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  • 1
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    Reductive carboxylation supports redox homeostasis during anchorage-independent growth (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-04-07
    Description: Cells receive growth and survival stimuli through their attachment to an extracellular matrix (ECM). Overcoming the addiction to ECM-induced signals is required for anchorage-independent growth, a property of most malignant cells. Detachment from ECM is associated with enhanced production of reactive oxygen species (ROS) owing to altered glucose metabolism. Here we identify an unconventional pathway that supports redox homeostasis and growth during adaptation to anchorage independence. We observed that detachment from monolayer culture and growth as anchorage-independent tumour spheroids was accompanied by changes in both glucose and glutamine metabolism. Specifically, oxidation of both nutrients was suppressed in spheroids, whereas reductive formation of citrate from glutamine was enhanced. Reductive glutamine metabolism was highly dependent on cytosolic isocitrate dehydrogenase-1 (IDH1), because the activity was suppressed in cells homozygous null for IDH1 or treated with an IDH1 inhibitor. This activity occurred in absence of hypoxia, a well-known inducer of reductive metabolism. Rather, IDH1 mitigated mitochondrial ROS in spheroids, and suppressing IDH1 reduced spheroid growth through a mechanism requiring mitochondrial ROS. Isotope tracing revealed that in spheroids, isocitrate/citrate produced reductively in the cytosol could enter the mitochondria and participate in oxidative metabolism, including oxidation by IDH2. This generates NADPH in the mitochondria, enabling cells to mitigate mitochondrial ROS and maximize growth. Neither IDH1 nor IDH2 was necessary for monolayer growth, but deleting either one enhanced mitochondrial ROS and reduced spheroid size, as did deletion of the mitochondrial citrate transporter protein. Together, the data indicate that adaptation to anchorage independence requires a fundamental change in citrate metabolism, initiated by IDH1-dependent reductive carboxylation and culminating in suppression of mitochondrial ROS.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860952/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860952/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Lei -- Shestov, Alexander A -- Swain, Pamela -- Yang, Chendong -- Parker, Seth J -- Wang, Qiong A -- Terada, Lance S -- Adams, Nicholas D -- McCabe, Michael T -- Pietrak, Beth -- Schmidt, Stan -- Metallo, Christian M -- Dranka, Brian P -- Schwartz, Benjamin -- DeBerardinis, Ralph J -- R01 CA157996/CA/NCI NIH HHS/ -- R01 CA188652/CA/NCI NIH HHS/ -- R01CA157996/CA/NCI NIH HHS/ -- R01CA188652/CA/NCI NIH HHS/ -- England -- Nature. 2016 Apr 14;532(7598):255-8. doi: 10.1038/nature17393. Epub 2016 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, Texas 75390-8502, USA. ; Department of Radiology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA. ; Seahorse Bioscience, 16 Esquire Road, North Billerica, Massachusetts 01862, USA. ; Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, USA. ; Touchstone Diabetes Center, UT Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA. ; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. ; Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas 75390, USA. ; McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27049945" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Adhesion ; Cell Hypoxia ; Cell Line, Tumor ; Cell Proliferation ; Citric Acid/*metabolism ; Contact Inhibition ; Cytosol/enzymology/metabolism ; Extracellular Matrix/metabolism ; Glucose/metabolism ; Glutamic Acid/metabolism ; Glutamine/metabolism ; *Homeostasis ; Humans ; Isocitrate Dehydrogenase/antagonists & inhibitors/deficiency/genetics/*metabolism ; Isocitrates/metabolism ; Mitochondria/*metabolism ; NADP/biosynthesis ; Neoplasms/enzymology/*metabolism/*pathology ; Oxidation-Reduction ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Spheroids, Cellular/metabolism/pathology
    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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  • 2
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    Lifetime measurements of ^{17} C excited states and three-body and continuum effects (2015)
    American Physical Society (APS)
    Details
    Publication Date: 2015-12-19
