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  • 1
    Publication Date: 2014-04-03
    Description: Klebsiella pneumoniae PmrA is a polymyxin-resistance-associated response regulator. The C-terminal effector/DNA-binding domain of PmrA (PmrA C ) recognizes tandem imperfect repeat sequences on the promoters of genes to induce antimicrobial peptide resistance after phosphorylation and dimerization of its N-terminal receiver domain (PmrA N ). However, structural information concerning how phosphorylation of the response regulator enhances DNA recognition remains elusive. To gain insights, we determined the nuclear magnetic resonance solution structure of PmrA C and characterized the interactions between PmrA C or BeF 3 – -activated full-length PmrA (PmrA F ) and two DNA sequences from the pbgP promoter of K. pneumoniae . We showed that PmrA C binds to the PmrA box, which was verified to contain two half-sites, 5'-CTTAAT-3' and 5'-CCTAAG-3', in a head-to-tail fashion with much stronger affinity to the first than the second site without cooperativity. The structural basis for the PmrA C –DNA complex was investigated using HADDOCK docking and confirmed by paramagnetic relaxation enhancement. Unlike PmrA C , PmrA F recognizes the two sites simultaneously and specifically. In the PmrA F –DNA complex, PmrA N may maintain an activated homodimeric conformation analogous to that in the free form and the interactions between two PmrA C molecules aid in bending and binding of the DNA duplex for transcription activation.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 2
    Publication Date: 2014-05-30
    Description: Elf3 drives β-catenin transactivation and associates with poor prognosis in colorectal cancer Cell Death and Disease 5, e1263 (May 2014). doi:10.1038/cddis.2014.206 Authors: J-L Wang, Z-F Chen, H-M Chen, M-Y Wang, X Kong, Y-C Wang, T-T Sun, J Hong, W Zou, J Xu & J-Y Fang
    Keywords: Elf3β-catenintransactivationcolorectal cancerprognosis
    Electronic ISSN: 2041-4889
    Topics: Biology , Medicine
    Published by Springer Nature
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  • 3
    Publication Date: 2014-04-11
    Description: In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity. Here we show, using DNA array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD(+), an important cofactor linking cellular redox states with energy metabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation. Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine-spermine N(1)-acetyltransferase (SSAT; encoded by Sat1) and by polyamine oxidase (PAO), and has a major role in energy metabolism. We report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD(+) levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and NAD(+)-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107212/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kraus, Daniel -- Yang, Qin -- Kong, Dong -- Banks, Alexander S -- Zhang, Lin -- Rodgers, Joseph T -- Pirinen, Eija -- Pulinilkunnil, Thomas C -- Gong, Fengying -- Wang, Ya-chin -- Cen, Yana -- Sauve, Anthony A -- Asara, John M -- Peroni, Odile D -- Monia, Brett P -- Bhanot, Sanjay -- Alhonen, Leena -- Puigserver, Pere -- Kahn, Barbara B -- K01 DK094943/DK/NIDDK NIH HHS/ -- K08 DK090149/DK/NIDDK NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P01CA120964/CA/NCI NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK0460200/DK/NIDDK NIH HHS/ -- P30 DK046200/DK/NIDDK NIH HHS/ -- P30 DK057521/DK/NIDDK NIH HHS/ -- P30 DK57521/DK/NIDDK NIH HHS/ -- P30CA006516-46/CA/NCI NIH HHS/ -- R01 DK069966/DK/NIDDK NIH HHS/ -- R01 DK100385/DK/NIDDK NIH HHS/ -- R01 DK69966/DK/NIDDK NIH HHS/ -- R37 DK043051/DK/NIDDK NIH HHS/ -- R37 DK43051/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 Apr 10;508(7495):258-62. doi: 10.1038/nature13198.