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  • 1
    Online Resource
    Online Resource
    O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 33 ( 2016-08-16), p. 9333-9338
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 33 ( 2016-08-16), p. 9333-9338
    Abstract: High-risk human papillomaviruses (HPVs) are causative agents of anogenital cancers and a fraction of head and neck cancers. The mechanisms involved in the progression of HPV neoplasias to cancers remain largely unknown. Here, we report that O-linked GlcNAcylation (O-GlcNAc) and O-GlcNAc transferase (OGT) were markedly increased in HPV-caused cervical neoplasms relative to normal cervix, whereas O-GlcNAcase (OGA) levels were not altered. Transduction of HPV16 oncogene E6 or E6/E 7 into mouse embryonic fibroblasts (MEFs) up-regulated OGT mRNA and protein, elevated the level of O-GlcNAc, and promoted cell proliferation while reducing cellular senescence. Conversely, in HPV-18–transformed HeLa cervical carcinoma cells, inhibition of O-GlcNAc with a low concentration of a chemical inhibitor impaired the transformed phenotypes in vitro. We showed that E6 elevated c-MYC via increased protein stability attributable to O-GlcNAcylation on Thr58. Reduction of HPV-mediated cell viability by a high concentration of O-GlcNAc inhibitor was partially rescued by elevated c-MYC. Finally, knockdown of OGT or O-GlcNAc inhibition in HeLa cells or in TC-1 cells, a mouse cell line transformed by HPV16 E6/E7 and activated K-RAS , reduced c-MYC and suppressed tumorigenesis and metastasis. Thus, we have uncovered a mechanism for HPV oncoprotein-mediated transformation. These findings may eventually aid in the development of effective therapeutics for HPV-associated malignancies by targeting aberrant O-GlcNAc.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1606801113
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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  • 2
    Online Resource
    Online Resource
    Pre-departure English language preparation of students on joint 2+2 programs
    Elsevier BV ; 2020
    In:  System Vol. 90 ( 2020-06), p. 102219-
    Details
    In: System, Elsevier BV, Vol. 90 ( 2020-06), p. 102219-
    Type of Medium: Online Resource
    ISSN: 0346-251X
    URL: Article
    DOI: 10.1016/j.system.2020.102219
    RVK:
    EQ 1000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 1500775-3
    detail.hit.zdb_id: 189289-7
    SSG: 7,11
    SSG: 5,3
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  • 3
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    Integration of pluripotency pathways regulates stem cell maintenance in the Arabidopsis shoot meristem
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 36 ( 2020-09-08), p. 22561-22571
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 36 ( 2020-09-08), p. 22561-22571
    Abstract: In the shoot meristem, both WUSCHEL (WUS) and SHOOT MERISTEMLESS (STM), two transcription factors with overlapping spatiotemporal expression patterns, are essential for maintaining stem cells in an undifferentiated state. Despite their importance, it remains unclear how these two pathways are integrated to coordinate stem cell development. Here, we show that the WUS and STM pathways in Arabidopsis thaliana converge through direct interaction between the WUS and STM proteins. STM binds to the promoter of CLAVATA3 ( CLV3 ) and enhances the binding of WUS to the same promoter through the WUS–STM interaction. Both the heterodimerization and simultaneous binding of WUS and STM at two sites on the CLV3 promoter are required to regulate CLV3 expression, which in turn maintains a constant number of stem cells. Furthermore, the expression of STM depends on WUS, and this WUS-activated STM expression enhances the WUS-mediated stem cell activity. Our data provide a framework for understanding how spatial expression patterns within the shoot meristem are translated into regulatory units of stem cell homeostasis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2015248117
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
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    detail.hit.zdb_id: 1461794-8
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  • 4
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    Online Resource
    The Upregulation of Translocator Protein (18 kDa) Promotes Recovery from Neuropathic Pain in Rats
    Society for Neuroscience ; 2013
    In:  The Journal of Neuroscience Vol. 33, No. 4 ( 2013-01-23), p. 1540-1551
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 33, No. 4 ( 2013-01-23), p. 1540-1551
    Abstract: At present, effective drug for treatment of neuropathic pain is still lacking. Recent studies have shown that the ligands of translocator protein (TSPO, 18 kDa), a peripheral receptor for benzodiazepine, modulate inflammatory pain. Here, we report that TSPO was upregulated in astrocytes and microglia in the ipsilateral spinal dorsal horn of rats following L5 spinal nerve ligation (L5 SNL), lasting until the vanishing of the behavioral signs of neuropathic pain (∼50 d). Importantly, a single intrathecal injection of specific TSPO agonists Ro5-4864 or FGIN-1-27 at 7 and 21 d after L5 SNL depressed the established mechanical allodynia and thermal hyperalgesia dramatically, and the effect was abolished by pretreatment with AMG, a neurosteroid synthesis inhibitor. Mechanically, Ro5-4864 substantially inhibited spinal astrocytes but not microglia, and reduced the production of tumor necrosis factor-α (TNF-α) in vivo and in vitro . The anti-neuroinflammatory effect was also prevented by AMG. Interestingly, TSPO expression returned to control levels or decreased substantially, when neuropathic pain healed naturally or was reversed by Ro5-4864, suggesting that the role of TSPO upregulation might be to promote recovery from the neurological disorder. Finally, the neuropathic pain and the upregulation of TSPO by L5 SNL were prevented by pharmacological blockage of Toll-like receptor 4 (TLR4). These data suggested that TSPO might be a novel therapeutic target for the treatment of neuropathic pain.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0324-12.2013
