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  • 1
    Online Resource
    Online Resource
    Inhibition of pluripotent stem cell-derived teratoma formation by small molecules
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 35 ( 2013-08-27)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 35 ( 2013-08-27)
    Abstract: The future of safe cell-based therapy rests on overcoming teratoma/tumor formation, in particular when using human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Because the presence of a few remaining undifferentiated hPSCs can cause undesirable teratomas after transplantation, complete removal of these cells with no/minimal damage to differentiated cells is a prerequisite for clinical application of hPSC-based therapy. Having identified a unique hESC signature of pro- and antiapoptotic gene expression profile, we hypothesized that targeting hPSC-specific antiapoptotic factor(s) (i.e., survivin or Bcl10) represents an efficient strategy to selectively eliminate pluripotent cells with teratoma potential. Here we report the successful identification of small molecules that can effectively inhibit these antiapoptotic factors, leading to selective and efficient removal of pluripotent stem cells through apoptotic cell death. In particular, a single treatment of hESC-derived mixed population with chemical inhibitors of survivin (e.g., quercetin or YM155) induced selective and complete cell death of undifferentiated hPSCs. In contrast, differentiated cell types (e.g., dopamine neurons and smooth-muscle cells) derived from hPSCs survived well and maintained their functionality. We found that quercetin-induced selective cell death is caused by mitochondrial accumulation of p53 and is sufficient to prevent teratoma formation after transplantation of hESC- or hiPSC-derived cells. Taken together, these results provide the “proof of concept” that small-molecule targeting of hPSC-specific antiapoptotic pathway(s) is a viable strategy to prevent tumor formation by selectively eliminating remaining undifferentiated pluripotent cells for safe hPSC-based therapy.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1303669110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
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    SSG: 11
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Stroke outcomes are worse with larger leukoaraiosis volumes
    Oxford University Press (OUP) ; 2017
    In:  Brain Vol. 140, No. 1 ( 2017-01), p. 158-170
    Details
    In: Brain, Oxford University Press (OUP), Vol. 140, No. 1 ( 2017-01), p. 158-170
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/aww259
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2017
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    The Clinical Significance of Preoperative Brain Magnetic Resonance Imaging in Pediatric Cochlear Implant Recipients
    S. Karger AG ; 2012
    In:  Audiology and Neurotology Vol. 17, No. 6 ( 2012), p. 373-380
    Details
    In: Audiology and Neurotology, S. Karger AG, Vol. 17, No. 6 ( 2012), p. 373-380
    Abstract: Although central nervous system abnormalities are incidentally detected in preoperative brain magnetic resonance imaging (MRI) studies in pediatric cochlear implant (CI) candidates, the clinical significance of the abnormalities remains unclear. We aimed to assess post-implantation auditory and speech performance in patients with brain lesions seen on MRI. Pediatric CI recipients (n = 177) who underwent preoperative MRI scans of the brain between January 2002 and June 2009 were included in this study. Patients with brain lesions on MRI were reviewed and categorized into the following groups: brain parenchymal lesions (focal vs. diffuse), ventriculomegaly, and extra-axial lesion. The main communication mode as well as progress in auditory perception and speech production were evaluated preoperatively and at 3, 6, 12, and 24 months postoperatively. Performance in patients with brain lesions was compared with the age- and sex-matched control group. Various brain lesions were found in 27 out of 177 patients. Children with brain lesions who received CIs showed gradual progress in auditory and speech outcomes for 2 years, though performance was reduced compared with the control group. In addition, there was a significant difference in the main communication mode between the two groups at 2 years following cochlear implantation. This difference was especially significant in patients with diffuse brain parenchymal lesions after further stratification of the brain lesion group. Preoperative brain MRI may have a role in improving the prediction of adverse outcomes in pediatric CI recipients. In particular, children with diffuse brain parenchymal lesions should be counseled regarding the poor prognosis preoperatively, and followed up with special attention.
