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  • 1
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 34 ( 2013-08-20), p. 13863-13868
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 34 ( 2013-08-20), p. 13863-13868
    Abstract: Mouse bone marrow-derived Lin − -Sca-1 + endothelial progenitor cell (EPC) has pluripotent abilities such as supporting neovascularization. Vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) (Flt1) recognizes various VEGF isoforms and is critically implicated in a wide range of physiological and pathological settings, including vasculogenesis. Mouse EPC expresses two isoforms of VEGFR1: mFlt1, which transmits ligand-induced signals; and sFlt1, which acts as a negative regulator by sequestering ligands of VEGF receptors. How the relative levels of mFlt1 and sFlt1 are regulated is not yet clear. We report here that tumor necrosis factor superfamily 15 (TNFSF15) (also known as VEGI or TL1A), an endothelial cell-secreted cytokine, simultaneously promotes mFlt1 degradation and up-regulates sFlt1 expression in EPC, giving rise to disruption of VEGF- or PlGF-induced activation of eNOS and MAPK p38 and effective inhibition of VEGF-driven, EPC-supported vasculogenesis in a murine Matrigel implant model. TNFSF15 treatment of EPC cultures facilitates Akt deactivation-dependent, ubiquitin-assisted degradation of mFlt1 and stimulates sFlt1 expression by activating the PKC, Src, and Erk1/2 signaling pathway. Additionally, TNFSF15 promotes alternative splicing of the Flt1 gene in favor of sFlt1 production by down-regulating nuclear protein Jumonji domain-containing protein 6 (Jmjd6), thus alleviating Jmjd6-inhibited sFlt1 expression. These findings indicate that TNFSF15 is a key component of a molecular mechanism that negatively modulates EPC-supported vasculogenesis through regulation of the relative levels of mFlt1 and sFlt1 in EPC.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
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  • 2
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 8 ( 2013-02-19), p. 3167-3172
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 8 ( 2013-02-19), p. 3167-3172
    Abstract: The phytohormone cytokinin (CK) positively regulates the activity and function of the shoot apical meristem (SAM), which is a major parameter determining seed production. The rice ( Oryza sativa L.) Gn1a / OsCKX2 ( Grain number 1a / Cytokinin oxidase 2 ) gene, which encodes a cytokinin oxidase, has been identified as a major quantitative trait locus contributing to grain number improvement in rice breeding practice. However, the molecular mechanism of how the expression of OsCKX2 is regulated in planta remains elusive. Here, we report that the zinc finger transcription factor DROUGHT AND SALT TOLERANCE (DST) directly regulates OsCKX2 expression in the reproductive meristem. DST-directed expression of OsCKX2 regulates CK accumulation in the SAM and, therefore, controls the number of the reproductive organs. We identify that DST reg1 , a semidominant allele of the DST gene, perturbs DST-directed regulation of OsCKX2 expression and elevates CK levels in the reproductive SAM, leading to increased meristem activity, enhanced panicle branching, and a consequent increase of grain number. Importantly, the DST reg1 allele provides an approach to pyramid the Gn1a -dependent and Gn1a -independent effects on grain production. Our study reveals that, as a unique regulator of reproductive meristem activity, DST may be explored to facilitate the genetic enhancement of grain production in rice and other small grain cereals.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 3
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 29 ( 2011-07-19), p. 11983-11988
    Abstract: High-throughput sequencing technology enables population-level surveys of human genomic variation. Here, we examine the joint allele frequency distributions across continental human populations and present an approach for combining complementary aspects of whole-genome, low-coverage data and targeted high-coverage data. We apply this approach to data generated by the pilot phase of the Thousand Genomes Project, including whole-genome 2–4× coverage data for 179 samples from HapMap European, Asian, and African panels as well as high-coverage target sequencing of the exons of 800 genes from 697 individuals in seven populations. We use the site frequency spectra obtained from these data to infer demographic parameters for an Out-of-Africa model for populations of African, European, and Asian descent and to predict, by a jackknife-based approach, the amount of genetic diversity that will be discovered as sample sizes are increased. We predict that the number of discovered nonsynonymous coding variants will reach 100,000 in each population after ∼1,000 sequenced chromosomes per population, whereas ∼2,500 chromosomes will be needed for the same number of synonymous variants. Beyond this point, the number of segregating sites in the European and Asian panel populations is expected to overcome that of the African panel because of faster recent population growth. Overall, we find that the majority of human genomic variable sites are rare and exhibit little sharing among diverged populations. Our results emphasize that replication of disease association for specific rare genetic variants across diverged populations must overcome both reduced statistical power because of rarity and higher population divergence.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
