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  • 1
    Publication Date: 2014-07-06
    Description: Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS by Ras-guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather than the ensemble average.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255705/" 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/PMC4255705/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Iversen, Lars -- Tu, Hsiung-Lin -- Lin, Wan-Chen -- Christensen, Sune M -- Abel, Steven M -- Iwig, Jeff -- Wu, Hung-Jen -- Gureasko, Jodi -- Rhodes, Christopher -- Petit, Rebecca S -- Hansen, Scott D -- Thill, Peter -- Yu, Cheng-Han -- Stamou, Dimitrios -- Chakraborty, Arup K -- Kuriyan, John -- Groves, Jay T -- P01 AI091580/AI/NIAID NIH HHS/ -- R01 AI104789/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Jul 4;345(6192):50-4. doi: 10.1126/science.1250373.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA. ; Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. ; Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. ; Department of Mechanical Engineering, University of California, Berkeley, Berkeley, CA 94720, USA. ; Department of Chemistry, MIT, Cambridge, MA 02139, USA. ; Mechanobiology Institute, National University of Singapore, Singapore. ; Department of Chemistry and Nano-Science Center, University of Copenhagen, Copenhagen, Denmark. ; Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Department of Chemistry, MIT, Cambridge, MA 02139, USA. Department of Biological Engineering, MIT, Cambridge, MA 02139, USA. Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Cambridge, MA 02139, USA. Department of Physics, MIT, Cambridge, MA 02139, USA. Institute for Medical Engineering and Science, MIT, Cambridge, MA 02139, USA. ; Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA. Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Physical Biosciences and Materials Sciences Divisions, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. ; Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA. Mechanobiology Institute, National University of Singapore, Singapore. Physical Biosciences and Materials Sciences Divisions, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Berkeley Education Alliance for Research in Singapore, 1 Create Way, CREATE tower level 11, University Town, Singapore 138602. jtgroves@lbl.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24994643" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Catalytic Domain ; Crystallography, X-Ray ; Enzyme Activation ; Humans ; Kinetics ; Nucleotides/chemistry ; *Protein Interaction Domains and Motifs ; Proto-Oncogene Proteins p21(ras)/*agonists ; Son of Sevenless Protein, Drosophila/*chemistry/genetics
    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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  • 2
    Abstract: Psoriasis is a common immune-mediated, chronic, inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although TNFalpha- and IL-17A-targeting drugs have recently proven to be highly effective, the molecular mechanism underlying the pathogenesis of psoriasis remains poorly understood. We found that expression of the atypical IkappaB member IkappaB (inhibitor of NF-kappaB) zeta, a selective coactivator of particular NF-kappaB target genes, was strongly increased in skin of patients with psoriasis. Moreover, in human keratinocytes IkappaBzeta was identified as a direct transcriptional activator of TNFalpha/IL-17A-inducible psoriasis-associated proteins. Using genetically modified mice, we found that imiquimod-induced psoriasis-like skin inflammation was completely absent in IkappaBzeta-deficient mice, whereas skin inflammation was still inducible in IL-17A- and TNFalpha-deficient mice. IkappaBzeta deficiency also conferred resistance against IL-23-induced psoriasis. In addition, local abrogation of IkappaBzeta function by intradermal injection of IkappaBzeta siRNA abolished psoriasis-like skin inflammation. Taken together, we identify IkappaBzeta as a hitherto unknown key regulator of IL-17A-driven effects in psoriasis. Thus, targeting IkappaBzeta could be a future strategy for treatment of psoriasis, and other inflammatory diseases for which IL-17 antagonists are currently tested in clinical trials.
