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  • 1
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    ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65 (2015)
    Oxford University Press
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    Publication Date: 2015-02-18
    Description: The NF-B is found in almost all animal cell types and is involved in a myriad of cellular responses. Aberrant expression of NF-B has been linked to cancer, inflammatory diseases and improper development. Little is known about transcriptional regulation of the NF-B family member gene RelA/p65 . Sp1 plays a key role in the expression of the RelA/p65 gene. ZBTB2 represses transcription of the gene by inhibiting Sp1 binding to a Sp1-binding GC-box in the RelA/p65 proximal promoter (bp, –31 to –21). Moreover, recent studies revealed that RelA/p65 directly binds to the peroxisome proliferator-activated receptor- coactivator1α (PGC1α) to decrease transcriptional activation of the PGC1α target gene PDK4 , whose gene product inhibits pyruvate dehydrogenase (PDH), a key regulator of TCA cycle flux. Accordingly, we observed that RelA/p65 repression by ZBTB2 indirectly results in increased PDK4 expression, which inhibits PDH. Consequently, in cells with ectopic ZBTB2, the concentrations of pyruvate and lactate were higher than those in normal cells, indicating changes in glucose metabolism flux favoring glycolysis over the TCA cycle. Knockdown of ZBTB2 in mouse xenografts decreased tumor growth. ZBTB2 may increase cell proliferation by reprogramming glucose metabolic pathways to favor glycolysis by upregulating PDK4 expression via repression of RelA/p65 expression.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Episodic Nucleotide Substitutions in Seasonal Influenza Virus H3N2 Can Be Explained by Stochastic Genealogical Process without Positive Selection (2015)
    Oxford University Press
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    Publication Date: 2015-02-14
    Description: Nucleotide substitutions in the HA1 domain of seasonal influenza virus H3N2 occur in temporal clusters, which was interpreted as a result of recurrent selective sweeps underlying antigenic drift. However, classical theory by Watterson suggests that episodic substitutions are mainly due to stochastic genealogy combined with unique genetic structure of influenza virus: High mutation rate over a nonrecombining viral segment. This explains why even larger variance in the number of allelic fixations per year is observed in nonantigenic gene segments of H3N2 than in antigenic (hemagglutinin and neuraminidase) segments. Using simulation, we confirm that allelic substitutions at nonrecombining segments with high mutation rate become temporally clustered without selection. We conclude that temporal clustering of fixations, as it is primarily caused by inherent randomness in genealogical process at linked sites, cannot be used as an evidence of positive selection in the H3N2 population. This effect of linkage and high mutation rate should be carefully considered in analyzing the genomic patterns of allelic substitutions in asexually reproducing systems in general.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Global transcription network incorporating distal regulator binding reveals selective cooperation of cancer drivers and risk genes (2015)
    Oxford University Press
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    Publication Date: 2015-07-12
    Description: Global network modeling of distal regulatory interactions is essential in understanding the overall architecture of gene expression programs. Here, we developed a Bayesian probabilistic model and computational method for global causal network construction with breast cancer as a model. Whereas physical regulator binding was well supported by gene expression causality in general, distal elements in intragenic regions or loci distant from the target gene exhibited particularly strong functional effects. Modeling the action of long-range enhancers was critical in recovering true biological interactions with increased coverage and specificity overall and unraveling regulatory complexity underlying tumor subclasses and drug responses in particular. Transcriptional cancer drivers and risk genes were discovered based on the network analysis of somatic and genetic cancer-related DNA variants. Notably, we observed that the risk genes were functionally downstream of the cancer drivers and were selectively susceptible to network perturbation by tumorigenic changes in their upstream drivers. Furthermore, cancer risk alleles tended to increase the susceptibility of the transcription of their associated genes. These findings suggest that transcriptional cancer drivers selectively induce a combinatorial misregulation of downstream risk genes, and that genetic risk factors, mostly residing in distal regulatory regions, increase transcriptional susceptibility to upstream cancer-driving somatic changes.
