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  • 1
    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
    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: 2012-09-01
    Description: Identification of the causal genes that control complex trait variation remains challenging, limiting our appreciation of the evolutionary processes that influence polymorphisms in nature. We cloned a quantitative trait locus that controls plant defensive chemistry, damage by insect herbivores, survival, and reproduction in the natural environments where this polymorphism evolved. These ecological effects are driven by duplications in the BCMA (branched-chain methionine allocation) loci controlling this variation and by two selectively favored amino acid changes in the glucosinolate-biosynthetic cytochrome P450 proteins that they encode. These changes cause a gain of novel enzyme function, modulated by allelic differences in catalytic rate and gene copy number. Ecological interactions in diverse environments likely contribute to the widespread polymorphism of this biochemical function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872477/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872477/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Prasad, Kasavajhala V S K -- Song, Bao-Hua -- Olson-Manning, Carrie -- Anderson, Jill T -- Lee, Cheng-Ruei -- Schranz, M Eric -- Windsor, Aaron J -- Clauss, Maria J -- Manzaneda, Antonio J -- Naqvi, Ibtehaj -- Reichelt, Michael -- Gershenzon, Jonathan -- Rupasinghe, Sanjeewa G -- Schuler, Mary A -- Mitchell-Olds, Thomas -- R01 GM086496/GM/NIGMS NIH HHS/ -- R01-GM079530/GM/NIGMS NIH HHS/ -- R01-GM086496/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2012 Aug 31;337(6098):1081-4. doi: 10.1126/science.1221636.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22936775" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Amino Acid Sequence ; Amino Acid Substitution ; Arabidopsis/genetics/metabolism/parasitology ; *Brassicaceae/genetics/metabolism/parasitology ; Cytochrome P-450 Enzyme System/*genetics ; Gene Dosage ; Gene-Environment Interaction ; Glucosinolates/biosynthesis/*genetics ; Herbivory/physiology ; Methionine/genetics/metabolism ; Molecular Sequence Data ; Plant Leaves/genetics/metabolism/parasitology ; Plants, Genetically Modified/genetics/metabolism/parasitology ; Polymorphism, Genetic ; *Quantitative Trait Loci ; *Quantitative Trait, Heritable ; *Selection, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2014-06-05
    Description: Cells maintain healthy mitochondria by degrading damaged mitochondria through mitophagy; defective mitophagy is linked to Parkinson's disease. Here we report that USP30, a deubiquitinase localized to mitochondria, antagonizes mitophagy driven by the ubiquitin ligase parkin (also known as PARK2) and protein kinase PINK1, which are encoded by two genes associated with Parkinson's disease. Parkin ubiquitinates and tags damaged mitochondria for clearance. Overexpression of USP30 removes ubiquitin attached by parkin onto damaged mitochondria and blocks parkin's ability to drive mitophagy, whereas reducing USP30 activity enhances mitochondrial degradation in neurons. Global ubiquitination site profiling identified multiple mitochondrial substrates oppositely regulated by parkin and USP30. Knockdown of USP30 rescues the defective mitophagy caused by pathogenic mutations in parkin and improves mitochondrial integrity in parkin- or PINK1-deficient flies. Knockdown of USP30 in dopaminergic neurons protects flies against paraquat toxicity in vivo, ameliorating defects in dopamine levels, motor function and organismal survival. Thus USP30 inhibition is potentially beneficial for Parkinson's disease by promoting mitochondrial clearance and quality control.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bingol, Baris -- Tea, Joy S -- Phu, Lilian -- Reichelt, Mike -- Bakalarski, Corey E -- Song, Qinghua -- Foreman, Oded -- Kirkpatrick, Donald S -- Sheng, Morgan -- England -- Nature. 2014 Jun 19;510(7505):370-5. doi: 10.1038/nature13418. Epub 2014 Jun 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080, USA [2]. ; Department of Protein Chemistry, Genentech, Inc., South San Francisco, California 94080, USA. ; Department of Pathology, Genentech, Inc., South San Francisco, California 94080, USA. ; Department of Bioinformatics & Computational Biology, Genentech, Inc., South San Francisco, California 94080, USA. ; Department of Non-Clinical Biostatistics, Genentech, Inc., South San Francisco, California 94080, USA. ; Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24896179" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cells, Cultured ; Drosophila melanogaster/genetics/metabolism ; Gene Knockdown Techniques ; HEK293 Cells ; HeLa Cells ; Humans ; Male ; Mitochondrial Degradation/*physiology ; Mitochondrial Proteins/genetics/*metabolism ; Neurons/metabolism ; Parkinson Disease/physiopathology ; Protein Kinases/metabolism ; Rats ; Thiolester Hydrolases/genetics/*metabolism ; Ubiquitin-Protein Ligases/genetics/*metabolism ; Ubiquitin-Specific Proteases/genetics/metabolism ; Ubiquitination
