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  • 1
    Publication Date: 2019
    Description: 〈p〉Mutation or transcriptional up-regulation of isocitrate dehydrogenases 1 and 2 (〈i〉IDH1〈/i〉 and 〈i〉IDH2〈/i〉) promotes cancer progression through metabolic reprogramming and epigenetic deregulation of gene expression. Here, we demonstrate that IDH3α, a subunit of the IDH3 heterotetramer, is elevated in glioblastoma (GBM) patient samples compared to normal brain tissue and promotes GBM progression in orthotopic glioma mouse models. IDH3α loss of function reduces tricarboxylic acid (TCA) cycle turnover and inhibits oxidative phosphorylation. In addition to its impact on mitochondrial energy metabolism, IDH3α binds to cytosolic serine hydroxymethyltransferase (cSHMT). This interaction enhances nucleotide availability during DNA replication, while the absence of IDH3α promotes methionine cycle activity, 〈i〉S〈/i〉-adenosyl methionine generation, and DNA methylation. Thus, the regulation of one-carbon metabolism via an IDH3α-cSHMT signaling axis represents a novel mechanism of metabolic adaptation in GBM.〈/p〉
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 2
    Publication Date: 2015-06-09
    Description: CRISPR/Cas9 has been used to genetically modify genomes in a variety of species, including non-human primates. Unfortunately, this new technology does cause mosaic mutations, and we do not yet know whether such mutations can functionally disrupt the targeted gene or cause the pathology seen in human disease. Addressing these issues is necessary if we are to generate large animal models of human diseases using CRISPR/Cas9. Here we used CRISPR/Cas9 to target the monkey dystrophin gene to create mutations that lead to Duchenne muscular dystrophy (DMD), a recessive X-linked form of muscular dystrophy. Examination of the relative targeting rate revealed that Crispr/Cas9 targeting could lead to mosaic mutations in up to 87% of the dystrophin alleles in monkey muscle. Moreover, CRISPR/Cas9 induced mutations in both male and female monkeys, with the markedly depleted dystrophin and muscle degeneration seen in early DMD. Our findings indicate that CRISPR/Cas9 can efficiently generate monkey models of human diseases, regardless of inheritance patterns. The presence of degenerated muscle cells in newborn Cas9-targeted monkeys suggests that therapeutic interventions at the early disease stage may be effective at alleviating the myopathy.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 3
    Publication Date: 2012-08-23
    Description: An agaran-type polysaccharide, GFP08, isolated from Grateloupia filicina (C. Agardh) Lamouroux, was mainly composed of 1,3-linked β- d -galactose partially sulfated at position O-2 and 1,4-linked α- l -galactose O-2, O-3-disulfate, α- l -galactose O-6-sulfate and 3,6-anhydro-α- l -galactose. Small quantities of xylose, 4,6- O -(1'-carboxyethylidene) and 6- O -methyl-β- d -galactose were also present. In mice bearing sarcoma-180 cells, GFP08 decreased tumor weight in a dose-dependent manner. The antiangiogenic activity of GFP08 was evaluated using the chicken chorioallantoic membrane assay, and the results showed that GFP08 dose-dependently reduced new vessel formation. Meanwhile, GFP08 inhibited the differentiation of human umbilical vein endothelial cells (HUVECs) into capillary-like structures in vitro and reduced the number of migrated cells. However, there was no observed cytotoxicity of GFP08 toward HUVECs. Further study revealed that GFP08 decreased tissue factor (TF) expression without affecting the activities of matrix metalloproteinase-2 and -9. All those data indicated that GFP08 had an antitumor effect that might be associated in part with its antiangiogenic effect through down-regulating the expression of TF protein.
