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  • 1
    Publikationsdatum: 2015-01-24
    Beschreibung: Mechanisms of unassisted delivery of RNA therapeutics, including inhibitors of microRNAs, remain poorly understood. We observed that the hepatocellular carcinoma cell line SKHEP1 retains productive free uptake of a miR-21 inhibitor (anti-miR-21). Uptake of anti-miR-21, but not a mismatch (MM) control, induces expression of known miR-21 targets (DDAH1, ANKRD46) and leads to dose-dependent inhibition of cell growth. To elucidate mechanisms of SKHEP1 sensitivity to anti-miR-21, we conducted an unbiased shRNA screen that revealed tumor susceptibility gene 101 (TSG101), a component of the endosomal sorting complex required for transport (ESCRT-I), as an important determinant of anti-proliferative effects of anti-miR-21. RNA interference-mediated knockdown of TSG101 and another ESCRT-I protein, VPS28, improved uptake of anti-miR-21 in parental SKHEP1 cells and restored productive uptake to SKHEP1 clones with acquired resistance to anti-miR-21. Depletion of ESCRT-I in several additional cancer cell lines with inherently poor uptake resulted in improved activity of anti-miR-21. Finally, knockdown of TSG101 increased uptake of anti-miR-21 by cancer cells in vivo following systemic delivery. Collectively, these data support an important role for the ESCRT-I complex in the regulation of productive free uptake of anti-miRs and reveal potential avenues for improving oligonucleotide free uptake by cancer cells.
    Print ISSN: 0305-1048
    Digitale ISSN: 1362-4962
    Thema: Biologie
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 2
    Digitale Medien
    Digitale Medien
    Amsterdam : Elsevier
    Phytochemistry 26 (1987), S. 2477-2480 
    ISSN: 0031-9422
    Schlagwort(e): 2-oxo-4-methylglutaric acid ; 4-methyleneglutamic acid ; 4-methyleneglutamine ; 4-methylglutamic acid ; 4-substituted glutamic acids ; Leguminoseae ; Sophora japonica ; transamination.
    Quelle: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Thema: Biologie , Chemie und Pharmazie
    Materialart: Digitale Medien
    Standort Signatur Erwartet Verfügbarkeit
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  • 3
    Publikationsdatum: 2015-05-16
    Beschreibung: In the process of modeling and simulation of bacterial growth, the calibration of a numerical model to the specific experimental setup is often necessary. This study addressed the question of whether it is possible to predict the growth of microorganisms based only on independent measurements without additional calibration. To this end, flow-through experiments with Escherichia coli (HB101 K12 pGLO) in a Hele–Shaw cell filled with quartz sand were simulated with a newly developed numerical code for reactive multiphase multicomponent flow based on an operator splitting approach. The hydraulic parameters of the sand were determined by multistep outflow experiments and the parameters of the microbial growth model from batch experiments. There was very good agreement between predicted and measured cell concentrations nondestructively determined from the fluorescence intensities of a green fluorescent protein produced by the bacterial strain. The correct description of the kinetics of gas–water phase exchange in the unsaturated zone and of cell attachment to the solid phase proved to be crucial. The operator splitting approach significantly reduced numerical dispersion in a convection-dominated test case. It allowed a flexible adaptation of the solution strategy to the specific problem.
    Digitale ISSN: 1539-1663
    Thema: Geologie und Paläontologie , Land- und Forstwirtschaft, Gartenbau, Fischereiwirtschaft, Hauswirtschaft
    Standort Signatur Erwartet Verfügbarkeit
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  • 4
    Publikationsdatum: 2018
    Beschreibung: 〈p〉In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper like transcription regulator 1 (〈i〉LZTR1〈/i〉) gene led to enhanced mitogen-activated protein kinase pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of the 〈i〉Drosophila LZTR1〈/i〉 ortholog 〈i〉CG3711〈/i〉 resulted in a RAS-dependent gain of function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of 〈i〉LZTR1〈/i〉 led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS. We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. As 〈i〉LZTR1〈/i〉 disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale for 〈i〉LZTR1〈/i〉 involvement in a variety of inherited and acquired human disorders.〈/p〉
    Print ISSN: 0036-8075
    Digitale ISSN: 1095-9203
    Thema: Allgemeine Naturwissenschaft
    Standort Signatur Erwartet Verfügbarkeit
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  • 5
    Publikationsdatum: 2015-12-24
    Beschreibung: We report an implementation of static and frequency-dependent excited state polarizabilities for the approximate coupled cluster single and doubles model CC2 as analytic second derivatives of an excited state quasienergy Lagrangian. By including appropriate conditions for the normalization and the phase of the eigenvectors, divergent secular terms are avoided. This leads to response equations in a subspace orthogonal to the unperturbed eigenvectors. It is shown how these projected equations can be solved without storage of the double excitation part of the eigenvectors. By exploiting the resolution-of-the-identity approximation and a numerical Laplace transformation, the quadratic scaling of the main memory demands of RI-CC2 with the system size could be preserved. This enables calculations of excited state polarizabilities for large molecules, e.g., linear polyacenes up to decacene with almost 2500 basis functions on a single compute node within a few days. For a test set of molecules where measurements are available as reference data, we compare the orbital-relaxed and unrelaxed CC2 approaches with experiment to validate its accuracy. The approach can be easily extended to other response methods, in particular CIS(D ∞ ). The latter gives results which, in the orbital-relaxed case, are within a few percent of the CC2 values, while coupled cluster singles results deviate typically by about 20% from orbital-relaxed CC2 and experimental reference data.