    Description: Author(s): D. Smalley, H. Iwasaki, P. Navrátil, R. Roth, J. Langhammer, V. M. Bader, D. Bazin, J. S. Berryman, C. M. Campbell, J. Dohet-Eraly, P. Fallon, A. Gade, C. Langer, A. Lemasson, C. Loelius, A. O. Macchiavelli, C. Morse, J. Parker, S. Quaglioni, F. Recchia, S. R. Stroberg, D. Weisshaar, K. Whitmore, and K. Wimmer We studied transition rates for the lowest 1 / 2 + and 5 / 2 + excited states of C 17 through lifetime measurements with the GRETINA array using the recoil-distance method. The present measurements provide a model-independent determination of transition strengths giving the values of B ( M 1 ; 1 / 2 + → 3 / 2 g . s . + ) = 1 . … [Phys. Rev. C 92, 064314] Published Fri Dec 18, 2015
    Keywords: Nuclear Structure
    Print ISSN: 0556-2813
    Electronic ISSN: 1089-490X
    Topics: Physics
    Published by American Physical Society (APS)
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  • 3
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    Phosphorylation of hnRNP K by cyclin-dependent kinase 2 controls cytosolic accumulation of TDP-43 (2015)
    Oxford University Press
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    Publication Date: 2015-02-26
    Description: Cytosolic accumulation of TAR DNA binding protein 43 (TDP-43) is a major neuropathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the mechanisms involved in TDP-43 accumulation remain largely unknown. Previously, we reported that inhibitors of cyclin-dependent kinases (CDKs) prevented cytosolic stress granule accumulation of TDP-43, correlating with depletion of heterogeneous ribonucleoprotein (hnRNP) K from stress granules. In the present study, we further investigated the relationship between TDP-43 and hnRNP K and their control by CDKs. Inhibition of CDK2 abrogated the accumulation of TDP-43 into stress granules. Phosphorylated CDK2 co-localized with accumulated TDP-43 and phosphorylated hnRNP K in stress granules. Inhibition of CDK2 phosphorylation blocked phosphorylation of hnRNP K, preventing its incorporation into stress granules. Due to interaction between hnRNP K with TDP-43, the loss of hnRNP K from stress granules prevented accumulation of TDP-43. Mutation of Ser216 and Ser284 phosphorylation sites on hnRNP K inhibited hnRNP K- and TDP-43-positive stress granule formation in transfected cells. The interaction between hnRNP K and TDP-43 was further confirmed by the loss of TDP-43 accumulation following siRNA-mediated inhibition of hnRNP K expression. A substantial decrease of CDK2 and hnRNP K expression in spinal cord motor neurons in ALS patients demonstrates a potential key role for these proteins in ALS and TDP-43 accumulation, indicating that further investigation of the association between hnRNP K and TDP-43 is warranted. Understanding how kinase activity modulates TDP-43 accumulation may provide new pharmacological targets for disease intervention.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 4
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    GBshape: a genome browser database for DNA shape annotations (2015)
    Oxford University Press
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    Publication Date: 2015-01-16
    Description: Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our G enome B rowser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/ ) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    The Interrelationships of Placental Mammals and the Limits of Phylogenetic Inference (2016)
    Oxford University Press
    Details
    Publication Date: 2016-02-12
    Description: Placental mammals comprise three principal clades: Afrotheria (e.g., elephants and tenrecs), Xenarthra (e.g., armadillos and sloths), and Boreoeutheria (all other placental mammals), the relationships among which are the subject of controversy and a touchstone for debate on the limits of phylogenetic inference. Previous analyses have found support for all three hypotheses, leading some to conclude that this phylogenetic problem might be impossible to resolve due to the compounded effects of incomplete lineage sorting (ILS) and a rapid radiation. Here we show, using a genome scale nucleotide data set, microRNAs, and the reanalysis of the three largest previously published amino acid data sets, that the root of Placentalia lies between Atlantogenata and Boreoeutheria. Although we found evidence for ILS in early placental evolution, we are able to reject previous conclusions that the placental root is a hard polytomy that cannot be resolved. Reanalyses of previous data sets recover Atlantogenata + Boreoeutheria and show that contradictory results are a consequence of poorly fitting evolutionary models; instead, when the evolutionary process is better-modeled, all data sets converge on Atlantogenata. Our Bayesian molecular clock analysis estimates that marsupials diverged from placentals 157–170 Ma, crown Placentalia diverged 86–100 Ma, and crown Atlantogenata diverged 84–97 Ma. Our results are compatible with placental diversification being driven by dispersal rather than vicariance mechanisms, postdating early phases in the protracted opening of the Atlantic Ocean.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Calibration with confidence: a principled method for panel assessment (2017)
