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  • Female  (18)
  • Amino Acid Sequence  (6)
  • Protein Binding  (6)
  • 1
    Publication Date: 2011-04-15
    Description: Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80-85%. Although post-mortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (Supplementary Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392969/" 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/PMC3392969/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brennand, Kristen J -- Simone, Anthony -- Jou, Jessica -- Gelboin-Burkhart, Chelsea -- Tran, Ngoc -- Sangar, Sarah -- Li, Yan -- Mu, Yangling -- Chen, Gong -- Yu, Diana -- McCarthy, Shane -- Sebat, Jonathan -- Gage, Fred H -- P01 NS028121/NS/NINDS NIH HHS/ -- P30 NS072031/NS/NINDS NIH HHS/ -- R01 MH083911/MH/NIMH NIH HHS/ -- England -- Nature. 2011 May 12;473(7346):221-5. doi: 10.1038/nature09915. Epub 2011 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Salk Institute for Biological Studies, Laboratory of Genetics, 10010 North Torrey Pines Road, La Jolla California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21490598" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Antipsychotic Agents/pharmacology ; Cell Differentiation ; Cells, Cultured ; Cellular Reprogramming/genetics ; Child ; Female ; Fibroblasts/cytology ; Gene Expression Profiling ; *Gene Expression Regulation/drug effects ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Loxapine/pharmacology ; Male ; Membrane Proteins/metabolism ; Models, Biological ; Neurites ; Neurons/*cytology/drug effects/*metabolism ; Phenotype ; Pluripotent Stem Cells/*cytology/*metabolism/pathology ; Receptors, Glutamate/metabolism ; Schizophrenia/*pathology ; Young Adult
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    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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  • 3
    Publication Date: 2012-09-21
    Description: The Pacific oyster Crassostrea gigas belongs to one of the most species-rich but genomically poorly explored phyla, the Mollusca. Here we report the sequencing and assembly of the oyster genome using short reads and a fosmid-pooling strategy, along with transcriptomes of development and stress response and the proteome of the shell. The oyster genome is highly polymorphic and rich in repetitive sequences, with some transposable elements still actively shaping variation. Transcriptome studies reveal an extensive set of genes responding to environmental stress. The expansion of genes coding for heat shock protein 70 and inhibitors of apoptosis is probably central to the oyster's adaptation to sessile life in the highly stressful intertidal zone. Our analyses also show that shell formation in molluscs is more complex than currently understood and involves extensive participation of cells and their exosomes. The oyster genome sequence fills a void in our understanding of the Lophotrochozoa.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Guofan -- Fang, Xiaodong -- Guo, Ximing -- Li, Li -- Luo, Ruibang -- Xu, Fei -- Yang, Pengcheng -- Zhang, Linlin -- Wang, Xiaotong -- Qi, Haigang -- Xiong, Zhiqiang -- Que, Huayong -- Xie, Yinlong -- Holland, Peter W H -- Paps, Jordi -- Zhu, Yabing -- Wu, Fucun -- Chen, Yuanxin -- Wang, Jiafeng -- Peng, Chunfang -- Meng, Jie -- Yang, Lan -- Liu, Jun -- Wen, Bo -- Zhang, Na -- Huang, Zhiyong -- Zhu, Qihui -- Feng, Yue -- Mount, Andrew -- Hedgecock, Dennis -- Xu, Zhe -- Liu, Yunjie -- Domazet-Loso, Tomislav -- Du, Yishuai -- Sun, Xiaoqing -- Zhang, Shoudu -- Liu, Binghang -- Cheng, Peizhou -- Jiang, Xuanting -- Li, Juan -- Fan, Dingding -- Wang, Wei -- Fu, Wenjing -- Wang, Tong -- Wang, Bo -- Zhang, Jibiao -- Peng, Zhiyu -- Li, Yingxiang -- Li, Na -- Wang, Jinpeng -- Chen, Maoshan -- He, Yan -- Tan, Fengji -- Song, Xiaorui -- Zheng, Qiumei -- Huang, Ronglian -- Yang, Hailong -- Du, Xuedi -- Chen, Li -- Yang, Mei -- Gaffney, Patrick M -- Wang, Shan -- Luo, Longhai -- She, Zhicai -- Ming, Yao -- Huang, Wen -- Zhang, Shu -- Huang, Baoyu -- Zhang, Yong -- Qu, Tao -- Ni, Peixiang -- Miao, Guoying -- Wang, Junyi -- Wang, Qiang -- Steinberg, Christian E W -- Wang, Haiyan -- Li, Ning -- Qian, Lumin -- Zhang, Guojie -- Li, Yingrui -- Yang, Huanming -- Liu, Xiao -- Wang, Jian -- Yin, Ye -- Wang, Jun -- 268513/European Research Council/International -- England -- Nature. 2012 Oct 4;490(7418):49-54. doi: 10.1038/nature11413. Epub 2012 Sep 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22992520" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological/*genetics ; Animal Shells/chemistry/*growth & development ; Animals ; Apoptosis Regulatory Proteins/genetics ; Crassostrea/*genetics ; DNA Transposable Elements/genetics ; Evolution, Molecular ; Female ; Gene Expression Regulation, Developmental/genetics ; Genes, Homeobox/genetics ; Genome/*genetics ; Genomics ; HSP70 Heat-Shock Proteins/genetics ; Humans ; Larva/genetics/growth & development ; Mass Spectrometry ; Molecular Sequence Annotation ; Molecular Sequence Data ; Polymorphism, Genetic/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Sequence Analysis, DNA ; Stress, Physiological/genetics/*physiology ; Transcriptome/genetics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    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
