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  • 1
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    BRD4 as a genetic regulator for fibrosis [Genetics] (2015)
    National Academy of Sciences
    Details
    Publication Date: 2015-12-24
    Description: Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Validation for Solar Wind Prediction at Earth: Comparison of Coronal and Heliospheric Models Installed at the CCMC (2015)
    Wiley
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    Publication Date: 2015-04-17
    Description: Multiple coronal and heliospheric models have been recently upgraded at the Community Coordinated Modeling Center (CCMC), including the Wang-Sheely-Arge (WSA)-Enlil model, MHD-Around-a-Sphere (MAS)-Enlil model, Space Weather Modeling Framework (SWMF), and heliospheric tomography using interplanetary scintillation data. To investigate the effects of photospheric magnetograms from different sources, different coronal models, and different model versions on the model performance, we run these models in 10 combinations. Choosing 7 Carrington rotations in 2007 as the time window, we compare the modeling results with the OMNI data for near-Earth space environment during the late declining phase of solar cycle 23. Visual comparison is proved to be a necessary addition to the quantitative assessment of the models’ capabilities in reproducing the time series and statistics of solar wind parameters. The MAS-Enlil model captures the time patterns of solar wind parameters better while the WSA-Enlil model matches with the time series of normalized solar wind parameters better. Models generally overestimate slow wind temperature, underestimate fast wind temperature and magnetic field. Using improved algorithms, we have identified magnetic field sector boundaries (SBs) and slow-to-fast stream interaction regions (SIRs) as focused structures. The success rate of capturing them and the time offset vary largely with models. For this quiet period, the new version of MAS-Enlil model works best for SBs, while heliospheric tomography works best for SIRs. The new version of SWMF with more physics added needs more development. General strengths and weaknesses for each model are diagnosed to provide an unbiased reference to model developers and users.
    Print ISSN: 1539-4964
    Electronic ISSN: 1542-7390
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 3
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    Super enhancer RNA regulation in macrophages [Immunology and Inflammation] (2015)
    National Academy of Sciences
    Details
    Publication Date: 2015-01-21
    Description: Enhancers are critical genomic elements that define cellular and functional identity through the spatial and temporal regulation of gene expression. Recent studies suggest that key genes regulating cell type-specific functions reside in enhancer-dense genomic regions (i.e., super enhancers, stretch enhancers). Here we report that enhancer RNAs (eRNAs) identified by global...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Treatment of NAFLD by FGF1 [Physiology] (2016)
    National Academy of Sciences
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    Publication Date: 2016-02-24
    Description: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with obesity and type 2 diabetes. Currently, there is no approved pharmacological treatment for this disease, but improvement of insulin resistance using peroxisome proliferator-activated receptor-γ (PPARγ) agonists, such as thiazolidinediones (TZDs), has been shown...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    Corepressor SMRT promotes oxidative phosphorylation in adipose tissue and protects against diet-induced obesity and insulin resistance [Physiology] (2011)
    National Academy of Sciences
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    Publication Date: 2011-02-23
    Description: The ligand-dependent competing actions of nuclear receptor (NR)-associated transcriptional corepressor and coactivator complexes allow for the precise regulation of NR-dependent gene expression in response to both temporal and environmental cues. Here we report the mouse model termed silencing mediator of retinoid and thyroid hormone receptors (SMRT)mRID1 in which targeted disruption of the first receptor interaction domain (RID) of the nuclear corepressor SMRT disrupts interactions with a subset of NRs and leads to diet-induced superobesity associated with a depressed respiratory exchange ratio, decreased ambulatory activity, and insulin resistance. Although apparently normal when chow fed, SMRTmRID1 mice develop multiple metabolic dysfunctions when challenged by a high-fat diet, manifested by marked lipid accumulation in white and brown adipose tissue and the liver. The increased weight gain of SMRTmRID1 mice on a high-fat diet occurs predominantly in fat with adipocyte hypertrophy evident in both visceral and s.c. depots. Importantly, increased inflammatory gene expression was detected only in the visceral depots. SMRTmRID1 mice are both insulin-insensitive and refractory to the glucose-lowering effects of TZD and AICAR. Increased serum cholesterol and triglyceride levels were observed, accompanied by increased leptin and decreased adiponectin levels. Aberrant storage of lipids in the liver occurred as triglycerides and cholesterol significantly compromised hepatic function. Lipid accumulation in brown adipose tissue was associated with reduced thermogenic capacity and mitochondrial biogenesis. Collectively, these studies highlight the essential role of NR corepressors in maintaining metabolic homeostasis and describe an essential role for SMRT in regulating the progression, severity, and therapeutic outcome of metabolic diseases.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 6
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    Signatures of two distinct driving mechanisms in the evolution of coronal mass ejections in the lower corona (2011)
    Wiley
    Details
    Publication Date: 2011-04-13
    Description: We present a comparison between two simulations of coronal mass ejections (CMEs), in the lower corona, driven by different flux rope mechanisms presented in the literature. Both mechanisms represent different magnetic field configurations regarding the amount of twist of the magnetic field lines and different initial energies. They are used as a “proof of concept” to explore how different initialization mechanisms can be distinguished from each other in the lower corona. The simulations are performed using the Space Weather Modeling Framework (SWMF) during solar minimum conditions with a steady state solar wind obtained through an empirical approach to mimic the physical processes driving the solar wind. Although the two CMEs possess different initial energies (differing by an order of magnitude) and magnetic configurations, the main observables such as acceleration, shock speed, Mach number, and $\theta$Bn (the angle between the shock normal and the upstream magnetic field) present very similar behavior between 2 and 6 R$\odot$. We believe that through the analysis of other quantities, such as sheath width and postshock compression (pileup and shock indentation compressions), the effect of different magnetic configurations and initializations can be distinguished. We discuss that coronal models that employ a reduced value of polytropic index (γ) may significantly change the energetics of the CME and that the background solar wind plays an important role in the CMEs' shock and sheath evolution.
