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  • 1
    In: Nature, Springer Science and Business Media LLC, Vol. 488, No. 7410 ( 2012-8), p. 185-188
    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
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  • 2
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 19 ( 2013-05-07)
    Abstract: The overexpression of Aurora kinases in multiple tumors makes these kinases appealing targets for the development of anticancer therapies. This study identified two small molecules with a furanopyrimidine core, IBPR001 and IBPR002, that target Aurora kinases and induce a DFG conformation change at the ATP site of Aurora A. Our results demonstrate the high potency of the IBPR compounds in reducing tumorigenesis in a colorectal cancer xenograft model in athymic nude mice. Human hepatoma up-regulated protein (HURP) is a substrate of Aurora kinase A, which plays a crucial role in the stabilization of kinetochore fibers. This study used the IBPR compounds as well as MLN8237, a proven Aurora A inhibitor, as chemical probes to investigate the molecular role of HURP in mitotic spindle formation. These compounds effectively eliminated HURP phosphorylation, thereby revealing the coexistence and continuous cycling of HURP between unphosphorylated and phosphorylated forms that are associated, respectively, with microtubules emanating from centrosomes and kinetochores. Furthermore, these compounds demonstrate a spatial hierarchical preference for HURP in the attachment of microtubules extending from the mother to the daughter centrosome. The finding of inequality in the centrosomal microtubules revealed by these small molecules provides a versatile tool for the discovery of new cell-division molecules for the development of antitumor drugs.
    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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  • 3
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 10 ( 2013-03-05), p. 3979-3984
    Abstract: Our anatomical analysis revealed that a dry maize seed contains four to five embryonic leaves at different developmental stages. Rudimentary kranz structure (KS) is apparent in the first leaf with a substantial density, but its density decreases toward younger leaves. Upon imbibition, leaf expansion occurs rapidly with new KSs initiated from the palisade-like ground meristem cells in the middle of the leaf. In parallel to the anatomical analysis, we obtained the time course transcriptomes for the embryonic leaves in dry and imbibed seeds every 6 h up to hour 72. Over this time course, the embryonic leaves exhibit transcripts of 30,255 genes at a level that can be regarded as “expressed.” In dry seeds, ∼25,500 genes are expressed, showing functional enrichment in transcription, RNA processing, protein synthesis, primary metabolic pathways, and calcium transport. During the 72-h time course, ∼13,900 genes, including 590 transcription factor genes, are differentially expressed. Indeed, by 30 h postimbibition, ∼2,200 genes expressed in dry seeds are already down-regulated, and ∼2,000 are up-regulated. Moreover, the top 1% expressed genes at 54 h or later are very different from those before 30 h, reflecting important developmental and physiological transitions. Interestingly, clusters of genes involved in hormone metabolism, signaling, and responses are differentially expressed at various time points and TF gene expression is also modular and stage specific. Our dataset provides an opportunity for hypothesizing the timing of regulatory actions, particularly in the context of KS development.
    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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  • 4
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 345, No. 6197 ( 2014-08-08), p. 688-693
    Abstract: Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 ( SMN1 ) gene. A paralogous gene in humans, SMN2 , produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.
    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: 2014
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  • 5
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 36 ( 2012-09-04), p. 14343-14347
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 36 ( 2012-09-04), p. 14343-14347
    Abstract: Improving a tropical cyclone’s forecast and mitigating its destructive potential requires knowledge of various environmental factors that influence the cyclone’s path and intensity. Herein, using a combination of observations and model simulations, we systematically demonstrate that tropical cyclone intensification is significantly affected by salinity-induced barrier layers, which are “quasi-permanent” features in the upper tropical oceans. When tropical cyclones pass over regions with barrier layers, the increased stratification and stability within the layer reduce storm-induced vertical mixing and sea surface temperature cooling. This causes an increase in enthalpy flux from the ocean to the atmosphere and, consequently, an intensification of tropical cyclones. On average, the tropical cyclone intensification rate is nearly 50% higher over regions with barrier layers, compared to regions without. Our finding, which underscores the importance of observing not only the upper-ocean thermal structure but also the salinity structure in deep tropical barrier layer regions, may be a key to more skillful predictions of tropical cyclone intensities through improved ocean state estimates and simulations of barrier layer processes. As the hydrological cycle responds to global warming, any associated changes in the barrier layer distribution must be considered in projecting future tropical cyclone activity.
    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
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  • 6
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 19 ( 2010-05-11), p. 8617-8622
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 19 ( 2010-05-11), p. 8617-8622
    Abstract: TcaR and IcaR are a weak and a strong negative regulator of transcription of the ica locus, respectively, and their presence prevents the poly- N -acetylglucosamine production and biofilm formation in Staphylococcus epidermidis . Although TcaR was shown to interact with the ica promoter, the precise binding region and the mechanism of interaction remained unclear. Here we present the 3D structure of TcaR in its apo form and in complex with salicylate as well as several aminoglycoside and β-lactam antibiotics. A comparison of the native and complex TcaR structures indicates that the mechanism of regulation involves a large conformational change in the DNA-binding lobe. Here, we deduced the consensus binding sequence of two [∼TTNNAA] hexamers embedded in a 16 bp sequence for a TcaR dimer. Six TcaR dimers bind specifically to three approximately 33 bp segments close to the IcaR binding region with varying affinities, and their repressor activity is directly interfered by salicylate and different classes of natural antimicrobial compounds. We also found in this study that the antimicrobial compounds we tested were shown not only to inhibit TcaR–DNA interaction but also to further induce biofilm formation in S. epidermidis in our in vivo assay. The results support a general mechanism for antibiotics in regulating TcaR–DNA interaction and thereby help understand the effect of antibiotic exposure on bacterial antibiotic resistance through biofilm formation.
