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  • 1
    Online Resource
    Online Resource
    Coupling of COPII vesicle trafficking to nutrient availability by the IRE1α-XBP1s axis
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 24 ( 2019-06-11), p. 11776-11785
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 24 ( 2019-06-11), p. 11776-11785
    Abstract: The cytoplasmic coat protein complex-II (COPII) is evolutionarily conserved machinery that is essential for efficient trafficking of protein and lipid cargos. How the COPII machinery is regulated to meet the metabolic demand in response to alterations of the nutritional state remains largely unexplored, however. Here, we show that dynamic changes of COPII vesicle trafficking parallel the activation of transcription factor X-box binding protein 1 (XBP1s), a critical transcription factor in handling cellular endoplasmic reticulum (ER) stress in both live cells and mouse livers upon physiological fluctuations of nutrient availability. Using live-cell imaging approaches, we demonstrate that XBP1s is sufficient to promote COPII-dependent trafficking, mediating the nutrient stimulatory effects. Chromatin immunoprecipitation (ChIP) coupled with high-throughput DNA sequencing (ChIP-seq) and RNA-sequencing analyses reveal that nutritional signals induce dynamic XBP1s occupancy of promoters of COPII traffic-related genes, thereby driving the COPII-mediated trafficking process. Liver-specific disruption of the inositol-requiring enzyme 1α (IRE1α)–XBP1s signaling branch results in diminished COPII vesicle trafficking. Reactivation of XBP1s in mice lacking hepatic IRE1α restores COPII-mediated lipoprotein secretion and reverses the fatty liver and hypolipidemia phenotypes. Thus, our results demonstrate a previously unappreciated mechanism in the metabolic control of liver protein and lipid trafficking: The IRE1α-XBP1s axis functions as a nutrient-sensing regulatory nexus that integrates nutritional states and the COPII vesicle trafficking.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1814480116
    RVK:
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    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 2
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    A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging
    American Association for the Advancement of Science (AAAS) ; 2015
    In:  Science Vol. 348, No. 6239 ( 2015-06-05), p. 1160-1163
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 348, No. 6239 ( 2015-06-05), p. 1160-1163
    Abstract: Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina–heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aaa1356
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2015
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  • 3
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    History of winning remodels thalamo-PFC circuit to reinforce social dominance
    American Association for the Advancement of Science (AAAS) ; 2017
    In:  Science Vol. 357, No. 6347 ( 2017-07-14), p. 162-168
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 357, No. 6347 ( 2017-07-14), p. 162-168
    Abstract: Mental strength and history of winning play an important role in the determination of social dominance. However, the neural circuits mediating these intrinsic and extrinsic factors have remained unclear. Working in mice, we identified a dorsomedial prefrontal cortex (dmPFC) neural population showing “effort”-related firing during moment-to-moment competition in the dominance tube test. Activation or inhibition of the dmPFC induces instant winning or losing, respectively. In vivo optogenetic-based long-term potentiation and depression experiments establish that the mediodorsal thalamic input to the dmPFC mediates long-lasting changes in the social dominance status that are affected by history of winning. The same neural circuit also underlies transfer of dominance between different social contests. These results provide a framework for understanding the circuit basis of adaptive and pathological social behaviors.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aak9726
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2017
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  • 4
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    Integrated analysis of phenome, genome, and transcriptome of hybrid rice uncovered multiple heterosis-related loci for yield increase
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 41 ( 2016-10-11)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 41 ( 2016-10-11)
    Abstract: Hybrid rice is the dominant form of rice planted in China, and its use has extended worldwide since the 1970s. It offers great yield advantages and has contributed greatly to the world’s food security. However, the molecular mechanisms underlying heterosis have remained a mystery. In this study we integrated genetics and omics analyses to determine the candidate genes for yield heterosis in a model two-line rice hybrid system, Liang-you-pei 9 (LYP9) and its parents. Phenomics study revealed that the better parent heterosis (BPH) of yield in hybrid is not ascribed to BPH of all the yield components but is specific to the BPH of spikelet number per panicle (SPP) and paternal parent heterosis (PPH) of effective panicle number (EPN). Genetic analyses then identified multiple quantitative trait loci (QTLs) for these two components. Moreover, a number of differentially expressed genes and alleles in the hybrid were mapped by transcriptome profiling to the QTL regions as possible candidate genes. In parallel, a major QTL for yield heterosis, rice heterosis 8 ( RH8 ), was found to be the DTH8 / Ghd8 / LHD1 gene. Based on the shared allelic heterozygosity of RH8 in many hybrid rice cultivars, a common mechanism for yield heterosis in the present commercial hybrid rice is proposed.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1610115113