    Type of Medium: Online Resource
    ISSN: 1420-3030 , 1421-9700
    URL: Article
    DOI: 10.1159/000341818
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2012
    detail.hit.zdb_id: 1481979-X
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  • 4
    Online Resource
    Online Resource
    Prediction of vowel identification for cochlear implant using a computational model
    Elsevier BV ; 2016
    In:  Speech Communication Vol. 85 ( 2016-12), p. 19-28
    Details
    In: Speech Communication, Elsevier BV, Vol. 85 ( 2016-12), p. 19-28
    Type of Medium: Online Resource
    ISSN: 0167-6393
    URL: Article
    DOI: 10.1016/j.specom.2016.10.005
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2016
    detail.hit.zdb_id: 625711-2
    detail.hit.zdb_id: 1460279-9
    SSG: 7,11
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  • 5
    Online Resource
    Online Resource
    Macrophage migration inhibitory factor mediates the antidepressant actions of voluntary exercise
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 32 ( 2012-08-07), p. 13094-13099
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 32 ( 2012-08-07), p. 13094-13099
    Abstract: Voluntary exercise is known to have an antidepressant effect. However, the underlying mechanism for this antidepressant action of exercise remains unclear, and little progress has been made in identifying genes that are directly involved. We have identified macrophage migration inhibitory factor (MIF) by analyzing existing mRNA microarray data and confirmed the augmented expression of selected genes under two experimental conditions: voluntary exercise and electroconvulsive seizure. A proinflammatory cytokine, MIF is expressed in the central nervous system and involved in innate and adaptive immune responses. A recent study reported that MIF is involved in antidepressant-induced hippocampal neurogenesis, but the mechanism remains elusive. In our data, tryptophan hydroxylase 2 ( Tph2 ) and brain-derived neurotrophic factor ( Bdnf ) expression were induced after MIF treatment in vitro, as well as during both exercise and electroconvulsive seizure in vivo. This increment of Tph2 was accompanied by increases in the levels of total serotonin in vitro. Moreover, the MIF receptor CD74 and the ERK1/2 pathway mediate the MIF-induced Tph2 and Bdnf gene expression as well as serotonin content. Experiments in Mif −/− mice revealed depression-like behaviors and a blunted antidepressant effect of exercise, as reflected by changes in Tph2 and Bdnf expression in the forced swim test. In addition, administration of recombinant MIF protein produced antidepressant-like behavior in rats in the forced swim test. Taken together, these results suggest a role of MIF in mediating the antidepressant action of exercise, probably by enhancing serotonin neurotransmission and neurotrophic factor-induced neurogenesis in the brain.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1205535109
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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  • 6
    Online Resource
    Online Resource
    Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 25 ( 2013-06-18), p. 10171-10176
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 25 ( 2013-06-18), p. 10171-10176
    Abstract: Glucokinase (GK) is a monomeric allosteric enzyme and plays a pivotal role in blood glucose homeostasis. GK is regulated by GK regulatory protein (GKRP), and indirectly by allosteric effectors of GKRP. Despite the critical roles of GK and GKRP, the molecular basis for the allosteric regulation mechanism of GK by GKRP remains unclear. We determined the crystal structure of Xenopus GK and GKRP complex in the presence of fructose-6-phosphate at 2.9 Å. GKRP binds to a super-open conformation of GK mainly through hydrophobic interaction, inhibiting the GK activity by locking a small domain of GK. We demonstrate the molecular mechanism for the modulation of GK activity by allosteric effectors of GKRP. Importantly, GKRP releases GK in a sigmoidal manner in response to glucose concentration by restricting a structural rearrangement of the GK small domain via a single ion pair. We find that GKRP acts as an allosteric switch for GK in blood glucose control by the liver.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1300457110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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  • 7
    Online Resource
    Online Resource
    Mechanochemical feedback underlies coexistence of qualitatively distinct cell polarity patterns within diverse cell populations
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 28 ( 2017-07-11)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 28 ( 2017-07-11)
    Abstract: Cell polarization and directional cell migration can display random, persistent, and oscillatory dynamic patterns. However, it is not clear whether these polarity patterns can be explained by the same underlying regulatory mechanism. Here, we show that random, persistent, and oscillatory migration accompanied by polarization can simultaneously occur in populations of melanoma cells derived from tumors with different degrees of aggressiveness. We demonstrate that all of these patterns and the probabilities of their occurrence are quantitatively accounted for by a simple mechanism involving a spatially distributed, mechanochemical feedback coupling the dynamically changing extracellular matrix (ECM)–cell contacts to the activation of signaling downstream of the Rho-family small GTPases. This mechanism is supported by a predictive mathematical model and extensive experimental validation, and can explain previously reported results for diverse cell types. In melanoma, this mechanism also accounts for the effects of genetic and environmental perturbations, including mutations linked to invasive cell spread. The resulting mechanistic understanding of cell polarity quantitatively captures the relationship between population variability and phenotypic plasticity, with the potential to account for a wide variety of cell migration states in diverse pathological and physiological conditions.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1700054114
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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