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  • 1
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    Molecular engineering of G-quadruplex ligands based on solvent effect of polyethylene glycol (2012)
    Oxford University Press
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    Publication Date: 2012-09-27
    Description: Because various non-parallel G-quadruplexes of human telomeric sequences in K + solution can be converted to a parallel G-quadruplex by adding polyethylene glycol (PEG) as a co-solvent, we have taken advantage of this property of PEG to study the covalent attachment of a PEG unit to a G-quadruplex ligand, 3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC). The hybrid ligand with the PEG unit, BMVC-8C3O or BMVC-6C2O by substituting either the tetraethylene glycol or the triethylene glycol terminated with a methyl-piperidinium cation in N-9 position of BMVC, not only induces structural change from different non-parallel G-quadruplexes to a parallel G-quadruplex but also increases the melting temperature of human telomeres in K + solution by more than 45°C. In addition, our ligand work provides further confidence that the local water structure plays the key to induce conformational change of human telomere.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Direct evidence of mitochondrial G-quadruplex DNA by using fluorescent anti-cancer agents (2015)
    Oxford University Press
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    Publication Date: 2015-12-02
    Description: G-quadruplex (G4) is a promising target for anti-cancer treatment. In this paper, we provide the first evidence supporting the presence of G4 in the mitochondrial DNA (mtDNA) of live cells. The molecular engineering of a fluorescent G4 ligand, 3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC), can change its major cellular localization from the nucleus to the mitochondria in cancer cells, while remaining primarily in the cytoplasm of normal cells. A number of BMVC derivatives with sufficient mitochondrial uptake can induce cancer cell death without damaging normal cells. Fluorescence studies of these anti-cancer agents in live cells and in isolated mitochondria from HeLa cells have demonstrated that their major target is mtDNA. In this study, we use fluorescence lifetime imaging microscopy to verify the existence of mtDNA G4s in live cells. Bioactivity studies indicate that interactions between these anti-cancer agents and mtDNA G4 can suppress mitochondrial gene expression. This work underlines the importance of fluorescence in the monitoring of drug-target interactions in cells and illustrates the emerging development of drugs in which mtDNA G4 is the primary target.
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    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    In-cell optical imaging of exogenous G-quadruplex DNA by fluorogenic ligands (2013)
    Oxford University Press
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    Publication Date: 2013-12-07
    Description: Guanine-rich oligonucleotides (GROs) are promising therapeutic candidate for cancer treatment and other biomedical application. We have introduced a G-quadruplex (G4) ligand, 3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide, to monitor the cellular uptake of naked GROs and map their intracellular localizations in living cells by using confocal microscopy. The GROs that form parallel G4 structures, such as PU22, T40214 and AS1411, are detected mainly in the lysosome of CL1-0 lung cancer cells after incubation for 2 h. On the contrary, the GROs that form non-parallel G4 structures, such as human telomeres (HT23) and thrombin binding aptamer (TBA), are rarely detected in the lysosome, but found mainly in the mitochondria. Moreover, the fluorescence resonant energy transfer studies of fluorophore-labeled GROs show that the parallel G4 structures can be retained in CL1-0 cells, whereas the non-parallel G4 structures are likely distorted in CL1-0 cells after cellular uptake. Of interest is that the distorted G4 structure of HT23 from the non-parallel G4 structure can reform to a probable parallel G4 structure induced by a G4 ligand in CL1-0 living cells. These findings are valuable to the design and rationale behind the possible targeted drug delivery to specific cellular organelles using GROs.