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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  • 5
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    Online Resource
    Genome sequence of the progenitor of the wheat D genome Aegilops tauschii
    Springer Science and Business Media LLC ; 2017
    In:  Nature Vol. 551, No. 7681 ( 2017-11), p. 498-502
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 551, No. 7681 ( 2017-11), p. 498-502
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/nature24486
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    RVK:
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
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  • 6
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    Transcriptional regulation of intermolecular Ca 2+ signaling in hibernating ground squirrel cardiomyocytes: The myocardin–junctophilin axis
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 14 ( 2021-04-06)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 14 ( 2021-04-06)
    Abstract: The contraction of heart cells is controlled by the intermolecular signaling between L-type Ca 2+ channels (LCCs) and ryanodine receptors (RyRs), and the nanodistance between them depends on the interaction between junctophilin-2 (JPH2) in the sarcoplasmic reticulum (SR) and caveolin-3 (CAV3) in the transversal tubule (TT). In heart failure, decreased expression of JPH2 compromises LCC–RyR communication leading to deficient blood-pumping power. In the present study, we found that JPH2 and CAV3 transcription was concurrently regulated by serum response factor (SRF) and myocardin. In cardiomyocytes from torpid ground squirrels, compared with those from euthermic counterparts, myocardin expression was up-regulated, which boosted both JPH2 and CAV3 expression. Transmission electron microscopic imaging showed that the physical coupling between TTs and SRs was tightened during hibernation and after myocardin overexpression. Confocal Ca 2+ imaging under the whole-cell patch clamp condition revealed that these changes enhanced the efficiency of LCC–RyR intermolecular signaling and fully compensated the adaptive down-regulation of LCCs, maintaining the power of heart contraction while avoiding the risk of calcium overload during hibernation. Our finding not only revealed an essential molecular mechanism underlying the survival of hibernating mammals, but also demonstrated a “reverse model of heart failure” at the molecular level, suggesting a strategy for treating heart diseases.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2025333118
    RVK:
    TA 1000
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
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  • 7
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    PGE 2 signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 20 ( 2019-05-14), p. 10019-10024
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 20 ( 2019-05-14), p. 10019-10024
    Abstract: The inflammatory prostaglandin E2 (PGE 2 ) EP2 receptor is a master suppressor of beneficial microglial function, and myeloid EP2 signaling ablation reduces pathology in models of inflammatory neurodegeneration. Here, we investigated the role of PGE 2 EP2 signaling in a model of stroke in which the initial cerebral ischemic event is followed by an extended poststroke inflammatory response. Myeloid lineage cell-specific EP2 knockdown in Cd11bCre;EP2 lox/lox mice attenuated brain infiltration of Cd11b + CD45 hi macrophages and CD45 + Ly6G hi neutrophils, indicating that inflammatory EP2 signaling participates in the poststroke immune response. Inducible global deletion of the EP2 receptor in adult ROSA26-CreER T2 (ROSACreER);EP2 lox/lox mice also reduced brain myeloid cell trafficking but additionally reduced stroke severity, suggesting that nonimmune EP2 receptor-expressing cell types contribute to cerebral injury. EP2 receptor expression was highly induced in neurons in the ischemic hemisphere, and postnatal deletion of the neuronal EP2 receptor in Thy1Cre;EP2 lox/lox mice reduced cerebral ischemic injury. These findings diverge from previous studies of congenitally null EP2 receptor mice where a global deletion increases cerebral ischemic injury. Moreover, ROSACreER;EP2 lox/lox mice, unlike EP2 −/− mice, exhibited normal learning and memory, suggesting a confounding effect from congenital EP2 receptor deletion. Taken together with a precedent that inhibition of EP2 signaling is protective in inflammatory neurodegeneration, these data lend support to translational approaches targeting the EP2 receptor to reduce inflammation and neuronal injury that occur after stroke.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1818544116