    Print ISSN: 0021-9606
    Digitale ISSN: 1089-7690
    Thema: Chemie und Pharmazie , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 6
    Publikationsdatum: 2015-06-13
    Beschreibung: For grain sizes finer than coarse sand, the first flow-transverse bedforms to develop are current ripples. Although numerous studies have analysed different aspects of bedform morphodynamics, to date no comprehensive physical explanation for the formation of ripples has been given. We offer such an explanation based on a virtual boundary layer concept, and present a model predicting ripple height on the basis of grain size, current velocity and water depth. The model contradicts the conventional view of current ripples as bedforms not scaling with flow depth. Furthermore, it confirms the dependence of ripple dimensions on grain size, and their relative insensitivity to flow strength. Scientific Reports 5 doi: 10.1038/srep11390
    Digitale ISSN: 2045-2322
    Thema: Allgemeine Naturwissenschaft
    Publiziert von Springer Nature
    Standort Signatur Erwartet Verfügbarkeit
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  • 7
    Publikationsdatum: 2016-02-20
    Beschreibung: A prominent control on the flow over subaqueous dunes is the slope of the downstream leeside. While previous work has focused on steep (~30°), asymmetric dunes with permanent flow separation, little is known about dunes with lower lee-slope angles for which flow separation is absent or intermittent. Here, we present a laboratory investigation where we systematically varied the dune lee-slope, holding other geometric parameters and flow hydraulics constant, to explore effects on the turbulent flow field and flow resistance. Three sets of fixed dunes (lee-slopes of 10°, 20° and 30°) were separately installed in a 15 m long and 1 m wide flume and subjected to 0.20 m deep flow. Measurements consisted of high-frequency, vertical profiles collected with a Laser Doppler Velocimeter (LDV). We show that the temporal and spatial occurrence of flow separation decreases with dune lee-slope. Velocity gradients in the dune leeside depict a free shear layer downstream of the 30° dunes and a weaker shear layer closer to the bed for the 20° and 10° dunes. The decrease in velocity gradients leads to lower magnitude of turbulence production for gentle lee-slopes. Aperiodic, strong ejection events dominate the shear layer, but decrease in strength and frequency for low-angle dunes. Flow resistance of dunes decreases with lee-slope; the transition being non-linear. Over the 10°, 20° and 30° dunes, shear stress is 8%, 33% and 90 % greater than a flat bed, respectively. Our results demonstrate that dune lee-slope plays an important, but often ignored role in flow resistance.
    Print ISSN: 0148-0227
    Thema: Geologie und Paläontologie , Physik
    Publiziert von Wiley im Namen von American Geophysical Union (AGU).
    Standort Signatur Erwartet Verfügbarkeit
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  • 8
    Publikationsdatum: 2016-01-19
    Beschreibung: The location of a shore-parallel nearshore sandbar derived from seven years of video imagery data at the single-barred embayed Tairua Beach (NZ) is investigated to assess the contribution of barline rotation to the overall morphodynamics of sandbars in embayed environments and to characterise the process of rotation in relation to external conditions. Rotation induces cross-shore barline variations at the embayment extremities on the order of magnitude of those induced by alongshore uniform cross-shore migration of the bar. Two semi-empirical models have been developed to relate the barline cross-shore migration and rotation to external wave forcing conditions. The rotation model is directly derived from the cross-shore migration model. Therefore its formulation advocates for a primary role of cross-shore processes in the rotation of sandbars at embayed beaches. The orientation evolves towards an equilibrium angle directly related to the alongshore wave energy gradient due to two different mechanisms. Either the bar extremities migrate in opposite directions with no overall cross-shore bar migration (pivotal rotation) or the rotation relates to an overall migration of the barline which is not uniform along the beach (migration-driven rotation). Migration and rotation characteristic response times are similar, ranging from 10 to 30 days for mild and energetic wave conditions and above 200 days during very calm conditions or when the bar is located far offshore. This article is protected by copyright. All rights reserved.
    Print ISSN: 0148-0227
    Thema: Geologie und Paläontologie , Physik
    Publiziert von Wiley im Namen von American Geophysical Union (AGU).
    Standort Signatur Erwartet Verfügbarkeit
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  • 9
    Publikationsdatum: 2012-07-14
    Beschreibung: Journal of Chemical & Engineering Data DOI: 10.1021/je300504f
    Print ISSN: 0021-9568
    Digitale ISSN: 1520-5134
    Thema: Chemie und Pharmazie , Werkstoffwissenschaften, Fertigungsverfahren, Fertigung
    Standort Signatur Erwartet Verfügbarkeit
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  • 10
    Publikationsdatum: 2012-04-25
    Beschreibung: The influence of Antarctica and the Southern Ocean on Late Pliocene global climate reconstructions has remained ambiguous due to a lack of well-dated Antarctic-proximal, paleoenvironmental records. Here we present ice sheet, sea-surface temperature, and sea ice reconstructions from the ANDRILL AND-1B sediment core recovered from beneath the Ross Ice Shelf. We provide evidence for a major expansion of an ice sheet in the Ross Sea that began at ∼3.3 Ma, followed by a coastal sea surface temperature cooling of ∼2.5 °C, a stepwise expansion of sea ice, and polynya-style deep mixing in the Ross Sea between 3.3 and 2.5 Ma. The intensification of Antarctic cooling resulted in strengthened westerly winds and invigorated ocean circulation. The associated northward migration of Southern Ocean fronts has been linked with reduced Atlantic Meridional Overturning Circulation by restricting surface water connectivity between the ocean basins, with implications for heat transport to the high latitudes of the North Atlantic. While our results do not exclude low-latitude mechanisms as drivers for Pliocene cooling, they indicate an additional role played by southern high-latitude cooling during development of the bipolar world.
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Standort Signatur Erwartet Verfügbarkeit
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