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  • 1
    Online Resource
    Online Resource
    A hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 11 ( 2020-03-17), p. 6103-6113
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 11 ( 2020-03-17), p. 6103-6113
    Abstract: Clinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1912146117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Oxidation of dCTP contributes to antibiotic lethality in stationary-phase mycobacteria
    Proceedings of the National Academy of Sciences ; 2018
    In:  Proceedings of the National Academy of Sciences Vol. 115, No. 9 ( 2018-02-27), p. 2210-2215
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 9 ( 2018-02-27), p. 2210-2215
    Abstract: Growing evidence shows that generation of reactive oxygen species (ROS) derived from antibiotic-induced metabolic perturbation contribute to antibiotic lethality. However, our knowledge of the mechanisms by which antibiotic-induced oxidative stress actually kills cells remains elusive. Here, we show that oxidation of dCTP underlies ROS-mediated antibiotic lethality via induction of DNA double-strand breaks (DSBs). Deletion of mazG -encoded 5-OH-dCTP–specific pyrophosphohydrolase potentiates antibiotic killing of stationary-phase mycobacteria, but did not affect antibiotic efficacy in exponentially growing cultures. Critically, the effect of mazG deletion on potentiating antibiotic killing is associated with antibiotic-induced ROS and accumulation of 5-OH-dCTP. Independent lines of evidence presented here indicate that the increased level of DSBs observed in the ΔmazG mutant is a dead-end event accounting for enhanced antibiotic killing. Moreover, we provided genetic evidence that 5-OH-dCTP is incorporated into genomic DNA via error-prone DNA polymerase DnaE2 and repair of 5-OH-dC lesions via the endonuclease Nth leads to the generation of lethal DSBs. This work provides a mechanistic view of ROS-mediated antibiotic lethality in stationary phase and may have broad implications not only with respect to antibiotic lethality but also to the mechanism of stress-induced mutagenesis in bacteria.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1719627115
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2018
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    A TIGAR-Regulated Metabolic Pathway Is Critical for Protection of Brain Ischemia
    Society for Neuroscience ; 2014
    In:  The Journal of Neuroscience Vol. 34, No. 22 ( 2014-05-28), p. 7458-7471
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 34, No. 22 ( 2014-05-28), p. 7458-7471
    Abstract: TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis and increases the flow of pentose phosphate pathway (PPP), which generates NADPH and pentose. We hypothesized that TIGAR plays a neuroprotective role in brain ischemia as neurons do not rely on glycolysis but are vulnerable to oxidative stress. We found that TIGAR was highly expressed in brain neurons and was rapidly upregulated in response to ischemia/reperfusion insult in a TP53-independent manner. Overexpression of TIGAR in normal mice with lentivirus reduced ischemic neuronal injury, whereas lentivirus-mediated TIGAR knockdown aggravated it. In cultured primary neurons, increasing TIGAR expression reduced oxygen and glucose deprivation (OGD)/reoxygenation-induced injury, whereas decreasing its expression worsened the injury. The glucose 6-phosphate dehydrogenase was upregulated in mouse and cellular models of stroke, and its upregulation was further enhanced by overexpression of TIGAR. Supplementation of NADPH also reduced ischemia/reperfusion brain injury and alleviated TIGAR knockdown-induced aggravation of ischemic injury. In animal and cellular stroke models, ischemia/reperfusion increased mitochondrial localization of TIGAR. OGD/reoxygenation-induced elevation of ROS, reduction of GSH, dysfunction of mitochondria, and activation of caspase-3 were rescued by overexpression of TIGAR or supplementation of NADPH, while knockdown of TIGAR aggravated these changes. Together, our results show that TIGAR protects ischemic brain injury via enhancing PPP flux and preserving mitochondria function, and thus may be a valuable therapeutic target for ischemic brain injury.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.4655-13.2014
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2014
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Examining the generalizability of research findings from archival data
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 30 ( 2022-07-26)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 30 ( 2022-07-26)
    Abstract: This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizability—for the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2120377119
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons
    Springer Science and Business Media LLC ; 2012
    In:  Nature Neuroscience Vol. 15, No. 2 ( 2012-2), p. 258-266
    Details
    In: Nature Neuroscience, Springer Science and Business Media LLC, Vol. 15, No. 2 ( 2012-2), p. 258-266
    Type of Medium: Online Resource
    ISSN: 1097-6256 , 1546-1726
    URL: Article
    DOI: 10.1038/nn.3005
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2012
    detail.hit.zdb_id: 1494955-6
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Statistical modeling of sonar performance and its variance due to ocean fluctuations
    Acoustical Society of America (ASA) ; 2004
    In:  The Journal of the Acoustical Society of America Vol. 115, No. 5_Supplement ( 2004-05-01), p. 2580-2580
    Details
    In: The Journal of the Acoustical Society of America, Acoustical Society of America (ASA), Vol. 115, No. 5_Supplement ( 2004-05-01), p. 2580-2580
    Abstract: Sonar performance can be characterized by its detection range, which is determined by the sonar equation. The sonar equation includes parameters of sonar systems, environments, and the detection algorithms. Though the detection algorithm is itself a statistical means, it does not describe the relationship between the statistical properties of the environmental parameters with the detection range. This paper presents a statistical model for detection range based on the statistical properties of the environments, namely transmission losses. Temperature data from local moorings and VLA in ASIAEX-SCS are used to establish an ensemble samples for sound-speed profiles, and transmission loss curves are generated, thus the ensemble samples for TLs. The resultant detection range and its error bar are estimated for the Continental Shelf region in the South China Sea.