    RVK:
    TA 1000
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 8
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    Metallacage-based enhanced PDT strategy for bacterial elimination via inhibiting endogenous NO production
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 29 ( 2023-07-18)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 29 ( 2023-07-18)
    Abstract: Antibiotics are among the most used weapons in fighting microbial infections and have greatly improved the quality of human life. However, bacteria can eventually evolve to exhibit antibiotic resistance to almost all prescribed antibiotic drugs. Photodynamic therapy (PDT) develops little antibiotic resistance and has become a promising strategy in fighting bacterial infection. To augment the killing effect of PDT, the conventional strategy is introducing excess ROS in various ways, such as applying high light doses, high photosensitizer concentrations, and exogenous oxygen. In this study, we report a metallacage-based PDT strategy that minimizes the use of ROS by jointly using gallium-metal organic framework rods to inhibit the production of bacterial endogenous NO, amplify ROS stress, and enhance the killing effect. The augmented bactericidal effect was demonstrated both in vitro and in vivo. This proposed enhanced PDT strategy will provide a new option for bacterial ablation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2218973120
    RVK:
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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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    A SUMOylation-Dependent Transcriptional Subprogram Is Required for Myc-Driven Tumorigenesis
    American Association for the Advancement of Science (AAAS) ; 2012
    In:  Science Vol. 335, No. 6066 ( 2012-01-20), p. 348-353
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 335, No. 6066 ( 2012-01-20), p. 348-353
    Abstract: Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we used a genome-wide RNA interference screen to search for Myc–synthetic lethal genes and uncovered a role for the SUMO-activating enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Inactivation of SAE2 leads to mitotic catastrophe and cell death upon Myc hyperactivation. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent Myc switchers (SMS genes) is required for mitotic spindle function and to support the Myc oncogenic program. SAE2 is required for growth of Myc-dependent tumors in mice, and gene expression analyses of Myc-high human breast cancers suggest that low SAE1 and SAE2 abundance in the tumors correlates with longer metastasis-free survival of the patients. Thus, inhibition of SUMOylation may merit investigation as a possible therapy for Myc-driven human cancers.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1212728
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2012
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  • 10
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    Screening membraneless organelle participants with machine-learning models that integrate multimodal features
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 24 ( 2022-06-14)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 24 ( 2022-06-14)
    Abstract: Protein self-assembly is one of the formation mechanisms of biomolecular condensates. However, most phase-separating systems (PS) demand multiple partners in biological conditions. In this study, we divided PS proteins into two groups according to the mechanism by which they undergo PS: PS-Self proteins can self-assemble spontaneously to form droplets, while PS-Part proteins interact with partners to undergo PS. Analysis of the amino acid composition revealed differences in the sequence pattern between the two protein groups. Existing PS predictors, when evaluated on two test protein sets, preferentially predicted self-assembling proteins. Thus, a comprehensive predictor is required. Herein, we propose that properties other than sequence composition can provide crucial information in screening PS proteins. By incorporating phosphorylation frequencies and immunofluorescence image-based droplet-forming propensity with other PS-related features, we built two independent machine-learning models to separately predict the two protein categories. Results of independent testing suggested the superiority of integrating multimodal features. We performed experimental verification on the top-scored proteins DHX9, K i -67, and NIFK. Their PS behavior in vitro revealed the effectiveness of our models in PS prediction. Further validation on the proteome of membraneless organelles confirmed the ability of our models to identify PS-Part proteins. We implemented a web server named PhaSePred ( http://predict.phasep.pro/ ) that incorporates our two models together with representative PS predictors. PhaSePred displays proteome-level quantiles of different features, thus profiling PS propensity and providing crucial information for identification of candidate proteins.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2115369119
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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