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  • 1
    Online Resource
    Online Resource
    Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 16 ( 2010-04-20), p. 7449-7454
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 16 ( 2010-04-20), p. 7449-7454
    Abstract: Cisplatin is a chemotherapeutic drug commonly used in clinics. However, acquired resistance confines its application in chemotherapeutics. To overcome the acquired resistance to cisplatin, it is reasoned, based on our previous findings of mediation of cellular responses by [Gd@C 82 (OH) 22 ] n nanoparticles, that [Gd@C 82 (OH) 22 ] n may reverse tumor resistance to cisplatin by reactivating the impaired endocytosis of cisplatin-resistant human prostate cancer (CP-r) cells. Here we report that exposure of the CP-r PC-3-luc cells to cisplatin in the presence of nontoxic [Gd@C 82 (OH) 22 ] n not only decreased the number of surviving CP-r cells but also inhibited growth of the CP-r tumors in athymic nude mice as measured by both optical and MRI. Labeling the CP-r PC-3 cells with transferrin, an endocytotic marker, demonstrated that pretreatment of the CP-r PC-3-luc cells with [Gd@C 82 (OH) 22 ] n enhanced intracellular accumulation of cisplatin and formation of cisplatin-DNA adducts by restoring the defective endocytosis of the CP-r cancer cells. The results suggest that [Gd@C 82 (OH) 22 ] n nanoparticles overcome tumor resistance to cisplatin by increasing its intracellular accumulation through the mechanism of restoring defective endocytosis. The technology can be extended to other challenges related to multidrug resistance often found in cancer treatments.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0909707107
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 2
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    Online Resource
    Breeding signatures of rice improvement revealed by a genomic variation map from a large germplasm collection
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 39 ( 2015-09-29)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 39 ( 2015-09-29)
    Abstract: Intensive rice breeding over the past 50 y has dramatically increased productivity especially in the indica subspecies, but our knowledge of the genomic changes associated with such improvement has been limited. In this study, we analyzed low-coverage sequencing data of 1,479 rice accessions from 73 countries, including landraces and modern cultivars. We identified two major subpopulations, indica I ( IndI ) and indica II ( IndII ), in the indica subspecies, which corresponded to the two putative heterotic groups resulting from independent breeding efforts. We detected 200 regions spanning 7.8% of the rice genome that had been differentially selected between IndI and IndII , and thus referred to as breeding signatures. These regions included large numbers of known functional genes and loci associated with important agronomic traits revealed by genome-wide association studies. Grain yield was positively correlated with the number of breeding signatures in a variety, suggesting that the number of breeding signatures in a line may be useful for predicting agronomic potential and the selected loci may provide targets for rice improvement.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1515919112
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
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  • 3
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    Online Resource
    CDK7 inhibition suppresses aberrant hedgehog pathway and overcomes resistance to smoothened antagonists
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 26 ( 2019-06-25), p. 12986-12995
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 26 ( 2019-06-25), p. 12986-12995
    Abstract: The aberrant hedgehog (Hh) pathway plays important roles in multiple cancer types, therefore serving as a promising drug target. Current clinically available hedgehog-targeted drugs act mostly by antagonizing the upstream component smoothened; however, both primary and acquired resistance to FDA-approved smoothened inhibitor (SMOi) drugs have been described. We have recently demonstrated that the BET inhibitor effectively suppresses SMOi-resistant Hh-driven cancers through antagonizing transcription of GLI1 and GLI2, the core transcriptional factors of Hh pathway, suggesting epigenetic or transcriptional targeted therapy represents an anti-Hh therapeutic strategy that can overcome SMOi resistance. Here we performed an unbiased screening of epigenetic or transcriptional targeted small molecules to test their inhibitory effects on GLI1 and GLI2 transcription or cell viability of Hh-driven tumor lines. THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), is identified as the top hit in our screening. We then confirmed that antagonizing CDK7 by either small-molecule inhibitors or the CRISPR-Cas9 approach causes substantial suppression of GLI1 and GLI2 transcription, resulting in effective inhibition of Hh-driven cancers in vitro and in vivo. More importantly, antagonizing CDK7 retains inhibitory activity against Hh-driven cancers with almost all so-far described primary or acquired SMOi resistance. Furthermore, we reveal a synergy between CDK7 inhibition and BET inhibition on antagonizing aberrant Hh pathway and Hh-driven cancers that are either responsive or resistant to SMOi. Our results illustrate transcriptional inhibition through targeting CDK7 as a promising therapeutic strategy for treating Hh-driven cancers, especially those with primary or acquired resistance to SMOi drugs.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1815780116
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 4