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    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    Structural basis of sodium-potassium exchange of a human telomeric DNA quadruplex without topological conversion (2014)
    Oxford University Press
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    Publication Date: 2014-04-15
    Description: Understanding the mechanism of Na + /K + -dependent spectral conversion of human telomeric G-quadruplex (G4) sequences has been limited not only because of the structural polymorphism but also the lack of sufficient structural information at different stages along the conversion process for one given oligonucleotide. In this work, we have determined the topology of the Na + form of Tel23 G4, which is the same hybrid form as the K + form of Tel23 G4 despite the distinct spectral patterns in their respective nuclear magnetic resonance (NMR) and circular dichroism spectra. The spectral difference, particularly the well-resolved imino proton NMR signals, allows us to monitor the structural conversion from Na + form to K + form during Na + /K + exchange. Time-resolved NMR experiments of hydrogen–deuterium exchange and hybridization clearly exclude involvement of the global unfolding for the fast Na + /K + spectral conversion. In addition, the K + titration monitored by NMR reveals that the Na + /K + exchange in Tel23 G4 is a two-step process. The addition of K + significantly stabilizes the unfolding kinetics of Tel23 G4. These results offer a possible explanation of rapid spectral conversion of Na + /K + exchange and insight into the mechanism of Na + /K + structural conversion in human telomeric G4s.
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    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    A novel transition pathway of ligand-induced topological conversion from hybrid forms to parallel forms of human telomeric G-quadruplexes (2016)
    Oxford University Press
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    Publication Date: 2016-05-06
    Description: The folding topology of DNA G-quadruplexes (G4s) depends not only on their nucleotide sequences but also on environmental factors and/or ligand binding. Here, a G4 ligand, 3,6-bis(1-methyl-4-vinylpyridium iodide)-9-(1-(1-methyl-piperidinium iodide)-3,6,9-trioxaundecane) carbazole (BMVC-8C3O), can induce topological conversion of non-parallel to parallel forms in human telomeric DNA G4s. Nuclear magnetic resonance (NMR) spectroscopy with hydrogen-deuterium exchange (HDX) reveals the presence of persistent imino proton signals corresponding to the central G-quartet during topological conversion of Tel23 and Tel25 G4s from hybrid to parallel forms, implying that the transition pathway mainly involves local rearrangements. In contrast, rapid HDX was observed during the transition of 22-CTA G4 from an anti-parallel form to a parallel form, resulting in complete disappearance of all the imino proton signals, suggesting the involvement of substantial unfolding events associated with the topological transition. Site-specific imino proton NMR assignments of Tel23 G4 enable determination of the interconversion rates of individual guanine bases and detection of the presence of intermediate states. Since the rate of ligand binding is much higher than the rate of ligand-induced topological conversion, a three-state kinetic model was evoked to establish the associated energy diagram for the topological conversion of Tel23 G4 induced by BMVC-8C3O.
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    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Combining galaxy and 21-cm surveys (2016)
    Oxford University Press
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    Publication Date: 2016-02-09
    Description: Acoustic waves travelling through the early Universe imprint a characteristic scale in the clustering of galaxies, QSOs and intergalactic gas. This scale can be used as a standard ruler to map the expansion history of the Universe, a technique known as baryon acoustic oscillations (BAO). BAO offer a high-precision, low-systematics means of constraining our cosmological model. The statistical power of BAO measurements can be improved if the ‘smearing’ of the acoustic feature by non-linear structure formation is undone in a process known as reconstruction. In this paper, we use low-order Lagrangian perturbation theory to study the ability of 21-cm experiments to perform reconstruction and how augmenting these surveys with galaxy redshift surveys at relatively low number densities can improve performance. We find that the critical number density which must be achieved in order to benefit 21-cm surveys is set by the linear theory power spectrum near its peak, and corresponds to densities achievable by upcoming surveys of emission line galaxies such as eBOSS and DESI. As part of this work, we analyse reconstruction within the framework of Lagrangian perturbation theory with local Lagrangian bias, redshift–space distortions, ${\boldsymbol {k}}$ -dependent noise and anisotropic filtering schemes.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 7
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    Erasing the Milky Way: new cleaning technique applied to GBT intensity mapping data (2016)
    Oxford University Press
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    Publication Date: 2016-11-29
    Description: We present the first application of a new foreground removal pipeline to the current leading H i intensity mapping data set, obtained by the Green Bank Telescope (GBT). We study the 15- and 1-h-field data of the GBT observations previously presented in Mausui et al. and Switzer et al., covering about 41 deg 2 at 0.6 〈 z 〈 1.0, for which cross-correlations may be measured with the galaxy distribution of the WiggleZ Dark Energy Survey. In the presented pipeline, we subtract the Galactic foreground continuum and the point-source contamination using an independent component analysis technique (FASTICA), and develop a Fourier-based optimal estimator to compute the temperature power spectrum of the intensity maps and cross-correlation with the galaxy survey data. We show that FASTICA is a reliable tool to subtract diffuse and point-source emission through the non-Gaussian nature of their probability distributions. The temperature power spectra of the intensity maps are dominated by instrumental noise on small scales which FASTICA, as a conservative subtraction technique of non-Gaussian signals, cannot mitigate. However, we determine similar GBT-WiggleZ cross-correlation measurements to those obtained by the singular value decomposition (SVD) method, and confirm that foreground subtraction with FASTICA is robust against 21 cm signal loss, as seen by the converged amplitude of these cross-correlation measurements. We conclude that SVD and FASTICA are complementary methods to investigate the foregrounds and noise systematics present in intensity mapping data sets.