    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: 2010
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 7
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 36 ( 2012-09-04), p. 14348-14352
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 36 ( 2012-09-04), p. 14348-14352
    Abstract: Both instrumental data analyses and coupled ocean-atmosphere models indicate that Atlantic meridional overturning circulation (AMOC) variability is tightly linked to abrupt tropical North Atlantic (TNA) climate change through both atmospheric and oceanic processes. Although a slowdown of AMOC results in an atmospheric-induced surface cooling in the entire TNA, the subsurface experiences an even larger warming because of rapid reorganizations of ocean circulation patterns at intermediate water depths. Here, we reconstruct high-resolution temperature records using oxygen isotope values and Mg/Ca ratios in both surface- and subthermocline-dwelling planktonic foraminifera from a sediment core located in the TNA over the last 22 ky. Our results show significant changes in the vertical thermal gradient of the upper water column, with the warmest subsurface temperatures of the last deglacial transition corresponding to the onset of the Younger Dryas. Furthermore, we present new analyses of a climate model simulation forced with freshwater discharge into the North Atlantic under Last Glacial Maximum forcings and boundary conditions that reveal a maximum subsurface warming in the vicinity of the core site and a vertical thermal gradient change at the onset of AMOC weakening, consistent with the reconstructed record. Together, our proxy reconstructions and modeling results provide convincing evidence for a subsurface oceanic teleconnection linking high-latitude North Atlantic climate to the tropical Atlantic during periods of reduced AMOC across the last deglacial transition.
    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
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 40 ( 2013-10), p. 16079-16084
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 40 ( 2013-10), p. 16079-16084
    Abstract: The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex, triggers caspase-1 activation and maturation of the proinflammatory cytokines IL-1β and IL-18 upon sensing a wide range of pathogen- and damage-associated molecules. Dysregulation of NLRP3 inflammasome activity contributes to the pathogenesis of many diseases, but its regulation remains poorly defined. Here we show that depletion of plasminogen activator inhibitor type 2 (PAI-2), a serine protease inhibitor, resulted in NLRP3- and ASC (apoptosis-associated Speck-like protein containing a C-terminal caspase recruitment domain)‐dependent caspase-1 activation and IL-1β secretion in macrophages upon Toll-like receptor 2 (TLR2) and TLR4 engagement. TLR2 or TLR4 agonist induced PAI-2 expression, which subsequently stabilized the autophagic protein Beclin 1 to promote autophagy, resulting in decreases in mitochondrial reactive oxygen species, NLRP3 protein level, and pro–IL-1β processing. Likewise, overexpressing Beclin 1 in PAI-2–deficient cells rescued the suppression of NLRP3 activation in response to LPS. Together, our data identify a tier of TLR signaling in controlling NLRP3 inflammasome activation and reveal a cell-autonomous mechanism which inversely regulates TLR- or Escherichia coli -induced mitochondrial dysfunction, oxidative stress, and IL-1β–driven inflammation.
    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
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 38 ( 2014-09-23), p. 13990-13995
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 38 ( 2014-09-23), p. 13990-13995
    Abstract: Although kainate receptors play important roles in ischemic stroke, the molecular mechanisms underlying postischemic regulation of kainate receptors remain unclear. In this study we demonstrate that Src family kinases contribute to the potentiation of kainate receptor function. Brain ischemia and reperfusion induce rapid and sustained phosphorylation of the kainate receptor subunit GluK2 by Src in the rat hippocampus, implicating a critical role for Src-mediated GluK2 phosphorylation in ischemic brain injury. The NMDA and kainate receptors are involved in the tyrosine phosphorylation of GluK2. GluK2 binds to Src, and the tyrosine residue at position 590 (Y590) on GluK2 is a major site of phosphorylation by Src kinases. GluK2 phosphorylation at Y590 is responsible for increases in whole-cell currents and calcium influx in response to transient kainate stimulation. In addition, GluK2 phosphorylation at Y590 facilitates the endocytosis of GluK2 subunits, and the activation of JNK3 and its substrate c-Jun after long-term kainate treatment. Thus, Src phosphorylation of GluK2 plays an important role in the opening of kainate receptor channels and downstream proapoptosis signaling after brain ischemia. The present study reveals an additional mechanism for the regulation of GluK2-containing kainate receptors by Src family kinases, which may be of pathological significance in ischemic stroke.
    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: 2014
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  • 10
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2010
    In:  Nature Vol. 467, No. 7312 ( 2010-9), p. 211-213
    In: Nature, Springer Science and Business Media LLC, Vol. 467, No. 7312 ( 2010-9), p. 211-213
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    RVK:
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2010
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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