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  • 1
    Online Resource
    Online Resource
    Mechanism of siRNA production by a plant Dicer-RNA complex in dicing-competent conformation
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Vol. 374, No. 6571 ( 2021-11-26), p. 1152-1157
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 374, No. 6571 ( 2021-11-26), p. 1152-1157
    Abstract: In eukaryotes, small RNAs (sRNAs) play critical roles in multiple biological processes. Dicer endonucleases are a central part of sRNA biogenesis. In plants, DICER-LIKE PROTEIN 3 (DCL3) produces 24-nucleotide (nt) small interfering RNAs (siRNAs) that determine the specificity of the RNA-directed DNA methylation pathway. Here, we determined the structure of a DCL3–pre-siRNA complex in an active dicing-competent state. The 5′-phosphorylated A1 of the guide strand and the 1-nt 3′ overhang of the complementary strand are specifically recognized by a positively charged pocket and an aromatic cap, respectively. The 24-nt siRNA length dependence relies on the separation between the 5′-phosphorylated end of the guide RNA and dual cleavage sites formed by the paired ribonuclease III domains. These structural studies, complemented by functional data, provide insight into the dicing principle for Dicers in general.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abl4546
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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    detail.hit.zdb_id: 2060783-0
    SSG: 11
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Brown-fat-mediated tumour suppression by cold-altered global metabolism
    Springer Science and Business Media LLC ; 2022
    In:  Nature Vol. 608, No. 7922 ( 2022-08-11), p. 421-428
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 608, No. 7922 ( 2022-08-11), p. 421-428
    Abstract: Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues 1–6 . Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis 2,7,8 . Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes 4,5,9 . However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1 —the key mediator for BAT-thermogenesis—ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-022-05030-3
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 3
    Online Resource
    Online Resource
    Deep learning guided optimization of human antibody against SARS-CoV-2 variants with broad neutralization
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 11 ( 2022-03-15)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 11 ( 2022-03-15)
    Abstract: The ability of viruses to mutate and evade the human immune system and neutralizing antibodies remains an obstacle to antiviral and vaccine development. Many neutralizing antibodies, including some approved for emergency use authorization (EUA), reduced or lost activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Here, we introduce a geometric deep learning algorithm that efficiently enhances antibody affinity to achieve broader and more potent neutralizing activity against such variants. We demonstrate the utility of our approach on a human antibody P36-5D2, which is effective against SARS-CoV-2 Alpha, Beta, and Gamma but not Delta. We show that our geometric neural network model optimizes this antibody’s complementarity-determining region (CDR) sequences to improve its binding affinity against multiple SARS-CoV-2 variants. Through iterative optimization of the CDR regions and experimental measurements, we enable expanded antibody breadth and improved potency by ∼10- to 600-fold against SARS-CoV-2 variants, including Delta. We have also demonstrated that our approach can identify CDR changes that alleviate the impact of two Omicron mutations on the epitope. These results highlight the power of our deep learning approach in antibody optimization and its potential application to engineering other protein molecules. Our optimized antibodies can potentially be developed into antibody drug candidates for current and emerging SARS-CoV-2 variants.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2122954119
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 4
    Online Resource
    Online Resource
    Drosophila YBX1 homolog YPS promotes ovarian germ line stem cell development by preferentially recognizing 5-methylcytosine RNAs
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 7 ( 2020-02-18), p. 3603-3609
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 7 ( 2020-02-18), p. 3603-3609
    Abstract: 5-Methylcytosine (m 5 C) is a RNA modification that exists in tRNAs and rRNAs and was recently found in mRNAs. Although it has been suggested to regulate diverse biological functions, whether m 5 C RNA modification influences adult stem cell development remains undetermined. In this study, we show that Ypsilon schachtel (YPS), a homolog of human Y box binding protein 1 (YBX1), promotes germ line stem cell (GSC) maintenance, proliferation, and differentiation in the Drosophila ovary by preferentially binding to m 5 C-containing RNAs. YPS is genetically demonstrated to function intrinsically for GSC maintenance, proliferation, and progeny differentiation in the Drosophila ovary, and human YBX1 can functionally replace YPS to support normal GSC development. Highly conserved cold-shock domains (CSDs) of YPS and YBX1 preferentially bind to m 5 C RNA in vitro. Moreover, YPS also preferentially binds to m 5 C-containing RNAs, including mRNAs, in germ cells. The crystal structure of the YBX1 CSD-RNA complex reveals that both hydrophobic stacking and hydrogen bonds are critical for m 5 C binding. Overexpression of RNA-binding–defective YPS and YBX1 proteins disrupts GSC development. Taken together, our findings show that m 5 C RNA modification plays an important role in adult stem cell development.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1910862117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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