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  • Amino Acid Sequence  (6)
  • Disease Models, Animal  (5)
  • 1
    Publication Date: 2012-08-03
    Description: Glioblastoma multiforme is the most common primary malignant brain tumour, with a median survival of about one year. This poor prognosis is due to therapeutic resistance and tumour recurrence after surgical removal. Precisely how recurrence occurs is unknown. Using a genetically engineered mouse model of glioma, here we identify a subset of endogenous tumour cells that are the source of new tumour cells after the drug temozolomide (TMZ) is administered to transiently arrest tumour growth. A nestin-DeltaTK-IRES-GFP (Nes-DeltaTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumour cells. On arrest of tumour cell proliferation with TMZ, pulse-chase experiments demonstrate a tumour re-growth cell hierarchy originating with the Nes-DeltaTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumour growth, and combined TMZ and ganciclovir treatment impeded tumour development. Thus, a relatively quiescent subset of endogenous glioma cells, with properties similar to those proposed for cancer stem cells, is responsible for sustaining long-term tumour growth through the production of transient populations of highly proliferative cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427400/" 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/PMC3427400/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Jian -- Li, Yanjiao -- Yu, Tzong-Shiue -- McKay, Renee M -- Burns, Dennis K -- Kernie, Steven G -- Parada, Luis F -- R01 CA131313/CA/NCI NIH HHS/ -- R01 NS048192-01/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Aug 23;488(7412):522-6. doi: 10.1038/nature11287.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22854781" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents, Alkylating/pharmacology/therapeutic use ; Brain Neoplasms/*drug therapy/*pathology ; Cell Proliferation/drug effects ; Cell Tracking ; Dacarbazine/*analogs & derivatives/pharmacology/therapeutic use ; Disease Models, Animal ; Disease Progression ; Female ; Ganciclovir/pharmacology ; Glioblastoma/*drug therapy/*pathology ; Green Fluorescent Proteins/genetics/metabolism ; Male ; Mice ; Mice, Transgenic ; Neoplastic Stem Cells/*drug effects/*pathology ; Neural Stem Cells/drug effects/pathology ; Transgenes/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2015-07-23
    Description: The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Ling -- Chen, Xiang-Jun -- Zhu, Jie -- Xi, Yi-Bo -- Yang, Xu -- Hu, Li-Dan -- Ouyang, Hong -- Patel, Sherrina H -- Jin, Xin -- Lin, Danni -- Wu, Frances -- Flagg, Ken -- Cai, Huimin -- Li, Gen -- Cao, Guiqun -- Lin, Ying -- Chen, Daniel -- Wen, Cindy -- Chung, Christopher -- Wang, Yandong -- Qiu, Austin -- Yeh, Emily -- Wang, Wenqiu -- Hu, Xun -- Grob, Seanna -- Abagyan, Ruben -- Su, Zhiguang -- Tjondro, Harry Christianto -- Zhao, Xi-Juan -- Luo, Hongrong -- Hou, Rui -- Perry, J Jefferson P -- Gao, Weiwei -- Kozak, Igor -- Granet, David -- Li, Yingrui -- Sun, Xiaodong -- Wang, Jun -- Zhang, Liangfang -- Liu, Yizhi -- Yan, Yong-Bin -- Zhang, Kang -- England -- Nature. 2015 Jul 30;523(7562):607-11. doi: 10.1038/nature14650. Epub 2015 Jul 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. ; BGI-Shenzhen, Shenzhen 518083, China. ; 1] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [2] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China. ; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. ; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] CapitalBio Genomics Co., Ltd., Dongguan 523808, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China. ; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA. ; Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China. ; Department of Biochemistry, University of California Riverside, Riverside, California 92521, USA. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA. ; King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia. ; Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China. ; Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [4] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA [5] Veterans Administration Healthcare System, San Diego, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26200341" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Amino Acid Sequence ; Amyloid/chemistry/drug effects/metabolism/ultrastructure ; Animals ; Base Sequence ; Cataract/congenital/*drug therapy/genetics/*metabolism/pathology ; Cell Line ; Child ; Crystallins/chemistry/genetics/metabolism/ultrastructure ; Dogs ; Female ; Humans ; Lanosterol/administration & dosage/*pharmacology/*therapeutic use ; Lens, Crystalline/drug effects/metabolism/pathology ; Male ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry/genetics/metabolism/ultrastructure ; Pedigree ; Protein Aggregates/*drug effects ; Protein Aggregation, Pathological/*drug therapy/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2011-05-21
