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  • American Association for the Advancement of Science (AAAS)  (9)
  • Cambridge University Press
  • 2015-2019  (13)
  • 1
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    A DNA methylation reader complex that enhances gene transcription (2018)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2018
    Description: 〈p〉DNA methylation generally functions as a repressive transcriptional signal, but it is also known to activate gene expression. In either case, the downstream factors remain largely unknown. By using comparative interactomics, we isolated proteins in 〈i〉Arabidopsis thaliana〈/i〉 that associate with methylated DNA. Two SU(VAR)3-9 homologs, the transcriptional antisilencing factor SUVH1, and SUVH3, were among the methyl reader candidates. SUVH1 and SUVH3 bound methylated DNA in vitro, were associated with euchromatic methylation in vivo, and formed a complex with two DNAJ domain-containing homologs, DNAJ1 and DNAJ2. Ectopic recruitment of DNAJ1 enhanced gene transcription in plants, yeast, and mammals. Thus, the SUVH proteins bind to methylated DNA and recruit the DNAJ proteins to enhance proximal gene expression, thereby counteracting the repressive effects of transposon insertion near genes.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Accretion-induced variability links young stellar objects, white dwarfs, and black holes (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-10-11
    Description: The central engines of disc-accreting stellar-mass black holes appear to be scaled down versions of the supermassive black holes that power active galactic nuclei. However, if the physics of accretion is universal, it should also be possible to extend this scaling to other types of accreting systems, irrespective of accretor mass, size, or type. We examine new observations, obtained with Kepler/K2 and ULTRACAM, regarding accreting white dwarfs and young stellar objects. Every object in the sample displays the same linear correlation between the brightness of the source and its amplitude of variability (rms-flux relation) and obeys the same quantitative scaling relation as stellar-mass black holes and active galactic nuclei. We also show that the most important parameter in this scaling relation is the physical size of the accreting object. This establishes the universality of accretion physics from proto-stars still in the star-forming process to the supermassive black holes at the centers of galaxies.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    A DNA methylation reader complex that enhances gene transcription (2018)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2018-12-07
    Description: DNA methylation generally functions as a repressive transcriptional signal, but it is also known to activate gene expression. In either case, the downstream factors remain largely unknown. By using comparative interactomics, we isolated proteins in Arabidopsis thaliana that associate with methylated DNA. Two SU(VAR)3-9 homologs, the transcriptional antisilencing factor SUVH1, and SUVH3, were among the methyl reader candidates. SUVH1 and SUVH3 bound methylated DNA in vitro, were associated with euchromatic methylation in vivo, and formed a complex with two DNAJ domain-containing homologs, DNAJ1 and DNAJ2. Ectopic recruitment of DNAJ1 enhanced gene transcription in plants, yeast, and mammals. Thus, the SUVH proteins bind to methylated DNA and recruit the DNAJ proteins to enhance proximal gene expression, thereby counteracting the repressive effects of transposon insertion near genes.