    Royal Society
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    Publication Date: 2017-02-10
    Description: Frequently, a set of objects has to be evaluated by a panel of assessors, but not every object is assessed by every assessor. A problem facing such panels is how to take into account different standards among panel members and varying levels of confidence in their scores. Here, a mathematically based algorithm is developed to calibrate the scores of such assessors, addressing both of these issues. The algorithm is based on the connectivity of the graph of assessors and objects evaluated, incorporating declared confidences as weights on its edges. If the graph is sufficiently well connected, relative standards can be inferred by comparing how assessors rate objects they assess in common, weighted by the levels of confidence of each assessment. By removing these biases, ‘true’ values are inferred for all the objects. Reliability estimates for the resulting values are obtained. The algorithm is tested in two case studies: one by computer simulation and another based on realistic evaluation data. The process is compared to the simple averaging procedure in widespread use, and to Fisher's additive incomplete block analysis. It is anticipated that the algorithm will prove useful in a wide variety of situations such as evaluation of the quality of research submitted to national assessment exercises; appraisal of grant proposals submitted to funding panels; ranking of job applicants; and judgement of performances on degree courses wherein candidates can choose from lists of options.
    Keywords: applied mathematics
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 7
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    Moist convection and its upscale effects in simulations of the Indian monsoon with explicit and parametrised convection (2016)
    Wiley
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    Publication Date: 2016-12-27
    Description: In common with many global models, the Met Office Unified Model (MetUM) climate simulations show large errors in Indian summer monsoon rainfall, with a wet bias over the equatorial Indian Ocean, a dry bias over India, and with too weak low-level flow into India. The representation of moist convection is a dominant source of error in global models, where convection must be parametrised, with the errors growing quickly enough to affect both weather and climate simulations. Here we use the first multi-week continental-scale MetUM simulations over India, with grid-spacings that allow explicit convection, to examine how convective parametrisation contributes to model biases in the region. Some biases are improved in the convection-permitting simulations with more intense rainfall over India, a later peak in the diurnal cycle of convective rainfall over land, and a reduced positive rainfall bias over the Indian Ocean. The simulations suggest that the reduced rainfall over the Indian Ocean leads to an enhanced monsoon circulation and transport of moisture into India. Increases in latent heating associated with increased convection over land deepen the monsoon trough and enhance water vapour transport into the continent. In addition, delayed continental convection allows greater surface insolation and, along with the same rain falling in more intense bursts, generates a drier land surface. This increases land-sea temperature contrasts, and further enhances onshore flow. Changes in the low-level water vapour advection into India are dominated by these changes to the flow, rather than to the moisture content in the flow. The results demonstrate the need to improve the representations of convection over both land and oceans to improve simulations of the monsoon.
    Print ISSN: 0035-9009
    Electronic ISSN: 1477-870X
    Topics: Geography , Physics
    Published by Wiley
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  • 8
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    Orion: a high contrast user facility (2016)
    Institute of Physics
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    Publication Date: 2016-03-01
    Print ISSN: 1742-6588
    Electronic ISSN: 1742-6596
    Topics: Physics
    Published by Institute of Physics
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