    Keywords: Computational Methods, Genomics, Transcriptome Mapping - Monitoring Gene Expression
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    Multivariate two-part statistics for analysis of correlated mass spectrometry data from multiple biological specimens (2016)
    Oxford University Press
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    Publication Date: 2016-12-30
    Description: Motivation: High through-put mass spectrometry (MS) is now being used to profile small molecular compounds across multiple biological sample types from the same subjects with the goal of leveraging information across biospecimens. Multivariate statistical methods that combine information from all biospecimens could be more powerful than the usual univariate analyses. However, missing values are common in MS data and imputation can impact between-biospecimen correlation and multivariate analysis results. Results: We propose two multivariate two-part statistics that accommodate missing values and combine data from all biospecimens to identify differentially regulated compounds. Statistical significance is determined using a multivariate permutation null distribution. Relative to univariate tests, the multivariate procedures detected more significant compounds in three biological datasets. In a simulation study, we showed that multi-biospecimen testing procedures were more powerful than single-biospecimen methods when compounds are differentially regulated in multiple biospecimens but univariate methods can be more powerful if compounds are differentially regulated in only one biospecimen. Availability and Implementation : We provide R functions to implement and illustrate our method as supplementary information . Contact: sltaylor@ucdavis.edu 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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  • 5
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    Structural features of influenza A virus panhandle RNA enabling the activation of RIG-I independently of 5'-triphosphate (2016)
    Oxford University Press
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    Publication Date: 2016-10-08
    Description: Retinoic acid-inducible gene I (RIG-I) recognizes specific molecular patterns of viral RNAs for inducing type I interferon. The C-terminal domain (CTD) of RIG-I binds to double-stranded RNA (dsRNA) with the 5'-triphosphate (5'-PPP), which induces a conformational change in RIG-I to an active form. It has been suggested that RIG-I detects infection of influenza A virus by recognizing the 5'-triphosphorylated panhandle structure of the viral RNA genome. Influenza panhandle RNA has a unique structure with a sharp helical bending. In spite of extensive studies of how viral RNAs activate RIG-I, whether the structural elements of the influenza panhandle RNA confer the ability to activate RIG-I signaling has been poorly explored. Here, we investigated the dynamics of the influenza panhandle RNA in complex with RIG-I CTD using NMR spectroscopy and showed that the bending structure of the panhandle RNA negates the requirement of a 5'-PPP moiety for RIG-I activation.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Molecular characterization of acidic peptide:N-glycanase from the dimorphic yeast Yarrowia lipolytica (2015)
    Oxford University Press
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    Publication Date: 2015-01-07
    Description: Peptide: N -glycanase (PNGase) A is used preferentially to cleave the glycans from plant and insect glycopeptides. Although many putative PNGase A homologous genes have been found in the plant and fungus kingdoms through sequence similarity analyses, only several PNGases from plants and one from a filamentous fungus have been characterized. In this study, we identified and characterized a PNGase A-like enzyme, PNGase Yl, in the dimorphic yeast Yarrowia lipolytica . The corresponding gene was cloned and recombinantly expressed in Pichia pastoris . The purified enzyme cleaved glycans from glycopeptides with the maximum activity at pH 5. No metal ions were required for full activity, and rather it was repressed by three metal ions (Fe 3+ , Cu 2+ and Zn 2+ ). Using glycopeptide substrates, PNGase Yl was shown to release various types of N -glycans including high-mannose and complex-type glycans as well as glycans containing core-linked α(1,3)-fucose that are frequently found in plants and insects. Moreover, in comparison with PNGase A, PNGase Yl was able to cleave with higher efficiency the glycans from some denatured glycoproteins. Taken together, our results suggest that PNGase Yl, the first biochemically characterized yeast PNGase A homologue, can be developed through protein engineering as a useful deglycosylation tool for N -glycosylation study.
    Print ISSN: 0021-924X
    Electronic ISSN: 1756-2651
    Topics: Biology , Chemistry and Pharmacology
    Published by Oxford University Press on behalf of The Japanese Biochemical Society (JBS).
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  • 7
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    Identifying kinase dependency in cancer cells by integrating high-throughput drug screening and kinase inhibition data (2015)
    Oxford University Press
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    Publication Date: 2015-11-21
    Description: Motivation: Targeted kinase inhibitors have dramatically improved cancer treatment, but kinase dependency for an individual patient or cancer cell can be challenging to predict. Kinase dependency does not always correspond with gene expression and mutation status. High-throughput drug screens are powerful tools for determining kinase dependency, but drug polypharmacology can make results difficult to interpret. Results: We developed Kinase Addiction Ranker (KAR), an algorithm that integrates high-throughput drug screening data, comprehensive kinase inhibition data and gene expression profiles to identify kinase dependency in cancer cells. We applied KAR to predict kinase dependency of 21 lung cancer cell lines and 151 leukemia patient samples using published datasets. We experimentally validated KAR predictions of FGFR and MTOR dependence in lung cancer cell line H1581, showing synergistic reduction in proliferation after combining ponatinib and AZD8055. Availability and implementation: KAR can be downloaded as a Python function or a MATLAB script along with example inputs and outputs at: http://tanlab.ucdenver.edu/KAR/ . Contact: aikchoon.tan@ucdenver.edu 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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  • 8
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    In-depth N-glycome profiling of paired colorectal cancer and non-tumorigenic tissues reveals cancer-, stage- and EGFR-specific protein N-glycosylation (2015)
    Oxford University Press
    Details
    Publication Date: 2015-08-28
    Description: Glycomics may assist in uncovering the structure–function relationships of protein glycosylation and identify glycoprotein markers in colorectal cancer (CRC) research. Herein, we performed label-free quantitative glycomics on a carbon-liquid chromatography–tandem mass spectrometry-based analytical platform to accurately profile the N-glycosylation changes associated with CRC malignancy. N -Glycome profiling was performed on isolated membrane proteomes of paired tumorigenic and adjacent non-tumorigenic colon tissues from a cohort of five males (62.6 ± 13.1 y.o.) suffering from colorectal adenocarcinoma. The CRC tissues were typed according to their epidermal growth factor receptor (EGFR) status by western blotting and immunohistochemistry. Detailed N -glycan characterization and relative quantitation identified an extensive structural heterogeneity with a total of 91 N -glycans. CRC-specific N-glycosylation phenotypes were observed including an overrepresentation of high mannose, hybrid and paucimannosidic type N -glycans and an under-representation of complex N -glycans ( P 〈 0.05). Sialylation, in particular α2,6-sialylation, was significantly higher in CRC tumors relative to non-tumorigenic tissues, whereas α2,3-sialylation was down-regulated ( P 〈 0.05). CRC stage-specific N-glycosylation was detected by high α2,3-sialylation and low bisecting β1,4-GlcNAcylation and Lewis-type fucosylation in mid-late relative to early stage CRC. Interestingly, a novel link between the EGFR status and the N-glycosylation was identified using hierarchical clustering of the N -glycome profiles. EGFR-specific N -glycan signatures included high bisecting β1,4-GlcNAcylation and low α2,3-sialylation (both P 〈 0.05) relative to EGFR-negative CRC tissues. This is the first study to correlate CRC stage and EGFR status with specific N -glycan features, thus advancing our understanding of the mechanisms causing the biomolecular deregulation associated with CRC.
