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  • 1
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-11-20
    Description: Phosphatidylinositol 4-phosphate 5-kinase (PIP5K), a representative member of the phosphatidylinositol phosphate kinase (PIPK) family, is a major enzyme that biosynthesizes the signaling molecule PI(4,5)P 2 (phosphatidylinositol 4,5-bisphosphate) in eukaryotic cells. The stringent specificity toward lipid substrates and the high sensitivity to the membrane environment strongly suggest a membrane-sensing mechanism, but the underlying structural basis is still largely unknown. We present a nuclear magnetic resonance (NMR) study on a peptide commensurate with a PIP5K’s activation loop, which has been reported to be a determinant of lipid substrate specificity and subcellular localization of PIP5K. Although the activation loop is severely disordered in the crystal structure of PIP5K, the NMR experiments showed that the largely unstructured peptide folded into an amphipathic helix upon its association with the 1,2-dihexanoyl- sn -glycero-3-phosphocholine (DHPC) micellar surface. Systematic mutagenesis and functional assays further demonstrated the crucial roles of the amphipathic helix and its hydrophobic surface in kinase activity and membrane-sensing function, supporting a working model in which the activation loop is a critical structural module conferring a membrane-sensing mechanism on PIP5K. The activation loop, surprisingly functioning as a membrane sensor, represents a new paradigm of kinase regulation by the activation loop through protein-membrane interaction, which also lays a foundation on the regulation of PIP5K (and other PIPKs) by membrane lipids for future studies.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 2
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    Royal Society
    Publication Date: 2018-08-02
    Description: Titanium (Ti) is an ideal bone substitute due to its superior bio-compatibility and remarkable corrosion resistance. However, in order to improve the osteoconduction and osteoinduction capacities in clinical applications, different kinds of surface modifications are typically applied to Ti alloys. In this study, we fabricated a tightly attached polydopamine-assisted Fe 3 O 4 nanoparticle coating on Ti with magnetic properties, aiming to improve the osteogenesis of the Ti substrates. The PDA-assisted Fe 3 O 4 nanoparticle coatings were characterized by scanning electron microscopy, energy dispersive spectroscopy, atomic force microscopy and water contact angle measurements. The cell attachment and proliferation rate of the human bone mesenchymal stem cells (hBMSCs) on the Ti surface significantly improved with the Fe 3 O 4 /PDA coating when compared with the pure Ti without a coating. Furthermore, the results of in vitro alkaline phosphatase (ALP) activity at 7 and 14 days and alizarin red S staining at 14 days showed that the Fe 3 O 4 /PDA coating on Ti promoted the osteogenic differentiation of hBMSCs. Moreover, hBMSCs co-cultured with the Fe 3 O 4 /PDA-coated Ti for approximately 14 days also exhibited a significantly higher mRNA expression level of ALP, osteocalcin and runt-related transcription factor-2 (RUNX2). Our in vitro results revealed that the present PDA-assisted Fe 3 O 4 nanoparticle surface coating is an innovative method for Ti surface modification and shows great potential for clinical applications.
    Keywords: materials science, bio materials, cellular biology
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 3
    Publication Date: 2012-08-17
    Description: Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690621/" 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/PMC3690621/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seshagiri, Somasekar -- Stawiski, Eric W -- Durinck, Steffen -- Modrusan, Zora -- Storm, Elaine E -- Conboy, Caitlin B -- Chaudhuri, Subhra -- Guan, Yinghui -- Janakiraman, Vasantharajan -- Jaiswal, Bijay S -- Guillory, Joseph -- Ha, Connie -- Dijkgraaf, Gerrit J P -- Stinson, Jeremy -- Gnad, Florian -- Huntley, Melanie A -- Degenhardt, Jeremiah D -- Haverty, Peter M -- Bourgon, Richard -- Wang, Weiru -- Koeppen, Hartmut -- Gentleman, Robert -- Starr, Timothy K -- Zhang, Zemin -- Largaespada, David A -- Wu, Thomas D -- de Sauvage, Frederic J -- R00 CA151672/CA/NCI NIH HHS/ -- R01 CA134759/CA/NCI NIH HHS/ -- R01-CA134759/CA/NCI NIH HHS/ -- T32 CA009138/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 30;488(7413):660-4. doi: 10.1038/nature11282.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA. sekar@gene.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22895193" target="_blank"〉PubMed〈/a〉
    Keywords: Ataxia Telangiectasia Mutated Proteins ; Base Sequence ; Cell Cycle Proteins/genetics ; Colonic Neoplasms/*genetics/metabolism/pathology ; DNA Copy Number Variations/genetics ; DNA-Binding Proteins/genetics ; Dioxygenases/genetics ; Exome/genetics ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/genetics ; Gene Fusion/*genetics ; Genes, APC ; Genes, Neoplasm/*genetics ; Humans ; Insulin-Like Growth Factor II/genetics ; Intercellular Signaling Peptides and Proteins/*genetics ; Molecular Sequence Data ; Mutation/genetics ; Polymorphism, Single Nucleotide/genetics ; Protein-Serine-Threonine Kinases/genetics ; Proto-Oncogene Proteins/genetics ; Receptor, ErbB-3/genetics ; Sequence Analysis, RNA ; Signal Transduction/genetics ; Thrombospondins/*genetics ; Transcription Factor 7-Like 2 Protein/genetics ; Tumor Suppressor Proteins/genetics ; Wnt Proteins/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Nature Publishing Group (NPG)