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-11-19
    Description: Prevailing dogma holds that cell-cell communication through Notch ligands and receptors determines binary cell fate decisions during progenitor cell divisions, with differentiated lineages remaining fixed. Mucociliary clearance in mammalian respiratory airways depends on secretory cells (club and goblet) and ciliated cells to produce and transport mucus. During development or repair, the closely related Jagged ligands (JAG1 and JAG2) induce Notch signalling to determine the fate of these lineages as they descend from a common proliferating progenitor. In contrast to such situations in which cell fate decisions are made in rapidly dividing populations, cells of the homeostatic adult airway epithelium are long-lived, and little is known about the role of active Notch signalling under such conditions. To disrupt Jagged signalling acutely in adult mammals, here we generate antibody antagonists that selectively target each Jagged paralogue, and determine a crystal structure that explains selectivity. We show that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrate a direct conversion of club cells to ciliated cells without proliferation, meeting a conservative definition of direct transdifferentiation. Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a therapeutic foundation. Our discovery that Jagged antagonism relieves a blockade of cell-to-cell conversion unveils unexpected plasticity, and establishes a model for Notch regulation of transdifferentiation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lafkas, Daniel -- Shelton, Amy -- Chiu, Cecilia -- de Leon Boenig, Gladys -- Chen, Yongmei -- Stawicki, Scott S -- Siltanen, Christian -- Reichelt, Mike -- Zhou, Meijuan -- Wu, Xiumin -- Eastham-Anderson, Jeffrey -- Moore, Heather -- Roose-Girma, Meron -- Chinn, Yvonne -- Hang, Julie Q -- Warming, Soren -- Egen, Jackson -- Lee, Wyne P -- Austin, Cary -- Wu, Yan -- Payandeh, Jian -- Lowe, John B -- Siebel, Christian W -- England -- Nature. 2015 Dec 3;528(7580):127-31. doi: 10.1038/nature15715. Epub 2015 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Structural Biology, 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 Translational Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Discovery Immunology, 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. ; Departments of Protein Chemistry, 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/26580007" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies/immunology/pharmacology/*therapeutic use ; Asthma/drug therapy/metabolism/pathology ; Calcium-Binding Proteins/antagonists & inhibitors/immunology/metabolism ; Cell Death/drug effects ; Cell Division/drug effects ; Cell Lineage/drug effects ; Cell Tracking ; *Cell Transdifferentiation/drug effects ; Cilia/metabolism ; Disease Models, Animal ; Female ; Goblet Cells/cytology/drug effects/pathology ; Homeostasis/drug effects ; Humans ; Intercellular Signaling Peptides and Proteins/immunology/metabolism ; Ligands ; Lung/*cytology/drug effects/*metabolism ; Male ; Membrane Proteins/antagonists & inhibitors/immunology/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Receptors, Notch/*metabolism ; Signal Transduction/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Keywords: transcription ; METABOLISM ; ACTIVATED PROTEIN-KINASE ; CHROMATIN ; acetylation ; TARGETS ; RIBOSOMAL-RNA ; BINDING PROTEIN ; sirtuins ; NAD(+)
    Abstract: Sirtuins are NAD(+)-dependent protein deacetylases that connect metabolism and cellular homeostasis. Here we show that the nuclear Sirtuin SIRT7 targets PAF53, a subunit of RNA polymerase I (Pol I). Acetylation of PAF53 at lysine 373 by CBP and deacetylation by SIRT7 modulate the association of Pol I with DNA, hypoacetylation correlating with increased rDNA occupancy of Pol I and transcription activation. SIRT7 is released from nucleoli in response to different stress conditions, leading to hyperacetylation of PAF53 and decreased Pol I transcription. Nucleolar detention requires binding of SIRT7 to nascent pre-rRNA, linking the spatial distribution of SIRT7 and deacetylation of PAF53 to ongoing transcription. The results identify a nonhistone target of SIRT7 and uncover an RNA-mediated mechanism that adapts nucleolar transcription to stress signaling.
