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  • 1
    Publication Date: 2018-03-06
    Description: Purpose: Glioblastoma (GBM) is highly resistant to treatment, largely due to disease heterogeneity and resistance mechanisms. We sought to investigate a promising drug that can inhibit multiple aspects of cancer cell survival mechanisms and become an effective therapeutic for GBM patients. Experimental Design: To investigate TG02, an agent with known penetration of the blood–brain barrier, we examined the effects as single agent and in combination with temozolomide, a commonly used chemotherapy in GBM. We used human GBM cells and a syngeneic mouse orthotopic GBM model, evaluating survival and the pharmacodynamics of TG02. Mechanistic studies included TG02-induced transcriptional regulation, apoptosis, and RNA sequencing in treated GBM cells as well as the investigation of mitochondrial and glycolytic function assays. Results: We demonstrated that TG02 inhibited cell proliferation, induced cell death, and synergized with temozolomide in GBM cells with different genetic background but not in astrocytes. TG02-induced cytotoxicity was blocked by the overexpression of phosphorylated CDK9, suggesting a CDK9-dependent cell killing. TG02 suppressed transcriptional progression of antiapoptotic proteins and induced apoptosis in GBM cells. We further demonstrated that TG02 caused mitochondrial dysfunction and glycolytic suppression and ultimately ATP depletion in GBM. A prolonged survival was observed in GBM mice receiving combined treatment of TG02 and temozolomide. The TG02-induced decrease of CDK9 phosphorylation was confirmed in the brain tumor tissue. Conclusions: TG02 inhibits multiple survival mechanisms and synergistically decreases energy production with temozolomide, representing a promising therapeutic strategy in GBM, currently under investigation in an ongoing clinical trial. Clin Cancer Res; 24(5); 1124–37. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
  • 3
    Keywords: carcinoma ; fibroblasts ; METAANALYSIS ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; REVERSE-TRANSCRIPTASE HTERT ; GENETIC-VARIATION ; COMMON VARIANTS ; TERT-CLPTM1L LOCUS ; BUCCAL CELLS
    Abstract: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
    Type of Publication: Journal article published
    PubMed ID: 23535731
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    The European physical journal 23 (2003), S. 299-303 
    ISSN: 1434-6079
    Keywords: PACS. 03.67.Lx Quantum computation – 03.67.-a Quantum information – 02.60.-x Numerical approximation and analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract: We study the effects of dissipation or leakage on the time evolution of Grover's algorithm for a quantum computer. We introduce an effective two-level model with dissipation and randomness (imperfections), which is based upon the idea that ideal Grover's algorithm operates in a 2-dimensional Hilbert space. The simulation results of this model and Grover's algorithm with imperfections are compared, and it is found that they are in good agreement for appropriately tuned parameters. It turns out that the main features of Grover's algorithm with imperfections can be understood in terms of two basic mechanisms, namely, a diffusion of probability density into the full Hilbert space and a stochastic rotation within the original 2-dimensional Hilbert space.
    Type of Medium: Electronic Resource
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  • 5
    Publication Date: 2011-01-29
    Description: Epidemiological studies of the naturally transformable bacterial pathogen Streptococcus pneumoniae have previously been confounded by high rates of recombination. Sequencing 240 isolates of the PMEN1 (Spain(23F)-1) multidrug-resistant lineage enabled base substitutions to be distinguished from polymorphisms arising through horizontal sequence transfer. More than 700 recombinations were detected, with genes encoding major antigens frequently affected. Among these were 10 capsule-switching events, one of which accompanied a population shift as vaccine-escape serotype 19A isolates emerged in the USA after the introduction of the conjugate polysaccharide vaccine. The evolution of resistance to fluoroquinolones, rifampicin, and macrolides was observed to occur on multiple occasions. This study details how genomic plasticity within lineages of recombinogenic bacteria can permit adaptation to clinical interventions over remarkably short time scales.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648787/" 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/PMC3648787/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Croucher, Nicholas J -- Harris, Simon R -- Fraser, Christophe -- Quail, Michael A -- Burton, John -- van der Linden, Mark -- McGee, Lesley -- von Gottberg, Anne -- Song, Jae Hoon -- Ko, Kwan Soo -- Pichon, Bruno -- Baker, Stephen -- Parry, Christopher M -- Lambertsen, Lotte M -- Shahinas, Dea -- Pillai, Dylan R -- Mitchell, Timothy J -- Dougan, Gordon -- Tomasz, Alexander -- Klugman, Keith P -- Parkhill, Julian -- Hanage, William P -- Bentley, Stephen D -- 076962/Wellcome Trust/United Kingdom -- 076964/Wellcome Trust/United Kingdom -- G0800596/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2011 Jan 28;331(6016):430-4. doi: 10.1126/science.1198545.