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2013
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    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Root exudates drive interspecific facilitation by enhancing nodulation and N 2 fixation
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 23 ( 2016-06-07), p. 6496-6501
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 23 ( 2016-06-07), p. 6496-6501
    Abstract: Plant diversity in experimental systems often enhances ecosystem productivity, but the mechanisms causing this overyielding are only partly understood. Intercropping faba beans ( Vicia faba L.) and maize ( Zea mays L.) result in overyielding and also, enhanced nodulation by faba beans. By using permeable and impermeable root barriers in a 2-y field experiment, we show that root–root interactions between faba bean and maize significantly increase both nodulation and symbiotic N 2 fixation in intercropped faba bean. Furthermore, root exudates from maize promote faba bean nodulation, whereas root exudates from wheat and barley do not. Thus, a decline of soil nitrate concentrations caused by intercropped cereals is not the sole mechanism for maize promoting faba bean nodulation. Intercropped maize also caused a twofold increase in exudation of flavonoids (signaling compounds for rhizobia) in the systems. Roots of faba bean treated with maize root exudates exhibited an immediate 11-fold increase in the expression of chalcone–flavanone isomerase (involved in flavonoid synthesis) gene together with a significantly increased expression of genes mediating nodulation and auxin response. After 35 d, faba beans treated with maize root exudate continued to show up-regulation of key nodulation genes, such as early nodulin 93 ( ENOD93 ), and promoted nitrogen fixation. Our results reveal a mechanism for how intercropped maize promotes nitrogen fixation of faba bean, where maize root exudates promote flavonoid synthesis in faba bean, increase nodulation, and stimulate nitrogen fixation after enhanced gene expression. These results indicate facilitative root–root interactions and provide a mechanism for a positive relationship between species diversity and ecosystem productivity.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1523580113
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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  • 6
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    Online Resource
    Elevation of Brain Magnesium Prevents and Reverses Cognitive Deficits and Synaptic Loss in Alzheimer's Disease Mouse Model
    Society for Neuroscience ; 2013
    In:  The Journal of Neuroscience Vol. 33, No. 19 ( 2013-05-08), p. 8423-8441
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 33, No. 19 ( 2013-05-08), p. 8423-8441
    Abstract: Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer's disease (AD) and might underlie memory impairment. Our previous work demonstrated that the magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we investigated whether elevation of brain magnesium by the use of a recently developed compound, magnesium- l -threonate (MgT), can ameliorate the AD-like pathologies and cognitive deficits in the APPswe/PS1dE9 mice, a transgenic (Tg) mouse model of AD. MgT treatment reduced Aβ plaque and prevented synapse loss and memory decline in the Tg mice. Strikingly, MgT treatment was effective even when given to the mice at the end stage of their AD-like pathological progression. To explore how elevation of brain magnesium ameliorates the AD-like pathologies in the brains of Tg mice, we studied molecules critical for APP metabolism and signaling pathways implicated in synaptic plasticity/density. In the Tg mice, the NMDAR/CREB/BDNF signaling was downregulated, whereas calpain/calcineurin/Cdk5 neurodegenerative signaling and β-secretase (BACE1) expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression, and reduced soluble APPβ and β-C-terminal fragments in the Tg mice. At the molecular level, elevation of extracellular magnesium prevented the high-Aβ-induced reductions in synaptic NMDARs by preventing calcineurin overactivation in hippocampal slices. Correlation studies suggested that the protection of NMDAR signaling might underlie the stabilization of BACE1 expression. Our results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of AD and may have therapeutic potential for treating AD in humans.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.4610-12.2013
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2013
    detail.hit.zdb_id: 1475274-8
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  • 7
    Online Resource
    Online Resource
    Epigenetic silencing of a Ca 2+ -regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers
    Proceedings of the National Academy of Sciences ; 2007
    In:  Proceedings of the National Academy of Sciences Vol. 104, No. 30 ( 2007-07-24), p. 12353-12358
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 30 ( 2007-07-24), p. 12353-12358
    Abstract: Ras has achieved notoriety as an oncogene aberrantly activated in multiple human tumors. Approximately 30% of all human tumors express an oncogenic form of this GTPase that is locked in an active conformation as a result of being insensitive to Ras GTPase-activating proteins (GAPs), proteins that normally regulate the inactivation of Ras by enhancing its intrinsic GTPase activity. Besides oncogenic mutations in Ras, signaling by wild-type Ras is also frequently deregulated in tumors through aberrant coupling to activated cell surface receptors. This indicates that alternative mechanisms of aberrant wild-type Ras activation may be involved in tumorigenesis. Here, we describe another mechanism through which aberrant Ras activation is achieved in human cancers. We have established that Ras GTPase-activating-like protein (RASAL), a Ca 2+ -regulated Ras GAP that decodes the frequency of Ca 2+ oscillations, is silenced through CpG methylation in multiple tumors. With the finding that ectopic expression of catalytically active RASAL leads to growth inhibition of these tumor cells by Ras inactivation, we have provided evidence that epigenetically silencing of this Ras GAP represents a mechanism of aberrant Ras activation in certain cancers. Our demonstration that RASAL constitutes a tumor suppressor gene has therefore further emphasized the importance of Ca 2+ in the regulation of Ras signaling and has established that deregulation of this pathway is an important step in Ras-mediated tumorigenesis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0700153104