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2013-09-13
    Description: Established infections with the human and simian immunodeficiency viruses (HIV and SIV, respectively) are thought to be permanent with even the most effective immune responses and antiretroviral therapies only able to control, but not clear, these infections. Whether the residual virus that maintains these infections is vulnerable to clearance is a question of central importance to the future management of millions of HIV-infected individuals. We recently reported that approximately 50% of rhesus macaques (RM; Macaca mulatta) vaccinated with SIV protein-expressing rhesus cytomegalovirus (RhCMV/SIV) vectors manifest durable, aviraemic control of infection with the highly pathogenic strain SIVmac239 (ref. 5). Here we show that regardless of the route of challenge, RhCMV/SIV vector-elicited immune responses control SIVmac239 after demonstrable lymphatic and haematogenous viral dissemination, and that replication-competent SIV persists in several sites for weeks to months. Over time, however, protected RM lost signs of SIV infection, showing a consistent lack of measurable plasma- or tissue-associated virus using ultrasensitive assays, and a loss of T-cell reactivity to SIV determinants not in the vaccine. Extensive ultrasensitive quantitative PCR and quantitative PCR with reverse transcription analyses of tissues from RhCMV/SIV vector-protected RM necropsied 69-172 weeks after challenge did not detect SIV RNA or DNA sequences above background levels, and replication-competent SIV was not detected in these RM by extensive co-culture analysis of tissues or by adoptive transfer of 60 million haematolymphoid cells to naive RM. These data provide compelling evidence for progressive clearance of a pathogenic lentiviral infection, and suggest that some lentiviral reservoirs may be susceptible to the continuous effector memory T-cell-mediated immune surveillance elicited and maintained by cytomegalovirus vectors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849456/" 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/PMC3849456/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hansen, Scott G -- Piatak, Michael Jr -- Ventura, Abigail B -- Hughes, Colette M -- Gilbride, Roxanne M -- Ford, Julia C -- Oswald, Kelli -- Shoemaker, Rebecca -- Li, Yuan -- Lewis, Matthew S -- Gilliam, Awbrey N -- Xu, Guangwu -- Whizin, Nathan -- Burwitz, Benjamin J -- Planer, Shannon L -- Turner, John M -- Legasse, Alfred W -- Axthelm, Michael K -- Nelson, Jay A -- Fruh, Klaus -- Sacha, Jonah B -- Estes, Jacob D -- Keele, Brandon F -- Edlefsen, Paul T -- Lifson, Jeffrey D -- Picker, Louis J -- HHSN261200800001E/PHS HHS/ -- P01 AI094417/AI/NIAID NIH HHS/ -- P51OD011092/OD/NIH HHS/ -- R01 AI060392/AI/NIAID NIH HHS/ -- R01 DE021291/DE/NIDCR NIH HHS/ -- R37 AI054292/AI/NIAID NIH HHS/ -- U19 AI095985/AI/NIAID NIH HHS/ -- U19 AI096109/AI/NIAID NIH HHS/ -- U24 OD010850/OD/NIH HHS/ -- U42 OD010426/OD/NIH HHS/ -- England -- Nature. 2013 Oct 3;502(7469):100-4. doi: 10.1038/nature12519. Epub 2013 Sep 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24025770" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cytomegalovirus/genetics/immunology ; Female ; Macaca mulatta ; Male ; Molecular Sequence Data ; SAIDS Vaccines/*immunology ; Simian Acquired Immunodeficiency Syndrome/*prevention & control/virology ; Simian Immunodeficiency Virus/*immunology ; Time Factors ; Vaccines, Attenuated/immunology ; Viral Load ; Virus Replication/physiology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2013-10-22
    Description: A large number of cis-regulatory sequences have been annotated in the human genome, but defining their target genes remains a challenge. One strategy is to identify the long-range looping interactions at these elements with the use of chromosome conformation capture (3C)-based techniques. However, previous studies lack either the resolution or coverage to permit a whole-genome, unbiased view of chromatin interactions. Here we report a comprehensive chromatin interaction map generated in human fibroblasts using a genome-wide 3C analysis method (Hi-C). We determined over one million long-range chromatin interactions at 5-10-kb resolution, and uncovered general principles of chromatin organization at different types of genomic features. We also characterized the dynamics of promoter-enhancer contacts after TNF-alpha signalling in these cells. Unexpectedly, we found that TNF-alpha-responsive enhancers are already in contact with their target promoters before signalling. Such pre-existing chromatin looping, which also exists in other cell types with different extracellular signalling, is a strong predictor of gene induction. Our observations suggest that the three-dimensional chromatin landscape, once established in a particular cell type, is relatively stable and could influence the selection or activation of target genes by a ubiquitous transcription activator in a cell-specific manner.