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  • 4
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 36 ( 2014-09-09), p. 13199-13204
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 36 ( 2014-09-09), p. 13199-13204
    Abstract: Cerebral edema is a potentially life-threatening illness, but knowledge of its underlying mechanisms is limited. Here we report that hypobaric hypoxia induces rat cerebral edema and neuronal apoptosis and increases the expression of corticotrophin releasing factor (CRF), CRF receptor type 1 (CRFR1), aquaporin-4 (AQP4), and endothelin-1 (ET-1) in the cortex. These effects, except for the increased expression of CRF itself, could all be blocked by pretreatment with an antagonist of the CRF receptor CRFR1. We also show that, in cultured primary astrocytes: ( i ) both CRFR1 and AQP4 are expressed; ( ii ) exogenous CRF, acting through CRFR1, triggers signaling of cAMP/PKA, intracellular Ca 2+ , and PKCε; and ( iii ) the up-regulated cAMP/PKA signaling contributes to the phosphorylation and expression of AQP4 to enhance water influx into astrocytes and produces an up-regulation of ET-1 expression. Finally, using CHO cells transfected with CRFR1 + and AQP4 + , we show that transfected CRFR1 + contributes to edema via transfected AQP4 + . In conclusion, hypoxia triggers cortical release of CRF, which acts on CRFR1 to trigger signaling of cAMP/PKA in cortical astrocytes, leading to activation of AQP4 and cerebral edema.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
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    detail.hit.zdb_id: 1461794-8
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  • 5
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 2 ( 2014-01-14), p. 769-774
    Abstract: A unique avian-origin A/H7N9 influenza virus has so far caused 134 cases with 44 deaths. Probing the host factors contributing to disease severity, we found that lower levels of plasma inflammatory cytokines on hospital admission correlated with faster recovery in 18 patients with A/H7N9 influenza virus, whereas high concentrations of (in particular) IL-6, IL-8, and macrophage inflammatory protein-1β were predictive of a less favorable or fatal outcome. Analysis of bronchoalveolar lavage samples showed up to 1,000-fold greater cytokine/chemokine levels relative to plasma. Furthermore, patients with the rs12252-C/C IFN-induced transmembrane protein-3 (IFITM3) genotype had more rapid disease progression and were less likely to survive. Compared with patients with the rs12252-T/T or rs12252-T/C genotype of IFITM3, patients with the C/C genotype had a shorter time from disease onset to the time point when they sought medical aid (hospital admission or antiviral therapy) and a shorter interval to development of the acute respiratory distress syndrome stage (reflected by shorter intervals between clinical onset and methylprednisolone treatments and higher rates of mechanical ventilator use), as well as experiencing elevated/prolonged lung virus titers and cytokine production and higher mortality. The present analysis provides reported data on the H7N9 influenza-induced “cytokine storm” at the site of infection in humans and identifies the rs12252-C genotype that compromises IFITM3 function as a primary genetic correlate of severe H7N9 pneumonia. Together with rs12252 sequencing, early monitoring of plasma cytokines is thus of prognostic value for the treatment and management of severe influenza pneumonia.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
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    detail.hit.zdb_id: 1461794-8
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  • 6
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 338, No. 6114 ( 2012-12-21), p. 1576-1582
    Abstract: The ATLAS detector measured several characteristic decay products of the standard model Higgs boson, allowing its mass to be determined.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2012
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
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  • 7
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 46 ( 2014-11-18)
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 46 ( 2014-11-18)