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] [3] Division of Nephrology, Department of Internal Medicine I, Wurzburg University Hospital, Oberdurrbacher Strasse 6, 97080 Wurzburg, Germany (D.K.); Department of Medicine, Physiology and Biophysics, Center for Diabetes Research and Treatment, and Center for Epigenetics and Metabolism, University of California, Irvine, California 92697, USA (Q.Y.); Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290, Helsinki, Finland (E.P.); Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie Medicine New Brunswick, Dalhousie University, Saint John, New Brunswick E2L4L5, USA (T.C.P.); Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China (F.G.); School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland (L.A.). ; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. ; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, Kuopio Campus, PO Box 1627, FI-70211 Kuopio, Finland [2] Division of Nephrology, Department of Internal Medicine I, Wurzburg University Hospital, Oberdurrbacher Strasse 6, 97080 Wurzburg, Germany (D.K.); Department of Medicine, Physiology and Biophysics, Center for Diabetes Research and Treatment, and Center for Epigenetics and Metabolism, University of California, Irvine, California 92697, USA (Q.Y.); Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290, Helsinki, Finland (E.P.); Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie Medicine New Brunswick, Dalhousie University, Saint John, New Brunswick E2L4L5, USA (T.C.P.); Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China (F.G.); School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland (L.A.). ; 1] Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Division of Nephrology, Department of Internal Medicine I, Wurzburg University Hospital, Oberdurrbacher Strasse 6, 97080 Wurzburg, Germany (D.K.); Department of Medicine, Physiology and Biophysics, Center for Diabetes Research and Treatment, and Center for Epigenetics and Metabolism, University of California, Irvine, California 92697, USA (Q.Y.); Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290, Helsinki, Finland (E.P.); Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie Medicine New Brunswick, Dalhousie University, Saint John, New Brunswick E2L4L5, USA (T.C.P.); Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China (F.G.); School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland (L.A.). ; Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA. ; Division of Signal Transduction, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave, Boston, Massachusetts 02215, USA. ; Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California 92008-7326, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24717514" target="_blank"〉PubMed〈/a〉
    Keywords: Acetyltransferases/metabolism ; Adipocytes/metabolism/secretion ; Adipose Tissue/enzymology/metabolism ; Adipose Tissue, White/enzymology/metabolism ; Animals ; Diabetes Mellitus, Type 2/enzymology/metabolism ; *Diet ; Energy Metabolism ; Fatty Liver ; Gene Knockdown Techniques ; Glucose Intolerance ; Glucose Transporter Type 4/deficiency/genetics/metabolism ; Insulin Resistance ; Liver/enzymology ; Male ; Mice ; Mice, Inbred C57BL ; NAD/metabolism ; Niacinamide/metabolism ; Nicotinamide N-Methyltransferase/*deficiency/genetics/*metabolism ; Obesity/*enzymology/etiology/genetics/*prevention & control ; Ornithine Decarboxylase/metabolism ; Oxidoreductases Acting on CH-NH Group Donors/metabolism ; S-Adenosylmethionine/metabolism ; Sirtuin 1/metabolism ; Spermine/analogs & derivatives/metabolism ; Thinness/enzymology/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2014-03-07
    Description: Overexpression of Aurora-C interferes with the spindle checkpoint by promoting the degradation of Aurora-B Cell Death and Disease 5, e1106 (March 2014). doi:10.1038/cddis.2014.37 Authors: B-W Lin, Y-C Wang, P-Y Chang-Liao, Y-J Lin, S-T Yang, J-H Tsou, K-C Chang, Y-W Liu, J T Tseng, C-T Lee, J-C Lee & L-Y Hung
    Keywords: Aurora-CAurora-Bspindle assembly checkpointchromosomal passenger proteins
    Electronic ISSN: 2041-4889
    Topics: Biology , Medicine
    Published by Springer Nature
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  • 5
    Publication Date: 2014-10-31
    Description: Caspase-9 mediates Puma activation in UCN-01-induced apoptosis Cell Death and Disease 5, e1495 (October 2014). doi:10.1038/cddis.2014.461 Authors: C Nie, Y Luo, X Zhao, N Luo, A Tong, X Liu, Z Yuan, C Wang & Y Wei
    Electronic ISSN: 2041-4889
    Topics: Biology , Medicine
    Published by Springer Nature