    Publication Date: 2013-03-15
    Description: The hepatocyte nuclear factor 4alpha (HNF-4alpha; also known as NR2A1) is a member of the nuclear receptor (NR) family of transcription factors, which have conserved DNA-binding domains and ligand-binding domains. HNF-4alpha is the most abundant DNA-binding protein in the liver, where some 40% of the actively transcribed genes have a HNF-4alpha response element. These regulated genes are largely involved in the hepatic gluconeogenic program and lipid metabolism. In the pancreas HNF-4alpha is also a master regulator, controlling an estimated 11% of islet genes. HNF-4alpha protein mutations are linked to maturity-onset diabetes of the young, type 1 (MODY1) and hyperinsulinaemic hypoglycaemia. Previous structural analyses of NRs, although productive in elucidating the structure of individual domains, have lagged behind in revealing the connectivity patterns of NR domains. Here we describe the 2.9 A crystal structure of the multidomain human HNF-4alpha homodimer bound to its DNA response element and coactivator-derived peptides. A convergence zone connects multiple receptor domains in an asymmetric fashion, joining distinct elements from each monomer. An arginine target of PRMT1 methylation protrudes directly into this convergence zone and sustains its integrity. A serine target of protein kinase C is also responsible for maintaining domain-domain interactions. These post-translational modifications lead to changes in DNA binding by communicating through the tightly connected surfaces of the quaternary fold. We find that some MODY1 mutations, positioned on the ligand-binding domain and hinge regions of the receptor, compromise DNA binding at a distance by communicating through the interjunctional surfaces of the complex. The overall domain representation of the HNF-4alpha homodimer is different from that of the PPAR-gamma-RXR-alpha heterodimer, even when both NR complexes are assembled on the same DNA element. Our findings suggest that unique quaternary folds and interdomain connections in NRs could be exploited by small-molecule allosteric modulators that affect distal functions in these polypeptides.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606643/" 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/PMC3606643/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chandra, Vikas -- Huang, Pengxiang -- Potluri, Nalini -- Wu, Dalei -- Kim, Youngchang -- Rastinejad, Fraydoon -- R01 DK094147/DK/NIDDK NIH HHS/ -- R01 DK097475/DK/NIDDK NIH HHS/ -- England -- Nature. 2013 Mar 21;495(7441):394-8. doi: 10.1038/nature11966. Epub 2013 Mar 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Metabolic Signaling and Disease Program, Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23485969" target="_blank"〉PubMed〈/a〉
    Keywords: Hepatocyte Nuclear Factor 4/*chemistry/genetics/metabolism ; Humans ; Hypoglycemia/genetics ; *Models, Molecular ; Mutation ; Point Mutation ; Protein Binding ; Protein Structure, Quaternary ; Protein Structure, Tertiary
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    BMJ Publishing
    In: BMJ Open
    Publication Date: 2018-02-14
    Description: Introduction Data based on electronic health records (EHRs) are rich with individual-level longitudinal measurement information and are becoming an increasingly common data source for clinical risk prediction worldwide. However, few EHR-based cohort studies are available in China. Harnessing EHRs for research requires a full understanding of data linkages, management, and data quality in large data sets, which presents unique analytical opportunities and challenges. The purpose of this study is to provide a framework to establish a uniquely integrated EHR database in China for scientific research. Methods and analysis The CHinese Electronic health Records Research in Yinzhou (CHERRY) Study will extract individual participant data within the regional health information system of an eastern coastal area of China to establish a longitudinal population-based ambispective cohort study for cardiovascular care and outcomes research. A total of 1 053 565 Chinese adults aged over 18 years were registered in the health information system in 2009, and there were 23 394 deaths from 1 January 2009 to 31 December 2015. The study will include information from multiple epidemiological surveys; EHRs for chronic disease management; and health administrative, clinical, laboratory, drug and electronic medical record (EMR) databases. Follow-up of fatal and non-fatal clinical events is achieved through records linkage to the regional system of disease surveillance, chronic disease management and EMRs (based on diagnostic codes from the International Classification of Diseases, tenth revision). The CHERRY Study will provide a unique platform and serve as a valuable big data resource for cardiovascular risk prediction and population management, for primary and secondary prevention of cardiovascular events in China. Ethics and dissemination The CHERRY Study was approved by the Peking University Institutional Review Board (IRB00001052-16011) in April 2016. Results of the study will be disseminated through published journal articles, conferences and seminar presentations, and on the study website ( http://www.cherry-study.org ).