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    A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption
    American Association for the Advancement of Science (AAAS) ; 2018
    In:  Science Vol. 360, No. 6393 ( 2018-06-08), p. 1087-1092
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 360, No. 6393 ( 2018-06-08), p. 1087-1092
    Abstract: A high concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease. Although LDL-C levels vary among humans and are heritable, the genetic factors affecting LDL-C are not fully characterized. We identified a rare frameshift variant in the LIMA1 (also known as EPLIN or SREBP3 ) gene from a Chinese family of Kazakh ethnicity with inherited low LDL-C and reduced cholesterol absorption. In a mouse model, LIMA1 was mainly expressed in the small intestine and localized on the brush border membrane. LIMA1 bridged NPC1L1, an essential protein for cholesterol absorption, to a transportation complex containing myosin Vb and facilitated cholesterol uptake. Similar to the human phenotype, Lima1 -deficient mice displayed reduced cholesterol absorption and were resistant to diet-induced hypercholesterolemia. Through our study of both mice and humans, we identify LIMA1 as a key protein regulating intestinal cholesterol absorption.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aao6575
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2018
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  • 5
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    Structural insights into Ras regulation by SIN1
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 19 ( 2022-05-10)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 19 ( 2022-05-10)
    Abstract: Over the years it has been established that SIN1, a key component of mTORC2, could interact with Ras family small GTPases through its Ras-binding domain (RBD). The physical association of Ras and SIN1/mTORC2 could potentially affect both mTORC2 and Ras-ERK pathways. To decipher the precise molecular mechanism of this interaction, we determined the high-resolution structures of HRas/KRas-SIN1 RBD complexes, showing the detailed interaction interface. Mutation of critical interface residues abolished Ras-SIN1 interaction and in SIN1 knockout cells we demonstrated that Ras-SIN1 association promotes SGK1 activity but inhibits insulin-induced ERK activation. With structural comparison and competition fluorescence resonance energy transfer (FRET) assays we showed that HRas-SIN1 RBD association is much weaker than HRas-Raf1 RBD but is slightly stronger than HRas-PI3K RBD interaction, providing a possible explanation for the different outcome of insulin or EGF stimulation. We also found that SIN1 isoform lacking the PH domain binds stronger to Ras than other longer isoforms and the PH domain appears to have an inhibitory effect on Ras-SIN1 binding. In addition, we uncovered a Ras dimerization interface that could be critical for Ras oligomerization. Our results advance our understanding of Ras-SIN1 association and crosstalk between growth factor-stimulated pathways.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2119990119
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
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  • 6
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    Online Resource
    Bug mapping and fitness testing of chemically synthesized chromosome X
    American Association for the Advancement of Science (AAAS) ; 2017
    In:  Science Vol. 355, No. 6329 ( 2017-03-10)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 355, No. 6329 ( 2017-03-10)
    Abstract: Debugging a genome sequence is imperative for successfully building a synthetic genome. As part of the effort to build a designer eukaryotic genome, yeast synthetic chromosome X (synX), designed as 707,459 base pairs, was synthesized chemically. SynX exhibited good fitness under a wide variety of conditions. A highly efficient mapping strategy called pooled PCRTag mapping (PoPM), which can be generalized to any watermarked synthetic chromosome, was developed to identify genetic alterations that affect cell fitness (“bugs”). A series of bugs were corrected that included a large region bearing complex amplifications, a growth defect mapping to a recoded sequence in FIP1 , and a loxPsym site affecting promoter function of ATP2 . PoPM is a powerful tool for synthetic yeast genome debugging and an efficient strategy for phenotype-genotype mapping.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aaf4706
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2017
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  • 7
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    Online Resource
    CRL4 Complex Regulates Mammalian Oocyte Survival and Reprogramming by Activation of TET Proteins
    American Association for the Advancement of Science (AAAS) ; 2013
    In:  Science Vol. 342, No. 6165 ( 2013-12-20), p. 1518-1521
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 342, No. 6165 ( 2013-12-20), p. 1518-1521
    Abstract: The duration of a woman’s reproductive period is determined by the size and persistence of a dormant oocyte pool. Specific oocyte genes are essential for follicle maintenance and female fertility. The mechanisms that regulate the expression of these genes are poorly understood. We found that a cullin-ring finger ligase-4 (CRL4) complex was crucial in this process. Oocyte-specific deletion of the CRL4 linker protein DDB1 or its substrate adaptor VPRBP (also known as DCAF1) caused rapid oocyte loss, premature ovarian insufficiency, and silencing of fertility maintaining genes. CRL4 VPRBP activates the TET methylcytosine dioxygenases, which are involved in female germ cell development and zygote genome reprogramming. Hence, CRL4 VPRBP ubiquitin ligase is a guardian of female reproductive life in germ cells and a maternal reprogramming factor after fertilization.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1244587