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  • 6
    Publication Date: 2014-09-20
    Description: Breast cancer is a highly heterogeneous disease that is characterized by genetic and epigenetic aberrations; however, our knowledge of epigenetic alterations of breast cancer subtypes remains limited. Here, we portrayed and compared the alterations of six types of histone modifications and DNA methylation between two breast cancer subtypes, luminal and basal. Widespread subtype-specific epigenetic alterations were observed in both subtypes, which preferentially occurred within CpG islands (CGIs) and promoter regions. Specifically, aberrant DNA methylation was mostly located inside CGIs in luminal subtype, whereas in basal subtype it was principally located within CGI shores. Moreover, different types and combinatorial patterns of epigenetic alterations were found to occupy at promoter regions between these two subtypes. And these epigenetic alterations regulated corresponding gene expression in a synergetic way in both subtypes. Functional enrichment analysis highlighted that epigenetically dysregulated genes were significantly involved in the hallmarks of cancers, most of which were subtype specific. Even genes involved in the same hallmarks associated biological processes were affected by various types of epi-modifications in different subtypes. Finally, we revealed distinct patterns of oncogenic pathways activation in different subtypes and provided novel insights into subtype specific therapeutic opportunities. In addition, genes in the key signaling pathways were able to discriminate between disease phenotypes, and subtype-specific progression associated genes were identified. This study presents the aberrant epigenetic patterns of breast cancer subtypes at a genome-wide level, which will be a highly valuable resource for investigations at understanding epigenetic regulation of breast cancer subtypes.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 7
    Publication Date: 2014-10-15
    Description: Lower Cretaceous pedogenic carbonates exposed in SE China have been dated by U–Pb isotope measurements on single zircons taken from intercalated volcanic rocks, and the ages integrated with existing stratigraphy. 13 C values of calcretes range from –7.0 to –3.0 and can be grouped into five episodes of increasing–decreasing values. The carbon isotope proxy derived from these palaeosol carbonates suggests p CO 2 mostly in the range 1000–2000 parts per million by volume (ppmV) at S ( z ) (CO 2 contributed by soil respiration) = 2500 ppmV and 25°C during the Hauterivian–Albian interval ( c . 30 Ma duration). Such atmospheric CO 2 levels are 4–8 times pre-industrial values, almost double those estimated by geochemical modelling and much higher than those established from stomatal indices in fossil plants. Rapid rises in p CO 2 are identified for early Hauterivian, middle Barremian, late Aptian, early Albian and middle Albian time, and rapid falls for intervening periods. These episodic cyclic changes in p CO 2 are not attributed to local tectonism and volcanism but rather to global changes. The relationship between reconstructed p CO 2 and the development of large igneous provinces (LIPs) remains unclear, although large-scale extrusion of basalt may well be responsible for relatively high atmospheric levels of this greenhouse gas. Suggested levels of relatively low p CO 2 correspond in timing to intervals of regional to global enrichment of marine carbon in sediments and negative carbon isotope ( 13 C) excursions characteristic of the oceanic anoxic events OAE1a (Selli Event), Kilian and Paquier events (constituting part of the OAE 1b cluster) and OAE1d. Short-term episodes of high p CO 2 coincide with negligible carbon isotope excursions associated with the Faraoni Event and the Jacob Event. Given that episodes of regional organic carbon burial would draw down CO 2 and negative 13 C excursions indicate the addition of isotopically light carbon to the ocean–atmosphere system, controls on the carbon cycle in controlling p CO 2 during Early Cretaceous time were clearly complex and made more so by atmospheric composition also being affected by changes in silicate weathering intensity.