    Keywords: Open access, Cardiovascular medicine
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 6
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    Nature Publishing Group (NPG)
    Publication Date: 2012-10-30
    Description: Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases and are maternally inherited through the egg's cytoplasm. Here we investigated the feasibility of mtDNA replacement in human oocytes by spindle transfer (ST; also called spindle-chromosomal complex transfer). Of 106 human oocytes donated for research, 65 were subjected to reciprocal ST and 33 served as controls. Fertilization rate in ST oocytes (73%) was similar to controls (75%); however, a significant portion of ST zygotes (52%) showed abnormal fertilization as determined by an irregular number of pronuclei. Among normally fertilized ST zygotes, blastocyst development (62%) and embryonic stem cell isolation (38%) rates were comparable to controls. All embryonic stem cell lines derived from ST zygotes had normal euploid karyotypes and contained exclusively donor mtDNA. The mtDNA can be efficiently replaced in human oocytes. Although some ST oocytes displayed abnormal fertilization, remaining embryos were capable of developing to blastocysts and producing embryonic stem cells similar to controls.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561483/" 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/PMC3561483/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tachibana, Masahito -- Amato, Paula -- Sparman, Michelle -- Woodward, Joy -- Sanchis, Dario Melguizo -- Ma, Hong -- Gutierrez, Nuria Marti -- Tippner-Hedges, Rebecca -- Kang, Eunju -- Lee, Hyo-Sang -- Ramsey, Cathy -- Masterson, Keith -- Battaglia, David -- Lee, David -- Wu, Diana -- Jensen, Jeffrey -- Patton, Phillip -- Gokhale, Sumita -- Stouffer, Richard -- Mitalipov, Shoukhrat -- 8P51OD011092/OD/NIH HHS/ -- EY021214/EY/NEI NIH HHS/ -- HD057121/HD/NICHD NIH HHS/ -- HD059946/HD/NICHD NIH HHS/ -- HD063276/HD/NICHD NIH HHS/ -- P51 OD011092/OD/NIH HHS/ -- P51 RR000163/RR/NCRR 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/ -- England -- Nature. 2013 Jan 31;493(7434):627-31. doi: 10.1038/nature11647. Epub 2012 Oct 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23103867" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Animals ; Cell Nucleus/genetics ; Cryopreservation ; Cytoplasm/genetics ; DNA, Mitochondrial/analysis/genetics ; Embryo, Mammalian/embryology ; Embryonic Stem Cells/cytology ; Female ; Fertilization ; *Genetic Therapy ; Humans ; Macaca mulatta/genetics/growth & development ; Microsatellite Repeats/genetics ; Mitochondrial Diseases/*genetics/*therapy ; Nuclear Transfer Techniques/*standards ; Oocytes/cytology ; Pregnancy ; Young Adult ; Zygote/cytology/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Unknown
    American Association for the Advancement of Science (AAAS)
    Publication Date: 2011-03-26
    Description: Eosinophils are associated with helminth immunity and allergy, often in conjunction with alternatively activated macrophages (AAMs). Adipose tissue AAMs are necessary to maintain glucose homeostasis and are induced by the cytokine interleukin-4 (IL-4). Here, we show that eosinophils are the major IL-4-expressing cells in white adipose tissues of mice, and, in their absence, AAMs are greatly attenuated. Eosinophils migrate into adipose tissue by an integrin-dependent process and reconstitute AAMs through an IL-4- or IL-13-dependent process. Mice fed a high-fat diet develop increased body fat, impaired glucose tolerance, and insulin resistance in the absence of eosinophils, and helminth-induced adipose tissue eosinophilia enhances glucose tolerance. Our results suggest that eosinophils play an unexpected role in metabolic homeostasis through maintenance of adipose AAMs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144160/" 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/PMC3144160/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Davina -- Molofsky, Ari