200b significantly correlated with shortened survival ( P = 0.025), lymph node metastasis ( P = 0.002) and advanced clinical stage ( P = 0.020) in ESCC patients. Quantitative mass spectrometry identified 57 putative miR-200b targets, including Kindlin-2, previously implicated in the regulation of tumor invasiveness and actin cytoskeleton in other cell types. Enforced expression of miR-200b mimic in ESCC cells led to a decrease of Kindlin-2 expression, whereas transfection of miR-200b inhibitor induced Kindlin-2 expression. Furthermore, transfection of miR-200b mimic or knockdown of Kindlin-2 in ESCC cells decreased cell protrusion and focal adhesion (FA) formation, reduced cell spreading and invasiveness/migration. Enforced expression of Kindlin-2 largely abrogated the inhibitory effects of miR-200b on ESCC cell invasiveness. Mechanistic studies revealed that Rho-family guanosine triphosphatases and FA kinase mediated the biological effects of the miR-200b—Kindlin-2 axis in ESCC cells. To conclude, loss of miR-200b, a frequent biochemical defect in ESCC, correlates with aggressive clinical features. The tumor suppressor effects of miR-200b may be due to its suppression of Kindlin-2, a novel target of miR-200b that modulates actin cytoskeleton, FA formation and the migratory/invasiveness properties of ESCC.
    Print ISSN: 0143-3334
    Electronic ISSN: 1460-2180
    Topics: Medicine
    Published by Oxford University Press
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  • 10
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    Hypoxia Induces Autophagy in Primary Human Trophoblasts (2012)
    Oxford University Press
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    Publication Date: 2012-09-22
    Description: Autophagy is a highly regulated and dynamic process that maintains cellular homeostasis and plays a prosurvival role in most cells. Although hypoxia has been shown to induce apoptosis in placental trophoblasts, the hypoxic effect on autophagy has not been studied. We hypothesized that autophagy plays a prosurvival role in the placental trophoblasts by antagonizing hypoxia-induced apoptosis. Our data show that the expression of Light chain 3-II (LC3-II), an autophagic marker and cleaved poly(ADP-ribose) polymerase, an apoptosis marker, are inversely related in cultured trophoblasts. Exposure to rapamycin or hypoxia inactivated mammalian target of rapamycin, as reflected by reduced phosphorylation of ribosomal protein S6, indicating that mammalian target of rapamycin regulates autophagy in cultured cytotrophoblasts. Bafilomycin prevented the degradation of cargo and increased LC3-II and p62 in cytotrophoblasts exposed to hypoxia, revealing enhanced autophagic flux. Importantly, bafilomycin enhanced expression of autophagy-related protein 7 (Atg7), parallel to the increased apoptosis measured by cleaved poly(ADP-ribose) polymerase. LY294002, a phosphatidylinositol 3-kinase inhibitor, increased apoptosis in the trophoblasts under hypoxia or standard conditions. Silencing of Atg7 decreased both apoptosis and LC3-II in the trophoblasts, suggesting a dual role of Atg7 in both autophagy and apoptosis. We conclude that there is a cross talk between autophagy and apoptosis in the placental trophoblasts; autophagy plays a prosurvival role and Atg7 has roles in both autophagy and apoptosis under hypoxia.
    Print ISSN: 0013-7227
    Topics: Medicine
    Published by Oxford University Press on behalf of The Endocrine Society.
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