    Type of Medium: Online Resource
    ISSN: 0001-4966 , 1520-8524
    URL: Article
    DOI: 10.1121/1.4784298
    RVK:
    EQ 1000
    Language: English
    Publisher: Acoustical Society of America (ASA)
    Publication Date: 2004
    detail.hit.zdb_id: 1461063-2
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  • 7
    Online Resource
    Online Resource
    Orexin-A Intensifies Mouse Pupillary Light Response by Modulating Intrinsically Photosensitive Retinal Ganglion Cells
    Society for Neuroscience ; 2021
    In:  The Journal of Neuroscience Vol. 41, No. 12 ( 2021-03-24), p. 2566-2580
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 41, No. 12 ( 2021-03-24), p. 2566-2580
    Abstract: We show for the first time that the neuropeptide orexin modulates pupillary light response, a non-image-forming visual function, in mice of either sex. Intravitreal injection of the orexin receptor (OXR) antagonist TCS1102 and orexin-A reduced and enhanced pupillary constriction in response to light, respectively. Orexin-A activated OX 1 Rs on M2-type intrinsically photosensitive retinal ganglion cells (M2 cells), and caused membrane depolarization of these cells by modulating inward rectifier potassium channels and nonselective cation channels, thus resulting in an increase in intrinsic excitability. The increased intrinsic excitability could account for the orexin-A-evoked increase in spontaneous discharges and light-induced spiking rates of M2 cells, leading to an intensification of pupillary constriction. Orexin-A did not alter the light response of M1 cells, which could be because of no or weak expression of OX 1 Rs on them, as revealed by RNAscope in situ hybridization. In sum, orexin-A is likely to decrease the pupil size of mice by influencing M2 cells, thereby improving visual performance in awake mice via enhancing the focal depth of the eye's refractive system. SIGNIFICANCE STATEMENT This study reveals the role of the neuropeptide orexin in mouse pupillary light response, a non-image-forming visual function. Intravitreal orexin-A administration intensifies light-induced pupillary constriction via increasing the excitability of M2 intrinsically photosensitive retinal ganglion cells by activating the orexin receptor subtype OX 1 R. Modulation of inward rectifier potassium channels and nonselective cation channels were both involved in the ionic mechanisms underlying such intensification. Orexin could improve visual performance in awake mice by reducing the pupil size and thereby enhancing the focal depth of the eye's refractive system.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0217-20.2021
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2021
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Suture Lateralization in Patients With Bilateral Vocal Fold Paralysis
    Elsevier BV ; 2014
    In:  Journal of Voice Vol. 28, No. 5 ( 2014-09), p. 644-651
    Details
    In: Journal of Voice, Elsevier BV, Vol. 28, No. 5 ( 2014-09), p. 644-651
    Type of Medium: Online Resource
    ISSN: 0892-1997
    URL: Article
    DOI: 10.1016/j.jvoice.2013.12.012
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
    detail.hit.zdb_id: 2111437-7
    SSG: 7,11
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  • 9
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    Online Resource
    A reconsideration of the syntax of Chinese relative structures
    Elsevier BV ; 2020
    In:  Lingua Vol. 240 ( 2020-06), p. 102834-
    Details
    In: Lingua, Elsevier BV, Vol. 240 ( 2020-06), p. 102834-
    Type of Medium: Online Resource
    ISSN: 0024-3841
    URL: Article
    DOI: 10.1016/j.lingua.2020.102834
    RVK:
    EQ 1000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 1480982-5
    SSG: 7,11
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  • 10
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    Online Resource
    PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 27 ( 2019-07-02), p. 13394-13403
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 27 ( 2019-07-02), p. 13394-13403
    Abstract: Increased glycolysis in the lung vasculature has been connected to the development of pulmonary hypertension (PH). We therefore investigated whether glycolytic regulator 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB3)-mediated endothelial glycolysis plays a critical role in the development of PH. Heterozygous global deficiency of Pfkfb3 protected mice from developing hypoxia-induced PH, and administration of the PFKFB3 inhibitor 3PO almost completely prevented PH in rats treated with Sugen 5416/hypoxia, indicating a causative role of PFKFB3 in the development of PH. Immunostaining of lung sections and Western blot with isolated lung endothelial cells showed a dramatic increase in PFKFB3 expression and activity in pulmonary endothelial cells of rodents and humans with PH. We generated mice that were constitutively or inducibly deficient in endothelial Pfkfb3 and found that these mice were incapable of developing PH or showed slowed PH progression. Compared with control mice, endothelial Pfkfb3 -knockout mice exhibited less severity of vascular smooth muscle cell proliferation, endothelial inflammation, and leukocyte recruitment in the lungs. In the absence of PFKFB3 , lung endothelial cells from rodents and humans with PH produced lower levels of growth factors (such as PDGFB and FGF2) and proinflammatory factors (such as CXCL12 and IL1β). This is mechanistically linked to decreased levels of HIF2A in lung ECs following PFKFB3 knockdown. Taken together, these results suggest that targeting PFKFB3 is a promising strategy for the treatment of PH.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1821401116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
    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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