    Print ISSN: 0959-6658
    Electronic ISSN: 1460-2423
    Topics: Biology , Medicine
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  • 4
    Publication Date: 2012-07-22
    Description: Despite the many advantages of Caenorhabditis elegans , biochemical approaches to study tissue-specific gene expression in post-embryonic stages are challenging. Here, we report a novel experimental approach for efficient determination of tissue-specific transcriptomes involving the rapid release and purification of nuclei from major tissues of post-embryonic animals by f luorescence- a ctivated n uclei s orting (FANS), followed by deep sequencing of linearly amplified 3'-end regions of transcripts (3'-end-seq). We employed these approaches to compile the transcriptome of the developed C. elegans intestine and used this to analyse tissue-specific cleavage and polyadenylation. In agreement with intestinal-specific gene expression, highly expressed genes have enriched GATA-elements in their promoter regions and their functional properties are associated with processes that are characteristic for the intestine. We systematically mapped pre-mRNA cleavage and polyadenylation sites, or polyA sites, including more than 3000 sites that have previously not been identified. The detailed analysis of the 3'-ends of the nuclear mRNA revealed widespread alternative polyA site use (APA) in intestinally expressed genes. Importantly, we found that intestinal polyA sites that undergo APA tend to have U-rich and/or A-rich upstream auxiliary elements that may contribute to the regulation of 3'-end formation in the intestine.
    Keywords: RNA characterisation and manipulation
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 5
    Publication Date: 2019
    Description: 〈p〉The cold-induced antisense transcript 〈i〉COOLAIR〈/i〉 represses 〈i〉FLOWERING LOCUS C〈/i〉 (〈i〉FLC〈/i〉) transcription with increased H3K27me3 and decreased H3K36me3 levels in response to cold temperatures. However, the molecular connection between 〈i〉COOLAIR〈/i〉 and histone modification factors in the absence of cold treatment remains unclear. We report that the RNA binding protein FCA interacts with the PRC2 subunit CURLY LEAF (CLF) and binds nascent 〈i〉COOLAIR〈/i〉 transcripts to allow deposition of H3K27me3 at 〈i〉FLC〈/i〉. Loss of 〈i〉COOLAIR〈/i〉 function results in a reduction in FCA and CLF enrichment, which, in turn, decreases H3K27me3 levels at 〈i〉FLC〈/i〉. The 〈i〉Arabidopsis〈/i〉 protein phosphatase SSU72 physically interacts with the RRM1 motif of FCA to antagonize FCA binding with 〈i〉COOLAIR〈/i〉. Mutations in 〈i〉SSU72〈/i〉 caused early flowering, reduced 〈i〉FLC〈/i〉 transcription, increased CLF enrichment and H3K27me3, and enhanced affinity between FCA and 〈i〉COOLAIR〈/i〉. Our results suggest that FCA binding of 〈i〉COOLAIR〈/i〉 and SSU72 is critical for PRC2 enrichment and H3K27me3 deposition in 〈i〉Arabidopsis〈/i〉.〈/p〉
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 6
    Publication Date: 2019
    Description: 〈p〉Understanding strongly correlated quantum many-body states is one of the most difficult challenges in modern physics. For example, there remain fundamental open questions on the phase diagram of the Hubbard model, which describes strongly correlated electrons in solids. In this work, we realize the Hubbard Hamiltonian and search for specific patterns within the individual images of many realizations of strongly correlated ultracold fermions in an optical lattice. Upon doping a cold-atom antiferromagnet, we find consistency with geometric strings, entities that may explain the relationship between hole motion and spin order, in both pattern-based and conventional observables. Our results demonstrate the potential for pattern recognition to provide key insights into cold-atom quantum many-body systems.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2015-03-20
    Description: Parkinson's disease (PD) is an age-dependent neurodegenerative disease that can be caused by genetic mutations in α-synuclein (α-syn) or duplication of wild-type α-syn; PD is characterized by the deposition of α-syn aggregates, indicating a gain of toxicity from accumulation of α-syn. Although the major neuropathologic feature of PD is the degeneration of dopaminergic (DA) neurons in the substantia nigra, non-motor symptoms including anxiety, cognitive defect and sleep disorder precede the onset of motor impairment, and many clinical symptoms of PD are not caused by degeneration of DA neurons. Non-human primate models of PD are important for revealing the early pathology in PD and identifying effective treatments. We established transgenic PD rhesus monkeys that express mutant α-syn (A53T). Six transgenic A53T monkeys were produced via lentiviral vector expressing A53T in fertilized monkey eggs and subsequent embryo transfer to surrogates. Transgenic A53T is expressed in the monkey brain and causes age-dependent non-motor symptoms, including cognitive defects and anxiety phenotype, without detectable sleeping disorders. The transgenic α-syn monkeys demonstrate the specific early symptoms caused by mutant α-syn and provide insight into treatment of early PD.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 8