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21273480" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological ; Anti-Bacterial Agents/pharmacology ; Antigenic Variation ; DNA Transposable Elements ; Drug Resistance, Multiple, Bacterial ; *Evolution, Molecular ; Genome, Bacterial ; Humans ; Molecular Epidemiology ; Phylogeny ; Phylogeography ; Pneumococcal Infections/drug therapy/*microbiology ; Pneumococcal Vaccines/immunology ; Polymorphism, Single Nucleotide ; Prophages/genetics ; *Recombination, Genetic ; Selection, Genetic ; Serotyping ; Streptococcus Phages/genetics ; Streptococcus pneumoniae/classification/drug effects/*genetics/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2012-09-01
    Description: Identification of the causal genes that control complex trait variation remains challenging, limiting our appreciation of the evolutionary processes that influence polymorphisms in nature. We cloned a quantitative trait locus that controls plant defensive chemistry, damage by insect herbivores, survival, and reproduction in the natural environments where this polymorphism evolved. These ecological effects are driven by duplications in the BCMA (branched-chain methionine allocation) loci controlling this variation and by two selectively favored amino acid changes in the glucosinolate-biosynthetic cytochrome P450 proteins that they encode. These changes cause a gain of novel enzyme function, modulated by allelic differences in catalytic rate and gene copy number. Ecological interactions in diverse environments likely contribute to the widespread polymorphism of this biochemical function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872477/" 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/PMC3872477/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Prasad, Kasavajhala V S K -- Song, Bao-Hua -- Olson-Manning, Carrie -- Anderson, Jill T -- Lee, Cheng-Ruei -- Schranz, M Eric -- Windsor, Aaron J -- Clauss, Maria J -- Manzaneda, Antonio J -- Naqvi, Ibtehaj -- Reichelt, Michael -- Gershenzon, Jonathan -- Rupasinghe, Sanjeewa G -- Schuler, Mary A -- Mitchell-Olds, Thomas -- R01 GM086496/GM/NIGMS NIH HHS/ -- R01-GM079530/GM/NIGMS NIH HHS/ -- R01-GM086496/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2012 Aug 31;337(6098):1081-4. doi: 10.1126/science.1221636.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22936775" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Amino Acid Sequence ; Amino Acid Substitution ; Arabidopsis/genetics/metabolism/parasitology ; *Brassicaceae/genetics/metabolism/parasitology ; Cytochrome P-450 Enzyme System/*genetics ; Gene Dosage ; Gene-Environment Interaction ; Glucosinolates/biosynthesis/*genetics ; Herbivory/physiology ; Methionine/genetics/metabolism ; Molecular Sequence Data ; Plant Leaves/genetics/metabolism/parasitology ; Plants, Genetically Modified/genetics/metabolism/parasitology ; Polymorphism, Genetic ; *Quantitative Trait Loci ; *Quantitative Trait, Heritable ; *Selection, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2018-12-01
    Description: Background: This study evaluated the efficacy of haematological markers for predicting the pathological complete regression (pCR) during and after neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients and Methods: A total of 297 patients with LARC underwent neoadjuvant CRT followed by surgical resection. Complete blood counts (CBCs) were performed before CRT, 3 weeks after the start of CRT (intra-therapy), and 4 weeks after CRT. Platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) were calculated using the serial CBC test. The ratio of change in PLR (cPLR) and NLR (cNLR) was calculated as the increase from the pre-therapy value to intra-therapy or post-therapy value divided by the pre-therapy value. Chi-square and t-test for univariate analysis and multivariate logistic regression were performed to identify significant predictors for pCR. Receiver operating characteristic (ROC) analysis was used to compare predictive values. Results: The overall rate of pCR was 15.9%. Pre-therapy high haemoglobin and low NLR; intra-therapy high PLR, high NLR, high cPLR, and high cNLR; and post-therapy low white blood cell count (WBC), high haemoglobin, and high cPLR were significantly associated with pCR. In multivariate logistic regression, pre-therapy high haemoglobin [odds ratio (OR)=1.500, p=0.016], high intra-therapy PLR (OR=1.006, p=0.011), high intra-therapy cPLR (OR=4.948, p〈0.001), and low post-therapy WBC (OR=0.639, p=0.003) were significant predictors for pCR. ROC analysis showed that high intra-therapy cPLR was the most accurate predictor of pCR (area under the curve=0.741). Conclusion: Changes of PLR during neoadjuvant CRT for LARC are significant predictors of pCR.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 8