    Description: The transmission of information from DNA to RNA is a critical process. We compared RNA sequences from human B cells of 27 individuals to the corresponding DNA sequences from the same individuals and uncovered more than 10,000 exonic sites where the RNA sequences do not match that of the DNA. All 12 possible categories of discordances were observed. These differences were nonrandom as many sites were found in multiple individuals and in different cell types, including primary skin cells and brain tissues. Using mass spectrometry, we detected peptides that are translated from the discordant RNA sequences and thus do not correspond exactly to the DNA sequences. These widespread RNA-DNA differences in the human transcriptome provide a yet unexplored aspect of genome variation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204392/" 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/PMC3204392/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Mingyao -- Wang, Isabel X -- Li, Yun -- Bruzel, Alan -- Richards, Allison L -- Toung, Jonathan M -- Cheung, Vivian G -- R01 HG005854/HG/NHGRI NIH HHS/ -- R01 HG005854-01/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Jul 1;333(6038):53-8. doi: 10.1126/science.1207018. Epub 2011 May 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21596952" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Amino Acid Sequence ; B-Lymphocytes ; Base Sequence ; Cell Line ; Cerebral Cortex/cytology ; DNA/chemistry/*genetics ; Exons ; Expressed Sequence Tags ; Fibroblasts ; Gene Expression Profiling ; *Genetic Variation ; *Genome, Human ; Genotype ; Humans ; Mass Spectrometry ; Middle Aged ; Molecular Sequence Data ; Polymorphism, Single Nucleotide ; Protein Biosynthesis ; Proteins/chemistry ; Proteome/chemistry ; RNA, Messenger/chemistry/*genetics ; Sequence Analysis, DNA ; Sequence Analysis, RNA ; Skin/cytology ; Untranslated Regions
    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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  • 4
    Publication Date: 2014-03-05
    Description: Recognition of modified histones by 'reader' proteins plays a critical role in the regulation of chromatin. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions after RNA polymerase II elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state, thus suppressing cryptic transcription. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies. Here we show that the candidate tumour suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates RNA polymerase II elongation. Structural studies show that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific 'Ser 31' residue in a composite pocket formed by the tandem bromo-PWWP domains of ZMYND11. Chromatin immunoprecipitation followed by sequencing shows a genome-wide co-localization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription co-repressor by modulating RNA polymerase II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumour cell growth; low expression levels of ZMYND11 in breast cancer patients correlate with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumour formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone-variant-mediated transcription elongation control to tumour suppression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142212/" 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/PMC4142212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wen, Hong -- Li, Yuanyuan -- Xi, Yuanxin -- Jiang, Shiming -- Stratton, Sabrina -- Peng, Danni -- Tanaka, Kaori -- Ren, Yongfeng -- Xia, Zheng -- Wu, Jun -- Li, Bing -- Barton, Michelle C -- Li, Wei -- Li, Haitao -- Shi, Xiaobing -- CA016672/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R01 GM090077/GM/NIGMS NIH HHS/ -- R01 HG007538/HG/NHGRI NIH HHS/ -- R01GM090077/GM/NIGMS NIH HHS/ -- R01HG007538/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Apr 10;508(7495):263-8. doi: 10.1038/nature13045. Epub 2014 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for Cancer Epigenetics, Center for Genetics and Genomics, and Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3]. ; 1] MOE Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China [2] Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China [3]. ; 1] Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2]. ; Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] MOE Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China [2] Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. ; Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for Cancer Epigenetics, Center for Genetics and Genomics, and Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences, Houston, Teaxs 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24590075" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Breast Neoplasms/*genetics/metabolism/*pathology ; Carrier Proteins/chemistry/*metabolism ; Chromatin/genetics/metabolism ; Co-Repressor Proteins/chemistry/metabolism ; Crystallography, X-Ray ; Disease-Free Survival ; Female ; Gene Expression Regulation, Neoplastic/genetics ; Histones/chemistry/*metabolism ; Humans ; Lysine/*metabolism ; Methylation ; Mice ; Mice, Nude ; Models, Molecular ; Molecular Sequence Data ; Oncogenes/genetics ; Prognosis ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; RNA Polymerase II/*metabolism ; Substrate Specificity ; *Transcription Elongation, Genetic
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2016-03-31
    Description: Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/beta-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864035/" 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/PMC4864035/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Zinan -- Tang, Alan T -- Wong, Weng-Yew -- Bamezai, Sharika -- Goddard, Lauren M -- Shenkar, Robert -- Zhou, Su -- Yang, Jisheng -- Wright, Alexander C -- Foley, Matthew -- Arthur, J Simon C -- Whitehead, Kevin J -- Awad, Issam A -- Li, Dean Y -- Zheng, Xiangjian -- Kahn, Mark L -- P01 HL075215/HL/NHLBI NIH HHS/ -- P01 HL120846/HL/NHLBI NIH HHS/ -- P01 NS092521/NS/NINDS NIH HHS/ -- P01NS092521/NS/NINDS NIH HHS/ -- R01 HL094326/HL/NHLBI NIH HHS/ -- R01HL-084516/HL/NHLBI NIH HHS/ -- R01HL094326/HL/NHLBI NIH HHS/ -- R01NS075168/NS/NINDS NIH HHS/ -- T32HL07439/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Apr 7;532(7597):122-6. doi: 10.1038/nature17178. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA. ; Laboratory of Cardiovascular Signaling, Centenary Institute, Sydney, New South Wales 2050, Australia. ; Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois 60637, USA. ; Department of Radiology, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA. ; Sydney Microscopy &Microanalysis, University of Sydney, Sydney, New South Wales 2050, Australia. ; Division of Cell Signaling and Immunology, University of Dundee, Dundee DD1 5EH, UK. ; Division of Cardiovascular Medicine and the Program in Molecular Medicine, University of Utah, Salt Lake City, Utah 84112, USA. ; The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences &Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China. ; Faculty of Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales 2050, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027284" target="_blank"〉PubMed〈/a〉
    Keywords: ADAM Proteins/metabolism ; Animals ; Animals, Newborn ; Carrier Proteins/genetics/metabolism ; Disease Models, Animal ; Endothelial Cells/enzymology/*metabolism ; Female ; Hemangioma, Cavernous, Central Nervous System/etiology/*metabolism/pathology ; Humans ; Kruppel-Like Transcription Factors/deficiency/*metabolism ; MAP Kinase Kinase Kinase 3/deficiency/*metabolism ; *MAP Kinase Signaling System ; Male ; Mice ; Protein Binding ; rho GTP-Binding Proteins/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2013-07-28
    Description: The essential bacterial protein FtsZ is a guanosine triphosphatase that self-assembles into a structure at the division site termed the "Z ring". During cytokinesis, the Z ring exerts a constrictive force on the membrane by using the chemical energy of guanosine triphosphate hydrolysis. However, the structural basis of this constriction remains unresolved. Here, we present the crystal structure of a guanosine diphosphate-bound Mycobacterium tuberculosis FtsZ protofilament, which exhibits a curved conformational state. The structure reveals a longitudinal interface that is important for function. The protofilament curvature highlights a hydrolysis-dependent conformational switch at the T3 loop that leads to longitudinal bending between subunits, which could generate sufficient force to drive cytokinesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816583/" 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/PMC3816583/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Ying -- Hsin, Jen -- Zhao, Lingyun -- Cheng, Yiwen -- Shang, Weina -- Huang, Kerwyn Casey -- Wang, Hong-Wei -- Ye, Sheng -- 1F32GM100677-01A1/GM/NIGMS NIH HHS/ -- DP2 OD006466/OD/NIH HHS/ -- DP2OD006466/OD/NIH HHS/ -- F32 GM100677/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Jul 26;341(6144):392-5. doi: 10.1126/science.1239248.