    Publication Date: 2019
    Description: 〈p〉About 257 million people with chronic infection of hepatitis B virus (HBV) worldwide are at high risk of developing terminal liver diseases. Reactivation of virus replication has been frequently reported in those patient populations receiving imatinib (an Abl kinase inhibitor) or bortezomib (a proteasome inhibitor) to treat concurrent diseases, but the underlying mechanism for this reactivation is unknown. We report that the HBV polymerase protein is recruited by Cdt2 to the cullin-RING ligase 4 (CRL4) for ubiquitination and proteasome degradation and that this process is stimulated by the c-Abl nonreceptor tyrosine kinase. Genetic ablation of the Abl-CRL4〈sup〉Cdt2〈/sup〉 axis or pharmaceutical inhibition of this process stabilizes HBV polymerase protein and increases viral loads in HBV-infected liver cancer cell lines. Our study reveals a kinase-dependent activation of CRL4 ubiquitin ligase that can be targeted for blocking HBV replication.〈/p〉
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 9
    Publication Date: 2013-03-16
    Description: The quantized version of the anomalous Hall effect has been predicted to occur in magnetic topological insulators, but the experimental realization has been challenging. Here, we report the observation of the quantum anomalous Hall (QAH) effect in thin films of chromium-doped (Bi,Sb)2Te3, a magnetic topological insulator. At zero magnetic field, the gate-tuned anomalous Hall resistance reaches the predicted quantized value of h/e(2), accompanied by a considerable drop in the longitudinal resistance. Under a strong magnetic field, the longitudinal resistance vanishes, whereas the Hall resistance remains at the quantized value. The realization of the QAH effect may lead to the development of low-power-consumption electronics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chang, Cui-Zu -- Zhang, Jinsong -- Feng, Xiao -- Shen, Jie -- Zhang, Zuocheng -- Guo, Minghua -- Li, Kang -- Ou, Yunbo -- Wei, Pang -- Wang, Li-Li -- Ji, Zhong-Qing -- Feng, Yang -- Ji, Shuaihua -- Chen, Xi -- Jia, Jinfeng -- Dai, Xi -- Fang, Zhong -- Zhang, Shou-Cheng -- He, Ke -- Wang, Yayu -- Lu, Li -- Ma, Xu-Cun -- Xue, Qi-Kun -- New York, N.Y. -- Science. 2013 Apr 12;340(6129):167-70. doi: 10.1126/science.1234414. Epub 2013 Mar 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Low-Dimensional Quantum Physics, Department of Physics, Tsinghua University, Beijing, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23493424" target="_blank"〉PubMed〈/a〉
    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
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 1981-08-07
    Description: Hypoxia was produced in isolated, hemoglobin-free, perfused rat liver by reducing the flow rate of oxygen-carrying fluid entering the organ. The procedure caused anoxia in centrilobular regions. In these anoxic areas, structural derangements developed rapidly, characterized by bleb-like protrusions of hepatocyte plasma membrane through fenestrations in the sinusoidal endothelium. Periportal tissue remained normoxic and was completely spared. Cellular injury resulting from localized anoxia may play an important role in the pathogenesis of centrilobular liver disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lemasters, J J -- Ji, S -- Thurman, R G -- AA-00033/AA/NIAAA NIH HHS/ -- AA-03624/AA/NIAAA NIH HHS/ -- AA-04853/AA/NIAAA NIH HHS/ -- New York, N.Y. -- Science. 1981 Aug 7;213(4508):661-3.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/7256265" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anoxia/*complications ; Cell Membrane/pathology ; Female ; Liver/*blood supply ; Liver Diseases/*etiology/pathology ; NAD/metabolism ; NADP/metabolism ; Oxidation-Reduction ; Rats ; Regional Blood Flow
    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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