    Publication Date: 2012-07-31
    Description: Adult neurogenesis arises from neural stem cells within specialized niches. Neuronal activity and experience, presumably acting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival. It is unknown whether local neuronal circuitry has a direct impact on adult neural stem cells. Here we show that, in the adult mouse hippocampus, nestin-expressing radial glia-like quiescent neural stem cells (RGLs) respond tonically to the neurotransmitter gamma-aminobutyric acid (GABA) by means of gamma2-subunit-containing GABAA receptors. Clonal analysis of individual RGLs revealed a rapid exit from quiescence and enhanced symmetrical self-renewal after conditional deletion of gamma2. RGLs are in close proximity to terminals expressing 67-kDa glutamic acid decarboxylase (GAD67) of parvalbumin-expressing (PV+) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of the activity of dentate PV+ interneurons, but not that of somatostatin-expressing or vasoactive intestinal polypeptide (VIP)-expressing interneurons, can dictate the RGL choice between quiescence and activation. Furthermore, PV+ interneuron activation restores RGL quiescence after social isolation, an experience that induces RGL activation and symmetrical division. Our study identifies a niche cell-signal-receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3438284/" 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/PMC3438284/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Song, Juan -- Zhong, Chun -- Bonaguidi, Michael A -- Sun, Gerald J -- Hsu, Derek -- Gu, Yan -- Meletis, Konstantinos -- Huang, Z Josh -- Ge, Shaoyu -- Enikolopov, Grigori -- Deisseroth, Karl -- Luscher, Bernhard -- Christian, Kimberly M -- Ming, Guo-li -- Song, Hongjun -- AG040209/AG/NIA NIH HHS/ -- HD069184/HD/NICHD NIH HHS/ -- MH089111/MH/NIMH NIH HHS/ -- NS048271/NS/NINDS NIH HHS/ -- R01 AG040209/AG/NIA NIH HHS/ -- R01 HD069184/HD/NICHD NIH HHS/ -- R01 NS047344/NS/NINDS NIH HHS/ -- R01 NS048271/NS/NINDS NIH HHS/ -- R01 NS065915/NS/NINDS NIH HHS/ -- R21 ES021957/ES/NIEHS NIH HHS/ -- R56 NS047344/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Sep 6;489(7414):150-4. doi: 10.1038/nature11306.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22842902" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Lineage/drug effects ; Cell Proliferation/drug effects ; Dentate Gyrus/cytology/drug effects/metabolism ; Female ; GABA Modulators/pharmacology ; GABA-A Receptor Agonists/pharmacology ; GABA-A Receptor Antagonists/pharmacology ; Interneurons/cytology/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neural Pathways/drug effects/*physiology ; Neural Stem Cells/*cytology/drug effects/metabolism ; *Neurogenesis/drug effects ; Neuroglia/cytology/drug effects/metabolism ; Parvalbumins/metabolism ; Receptors, GABA-A/metabolism ; Signal Transduction/drug effects ; Somatostatin/metabolism ; Stem Cell Niche/drug effects/physiology ; Vasoactive Intestinal Peptide/metabolism ; gamma-Aminobutyric Acid/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2014-08-19
    Description: Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders, and 'a disease of synapses' is the major hypothesis for the biological basis of schizophrenia. Although this hypothesis has gained indirect support from human post-mortem brain analyses and genetic studies, little is known about the pathophysiology of synapses in patient neurons and how susceptibility genes for mental disorders could lead to synaptic deficits in humans. Genetics of most psychiatric disorders are extremely complex due to multiple susceptibility variants with low penetrance and variable phenotypes. Rare, multiply affected, large families in which a single genetic locus is probably responsible for conferring susceptibility have proven invaluable for the study of complex disorders. Here we generated induced pluripotent stem (iPS) cells from four members of a family in which a frameshift mutation of disrupted in schizophrenia 1 (DISC1) co-segregated with major psychiatric disorders and we further produced different isogenic iPS cell lines via gene editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPS-cell-derived forebrain neurons. Mutant DISC1 depletes wild-type DISC1 protein and, furthermore, dysregulates expression of many genes related to synapses and psychiatric disorders in human forebrain neurons. Our study reveals that a psychiatric disorder relevant mutation causes synapse deficits and transcriptional dysregulation in human neurons and our findings provide new insight into the molecular and synaptic etiopathology of psychiatric disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501856/" 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/PMC4501856/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wen, Zhexing -- Nguyen, Ha Nam -- Guo, Ziyuan -- Lalli, Matthew A -- Wang, Xinyuan -- Su, Yijing -- Kim, Nam-Shik -- Yoon, Ki-Jun -- Shin, Jaehoon -- Zhang, Ce -- Makri, Georgia -- Nauen, David -- Yu, Huimei -- Guzman, Elmer -- Chiang, Cheng-Hsuan -- Yoritomo, Nadine -- Kaibuchi, Kozo -- Zou, Jizhong -- Christian, Kimberly M -- Cheng, Linzhao -- Ross, Christopher A -- Margolis, Russell L -- Chen, Gong -- Kosik, Kenneth S -- Song, Hongjun -- Ming, Guo-li -- AG045656/AG/NIA NIH HHS/ -- F31 MH102978/MH/NIMH NIH HHS/ -- MH087874/MH/NIMH NIH HHS/ -- MH102978/MH/NIMH NIH HHS/ -- NS047344/NS/NINDS NIH HHS/ -- NS048271/NS/NINDS NIH HHS/ -- R01 AG024984/AG/NIA NIH HHS/ -- R01 AG045656/AG/NIA NIH HHS/ -- R01 MH083911/MH/NIMH NIH HHS/ -- R01 MH105128/MH/NIMH NIH HHS/ -- R01 NS047344/NS/NINDS NIH HHS/ -- R01 NS048271/NS/NINDS NIH HHS/ -- R21 ES021957/ES/NIEHS NIH HHS/ -- R21 MH092740/MH/NIMH NIH HHS/ -- T32 GM008752/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Nov 20;515(7527):414-8. doi: 10.1038/nature13716. Epub 2014 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3]. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3]. ; 1] Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA [2]. ; Neuroscience Research Institute, Department of Molecular Cellular and Developmental Biology, Biomolecular Science and Engineering Program, University of California, Santa Barbara, California 93106, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa, Nagoya 466-8550, Japan. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [4] The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25132547" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation ; Fibroblasts ; Glutamine/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism/*pathology ; Male ; Mental Disorders/genetics/metabolism/*pathology ; Mice ; Mutant Proteins/genetics/metabolism ; Mutation/genetics ; Nerve Tissue Proteins/genetics/metabolism ; Neurons/cytology/metabolism/pathology ; Pedigree ; Presynaptic Terminals/metabolism/pathology ; Prosencephalon/metabolism/pathology ; Protein Binding ; Synapses/metabolism/*pathology ; Transcriptome
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2015-11-03
    Description: Many peroxy-containing secondary metabolites have been isolated and shown to provide beneficial effects to human health. Yet, the mechanisms of most endoperoxide biosyntheses are not well understood. Although endoperoxides have been suggested as key reaction intermediates in several cases, the only well-characterized endoperoxide biosynthetic enzyme is prostaglandin H synthase, a haem-containing enzyme. Fumitremorgin B endoperoxidase (FtmOx1) from Aspergillus fumigatus is the first reported alpha-ketoglutarate-dependent mononuclear non-haem iron enzyme that can catalyse an endoperoxide formation reaction. To elucidate the mechanistic details for this unique chemical transformation, we report the X-ray crystal structures of FtmOx1 and the binary complexes it forms with either the co-substrate (alpha-ketoglutarate) or the substrate (fumitremorgin B). Uniquely, after alpha-ketoglutarate has bound to the mononuclear iron centre in a bidentate fashion, the remaining open site for oxygen binding and activation is shielded from the substrate or the solvent by a tyrosine residue (Y224). Upon replacing Y224 with alanine or phenylalanine, the FtmOx1 catalysis diverts from endoperoxide formation to the more commonly observed hydroxylation. Subsequent characterizations by a combination of stopped-flow optical absorption spectroscopy and freeze-quench electron paramagnetic resonance spectroscopy support the presence of transient radical species in FtmOx1 catalysis. Our results help to unravel the novel mechanism for this endoperoxide formation reaction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yan, Wupeng -- Song, Heng -- Song, Fuhang -- Guo, Yisong -- Wu, Cheng-Hsuan -- Sae Her, Ampon -- Pu, Yi -- Wang, Shu -- Naowarojna, Nathchar -- Weitz, Andrew -- Hendrich, Michael P -- Costello, Catherine E -- Zhang, Lixin -- Liu, Pinghua -- Zhang, Yan Jessie -- P41 GM104603/GM/NIGMS NIH HHS/ -- R01 GM077387/GM/NIGMS NIH HHS/ -- R01 GM093903/GM/NIGMS NIH HHS/ -- R01 GM104896/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Nov 26;527(7579):539-43. doi: 10.1038/nature15519. Epub 2015 Nov 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712, USA. ; Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA. ; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. ; Department of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA. ; Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, Massachusetts 02118, USA. ; Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524521" target="_blank"〉PubMed〈/a〉
    Keywords: Aspergillus fumigatus/*enzymology ; Binding Sites ; *Biocatalysis ; Crystallography, X-Ray ; Electron Spin Resonance Spectroscopy ; Heme ; Hydroxylation ; Indoles/metabolism ; Iron/metabolism ; Ketoglutaric Acids/*metabolism ; Oxygen/metabolism ; Prostaglandin Endoperoxides/*biosynthesis ; Tyrosine/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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