    Print ISSN: 0016-7568
    Electronic ISSN: 1469-5081
    Topics: Geosciences
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  • 8
    Publication Date: 2014-10-18
    Description: Motivation: A rapid progression of esophageal squamous cell carcinoma (ESCC) causes a high mortality rate because of the propensity for metastasis driven by genetic and epigenetic alterations. The identification of prognostic biomarkers would help prevent or control metastatic progression. Expression analyses have been used to find such markers, but do not always validate in separate cohorts. Epigenetic marks, such as DNA methylation, are a potential source of more reliable and stable biomarkers. Importantly, the integration of both expression and epigenetic alterations is more likely to identify relevant biomarkers. Results: We present a new analysis framework, using ESCC progression-associated gene regulatory network (GRN escc ), to identify differentially methylated CpG sites prognostic of ESCC progression. From the CpG loci differentially methylated in 50 tumor–normal pairs, we selected 44 CpG loci most highly associated with survival and located in the promoters of genes more likely to belong to GRN escc . Using an independent ESCC cohort, we confirmed that 8/10 of CpG loci in the promoter of GRN escc genes significantly correlated with patient survival. In contrast, 0/10 CpG loci in the promoter genes outside the GRN escc were correlated with patient survival. We further characterized the GRN escc network topology and observed that the genes with methylated CpG loci associated with survival deviated from the center of mass and were less likely to be hubs in the GRN escc . We postulate that our analysis framework improves the identification of bona fide prognostic biomarkers from DNA methylation studies, especially with partial genome coverage. Contact: tsengsm@mail.ncku.edu.tw or ycw5798@mail.ncku.edu.tw Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
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  • 9
    Publication Date: 2014-06-20
    Description: The electronic and magnetic properties of tetravalent-ion-doped La 0.85 Zr 0.15 MnO 3 (LZMO) thin films that were epitaxially grown on SrTiO 3 (STO) and MgO substrates were studied using temperature-dependent x-ray diffraction (XRD), x-ray absorption near-edge structure, x-ray linear dichroism, and x-ray magnetic circular dichroism at the Mn L 3,2 - and K -edge. XRD studies reveal that the LZMO thin films have compressive and tensile strains (along the c -axis) on the STO and MgO substrates, respectively. As the temperature is reduced from room temperature to below magnetic transition temperature, the preferentially occupied Mn majority-spin e g orbital changes from the in-plane d x 2 -y 2 to the out-of-plane d 3 z 2 -r 2 orbital for LZMO/STO, and vice versa for LZMO/MgO. Experimental results suggest that the new hopping path that is mediated by the Mn 2+ ions triggers a stronger d 3 z 2 -r 2 orbital ordering of Mn 3+ ions and enhances the ferromagnetic coupling between the Mn spin moments of t 2g electrons in LZMO/STO, whereas the strong tensile strain stabilizes the d x 2 -y 2 orbital by inducing lattice distortions of the MnO 6 octahedra in LZMO/MgO.
    Print ISSN: 0021-8979
    Electronic ISSN: 1089-7550
    Topics: Physics
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  • 10
    Publication Date: 2014-04-11
    Description: Electronic structures of graphene oxide (GO) and hydro-thermally reduced graphene oxides (rGOs) processed at low temperatures (120180C) were studied using X-ray absorption near-edge structure (XANES), X-ray emission spectroscopy (XES) and resonant inelastic X-ray scattering (RIXS). C K-edge XANES spectra of rGOs reveal that thermal reduction restores C = C sp2 bonds and removes some of the oxygen and hydroxyl groups of GO, which initiates the evolution of carbonaceous species. The combination of C K-edge XANES and K XES spectra shows that the overlapping and * orbitals in rGOs and GO are similar to that of highly ordered pyrolytic graphite (HOPG), which has no band-gap. C K RIXS spectra provide evidence that thermal reduction changes the density of states (DOSs) that is generated in the -region and/or in the gap between the and * levels of the GO and rGOs. Two-dimensional C K RIXS mapping of the heavy reduction of rGOs further confirms that the residual oxygen and/or oxygen-containing functional groups modify the and features, which are dispersed by the photon excitation energy. The dispersion behavior near the K point is approximately linear and differs from the parabolic-like dispersion observed in HOPG. Scientific Reports 4 doi: 10.1038/srep04525
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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