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  • 2015-2019
  • 2010-2014  (4)
  • 1915-1919
  • 2011  (4)
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  • 2015-2019
  • 2010-2014  (4)
  • 1915-1919
Year
  • 1
    Publication Date: 2011-09-28
    Description: Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebrafish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in p53 wild-type zebrafish, 6% in p53 heterozygotes, and 29% in p53-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS pathogenesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphorylation in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 2
    Publication Date: 2011-02-23
    Description: Mammalian somatosensory topographic maps contain specialized neuronal structures that precisely recapitulate the spatial pattern of peripheral sensory organs. In the mouse, whiskers are orderly mapped onto several brainstem nuclei as a set of modular structures termed barrelettes. Using a dual-color iontophoretic labeling strategy, we found that the precise topography of barrelettes is not a result of ordered positions of sensory neurons within the ganglion. We next explored another possibility that formation of the whisker map is influenced by periphery-derived mechanisms. During the period of peripheral sensory innervation, several TGF-β ligands are exclusively expressed in whisker follicles in a dynamic spatiotemporal pattern. Disrupting TGF-β signaling, specifically in sensory neurons by conditional deletion of Smad4 at the late embryonic stage, results in the formation of abnormal barrelettes in the principalis and interpolaris brainstem nuclei and a complete absence of barrelettes in the caudalis nucleus. We further show that this phenotype is not derived from defective peripheral innervation or central axon outgrowth but is attributable to the misprojection and deficient segregation of trigeminal axonal collaterals into proper barrelettes. Furthermore, Smad4-deficient neurons develop simpler terminal arbors and form fewer synapses. Together, our findings substantiate the involvement of whisker-derived TGF-β/Smad4 signaling in the formation of the whisker somatotopic maps.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 3
    Publication Date: 2011-04-06
    Description: Remembering an event from the past is often complicated by the fact that our memories are cluttered with similar events. Though competition is a fundamental part of remembering, there is little evidence of how mnemonic competition is neurally represented. Here, we assessed whether competition between visual memories is captured in the relative degree to which target vs. competing memories are reactivated within the ventral occipitotemporal cortex (VOTC). To assess reactivation, we used multivoxel pattern analysis of fMRI data, quantifying the degree to which retrieval events elicited patterns of neural activity that matched those elicited during encoding. Consistent with recent evidence, we found that retrieval of visual memories was associated with robust VOTC reactivation and that the degree of reactivation scaled with behavioral expressions of target memory retrieval. Critically, competitive remembering was associated with more ambiguous patterns of VOTC reactivation, putatively reflecting simultaneous reactivation of target and competing memories. Indeed, the more weakly that target memories were reactivated, the more likely that competing memories were later remembered. Moreover, when VOTC reactivation indicated that conflict between target and competing memories was high, frontoparietal mechanisms were markedly engaged, revealing specific neural mechanisms that tracked competing mnemonic evidence. Together, these findings provide unique evidence that neural reactivation captures competition between individual memories, providing insight into how well target memories are retrieved in the present and how likely competing memories will be remembered in the future.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 4
    Publication Date: 2011-07-20
    Description: The mesoscale structure of a mature polar low was studied on the basis of high-resolution airborne measurements and numerical modelling. A polar low was measured by light detection and ranging (lidar) and dropsonde observations over the Norwegian Sea on 3 and 4 March 2008. Lidar observations provided cross-sections of water-vapour mixing ratio, backscatter ratio and horizontal wind speed around the polar low and through its centre. Mesoscale structures, such as shallow convection in a cold-air outbreak, a dry intrusion in the eye-like centre of the cyclone and deep convection surrounding it could be identified. Numerical simulations were performed with the European Centre for Medium-Range Weather Forecasts (ECMWF) Integrated Forecast System (IFS) and a high-resolution, polar version of the Weather Research and Forecasting (WRF) model. WRF simulations reproduced these structures and showed that the polar low had a warm, upper-level core with descending motions. The eye-like centre had a diameter of about 100–150 km and was characterized by rather stable stratification, horizontally constant potential temperatures and calm winds. Beyond the centre, wind speeds increased rapidly. The observed radial wind and temperature profiles support previous idealized simulations. Several WRF sensitivity tests showed the influence of the initialization time and sensible and latent heat fluxes from the surface on the simulated polar-low development. The polar-low simulations were more accurate in runs starting at the mature stage. Heat fluxes from the surface were important for the polar-low energetics, especially at the final stages. Copyright © 2011 Royal Meteorological Society
    Print ISSN: 0035-9009
    Electronic ISSN: 1477-870X
    Topics: Geography , Physics
    Published by Wiley-Blackwell
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