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2013
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  • 8
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    Actuation-enhanced multifunctional sensing and information recognition by magnetic artificial cilia arrays
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 42 ( 2023-10-17)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 42 ( 2023-10-17)
    Abstract: Artificial cilia integrating both actuation and sensing functions allow simultaneously sensing environmental properties and manipulating fluids in situ, which are promising for environment monitoring and fluidic applications. However, existing artificial cilia have limited ability to sense environmental cues in fluid flows that have versatile information encoded. This limits their potential to work in complex and dynamic fluid-filled environments. Here, we propose a generic actuation-enhanced sensing mechanism to sense complex environmental cues through the active interaction between artificial cilia and the surrounding fluidic environments. The proposed mechanism is based on fluid–cilia interaction by integrating soft robotic artificial cilia with flexible sensors. With a machine learning-based approach, complex environmental cues such as liquid viscosity, environment boundaries, and distributed fluid flows of a wide range of velocities can be sensed, which is beyond the capability of existing artificial cilia. As a proof of concept, we implement this mechanism on magnetically actuated cilia with integrated laser-induced graphene-based sensors and demonstrate sensing fluid apparent viscosity, environment boundaries, and fluid flow speed with a reconfigurable sensitivity and range. The same principle could be potentially applied to other soft robotic systems integrating other actuation and sensing modalities for diverse environmental and fluidic applications.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2308301120
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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  • 9
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    Reduced default mode network functional connectivity in patients with recurrent major depressive disorder
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 18 ( 2019-04-30), p. 9078-9083
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 18 ( 2019-04-30), p. 9078-9083
    Abstract: Major depressive disorder (MDD) is common and disabling, but its neuropathophysiology remains unclear. Most studies of functional brain networks in MDD have had limited statistical power and data analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. Twenty-five research groups in China established the REST-meta-MDD Consortium by contributing R-fMRI data from 1,300 patients with MDD and 1,128 normal controls (NCs). Data were preprocessed locally with a standardized protocol before aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to be increased in MDD. Instead, we found decreased DMN FC when we compared 848 patients with MDD to 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naïve MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDD. Exploratory analyses also revealed alterations in FC of visual, sensory-motor, and dorsal attention networks in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates response to treatment. All R-fMRI indices of data contributed by the REST-meta-MDD consortium are being shared publicly via the R-fMRI Maps Project.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1900390116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 10
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    Induction of USP25 by viral infection promotes innate antiviral responses by mediating the stabilization of TRAF3 and TRAF6
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 36 ( 2015-09-08), p. 11324-11329
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 36 ( 2015-09-08), p. 11324-11329
    Abstract: Host pathogen-recognition receptors detect nucleic acid from invading viruses and initiate a series of signaling pathways that lead to the production of type I interferons (IFNs) and proinflammatory cytokines. Here, we found that a viral infection-induced deubiquitinase (DUB), ubiquitin-specific protease 25 (USP25) was required for host defense against RNA and DNA viruses. The activation of transcription factors IRF3 and NF-κB was impaired and the production of type I IFNs and proinflammatory cytokines was inhibited in Usp25 −/− cells compared with the wild-type counterparts after RNA or DNA viruses infection. Consistently, USP25 deficient mice were more susceptible to H5N1 or HSV-1 infection compared with the wild-type mice. USP25 was associated with TRAF3 and TRAF6 after infection by RNA or DNA viruses and protected virus-induced proteasome-dependent or independent degradation of TRAF3 and TRAF6, respectively. Moreover, reconstitution of TRAF3 and TRAF6 into Usp25 −/− MEFs restored virus-triggered production of type I IFNs and proinflammatory cytokines. Our findings thus reveal a previously uncovered positive feedback regulation of innate immune responses against RNA and DNA viruses by USP25.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1509968112
    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
    detail.hit.zdb_id: 1461794-8
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