    Print ISSN: 0148-0227
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 7
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    A transcriptional switch mediated by cofactor methylation (2001)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2001-11-10
    Description: We describe a molecular switch based on the controlled methylation of nucleosome and the transcriptional cofactors, the CREB-binding proteins (CBP)/p300. The CBP/p300 methylation site is localized to an arginine residue that is essential for stabilizing the structure of the KIX domain, which mediates CREB recruitment. Methylation of KIX by coactivator-associated arginine methyltransferase 1 (CARM1) blocks CREB activation by disabling the interaction between KIX and the kinase inducible domain (KID) of CREB. Thus, CARM1 functions as a corepressor in cyclic adenosine monophosphate signaling pathway via its methyltransferase activity while acting as a coactivator for nuclear hormones. These results provide strong in vivo and in vitro evidence that histone methylation plays a key role in hormone-induced gene activation and define cofactor methylation as a new regulatory mechanism in hormone signaling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, W -- Chen, H -- Du, K -- Asahara, H -- Tini, M -- Emerson, B M -- Montminy, M -- Evans, R M -- 9R01DK57978/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2001 Dec 21;294(5551):2507-11. Epub 2001 Nov 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Expression Laboratory, Department of Biological Chemistry, University of California Davis Cancer Center/Basic Science, Sacramento, CA 95817, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11701890" target="_blank"〉PubMed〈/a〉
    Keywords: Acetyltransferases/metabolism ; Amino Acid Sequence ; Animals ; Apoptosis ; Cell Line ; Cyclic AMP Response Element-Binding Protein/metabolism ; Dimerization ; E1A-Associated p300 Protein ; *Gene Expression Regulation ; Genes, Reporter ; Histone Acetyltransferases ; Histones/metabolism ; Methylation ; Molecular Sequence Data ; Nerve Growth Factor/pharmacology ; Nuclear Proteins/chemistry/*metabolism ; PC12 Cells ; Protein Structure, Tertiary ; Protein-Arginine N-Methyltransferases/*metabolism ; Rats ; Receptors, Retinoic Acid/*metabolism ; Recombinant Fusion Proteins/metabolism ; Retinoid X Receptors ; *Saccharomyces cerevisiae Proteins ; Signal Transduction ; Somatostatin/genetics ; Trans-Activators/chemistry/*metabolism ; Transcription Factors/metabolism ; *Transcription, Genetic ; Transcriptional Activation ; Transfection ; Tretinoin/metabolism/pharmacology
    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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  • 8
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    Nuclear receptors and lipid physiology: opening the X-files (2001)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2001-12-01
    Description: Cholesterol, fatty acids, fat-soluble vitamins, and other lipids present in our diets are not only nutritionally important but serve as precursors for ligands that bind to receptors in the nucleus. To become biologically active, these lipids must first be absorbed by the intestine and transformed by metabolic enzymes before they are delivered to their sites of action in the body. Ultimately, the lipids must be eliminated to maintain a normal physiological state. The need to coordinate this entire lipid-based metabolic signaling cascade raises important questions regarding the mechanisms that govern these pathways. Specifically, what is the nature of communication between these bioactive lipids and their receptors, binding proteins, transporters, and metabolizing enzymes that links them physiologically and speaks to a higher level of metabolic control? Some general principles that govern the actions of this class of bioactive lipids and their nuclear receptors are considered here, and the scheme that emerges reveals a complex molecular script at work.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chawla, A -- Repa, J J -- Evans, R M -- Mangelsdorf, D J -- New York, N.Y. -- Science. 2001 Nov 30;294(5548):1866-70.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, Post Office Box 85800, San Diego, CA 92186-5800, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11729302" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bile Acids and Salts/metabolism ; Cholesterol/analogs & derivatives/metabolism ; DNA-Binding Proteins/metabolism ; Dimerization ; Fatty Acids/metabolism ; Humans ; Ligands ; *Lipid Metabolism ; Orphan Nuclear Receptors ; Receptors, Cytoplasmic and Nuclear/classification/*metabolism ; Receptors, Retinoic Acid/*metabolism ; *Receptors, Steroid/metabolism ; Retinoid X Receptors ; Signal Transduction ; Transcription Factors/*metabolism ; Xenobiotics/metabolism
