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  • Proceedings of the National Academy of Sciences  (24)
  • 11
    Online Resource
    Online Resource
    Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 33 ( 2014-08-19), p. 12163-12168
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 33 ( 2014-08-19), p. 12163-12168
    Abstract: The RAR-related orphan receptor gamma t (RORγt) is a nuclear receptor required for generating IL-17–producing CD4 + Th17 T cells, which are essential in host defense and may play key pathogenic roles in autoimmune diseases. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol and lipid metabolism. Here, we describe the identification of several naturally occurring oxysterols as RORγt agonists. The most potent and selective activator for RORγt is 7β, 27-dihydroxycholesterol (7β, 27-OHC). We show that these oxysterols reverse the inhibitory effect of an RORγt antagonist, ursolic acid, in RORγ- or RORγt-dependent cell-based reporter assays. These ligands bind directly to recombinant RORγ ligand binding domain (LBD), promote recruitment of a coactivator peptide, and reduce binding of a corepressor peptide to RORγ LBD. In primary cells, 7β, 27-OHC and 7α, 27-OHC enhance the differentiation of murine and human IL-17–producing Th17 cells in an RORγt-dependent manner. Importantly, we showed that Th17, but not Th1 cells, preferentially produce these two oxysterols. In vivo, administration of 7β, 27-OHC in mice enhanced IL-17 production. Mice deficient in CYP27A1, a key enzyme in generating these oxysterols, showed significant reduction of IL-17–producing cells, including CD4 + and γδ + T cells, similar to the deficiency observed in RORγt knockout mice. Our results reveal a previously unknown mechanism for selected oxysterols as immune modulators and a direct role for CYP27A1 in generating these RORγt agonist ligands, which we propose as RORγt endogenous ligands, driving both innate and adaptive IL-17–dependent immune responses.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1322807111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
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  • 12
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    Superresolution fluorescence mapping of single-nanoparticle catalysts reveals spatiotemporal variations in surface reactivity
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 29 ( 2015-07-21), p. 8959-8964
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 29 ( 2015-07-21), p. 8959-8964
    Abstract: For the practical application of nanocatalysts, it is desirable to understand the spatiotemporal fluctuations of nanocatalytic activity at the single-nanoparticle level. Here we use time-lapsed superresolution mapping of single-molecule catalysis events on individual nanoparticles to observe time-varying changes in the spatial distribution of catalysis events on Sb-doped TiO 2 nanorods and Au triangle nanoplates. Compared with the active sites on well-defined surface facets, the defects of the nanoparticle catalysts possess higher intrinsic reactivity but lower stability. Corners and ends are more reactive but also less stable than flat surfaces. Averaged over time, the most stable sites dominate the total apparent activity of single nanocatalysts. However, the active sites with higher intrinsic activity but lower stability show activity at earlier time points before deactivating. Unexpectedly, some active sites are found to recover their activity (“self-healing”) after deactivation, which is probably due to desorption of the adsorbate. Our superresolution measurement of different types of active catalytic sites, over both space and time, leads to a more comprehensive understanding of reactivity patterns and may enable the design of new and more productive heterogeneous catalysts.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1502005112
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
    detail.hit.zdb_id: 209104-5
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  • 13
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    Integrated soil–crop system management for food security
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 16 ( 2011-04-19), p. 6399-6404
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 16 ( 2011-04-19), p. 6399-6404
    Abstract: China and other rapidly developing economies face the dual challenge of substantially increasing yields of cereal grains while at the same time reducing the very substantial environmental impacts of intensive agriculture. We used a model-driven integrated soil–crop system management approach to develop a maize production system that achieved mean maize yields of 13.0 t ha −1 on 66 on-farm experimental plots—nearly twice the yield of current farmers’ practices—with no increase in N fertilizer use. Such integrated soil–crop system management systems represent a priority for agricultural research and implementation, especially in rapidly growing economies.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1101419108
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
    detail.hit.zdb_id: 209104-5
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  • 14
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    STIM1 is a core trigger of airway smooth muscle remodeling and hyperresponsiveness in asthma
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 1 ( 2022-01-05)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 1 ( 2022-01-05)
    Abstract: Airway remodeling and airway hyperresponsiveness are central drivers of asthma severity. Airway remodeling is a structural change involving the dedifferentiation of airway smooth muscle (ASM) cells from a quiescent to a proliferative and secretory phenotype. Here, we show up-regulation of the endoplasmic reticulum Ca 2+ sensor stromal-interacting molecule 1 (STIM1) in ASM of asthmatic mice. STIM1 is required for metabolic and transcriptional reprogramming that supports airway remodeling, including ASM proliferation, migration, secretion of cytokines and extracellular matrix, enhanced mitochondrial mass, and increased oxidative phosphorylation and glycolytic flux. Mechanistically, STIM1-mediated Ca 2+ influx is critical for the activation of nuclear factor of activated T cells 4 and subsequent interleukin-6 secretion and transcription of pro-remodeling transcription factors, growth factors, surface receptors, and asthma-associated proteins. STIM1 drives airway hyperresponsiveness in asthmatic mice through enhanced frequency and amplitude of ASM cytosolic Ca 2+ oscillations. Our data advocates for ASM STIM1 as a target for asthma therapy.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2114557118