    Keywords: Botany, Molecular Biology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    A functional proteomics platform to reveal the sequence determinants of lysine methyltransferase substrate selectivity (2018)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2018
    Description: 〈p〉Lysine methylation is a key regulator of histone protein function. Beyond histones, few connections have been made to the enzymes responsible for the deposition of these posttranslational modifications. Here, we debut a high-throughput functional proteomics platform that maps the sequence determinants of lysine methyltransferase (KMT) substrate selectivity without a priori knowledge of a substrate or target proteome. We demonstrate the predictive power of this approach for identifying KMT substrates, generating scaffolds for inhibitor design, and predicting the impact of missense mutations on lysine methylation signaling. By comparing KMT selectivity profiles to available lysine methylome datasets, we reveal a disconnect between preferred KMT substrates and the ability to detect these motifs using standard mass spectrometry pipelines. Collectively, our studies validate the use of this platform for guiding the study of lysine methylation signaling and suggest that substantial gaps exist in proteome-wide curation of lysine methylomes.〈/p〉
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 5
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    A functional proteomics platform to reveal the sequence determinants of lysine methyltransferase substrate selectivity (2018)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2018-11-29
    Description: Lysine methylation is a key regulator of histone protein function. Beyond histones, few connections have been made to the enzymes responsible for the deposition of these posttranslational modifications. Here, we debut a high-throughput functional proteomics platform that maps the sequence determinants of lysine methyltransferase (KMT) substrate selectivity without a priori knowledge of a substrate or target proteome. We demonstrate the predictive power of this approach for identifying KMT substrates, generating scaffolds for inhibitor design, and predicting the impact of missense mutations on lysine methylation signaling. By comparing KMT selectivity profiles to available lysine methylome datasets, we reveal a disconnect between preferred KMT substrates and the ability to detect these motifs using standard mass spectrometry pipelines. Collectively, our studies validate the use of this platform for guiding the study of lysine methylation signaling and suggest that substantial gaps exist in proteome-wide curation of lysine methylomes.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 6
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    Organic chemistry. A rhodium catalyst for single-step styrene production from benzene and ethylene (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-04-25
    Description: Rising global demand for fossil resources has prompted a renewed interest in catalyst technologies that increase the efficiency of conversion of hydrocarbons from petroleum and natural gas to higher-value materials. Styrene is currently produced from benzene and ethylene through the intermediacy of ethylbenzene, which must be dehydrogenated in a separate step. The direct oxidative conversion of benzene and ethylene to styrene could provide a more efficient route, but achieving high selectivity and yield for this reaction has been challenging. Here, we report that the Rh catalyst ((Fl)DAB)Rh(TFA)(eta(2)-C2H4) [(Fl)DAB is N,N'-bis(pentafluorophenyl)-2,3-dimethyl-1,4-diaza-1,3-butadiene; TFA is trifluoroacetate] converts benzene, ethylene, and Cu(II) acetate to styrene, Cu(I) acetate, and acetic acid with 100% selectivity and yields 〉/=95%. Turnover numbers 〉800 have been demonstrated, with catalyst stability up to 96 hours.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vaughan, Benjamin A -- Webster-Gardiner, Michael S -- Cundari, Thomas R -- Gunnoe, T Brent -- New York, N.Y. -- Science. 2015 Apr 24;348(6233):421-4. doi: 10.1126/science.aaa2260.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of Virginia, Charlottesville, VA 22903, USA. ; Center for Advanced Scientific Computing and Modeling, Department of Chemistry, University of North Texas, Denton, TX 76203, USA. tbg7h@virginia.edu t@unt.edu. ; Department of Chemistry, University of Virginia, Charlottesville, VA 22903, USA. tbg7h@virginia.edu t@unt.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25908817" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
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    PAI-1 is a critical regulator of FGF23 homeostasis (2017)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2017-09-14
    Description: Elevated levels of fibroblast growth factor 23 (FGF23), a bone-derived phosphaturic hormone, are associated with a number of pathologic conditions including chronic kidney disease, cardiac hypertrophy, and congestive heart failure. Currently, there are no specific treatments available to lower plasma FGF23 levels. We have recently reported that genetic plasminogen activator inhibitor–1 (PAI-1) deficiency provided a significant reduction in circulating FGF23 levels while simultaneously prolonging the life span of Klotho -deficient mice. We extend our investigations into the effect of PAI-1 on FGF23 homeostasis. Transgenic overexpression of PAI-1 resulted in threefold increase in FGF23 levels compared to wild-type littermates. Moreover, pharmacological modulation of PAI-1 activity with the small-molecule PAI-1 antagonist TM5441 significantly reduced FGF23 levels in PAI-1 transgenic and Klotho -deficient mice. In addition, TM5441 treatment or PAI-1 deficiency significantly accelerated the clearance of endogenous FGF23 and recombinant human FGF23 from circulation in mice with acute kidney injury. On the basis of these observations, we studied the effects of plasminogen activators (PAs), tissue-type PA (tPA) and urokinase-type PA (uPA), on FGF23. We demonstrate that both PAs directly cleave FGF23; however, it is not known whether the PA-generated FGF23 peptides retain or acquire functions that affect binding and/or signaling properties of intact FGF23. PAI-1 inhibits the PA-dependent cleavage of FGF23, and TM5441 inhibition of PAI-1 restores the proteolysis of FGF23. Furthermore, top-down proteomic analysis indicates that tPA cleaves FGF23 at multiple arginines including the proconvertase sensitive site R176. In summary, our results indicate that PAI-1 prevents the PA-driven proteolysis of FGF23 and PAI-1 inhibition provides a novel therapeutic approach to prevent the pathologic consequences of increased FGF23.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 8
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    A null mutation in SERPINE1 protects against biological aging in humans (2017)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2017-11-16
    Description: Plasminogen activator inhibitor–1 (PAI-1) has been shown to be a key component of the senescence-related secretome and a direct mediator of cellular senescence. In murine models of accelerated aging, genetic deficiency and targeted inhibition of PAI-1 protect against aging-like pathology and prolong life span. However, the role of PAI-1 in human longevity remains unclear. We hypothesized that a rare loss-of-function mutation in SERPINE1 (c.699_700dupTA), which encodes PAI-1, could play a role in longevity and metabolism in humans. We studied 177 members of the Berne Amish community, which included 43 carriers of the null SERPINE1 mutation. Heterozygosity was associated with significantly longer leukocyte telomere length, lower fasting insulin levels, and lower prevalence of diabetes mellitus. In the extended Amish kindred, carriers of the null SERPINE1 allele had a longer life span. Our study indicates a causal effect of PAI-1 on human longevity, which may be mediated by alterations in metabolism. Our findings demonstrate the utility of studying loss-of-function mutations in populations with geographic and genetic isolation and shed light on a novel therapeutic target for aging.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 9
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    Multiplexed analysis of the secretin-like GPCR-RAMP interactome (2019)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2019
    Description: 〈p〉Receptor activity–modifying proteins (RAMPs) have been shown to modulate the functions of several G protein–coupled receptors (GPCRs), but potential direct interactions among the three known RAMPs and hundreds of GPCRs have never been investigated. Focusing mainly on the secretin-like family of GPCRs, we engineered epitope-tagged GPCRs and RAMPs, and developed a multiplexed suspension bead array (SBA) immunoassay to detect GPCR-RAMP complexes from detergent-solubilized lysates. Using 64 antibodies raised against the native proteins and 4 antibodies targeting the epitope tags, we mapped the interactions among 23 GPCRs and 3 RAMPs. We validated nearly all previously reported secretin-like GPCR-RAMP interactions, and also found previously unidentified RAMP interactions with additional secretin-like GPCRs, chemokine receptors, and orphan receptors. The results provide a complete interactome of secretin-like GPCRs with RAMPs. The SBA strategy will be useful to search for additional GPCR-RAMP complexes and other interacting membrane protein pairs in cell lines and tissues.〈/p〉
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 10
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    Splitting of a two-dimensional liquid plug at an airway bifurcation (2016)
    Cambridge University Press
    Details
    Publication Date: 2016-03-14
    Description: Certain medical treatments involve the introduction of exogenous liquids in the lungs. These liquids can form plugs within the airways. The plugs propagate throughout the branching network in the lungs being forced by airflow. They leave a deposited film on the airway walls and split at bifurcations. Understanding the resulting distribution of liquid throughout the lungs is important for the effective administration of the prescribed treatments. In this paper, we investigate numerically the splitting of a liquid plug by a two-dimensional pulmonary bifurcation under the influence of a transverse gravitational field. The splitting is characterized by the splitting ratio, which is the ratio of volume of the liquid plug in the daughter channels and depends on the capillary number and the orientation of the bifurcation plane with respect to a three-dimensional gravitational field. It is observed that gravity induces asymmetry in the splitting, causing the splitting ratio to be reduced. This effect is mitigated as the capillary number is increased. It is also observed that there exists a critical capillary number where the plug will not split and will instead propagate entirely into the gravitationally favoured daughter channel. We also compute the wall stresses on the bifurcation walls and observe the locations where stresses and their gradients are the highest in magnitude. © 2016 Cambridge University Press.
    Print ISSN: 0022-1120
    Electronic ISSN: 1469-7645
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Published by Cambridge University Press
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