B -- Liang, Hong-Erh -- Ricardo-Gonzalez, Roberto R -- Jouihan, Hani A -- Bando, Jennifer K -- Chawla, Ajay -- Locksley, Richard M -- 5F30DK083194-02/DK/NIDDK NIH HHS/ -- AI026918/AI/NIAID NIH HHS/ -- DK063720/DK/NIDDK NIH HHS/ -- DP1 OD006415/OD/NIH HHS/ -- F30 DK083194-03/DK/NIDDK NIH HHS/ -- R01 AI030663/AI/NIAID NIH HHS/ -- R01 DK076760/DK/NIDDK NIH HHS/ -- R01 DK081405/DK/NIDDK NIH HHS/ -- R01 HL076746/HL/NHLBI NIH HHS/ -- R37 AI026918/AI/NIAID NIH HHS/ -- R37 AI026918-24/AI/NIAID NIH HHS/ -- T32 AI007290/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Apr 8;332(6026):243-7. doi: 10.1126/science.1201475. Epub 2011 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143-0795, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21436399" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue ; Adipose Tissue, White/cytology/*immunology/*metabolism ; Animals ; Blood Glucose/*metabolism ; Cell Movement ; Dietary Fats/administration & dosage ; Eosinophilia/immunology ; Eosinophils/immunology/*physiology ; Glucose Intolerance ; Homeostasis ; Insulin/metabolism ; Insulin Resistance ; Interleukin-13/genetics/metabolism ; Interleukin-4/genetics/metabolism ; *Macrophage Activation ; Macrophages/*immunology/*metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Nippostrongylus ; Strongylida Infections/immunology/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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  • 8
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    Nature Publishing Group (NPG)
    Publication Date: 2012-12-12
    Description: Although recent studies have revealed that heart cells are generated in adult mammals, the frequency of generation and the source of new heart cells are not yet known. Some studies suggest a high rate of stem cell activity with differentiation of progenitors to cardiomyocytes. Other studies suggest that new cardiomyocytes are born at a very low rate, and that they may be derived from the division of pre-existing cardiomyocytes. Here we show, by combining two different pulse-chase approaches--genetic fate-mapping with stable isotope labelling, and multi-isotope imaging mass spectrometry--that the genesis of cardiomyocytes occurs at a low rate by the division of pre-existing cardiomyocytes during normal ageing, a process that increases adjacent to areas of myocardial injury. We found that cell cycle activity during normal ageing and after injury led to polyploidy and multinucleation, but also to new diploid, mononucleate cardiomyocytes. These data reveal pre-existing cardiomyocytes as the dominant source of cardiomyocyte replacement in normal mammalian myocardial homeostasis as well as after myocardial injury.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548046/" 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/PMC3548046/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Senyo, Samuel E -- Steinhauser, Matthew L -- Pizzimenti, Christie L -- Yang, Vicky K -- Cai, Lei -- Wang, Mei -- Wu, Ting-Di -- Guerquin-Kern, Jean-Luc -- Lechene, Claude P -- Lee, Richard T -- AG032977/AG/NIA NIH HHS/ -- AG034641/AG/NIA NIH HHS/ -- AG040019/AG/NIA NIH HHS/ -- EB001974/EB/NIBIB NIH HHS/ -- F32 HL108570/HL/NHLBI NIH HHS/ -- K08 DK090147/DK/NIDDK NIH HHS/ -- P41 EB001974/EB/NIBIB NIH HHS/ -- R01 AG040019/AG/NIA NIH HHS/ -- R21 AG034641/AG/NIA NIH HHS/ -- England -- Nature. 2013 Jan 17;493(7432):433-6. doi: 10.1038/nature11682. Epub 2012 Dec 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23222518" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/physiology ; Animals ; Cell Cycle ; DNA/biosynthesis ; Female ; *Heart ; Homeostasis ; Isotope Labeling ; Male ; Mammals ; Mass Spectrometry ; Mice ; Myoblasts, Cardiac/cytology ; Myocardial Infarction/genetics/metabolism/pathology ; Myocardium/*cytology/metabolism/pathology ; Myocytes, Cardiac/*cytology/metabolism ; Polyploidy ; *Regeneration
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
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    Nature Publishing Group (NPG)