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
    detail.hit.zdb_id: 209104-5
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  • 15
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    Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay
    Proceedings of the National Academy of Sciences ; 2018
    In:  Proceedings of the National Academy of Sciences Vol. 115, No. 12 ( 2018-03-20)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 12 ( 2018-03-20)
    Abstract: Frontotemporal dementia (FTD) is the most common neurodegenerative disorder in individuals under age 60 and has no treatment or cure. Because many cases of FTD result from GRN nonsense mutations, an animal model for this type of mutation is highly desirable for understanding pathogenesis and testing therapies. Here, we generated and characterized Grn R493X knockin mice, which model the most common human GRN mutation, a premature stop codon at arginine 493 (R493X). Homozygous Grn R493X mice have markedly reduced Grn mRNA levels, lack detectable progranulin protein, and phenocopy Grn knockout mice, with CNS microgliosis, cytoplasmic TDP-43 accumulation, reduced synaptic density, lipofuscinosis, hyperinflammatory macrophages, excessive grooming behavior, and reduced survival. Inhibition of nonsense-mediated mRNA decay (NMD) by genetic, pharmacological, or antisense oligonucleotide-based approaches showed that NMD contributes to the reduced mRNA levels in Grn R493X mice and cell lines and in fibroblasts from patients containing the GRN R493X mutation. Moreover, the expressed truncated R493X mutant protein was functional in several assays in progranulin-deficient cells. Together, these findings establish a murine model for in vivo testing of NMD inhibition or other therapies as potential approaches for treating progranulin deficiency caused by the R493X mutation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1722344115
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2018
    detail.hit.zdb_id: 209104-5
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  • 16
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    Role for G protein-coupled receptor kinase in agonist-specific regulation of μ-opioid receptor responsiveness
    Proceedings of the National Academy of Sciences ; 1998
    In:  Proceedings of the National Academy of Sciences Vol. 95, No. 12 ( 1998-06-09), p. 7157-7162
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 95, No. 12 ( 1998-06-09), p. 7157-7162
    Abstract: The G protein-coupled μ-opioid receptor (μOR) mediates the physiological effects of endogenous opioid peptides as well as the structurally distinct opioid alkaloids morphine and etorphine. An intriguing feature of μOR signaling is the differential receptor trafficking and desensitization properties following activation by distinct agonists, which have been proposed as possible mechanisms related to opioid tolerance. Here we report that the ability of distinct opioid agonists to differentially regulate μOR internalization and desensitization is related to their ability to promote G protein-coupled receptor kinase (GRK)-dependent phosphorylation of the μOR. Although both etorphine and morphine effectively activate the μOR, only etorphine elicits robust μOR phosphorylation followed by plasma membrane translocation of β-arrestin and dynamin-dependent receptor internalization. In contrast, corresponding to its inability to cause μOR internalization, morphine is unable to either elicit μOR phosphorylation or stimulate β-arrestin translocation. However, upon the overexpression of GRK2, morphine gains the capacity to induce μOR phosphorylation, accompanied by the rescue of β-arrestin translocation and receptor sequestration. Moreover, overexpression of GRK2 also leads to an attenuation of morphine-mediated inhibition of adenylyl cyclase. These findings point to the existence of marked differences in the ability of different opioid agonists to promote μOR phosphorylation by GRK. These differences may provide the molecular basis underlying the different analgesic properties of opioid agonists and contribute to the distinct ability of various opioids to induce drug tolerance.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.95.12.7157
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1998
    detail.hit.zdb_id: 209104-5
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  • 17
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    Large enhancement of thermoelectric performance in MoS 2 / h -BN heterostructure due to vacancy-induced band hybridization
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 25 ( 2020-06-23), p. 13929-13936
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 25 ( 2020-06-23), p. 13929-13936
    Abstract: Local impurity states arising from atomic vacancies in two-dimensional (2D) nanosheets are predicted to have a profound effect on charge transport due to resonant scattering and can be used to manipulate thermoelectric properties. However, the effects of these impurities are often masked by external fluctuations and turbostratic interfaces; therefore, it is challenging to probe the correlation between vacancy impurities and thermoelectric parameters experimentally. In this work, we demonstrate that n-type molybdenum disulfide (MoS 2 ) supported on hexagonal boron nitride ( h -BN) substrate reveals a large anomalous positive Seebeck coefficient with strong band hybridization. The presence of vacancies on MoS 2 with a large conduction subband splitting of 50.0 ± 5.0 meV may contribute to Kondo insulator-like properties. Furthermore, by tuning the chemical potential, the thermoelectric power factor can be enhanced by up to two orders of magnitude to 50 mW m −1 K −2 . Our work shows that defect engineering in 2D materials provides an effective strategy for controlling band structure and tuning thermoelectric transport.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2007495117