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838900/" 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/PMC3838900/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jin, Fulai -- Li, Yan -- Dixon, Jesse R -- Selvaraj, Siddarth -- Ye, Zhen -- Lee, Ah Young -- Yen, Chia-An -- Schmitt, Anthony D -- Espinoza, Celso A -- Ren, Bing -- P50 GM085764/GM/NIGMS NIH HHS/ -- P50 GM085764-03/GM/NIGMS NIH HHS/ -- T32 GM008666/GM/NIGMS NIH HHS/ -- U01 ES017166/ES/NIEHS NIH HHS/ -- England -- Nature. 2013 Nov 14;503(7475):290-4. doi: 10.1038/nature12644. Epub 2013 Oct 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24141950" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Chromatin/chemistry/genetics/*metabolism ; *Chromosome Mapping ; Enhancer Elements, Genetic/physiology ; Gene Expression Regulation ; *Genome, Human ; Humans ; Imaging, Three-Dimensional ; Promoter Regions, Genetic/physiology ; Protein Binding ; Signal Transduction ; Tumor Necrosis Factor-alpha/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2014-02-21
    Description: Crohn's disease is a debilitating inflammatory bowel disease (IBD) that can involve the entire digestive tract. A single-nucleotide polymorphism (SNP) encoding a missense variant in the autophagy gene ATG16L1 (rs2241880, Thr300Ala) is strongly associated with the incidence of Crohn's disease. Numerous studies have demonstrated the effect of ATG16L1 deletion or deficiency; however, the molecular consequences of the Thr300Ala (T300A) variant remains unknown. Here we show that amino acids 296-299 constitute a caspase cleavage motif in ATG16L1 and that the T300A variant (T316A in mice) significantly increases ATG16L1 sensitization to caspase-3-mediated processing. We observed that death-receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knock-in mice harbouring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of the caspase-3-encoding gene, Casp3, or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. These findings demonstrate that caspase 3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli and impaired autophagy in a unified pathway that predisposes to Crohn's disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Murthy, Aditya -- Li, Yun -- Peng, Ivan -- Reichelt, Mike -- Katakam, Anand Kumar -- Noubade, Rajkumar -- Roose-Girma, Merone -- DeVoss, Jason -- Diehl, Lauri -- Graham, Robert R -- van Lookeren Campagne, Menno -- England -- Nature. 2014 Feb 27;506(7489):456-62. doi: 10.1038/nature13044. Epub 2014 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; ITGR Human Genetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24553140" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Autophagy/genetics ; Carrier Proteins/chemistry/*genetics/*metabolism ; Caspase 3/deficiency/genetics/*metabolism ; Cell Line ; Cells, Cultured ; Crohn Disease/*genetics/pathology ; Cytokines/immunology ; Enzyme Activation ; Female ; Food Deprivation ; Humans ; Macrophages/immunology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mutagenesis, Site-Directed ; Polymorphism, Single Nucleotide/*genetics ; *Proteolysis ; Stress, Physiological ; Yersinia enterocolitica/immunology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2014-03-29
    Description: Successful mammalian cloning using somatic cell nuclear transfer (SCNT) into unfertilized, metaphase II (MII)-arrested oocytes attests to the cytoplasmic presence of reprogramming factors capable of inducing totipotency in somatic cell nuclei. However, these poorly defined maternal factors presumably decline sharply after fertilization, as the cytoplasm of pronuclear-stage zygotes is reportedly inactive. Recent evidence suggests that zygotic cytoplasm, if maintained at metaphase, can also support derivation of embryonic stem (ES) cells after SCNT, albeit at low efficiency. This led to the conclusion that critical oocyte reprogramming factors present in the metaphase but not in the interphase cytoplasm are 'trapped' inside the nucleus during interphase and effectively removed during enucleation. Here we investigated the presence of reprogramming activity in the cytoplasm of interphase two-cell mouse embryos (I2C). First, the presence of candidate reprogramming factors was documented in