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
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  • 8
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    Online Resource
    Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 20 ( 2017-05-16), p. 5237-5242
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 20 ( 2017-05-16), p. 5237-5242
    Abstract: DNMT3A is frequently mutated in acute myeloid leukemia (AML). To explore the features of human AML with the hotspot DNMT3A R882H mutation, we generated Dnmt3a R878H conditional knockin mice, which developed AML with enlarged Lin − Sca1 + cKit + cell compartments. The transcriptome and DNA methylation profiling of bulk leukemic cells and the single-cell RNA sequencing of leukemic stem/progenitor cells revealed significant changes in gene expression and epigenetic regulatory patterns that cause differentiation arrest and growth advantage. Consistent with leukemic cell accumulation in G 2 /M phase, CDK1 was up-regulated due to mTOR activation associated with DNA hypomethylation. Overexpressed CDK1-mediated EZH2 phosphorylation resulted in an abnormal trimethylation of H3K27 profile. The mTOR inhibitor rapamycin elicited a significant therapeutic response in Dnmt3a R878H/WT mice.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1703476114
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
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  • 9
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    A mineral-based origin of Earth’s initial hydrogen peroxide and molecular oxygen
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 13 ( 2023-03-28)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 13 ( 2023-03-28)
    Abstract: Terrestrial reactive oxygen species (ROS) may have played a central role in the formation of oxic environments and evolution of early life. The abiotic origin of ROS on the Archean Earth has been heavily studied, and ROS are conventionally thought to have originated from H 2 O/CO 2 dissociation. Here, we report experiments that lead to a mineral-based source of oxygen, rather than water alone. The mechanism involves ROS generation at abraded mineral–water interfaces in various geodynamic processes (e.g., water currents and earthquakes) which are active where free electrons are created via open-shell electrons and point defects, high pressure, water/ice interactions, and combinations of these processes. The experiments reported here show that quartz or silicate minerals may produce reactive oxygen-containing sites (≡SiO•, ≡SiOO•) that initially emerge in cleaving Si–O bonds in silicates and generate ROS during contact with water. Experimental isotope-labeling experiments show that the hydroxylation of the peroxy radical (≡SiOO•) is the predominant pathway for H 2 O 2 generation. This heterogeneous ROS production chemistry allows the transfer of oxygen atoms between water and rocks and alters their isotopic compositions. This process may be pervasive in the natural environment, and mineral-based production of H 2 O 2 and accompanying O 2 could occur on Earth and potentially on other terrestrial planets, providing initial oxidants and free oxygen, and be a component in the evolution of life and planetary habitability.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2221984120
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 10
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    Csi-let-7a-5p delivered by extracellular vesicles from a liver fluke activates M1-like macrophages and exacerbates biliary injuries
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 46 ( 2021-11-16)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 46 ( 2021-11-16)
    Abstract: Chronic infection with liver flukes (such as Clonorchis sinensis ) can induce severe biliary injuries, which can cause cholangitis, biliary fibrosis, and even cholangiocarcinoma. The release of extracellular vesicles by C. sinensis (CsEVs) is of importance in the long-distance communication between the hosts and worms. However, the biological effects of EVs from liver fluke on biliary injuries and the underlying molecular mechanisms remain poorly characterized. In the present study, we found that CsEVs induced M1-like activation. In addition, the mice that were administrated with CsEVs showed severe biliary injuries associated with remarkable activation of M1-like macrophages. We further characterized the signatures of miRNAs packaged in CsEVs and identified a miRNA Csi-let-7a-5p, which was highly enriched. Further study showed that Csi-let-7a-5p facilitated the activation of M1-like macrophages by targeting Socs1 and Clec7a ; however, CsEVs with silencing Csi-let-7a-5p showed a decrease in proinflammatory responses and biliary injuries, which involved in the Socs1- and Clec7a -regulated NF-κB signaling pathway. Our study demonstrates that Csi-let-7a-5p delivered by CsEVs plays a critical role in the activation of M1-like macrophages and contributes to the biliary injuries by targeting the Socs1- and Clec7a -mediated NF-κB signaling pathway, which indicates a mechanism contributing to biliary injuries caused by fluke infection. However, molecules other than Csi-let-7a-5p from CsEVs that may also promote M1-like polarization and exacerbate biliary injuries are not excluded.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2102206118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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