    Type of Publication: Journal article published
    PubMed ID: 24207024
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  • 6
    Keywords: EXPRESSION ; GROWTH ; CELL ; Germany ; PATHWAY ; GENE ; GENES ; GENOME ; PROTEIN ; METABOLISM ; LINES ; REDUCTION ; BIOLOGY ; METABOLITES ; ACID ; IDENTIFICATION ; PROMOTER ; LINE ; REGION ; ARABIDOPSIS-THALIANA ; SCIENCE ; GENE FAMILY ; development ; SULFUR METABOLISM ; OXIDASE ; CELL BIOLOGY ; SYNTHASE PROTEIN COMPLEX ; Type ; 5'-ADENYLYLSULFATE REDUCTASE ; GLUTAMATE-CYSTEINE LIGASE ; GLUTATHIONE BIOSYNTHESIS ; SERINE ACETYLTRANSFERASE ; TRANSGENIC PLANTS
    Abstract: The role of sulfite reductase (SiR) in assimilatory reduction of inorganic sulfate to sulfide has long been regarded as insignificant for control of flux in this pathway. Two independent Arabidopsis thaliana T-DNA insertion lines (sir1-1 and sir1-2), each with an insertion in the promoter region of SiR, were isolated. sir1-2 seedlings had 14% SiR transcript levels compared with the wild type and were early seedling lethal. sir1-1 seedlings had 44% SiR transcript levels and were viable but strongly retarded in growth. In mature leaves of sir1-1 plants, the levels of SiR transcript, protein, and enzymatic activity ranged between 17 and 28% compared with the wild type. The 28-fold decrease of incorporation of S-35 label into Cys, glutathione, and protein in sir1-1 showed that the decreased activity of SiR generated a severe bottleneck in the assimilatory sulfate reduction pathway. Root sulfate uptake was strongly enhanced, and steady state levels of most of the sulfur-related metabolites, as well as the expression of many primary metabolism genes, were changed in leaves of sir1-1. Hexose and starch contents were decreased, while free amino acids increased. Inorganic carbon, nitrogen, and sulfur composition was also severely altered, demonstrating strong perturbations in metabolism that differed markedly from known sulfate deficiency responses. The results support that SiR is the only gene with this function in the Arabidopsis genome, that optimal activity of SiR is essential for normal growth, and that its downregulation causes severe adaptive reactions of primary and secondary metabolism
    Type of Publication: Journal article published
    PubMed ID: 20424176
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  • 7
    ISSN: 1432-1130
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A new analytical strategy was established to improve the determination and identification performance during analyses of microcystins and diarrhetic shellfish poisoning (DSP) toxins in different matrices. Automated high performance size exclusion chromatography (gel permeation chromatography, SEC) was applied for the clean-up of raw extracts from algae and mussel tissue containing either microcystins or DSP toxins. The cleaned raw extracts are well suited for the direct determination of microcystins and DSP toxins by HPLC/MS. The analyses of cleaned raw extracts containing microcystin by HPLC and UV/diode array detection (DAD) revealed chromatograms without interfering peaks. Additionally, methods for the identification of unknown microcystins and those not available as standards were developed and established. The proposed strategy is exemplarily demonstrated for the analyses of a natural algae community from a lake in Slowakia and a naturally contaminated mussel from Portugal.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-8798
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary.  SV40 and/ or DNA sequences indistinguishable from SV40 have been detected in several types of human tumours. The oncoprotein of Simian virus 40, SV40 large T-antigen (Tag), is known to bind and inactivate tumour suppressor proteins, such as members of the retinoblastoma family and p53, thereby promoting cell transformation. In this study, we used the yeast two-hybrid system to investigate whether the Simian virus 40 (SV40) large T-antigen is able to interact with p73, a noval discovered putative tumour suppressor, that is homologous both structurally and functionally to p53. The yeast two-hybrid system is a genetic method to detect protein-protein-interactions in vivo. Our results suggest that the SV40 large T-antigen is not able to bind p73 in yeast although both proteins are expressed in the transformed yeast strain as was shown by western blot analysis.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Chromatographia 49 (1999), S. 671-677 
    ISSN: 1612-1112
    Keywords: Column liquid chromatography ; Microwave hydrolysis ; Microcystin ; Nodularin ; D- and L-selective amino acid determination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Microwave radiation has been successfully used for hydrolysis of the hepatotoxic cyclic peptides microcystins and nodularin. Set-up of the microwave device and the operating conditions for microwave hydrolysis were optimized. Results of the microwave hydrolysis were compared with results from conventional hydrolysis for 24 h at 110°C. Microwave hydrolysis of microcystins and nodularin for as little as 10 min at 160°C results in complete cleavage of peptide bonds and high recoveries of amino acids. Enantioselective determination of amino acids was achieved by use of a previously described HPLC method after pre-column derivatization withortho-phthaldialdehyde and the chiral thiolN-iso-butyryl-cysteine.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Lung 136 (1967), S. 72-72 
    ISSN: 1432-1750
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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