    Publication Date: 2015-08-08
    Description: The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-alpha and ARNT (also called HIF-1beta) subunits. Here we describe crystal structures for each of mouse HIF-2alpha-ARNT and HIF-1alpha-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2alpha-ARNT and HIF-1alpha-ARNT, wherein ARNT spirals around the outside of each HIF-alpha subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-alpha mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Dalei -- Potluri, Nalini -- Lu, Jingping -- Kim, Youngchang -- Rastinejad, Fraydoon -- England -- Nature. 2015 Aug 20;524(7565):303-8. doi: 10.1038/nature14883. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Metabolic Disease Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827, USA. ; Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245371" target="_blank"〉PubMed〈/a〉
    Keywords: ARNTL Transcription Factors/chemistry/metabolism ; Animals ; Aryl Hydrocarbon Receptor Nuclear Translocator/*chemistry/metabolism ; Basic Helix-Loop-Helix Transcription Factors/*chemistry/metabolism ; Binding Sites ; CLOCK Proteins/chemistry/metabolism ; Cell Hypoxia/genetics ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/*chemistry/metabolism ; Mice ; Models, Molecular ; Mutation/genetics ; Neoplasms/genetics ; Phosphorylation ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Response Elements/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
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    Nature Publishing Group (NPG)
    Publication Date: 2016-04-21
    Description: The CRISPR-Cas systems, as exemplified by CRISPR-Cas9, are RNA-guided adaptive immune systems used by bacteria and archaea to defend against viral infection. The CRISPR-Cpf1 system, a new class 2 CRISPR-Cas system, mediates robust DNA interference in human cells. Although functionally conserved, Cpf1 and Cas9 differ in many aspects including their guide RNAs and substrate specificity. Here we report the 2.38 A crystal structure of the CRISPR RNA (crRNA)-bound Lachnospiraceae bacterium ND2006 Cpf1 (LbCpf1). LbCpf1 has a triangle-shaped architecture with a large positively charged channel at the centre. Recognized by the oligonucleotide-binding domain of LbCpf1, the crRNA adopts a highly distorted conformation stabilized by extensive intramolecular interactions and the (Mg(H2O)6)(2+) ion. The oligonucleotide-binding domain also harbours a looped-out helical domain that is important for LbCpf1 substrate binding. Binding of crRNA or crRNA lacking the guide sequence induces marked conformational changes but no oligomerization of LbCpf1. Our study reveals the crRNA recognition mechanism and provides insight into crRNA-guided substrate binding of LbCpf1, establishing a framework for engineering LbCpf1 to improve its efficiency and specificity for genome editing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, De -- Ren, Kuan -- Qiu, Xiaolin -- Zheng, Jianlin -- Guo, Minghui -- Guan, Xiaoyu -- Liu, Hongnan -- Li, Ningning -- Zhang, Bailing -- Yang, Daijun -- Ma, Chuang -- Wang, Shuo -- Wu, Dan -- Ma, Yunfeng -- Fan, Shilong -- Wang, Jiawei -- Gao, Ning -- Huang, Zhiwei -- England -- Nature. 2016 Apr 28;532(7600):522-6. doi: 10.1038/nature17944. Epub 2016 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China. ; Ministry of Education Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27096363" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/*metabolism ; CRISPR-Associated Proteins/*chemistry/*metabolism ; CRISPR-Cas Systems ; Clustered Regularly Interspaced Short Palindromic Repeats/*genetics ; Crystallography, X-Ray ; Firmicutes/*enzymology ; Genetic Engineering ; Models, Molecular ; Nucleic Acid Conformation ; Protein Binding ; Protein Structure, Tertiary ; RNA Stability ; RNA, Bacterial/*chemistry/genetics/*metabolism ; RNA, Guide/chemistry/genetics/metabolism ; Substrate Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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