both intact and enucleated metaphase and interphase zygotes and two-cell embryos. Consequently, enucleation did not provide a likely explanation for the inability of interphase cytoplasm to induce reprogramming. Second, when we carefully synchronized the cell cycle stage between the transplanted nucleus (ES cell, fetal fibroblast or terminally differentiated cumulus cell) and the recipient I2C cytoplasm, the reconstructed SCNT embryos developed into blastocysts and ES cells capable of contributing to traditional germline and tetraploid chimaeras. Last, direct transfer of cloned embryos, reconstructed with ES cell nuclei, into recipients resulted in live offspring. Thus, the cytoplasm of I2C supports efficient reprogramming, with cell cycle synchronization between the donor nucleus and recipient cytoplasm as the most critical parameter determining success. The ability to use interphase cytoplasm in SCNT could aid efforts to generate autologous human ES cells for regenerative applications, as donated or discarded embryos are more accessible than unfertilized MII oocytes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124901/" 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/PMC4124901/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Eunju -- Wu, Guangming -- Ma, Hong -- Li, Ying -- Tippner-Hedges, Rebecca -- Tachibana, Masahito -- Sparman, Michelle -- Wolf, Don P -- Scholer, Hans R -- Mitalipov, Shoukhrat -- P51 OD011092/OD/NIH HHS/ -- P51OD011092/OD/NIH HHS/ -- R01 EY021214/EY/NEI NIH HHS/ -- R01 HD057121/HD/NICHD NIH HHS/ -- R01 HD059946/HD/NICHD NIH HHS/ -- R01 HD063276/HD/NICHD NIH HHS/ -- R01EY021214/EY/NEI NIH HHS/ -- R01HD057121/HD/NICHD NIH HHS/ -- R01HD059946/HD/NICHD NIH HHS/ -- R01HD063276/HD/NICHD NIH HHS/ -- England -- Nature. 2014 May 1;509(7498):101-4. doi: 10.1038/nature13134. Epub 2014 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA. ; Max Planck Institute for Molecular Biomedicine, Munster 48149, Germany. ; 1] Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA [2] South Miyagi Medical Center, Miyagi 989-1253, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670652" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Count ; *Cellular Reprogramming ; Cloning, Organism ; Cytoplasm/*metabolism ; Embryo, Mammalian/*cytology ; Embryonic Stem Cells/*cytology ; Female ; Induced Pluripotent Stem Cells/*cytology ; *Interphase ; Male ; Metaphase ; Mice ; *Nuclear Transfer Techniques
    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: 2015-12-25
    Description: The carboxy-terminal domain (CTD) of the RNA polymerase II (RNAP II) subunit POLR2A is a platform for modifications specifying the recruitment of factors that regulate transcription, mRNA processing, and chromatin remodelling. Here we show that a CTD arginine residue (R1810 in human) that is conserved across vertebrates is symmetrically dimethylated (me2s). This R1810me2s modification requires protein arginine methyltransferase 5 (PRMT5) and recruits the Tudor domain of the survival of motor neuron (SMN, also known as GEMIN1) protein, which is mutated in spinal muscular atrophy. SMN interacts with senataxin, which is sometimes mutated in ataxia oculomotor apraxia type 2 and amyotrophic lateral sclerosis. Because POLR2A R1810me2s and SMN, like senataxin, are required for resolving RNA-DNA hybrids created by RNA polymerase II that form R-loops in transcription termination regions, we propose that R1810me2s, SMN, and senataxin are components of an R-loop resolution pathway. Defects in this pathway can influence transcription termination and may contribute to neurodegenerative disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Dorothy Yanling -- Gish, Gerald -- Braunschweig, Ulrich -- Li, Yue -- Ni, Zuyao -- Schmitges, Frank W -- Zhong, Guoqing -- Liu, Ke -- Li, Weiguo -- Moffat, Jason -- Vedadi, Masoud -- Min, Jinrong -- Pawson, Tony J -- Blencowe, Benjamin J -- Greenblatt, Jack F -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2016 Jan 7;529(7584):48-53. doi: 10.1038/nature16469. Epub 2015 Dec 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada. ; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada. ; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26700805" target="_blank"〉PubMed〈/a〉
    Keywords: Arginine/*metabolism ; Cell Line ; DNA Damage ; Humans ; Methylation ; Neurodegenerative Diseases/genetics ; Protein Binding ; Protein Structure, Tertiary ; Protein-Arginine N-Methyltransferases/genetics/metabolism ; RNA Helicases/genetics/metabolism ; RNA Polymerase II/*chemistry/*metabolism ; Survival of Motor Neuron 1 Protein/genetics/*metabolism ; Transcription Elongation, Genetic ; *Transcription Termination, Genetic
    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: 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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