    Type of Publication: Journal article published
    PubMed ID: 26460049
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  • 3
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Social Science & Medicine 32 (1991), S. 767-771 
    ISSN: 0277-9536
    Keywords: age ; measurement ; psychological well-being ; social support
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 0277-9536
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 23 (1974), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract— Desheathed rat dorsal root ganglia were incubated in a medium containing amino-oxyacetic acid and [3H]GABA. Under these conditions, [3H]GABA is taken up exclusively by the satellite glial cells in the ganglia. Efflux of [3H]GABA from the tissue was measured after passing the ganglia through a series of wash solutions. The spontaneous efflux of radioactivity, mostly [3H]GABA, was more rapid in the absence of amino-oxyacetic acid in the incubation and wash media.Raising the potassium concentration in the wash media caused an increase in the efflux of [3H]GABA. This increase was sigmoidally related to the potassium concentration in the wash media, reaching a maximum at 64 mm-K+. The releasing effect of K+ was inhibited by removing calcium from the media. Reducing the calcium and raising the magnesium concentration in the wash solutions inhibited the increased efflux of [3H]GABA due to 64 mm-K+ by 48 per cent, while 5 mM-La3+ and diphenylhydantoin (0·005 and 0·5 mm) had no effect on this increase.Only a small increase in the efflux of [14C]glutamate was produced by 64 mm-K+ and it had no effect upon the effluxes of [3H]glycine, [3H]alanine or [3H]leucine. The efflux of lactate dehydrogenase was similarly unaffected by 64 mM-K+. The results suggest that glial cells in spinal ganglia can respond to depolarizing concentrations of potassium by releasing GABA in a calcium-dependent process.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: —The period during which trans-synaptic stimulation is required by the rat superior cervical ganglion for induction of tyrosine hydroxylase by reserpine has been studied. Ganglia were decentralized on one side at various times before or after an injection of reserpine. The tyrosine hydroxylase activity of the denervated and control ganglia was assayed 72 h after drug treatment. When decentralization was performed 8 h after an injection of reserpine the increase in tyrosine hydroxylase activity was blocked in the denervated ganglia. Decentralization 12 h after reserpine treatment or later had no effect on the enzyme induction. The actual increase in tyrosine hydroxylase activity occurred between 24 and 48 h after injection of reserpine.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: —The injection of 50 μg of 5,6-dihydroxytryptamine (5,6-HT) into a lateral ventricle of the rat depleted the spinal cord and various regions of the brain of indoleamines (presumably 5-HT) and 5-hydroxyindole acetic acid. The concentrations of 5-HT were measured by two different methods: the formation of a fluorescent derivative with o-phthalaldehyde, and the native fluorescence in hydrochloric acid. When the results of both methods were compared on the pons and medulla 4 days after injecting 5,6-HT, the loss in indoleamine appeared to be greater when o-phthalaldehyde was used. This suggests that the two methods may be measuring different compounds. According to both methods, the loss of 5-HT persisted for several days after the injection of 5,6-HT, but by 2 months 5-HT concentrations (measured only by the native fluorescence procedure), had recovered to near-normal values. The depletion of 5-HT was most pronounced in regions adjacent to the ventricular system and in the spinal cord. Initially, caudate and septum were more affected on the side of the injection, and later showed some permanent atrophy. The injection of up to 50 μg of 5,6-HT did not lead to any significant loss of noradrenaline or dopamine from the brain, or to any reduction in the activity of the enzyme tyrosine hydroxylase. The drug was a potent inhibitor of the uptake of [3H]5-HT by brain slices, but was less effective in inhibiting catecholamine uptake systems. These observations suggest a preferential action on tryptaminergic neurones. Larger doses of 5,6-HT caused a loss of catecholamines and tyrosine hydroxylase from the brain, and were severely toxic.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 18 (1971), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: —A surgical technique for sympathetically denervating the vas deferens has been evaluated biochemically. A slight fall in soluble muscle protein content and no significant change in DNA content of the operated vas deferens were found. This indicates that the surgical procedure causes only a slight degree of tissue damage and may be useful for investigating the cellular localization and properties of noradrenaline metabolizing enzymes. In three species examined (rat, guinea pig and rabbit), monoamine oxidase activity of the vas deferens fell by approximately 50 per cent after denervation. The time course of the fall in monoamine oxidase activity of rat vas deferens was parallel to that of the disappearance of noradrenaline suggesting that this proportion of the total enzyme activity had a neuronal localization. The remaining enzyme activity is presumably located extraneuronally.Significant falls in catechol-O-methyl transferase activity were found in rat and rabbit vas deferens after denervation but not in guinea pig. The rabbit and rat vas deferens had respectively approximately 60 and 30 per cent of the catechol-O-methyl transferase activity associated with the sympathetic nerves. A complete loss of DOPA decarboxylase and tyrosine hydroxylase activities occurred in rat vas deferens after denervation, suggesting that these noradrenaline synthesizing enzymes have an entirely neuronal localization.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 16 (1969), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract— Slices of rat cerebral cortex were labelled by incubation with [3H]γ-aminobutyric acid (GABA) and homogenized in isotonic sucrose. The subcellular distributions of endogenous GAB A, [3H]GABA and glutamate decarboxylase (GAD) were studied by density gradient centrifugation. The subcellular distributions of the labelled and endogenous amino acid were remarkably similar, indicating that [3H]GABA is taken up into the endogenous GABA pool. About 40 per cent of both endogenous and [3H]GABA were recovered in particles which were tentatively identified as synaptosomes from their equilibrium density and sensitivity to osmotic shock. In slices labelled with [3H]GABA and [14C]α-aminoisobutyric (AIB) acid, significantly more [3H]GABA was recovered in paniculate fractions than [14C]AIB. About 80 per cent of the enzyme GAD was also recovered in the same particle fractions which contained [3H]GABA and endogenous GABA. Evidence is presented which suggests that a loss of particle-bound GABA occurs during subcellular fractionation procedures.
    Type of Medium: Electronic Resource
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