    Print ISSN: 0959-6658
    Electronic ISSN: 1460-2423
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 9
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    KIC 6220497: a new Algol-type eclipsing binary with multiperiodic pulsations (2016)
    Oxford University Press
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    Publication Date: 2016-06-30
    Description: We present both binarity and pulsation of KIC 6220497 from the Kepler observations. The light curve synthesis shows that the eclipsing system is a semidetached Algol with parameters of q = 0.243 ± 0.001, i = 77.3 ± 0.3 deg, and T = 3372 ± 58 K, in which the detached primary component fills its Roche lobe by ~87 per cent. A multiple frequency analysis of the eclipse-subtracted light residuals reveals 33 frequencies in the range of 0.75–20.22 d –1 with amplitudes between 0.27 and 4.56 mmag. Among these, four are pulsation frequencies in fundamental ( f 1 , f 5 ) and p ( f 2 , f 7 ) modes, and six are orbital frequency ( f 8 , f 31 ) and its harmonics ( f 6 , f 11 , f 20 , f 24 ), which can be attributed to tidally excited modes. For the pulsation frequencies, the pulsation constants of 0.16–0.33 d and the period ratios of P pul / P orb = 0.042–0.089 indicate that the primary component is a Sct pulsating star and, thus, KIC 6220497 is an oscillating eclipsing Algol (oEA) star. The dominant pulsation period of 0.117 4051 ± 0.000 0004 d is significantly longer than that expected from empirical relations that link the pulsation period with the orbital period. The surface gravity of log g 1 = 3.78 ± 0.03 is clearly smaller than those of the other oEA stars with similar orbital periods. The pulsation period and the surface gravity of the pulsating primary demonstrate that KIC 6220497 would be the more evolved eclipsing binary, compared with normal oEA stars.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 10
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    Heparosan-glucuronate 5-epimerase: Molecular cloning and characterization of a novel enzyme (2015)
    Oxford University Press
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    Publication Date: 2015-06-04
    Description: Iduronic acid (IdoA) is a critical component of heparan sulfate in its interaction with functional proteins. Heparosan- N -sulfate-glucuronate 5-epimerase (HNSG-5epi) converts d -glucuronic acid (GlcA) residues in N -sulfated heparosan (NS-heparosan), as an intermediate in heparan sulfate biosynthesis, to IdoA. In the present study, the authors discovered a different 5-epimerase, designated HG-5epi (heparosan-glucuronate 5-epimerase), that is involved in acharan sulfate biosynthesis and possesses novel substrate specificity. A candidate cDNA of HG-5epi was cloned from the cDNA library of Achatina fulica . The cloned cDNA contained a whole coding region that predicts a type II transmembrane protein composed of 601 amino acid residues. The amino acid sequence of HG-5epi is homologous to that of HNSG-5epi. Recombinant HG-5epi was expressed in insect cells and its enzymatic properties characterized. As expected, HG-5epi epimerizes GlcA residues in heparosan, but not in NS-heparosan. Conversion of IdoA to GlcA was also catalyzed by HG-5epi when completely desulfated N -acetylated heparin was used as the substrate, indicating a reversible reaction mechanism. At equilibrium of the epimerization, the proportion of IdoA in the reaction product reached up to 30% of total hexuronic acid. To our knowledge, this is the first report to describe an enzyme that catalyzes the epimerization of non-sulfated heparosan. This new enzyme may be applied to the study of synthetic heparan sulfate-related polysaccharides having certain biological and pharmacological activities. In addition, a new method using anion-exchange HPLC connected to a post-column fluorescent labeling system was developed for analyzing hexuronic acid isomers.
    Print ISSN: 0959-6658
    Electronic ISSN: 1460-2423
    Topics: Biology , Medicine
    Published by Oxford University Press
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