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
    detail.hit.zdb_id: 209104-5
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  • 18
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    Gap junction-mediated intercellular biochemical coupling in cochlear supporting cells is required for normal cochlear functions
    Proceedings of the National Academy of Sciences ; 2005
    In:  Proceedings of the National Academy of Sciences Vol. 102, No. 42 ( 2005-10-18), p. 15201-15206
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 42 ( 2005-10-18), p. 15201-15206
    Abstract: Dysfunction of gap junctions (GJs) caused by mutations in connexin26 (Cx26) and Cx30 accounts for nearly half of all cases of hereditary nonsyndromic deafness cases. Although it is widely held that GJs connecting supporting cells in the organ of Corti mainly provide ionic pathways for rapid removal of K + around the base of hair cells, the function of GJs in the cochlea remains unknown. Here we show that GJs were not assembled in the supporting cells of the organ of Corti until 3 days after birth in mice and then gradually matured to connect supporting cells before the onset of hearing. In organotypic cochlear cultures that were confirmed to express GJs, GJs mediated the propagation of intracellular Ca 2+ concentration waves in supporting cells by allowing intercellular diffusion of inositol 1,4,5-trisphosphate. We found that a subset of structurally mild Cx26 mutations located at the second transmembrane region (V84L, V95M, and A88S) and a Cx30 mutation located at the first cytoplasmic segment (T5M) specifically affect the intercellular exchange of larger molecules but leave the ionic permeability intact. Our results indicated that Cx26 and Cx30 mutations that are linked to sensorineural deafness retained ionic coupling but were deficient in biochemical permeability. Therefore, GJ-mediated intercellular exchange of biochemically important molecules is required for normal cochlear functions.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0501859102
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2005
    detail.hit.zdb_id: 209104-5
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  • 19
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    Inducible protein knockout reveals temporal requirement of CaMKII reactivation for memory consolidation in the brain
    Proceedings of the National Academy of Sciences ; 2003
    In:  Proceedings of the National Academy of Sciences Vol. 100, No. 7 ( 2003-04), p. 4287-4292
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 100, No. 7 ( 2003-04), p. 4287-4292
    Abstract: By integrating convergent protein engineering and rational inhibitor design, we have developed an in vivo conditional protein knockout and/or manipulation technology. This method is based on the creation of a specific interaction interface between a modified protein domain and sensitized inhibitors. By introducing this system into genetically modified mice, we can readily manipulate the activity of a targeted protein, such as α-Ca 2+ /calmodulin-dependent protein kinase II (αCAMKII), on the time scale of minutes in specific brain subregions of freely behaving mice. With this inducible and region-specific protein knockout technique, we analyzed the temporal stages of memory consolidation process and revealed the first postlearning week as the critical time window during which a precise level of CaMKII reactivation is essential for the consolidation of long-term memories in the brain.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0636870100
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2003
    detail.hit.zdb_id: 209104-5
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  • 20
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    Simultaneous inhibition of two regulatory T-cell subsets enhanced Interleukin-15 efficacy in a prostate tumor model
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 16 ( 2012-04-17), p. 6187-6192
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 16 ( 2012-04-17), p. 6187-6192
    Abstract: IL-15 has potential as an immunotherapeutic agent for cancer treatment because of its ability to effectively stimulate CD8 T cell, natural killer T cell, and natural killer cell immunity. However, its effectiveness may be limited by negative immunological checkpoints that attenuate immune responses. Recently a clinical trial of IL-15 in cancer immunotherapy was initiated. Finding strategies to conquer negative regulators and enhance efficacy of IL-15 is critical and meaningful for such clinical trials. In a preclinical study, we evaluated IL-15 combined with antibodies to block negative immune regulator cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) in an established murine transgenic adenocarcinoma of mouse prostate (TRAMP)-C2 prostate tumor model. IL-15 treatment resulted in a significant prolongation of survival in tumor-bearing animals. Coadministration of anti-PD-L1 or anti-CTLA-4 singly with IL-15 did not improve animal survival over that of IL-15 alone. However, simultaneous administration of IL-15 with anti-CTLA-4 and anti-PD-L1 was associated with increased numbers of tumor antigen-specific tetramer-positive CD8 T cells, increased CD8 T-cell tumor lytic activity, augmented antigen-specific IFN-γ release, decreased rates of tumor growth, and improved animal survival compared with IL-15 alone. Furthermore, triple combination therapy was associated with inhibition of suppressive functions of CD4 + CD25 + regulatory T cells and CD8 + CD122 + regulatory T cells. Thus, simultaneous blockade of CTLA-4 and PD-L1 protected CD4 and/or CD8 T-cell activity from these regulatory T cells. Combining the immune stimulatory properties of IL-15 with simultaneous removal of two critical immune inhibitory checkpoints, we showed enhancement of immune responses, leading to increased antitumor activity.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1203479109
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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