    Abstract: Comparative genomic analyses among closely related species can greatly enhance our understanding of plant gene and genome evolution. We report de novo-assembled AA-genome sequences for Oryza nivara , Oryza glaberrima , Oryza barthii , Oryza glumaepatula , and Oryza meridionalis . Our analyses reveal massive levels of genomic structural variation, including segmental duplication and rapid gene family turnover, with particularly high instability in defense-related genes. We show, on a genomic scale, how lineage-specific expansion or contraction of gene families has led to their morphological and reproductive diversification, thus enlightening the evolutionary process of speciation and adaptation. Despite strong purifying selective pressures on most Oryza genes, we documented a large number of positively selected genes, especially those genes involved in flower development, reproduction, and resistance-related processes. These diversifying genes are expected to have played key roles in adaptations to their ecological niches in Asia, South America, Africa and Australia. Extensive variation in noncoding RNA gene numbers, function enrichment, and rates of sequence divergence might also help account for the different genetic adaptations of these rice species. Collectively, these resources provide new opportunities for evolutionary genomics, numerous insights into recent speciation, a valuable database of functional variation for crop improvement, and tools for efficient conservation of wild rice germplasm.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
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    SSG: 11
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  • 8
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 52 ( 2012-12-26), p. 21360-21365
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 52 ( 2012-12-26), p. 21360-21365
    Abstract: Ezh2 (Enhancer of zeste homolog 2) protein is the enzymatic component of the Polycomb repressive complex 2 (PRC2), which represses gene expression by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation and differentiation during embryonic development. Recently, hot-spot mutations of Ezh2 were identified in diffused large B-cell lymphomas and follicular lymphomas. To investigate if tumor growth is dependent on the enzymatic activity of Ezh2, we developed a potent and selective small molecule inhibitor, EI1, which inhibits the enzymatic activity of Ezh2 through direct binding to the enzyme and competing with the methyl group donor S-Adenosyl methionine. EI1-treated cells exhibit genome-wide loss of H3K27 methylation and activation of PRC2 target genes. Furthermore, inhibition of Ezh2 by EI1 in diffused large B-cell lymphomas cells carrying the Y641 mutations results in decreased proliferation, cell cycle arrest, and apoptosis. These results provide strong validation of Ezh2 as a potential therapeutic target for the treatment of cancer.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
    detail.hit.zdb_id: 209104-5
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    SSG: 11
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 22 ( 2012-05-29), p. 8629-8634
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 22 ( 2012-05-29), p. 8629-8634
    Abstract: The rhizobium–legume symbiosis has been widely studied as the model of mutualistic evolution and the essential component of sustainable agriculture. Extensive genetic and recent genomic studies have led to the hypothesis that many distinct strategies, regardless of rhizobial phylogeny, contributed to the varied rhizobium–legume symbiosis. We sequenced 26 genomes of Sinorhizobium and Bradyrhizobium nodulating soybean to test this hypothesis. The Bradyrhizobium core genome is disproportionally enriched in lipid and secondary metabolism, whereas several gene clusters known to be involved in osmoprotection and adaptation to alkaline pH are specific to the Sinorhizobium core genome. These features are consistent with biogeographic patterns of these bacteria. Surprisingly, no genes are specifically shared by these soybean microsymbionts compared with other legume microsymbionts. On the other hand, phyletic patterns of 561 known symbiosis genes of rhizobia reflected the species phylogeny of these soybean microsymbionts and other rhizobia. Similar analyses with 887 known functional genes or the whole pan genome of rhizobia revealed that only the phyletic distribution of functional genes was consistent with the species tree of rhizobia. Further evolutionary genetics revealed that recombination dominated the evolution of core genome. Taken together, our results suggested that faithfully vertical genes were rare compared with those with history of recombination including lateral gene transfer, although rhizobial adaptations to symbiotic interactions and other environmental conditions extensively recruited lineage-specific shell genes under direct or indirect control through the speciation process.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 10
    In: Nature, Springer Science and Business Media LLC, Vol. 490, No. 7420 ( 2012-10), p. 407-411
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2012
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
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