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Life Sciences Institute, Zhejiang University, Hangzhou, 310058 Zhejiang, P.R. China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23888039" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Bacterial Proteins/*chemistry/genetics/*metabolism ; Cell Membrane/physiology ; Crystallography, X-Ray ; *Cytokinesis ; Cytoskeletal Proteins/*chemistry/genetics/*metabolism ; Escherichia coli/chemistry ; Guanosine Diphosphate/chemistry/metabolism ; Guanosine Triphosphate/metabolism ; Hydrolysis ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Molecular Dynamics Simulation ; Molecular Sequence Data ; Mycobacterium tuberculosis/*chemistry/physiology ; Point Mutation ; Protein Conformation ; Protein Multimerization ; Protein Subunits/chemistry/metabolism ; Staphylococcus aureus/chemistry
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2012-07-18
    Description: Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408792/" 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/PMC3408792/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Youngjin -- Morrison, Brett M -- Li, Yun -- Lengacher, Sylvain -- Farah, Mohamed H -- Hoffman, Paul N -- Liu, Yiting -- Tsingalia, Akivaga -- Jin, Lin -- Zhang, Ping-Wu -- Pellerin, Luc -- Magistretti, Pierre J -- Rothstein, Jeffrey D -- NS33958/NS/NINDS NIH HHS/ -- P01NS16375/NS/NINDS NIH HHS/ -- P50AG05146/AG/NIA NIH HHS/ -- R01 NS033958/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Jul 26;487(7408):443-8. doi: 10.1038/nature11314.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, The Johns Hopkins University, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22801498" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/genetics/*metabolism/*pathology ; Animals ; Axons/*metabolism/pathology ; Cell Line ; Cell Survival ; Disease Models, Animal ; Down-Regulation ; Heterozygote ; Humans ; Lactic Acid/metabolism ; Mice ; Mice, Transgenic ; Monocarboxylic Acid Transporters/deficiency/genetics/*metabolism ; Motor Neurons/metabolism/*pathology ; Myelin Sheath/metabolism ; Nerve Degeneration/*metabolism ; Oligodendroglia/*metabolism ; Protein Transport ; RNA, Small Interfering ; Superoxide Dismutase/genetics/metabolism ; Symporters/deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2012-07-06
    Description: Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas and cytogenetically normal acute myeloid leukaemias (AML). These alterations are gain-of-function mutations in that they drive the synthesis of the 'oncometabolite' R-2-hydroxyglutarate (2HG). It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005896/" 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/PMC4005896/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sasaki, Masato -- Knobbe, Christiane B -- Munger, Joshua C -- Lind, Evan F -- Brenner, Dirk -- Brustle, Anne -- Harris, Isaac S -- Holmes, Roxanne -- Wakeham, Andrew -- Haight, Jillian -- You-Ten, Annick -- Li, Wanda Y -- Schalm, Stefanie -- Su, Shinsan M -- Virtanen, Carl -- Reifenberger, Guido -- Ohashi, Pamela S -- Barber, Dwayne L -- Figueroa, Maria E -- Melnick, Ari -- Zuniga-Pflucker, Juan-Carlos -- Mak, Tak W -- R01 AI081773/AI/NIAID NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2012 Aug 30;488(7413):656-9. doi: 10.1038/nature11323.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763442" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Animals ; Bone Marrow/pathology ; Cell Lineage ; CpG Islands/genetics ; DNA Methylation ; Disease Models, Animal ; Epigenesis, Genetic/*genetics ; Female ; Gene Knock-In Techniques ; Glioma/pathology ; Hematopoiesis ; Hematopoietic Stem Cells/*cytology/metabolism ; Histones/metabolism ; Humans ; Isocitrate Dehydrogenase/*genetics/*metabolism ; Leukemia, Myeloid, Acute/genetics ; Male ; Mice ; Mutant Proteins/genetics/*metabolism ; Mutation/*genetics ; Myeloid Cells/cytology/metabolism ; Spleen/pathology
    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: 2014-09-27
    Description: Epigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles of human monocytes trained with the Candida albicans cell wall constituent beta-glucan, together with a genome-wide transcriptome, we identified the induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD(+)) to its reduced form (NADH), reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1-Akt-HIF-1alpha (hypoxia-inducible factor-1alpha) pathway. Inhibition of Akt, mTOR, or HIF-1alpha blocked monocyte induction of trained immunity, whereas the adenosine monophosphate-activated protein kinase activator metformin inhibited the innate immune response to fungal infection. Mice with a myeloid cell-specific defect in HIF-1alpha were unable to mount trained immunity against