    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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  • 9
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    Vitamin D receptor as an intestinal bile acid sensor (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-05-23
    Description: The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We show that VDR also functions as a receptor for the secondary bile acid lithocholic acid (LCA), which is hepatotoxic and a potential enteric carcinogen. VDR is an order of magnitude more sensitive to LCA and its metabolites than are other nuclear receptors. Activation of VDR by LCA or vitamin D induced expression in vivo of CYP3A, a cytochrome P450 enzyme that detoxifies LCA in the liver and intestine. These studies offer a mechanism that may explain the proposed protective effects of vitamin D and its receptor against colon cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Makishima, Makoto -- Lu, Timothy T -- Xie, Wen -- Whitfield, G Kerr -- Domoto, Hideharu -- Evans, Ronald M -- Haussler, Mark R -- Mangelsdorf, David J -- New York, N.Y. -- Science. 2002 May 17;296(5571):1313-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9050, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12016314" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Aryl Hydrocarbon Hydroxylases ; Binding, Competitive ; COS Cells ; Cell Line ; Colonic Neoplasms/prevention & control ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System/genetics/metabolism ; DNA-Binding Proteins/metabolism ; Dimerization ; Gene Expression Regulation, Enzymologic ; Histone Acetyltransferases ; Humans ; Intestine, Small/*metabolism ; Ligands ; Lithocholic Acid/analogs & derivatives/*metabolism/pharmacology ; Male ; Mice ; Nuclear Receptor Coactivator 1 ; Oxidoreductases, N-Demethylating/genetics/metabolism ; Promoter Regions, Genetic ; Rats ; Receptors, Calcitriol/agonists/genetics/*metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; Receptors, Steroid/metabolism ; Transcription Factors/metabolism ; Transfection
    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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  • 10
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    Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-02-22
    Description: Glucose flux through the hexosamine biosynthetic pathway leads to the post-translational modification of cytoplasmic and nuclear proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc). This tandem system serves as a nutrient sensor to couple systemic metabolic status to cellular regulation of signal transduction, transcription, and protein degradation. Here we show that O-GlcNAc transferase (OGT) harbours a previously unrecognized type of phosphoinositide-binding domain. After induction with insulin, phosphatidylinositol 3,4,5-trisphosphate recruits OGT from the nucleus to the plasma membrane, where the enzyme catalyses dynamic modification of the insulin signalling pathway by O-GlcNAc. This results in the alteration in phosphorylation of key signalling molecules and the attenuation of insulin signal transduction. Hepatic overexpression of OGT impairs the expression of insulin-responsive genes and causes insulin resistance and dyslipidaemia. These findings identify a molecular mechanism by which nutritional cues regulate insulin signalling through O-GlcNAc, and underscore the contribution of this modification to the aetiology of insulin resistance and type 2 diabetes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Xiaoyong -- Ongusaha, Pat P -- Miles, Philip D -- Havstad, Joyce C -- Zhang, Fengxue -- So, W Venus -- Kudlow, Jeffrey E -- Michell, Robert H -- Olefsky, Jerrold M -- Field, Seth J -- Evans, Ronald M -- P30 CA014195/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Feb 21;451(7181):964-9. doi: 10.1038/nature06668.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18288188" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylglucosamine/metabolism/pharmacology ; Animals ; COS Cells ; Cell Membrane/metabolism ; Cercopithecus aethiops ; Insulin/pharmacology ; Insulin Resistance/*physiology ; Lipid Metabolism ; Liver/enzymology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; N-Acetylglucosaminyltransferases/chemistry/genetics/*metabolism ; Phosphatidylinositol Phosphates/metabolism ; Phosphatidylinositols/*metabolism ; Phosphorylation/drug effects ; Protein Structure, Tertiary ; Protein Transport ; *Second Messenger Systems/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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