    Print ISSN: 0035-8711
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    Topics: Physics
    Published by Oxford University Press
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  • 8
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    A cis-element with mixed G-quadruplex structure of NPGPx promoter is essential for nucleolin-mediated transactivation on non-targeting siRNA stress (2013)
    Oxford University Press
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    Publication Date: 2013-02-02
    Description: We reported that non-targeting siRNA (NT-siRNA) stress induces non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) expression to cooperate with exoribonuclease XRN2 for releasing the stress [Wei,P.C., Lo,W.T., Su,M.I., Shew,J.Y. and Lee,W.H. (2011) Non-targeting siRNA induces NPGPx expression to cooperate with exoribonuclease XRN2 for releasing the stress. Nucleic Acids Res ., 40 , 323–332]. However, how NT-siRNA stress inducing NPGPx expression remains elusive. In this communication, we showed that the proximal promoter of NPGPx contained a mixed G-quadruplex (G4) structure, and disrupting the structure diminished NT-siRNA induced NPGPx promoter activity. We also demonstrated that nucleolin (NCL) specifically bonded to the G4-containing sequences to replace the originally bound Sp1 at the NPGPx promoter on NT-siRNA stress. Consistently, overexpression of NCL further increased NPGPx promoter activity, whereas depletion of NCL desensitized NPGPx promoter to NT-siRNA stress. These results suggest that the cis -element with mixed G4 structure at the NPGPx promoter plays an essential role for its transactivation mediated by NCL to release cells from NT-siRNA stress.
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    Topics: Biology
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  • 9
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    A simulation-calibrated limit on the H I power spectrum from the GMRT Epoch of Reionization experiment (2013)
    Oxford University Press
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    Publication Date: 2013-06-30
    Description: The Giant Metrewave Radio Telescope Epoch of Reionization experiment is an ongoing effort to measure the power spectrum from neutral hydrogen at high redshift. We have previously reported an upper limit of (70 mK) 2 at wavenumbers of k 0.65 h Mpc –1 using a basic piecewise-linear foreground subtraction. In this paper, we explore the use of a singular value decomposition to remove foregrounds with fewer assumptions about the foreground structure. Using this method, we also quantify, for the first time, the signal loss due to the foreground filter and present new power spectra adjusted for this loss, providing a revised measurement of a 2 upper limit at (248 mK) 2 for k  = 0.50 h Mpc –1 . While this revised limit is larger than previously reported, we believe it to be more robust and still represents the best current constraint on reionization at z 8.6.
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    Topics: Physics
    Published by Oxford University Press
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  • 10
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    Low-amplitude clustering in low-redshift 21-cm intensity maps cross-correlated with 2dF galaxy densities (2018)
    Oxford University Press
    Details
    Publication Date: 2018-05-01
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press on behalf of The Royal Astronomical Society.
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