bacterial sepsis. Our results indicate that induction of aerobic glycolysis through an Akt-mTOR-HIF-1alpha pathway represents the metabolic basis of trained immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226238/" 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/PMC4226238/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheng, Shih-Chin -- Quintin, Jessica -- Cramer, Robert A -- Shepardson, Kelly M -- Saeed, Sadia -- Kumar, Vinod -- Giamarellos-Bourboulis, Evangelos J -- Martens, Joost H A -- Rao, Nagesha Appukudige -- Aghajanirefah, Ali -- Manjeri, Ganesh R -- Li, Yang -- Ifrim, Daniela C -- Arts, Rob J W -- van der Veer, Brian M J W -- Deen, Peter M T -- Logie, Colin -- O'Neill, Luke A -- Willems, Peter -- van de Veerdonk, Frank L -- van der Meer, Jos W M -- Ng, Aylwin -- Joosten, Leo A B -- Wijmenga, Cisca -- Stunnenberg, Hendrik G -- Xavier, Ramnik J -- Netea, Mihai G -- 1P30GM106394-01/GM/NIGMS NIH HHS/ -- 5P30GM103415-03/GM/NIGMS NIH HHS/ -- DK097485/DK/NIDDK NIH HHS/ -- DK43351/DK/NIDDK NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- P30 GM103415/GM/NIGMS NIH HHS/ -- P30 GM106394/GM/NIGMS NIH HHS/ -- R01 AI081838/AI/NIAID NIH HHS/ -- R01 DK097485/DK/NIDDK NIH HHS/ -- R01AI81838/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2014 Sep 26;345(6204):1250684. doi: 10.1126/science.1250684.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. ; Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands. ; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands. ; 4th Department of Internal Medicine, University of Athens Medical School, 12462 Athens, Greece. ; Department of Biochemistry, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands. ; Department of Physiology, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. ; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. ; Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard School of Medicine, Boston, MA 02114, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. mihai.netea@radboudumc.nl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25258083" target="_blank"〉PubMed〈/a〉
    Keywords: Aerobiosis/immunology ; Animals ; Candida albicans/immunology ; Candidiasis/immunology/metabolism ; Disease Models, Animal ; *Epigenesis, Genetic ; Female ; Glucose/metabolism ; Glycolysis/*immunology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism ; Immunity, Innate/*genetics ; Immunologic Memory/*genetics ; Male ; Mice ; Mice, Inbred C57BL ; Monocytes/*immunology/metabolism ; Sepsis/genetics/immunology/metabolism ; Staphylococcal Infections/immunology/metabolism ; Staphylococcus aureus ; TOR Serine-Threonine Kinases/genetics/*metabolism ; Transcriptome ; beta-Glucans/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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  • 10
    Publication Date: 2012-08-28
    Description: Plants possess arrays of functionally diverse specialized metabolites, many of which are distributed taxonomically. Here, we describe the evolution of a class of substituted alpha-pyrone metabolites in Arabidopsis, which we have named arabidopyrones. The biosynthesis of arabidopyrones requires a cytochrome P450 enzyme (CYP84A4) to generate the catechol-substituted substrate for an extradiol ring-cleavage dioxygenase (AtLigB). Unlike other ring-cleavage-derived plant metabolites made from tyrosine, arabidopyrones are instead derived from phenylalanine through the early steps of phenylpropanoid metabolism. Whereas CYP84A4, an Arabidopsis-specific paralog of the lignin-biosynthetic enzyme CYP84A1, has neofunctionalized relative to its ancestor, AtLigB homologs are widespread among land plants and many bacteria. This study exemplifies the rapid evolution of a biochemical pathway formed by the addition of a new biological activity into an existing metabolic infrastructure.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Weng, Jing-Ke -- Li, Yi -- Mo, Huaping -- Chapple, Clint -- New York, N.Y. -- Science. 2012 Aug 24;337(6097):960-4. doi: 10.1126/science.1221614.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22923580" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis/enzymology/genetics/*metabolism ; Arabidopsis Proteins/chemistry/genetics/*metabolism ; Base Sequence ; Biosynthetic Pathways ; Catalytic Domain ; Cytochrome P-450 Enzyme System/chemistry/genetics/*metabolism ; Dioxygenases/genetics/metabolism ; Evolution, Molecular ; Gene Duplication ; Genome, Plant ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Phenylalanine/metabolism ; Phylogeny ; Plant Stems/metabolism ; Plants, Genetically Modified ; Pyrones/chemistry/*metabolism
    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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