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  • 1
    Online Resource
    Online Resource
    A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 22 ( 2021-06)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 22 ( 2021-06)
    Abstract: Genes that are primarily expressed in cochlear glia-like supporting cells (GLSs) have not been clearly associated with progressive deafness. Herein, we present a deafness locus mapped to chromosome 3p25.1 and an auditory neuropathy spectrum disorder (ANSD) gene, TMEM43 , mainly expressed in GLSs. We identify p.(Arg372Ter) of TMEM43 by linkage analysis and exome sequencing in two large Asian families segregating ANSD, which is characterized by inability to discriminate speech despite preserved sensitivity to sound. The knock-in mouse with the p.(Arg372Ter) variant recapitulates a progressive hearing loss with histological abnormalities in GLSs. Mechanistically, TMEM43 interacts with the Connexin26 and Connexin30 gap junction channels, disrupting the passive conductance current in GLSs in a dominant-negative fashion when the p.(Arg372Ter) variant is introduced. Based on these mechanistic insights, cochlear implant was performed on three subjects, and speech discrimination was successfully restored. Our study highlights a pathological role of cochlear GLSs by identifying a deafness gene and its causal relationship with ANSD.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2019681118
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    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Abstract: De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains 〈 1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability ( h 2 ), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1902766117
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
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  • 3
    Online Resource
    Online Resource
    “Perfect” designer chromosome V and behavior of a ring derivative
    American Association for the Advancement of Science (AAAS) ; 2017
    In:  Science Vol. 355, No. 6329 ( 2017-03-10)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 355, No. 6329 ( 2017-03-10)
    Abstract: Perfect matching of an assembled physical sequence to a specified designed sequence is crucial to verify design principles in genome synthesis. We designed and de novo synthesized 536,024–base pair chromosome synV in the “Build-A-Genome China” course. We corrected an initial isolate of synV to perfectly match the designed sequence using integrative cotransformation and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)–mediated editing in 22 steps; synV strains exhibit high fitness under a variety of culture conditions, compared with that of wild-type V strains. A ring synV derivative was constructed, which is fully functional in Saccharomyces cerevisiae under all conditions tested and exhibits lower spore viability during meiosis. Ring synV chromosome can extends Sc2.0 design principles and provides a model with which to study genomic rearrangement, ring chromosome evolution, and human ring chromosome disorders.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aaf4704
    RVK:
    TA 1000
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2017
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  • 4
    Online Resource
    Online Resource
    Ancient DNA and multimethod dating confirm the late arrival of anatomically modern humans in southern China
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 8 ( 2021-02-23)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 8 ( 2021-02-23)
    Abstract: The expansion of anatomically modern humans (AMHs) from Africa around 65,000 to 45,000 y ago (ca. 65 to 45 ka) led to the establishment of present-day non-African populations. Some paleoanthropologists have argued that fossil discoveries from Huanglong, Zhiren, Luna, and Fuyan caves in southern China indicate one or more prior dispersals, perhaps as early as ca. 120 ka. We investigated the age of the human remains from three of these localities and two additional early AMH sites (Yangjiapo and Sanyou caves, Hubei) by combining ancient DNA (aDNA) analysis with a multimethod geological dating strategy. Although U–Th dating of capping flowstones suggested they lie within the range ca. 168 to 70 ka, analyses of aDNA and direct AMS 14 C dating on human teeth from Fuyan and Yangjiapo caves showed they derive from the Holocene. OSL dating of sediments and AMS 14 C analysis of mammal teeth and charcoal also demonstrated major discrepancies from the flowstone ages; the difference between them being an order of magnitude or more at most of these localities. Our work highlights the surprisingly complex depositional history recorded at these subtropical caves which involved one or more episodes of erosion and redeposition or intrusion as recently as the late Holocene. In light of our findings, the first appearance datum for AMHs in southern China should probably lie within the timeframe set by molecular data of ca. 50 to 45 ka.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2019158118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
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  • 5
    Online Resource
    Online Resource
    Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 8 ( 2010-02-23), p. 3728-3733
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 8 ( 2010-02-23), p. 3728-3733
    Abstract: p53, apoptosis, and senescence are frequently activated in preneoplastic lesions and are barriers to progression to malignancy. These barriers have been suggested to result from an ATM-mediated DNA damage response (DDR), which may follow oncogene-induced hyperproliferation and ensuing DNA replication stress. To elucidate the currently untested role of DDR in breast cancer initiation, we examined the effect of oncogene expression in several murine models of breast cancer. We did not observe a detectable DDR in early hyperplastic lesions arising in transgenic mice expressing several different oncogenes. However, DDR signaling was strongly induced in preneoplastic lesions arising from individual mammary cells transduced in vivo by retroviruses expressing either PyMT or ErbB2 . Thus, activation of an oncogene after normal tissue development causes a DDR. Furthermore, in this somatic ErbB2 tumor model, ATM, and thus DDR, is required for p53 stabilization, apoptosis, and senescence. In palpable tumors in this model, p53 stabilization and apoptosis are lost, but unexpectedly senescence remains in many tumor cells. Thus, this murine model fully recapitulates early DDR signaling; the eventual suppression of its endpoints in tumorigenesis provides compelling evidence that ErbB2-induced aberrant mammary cell proliferation leads to an ATM-mediated DDR that activates apoptosis and senescence, and at least the former must be overcome to progress to malignancy. This in vivo study also uncovers an unexpected effect of ErbB2 activation previously known for its prosurvival roles, and suggests that protection of the ATM-mediated DDR-p53 signaling pathway may be important in breast cancer prevention.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0910665107
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 6
    Online Resource
    Online Resource
    Long-term functional maintenance of primary human hepatocytes in vitro
    American Association for the Advancement of Science (AAAS) ; 2019
    In:  Science Vol. 364, No. 6438 ( 2019-04-26), p. 399-402
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 364, No. 6438 ( 2019-04-26), p. 399-402
    Abstract: The maintenance of terminally differentiated cells, especially hepatocytes, in vitro has proven challenging. Here we demonstrated the long-term in vitro maintenance of primary human hepatocytes (PHHs) by modulating cell signaling pathways with a combination of five chemicals (5C). 5C-cultured PHHs showed global gene expression profiles and hepatocyte-specific functions resembling those of freshly isolated counterparts. Furthermore, these cells efficiently recapitulated the entire course of hepatitis B virus (HBV) infection over 4 weeks with the production of infectious viral particles and formation of HBV covalently closed circular DNA. Our study demonstrates that, with a chemical approach, functional maintenance of PHHs supports long-term HBV infection in vitro, providing an efficient platform for investigating HBV cell biology and antiviral drug screening.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aau7307
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2019
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  • 7
    Online Resource
    Online Resource
    TMS Reveals Dynamic Interaction between Inferior Frontal Gyrus and Posterior Middle Temporal Gyrus in Gesture-Speech Semantic Integration
    Society for Neuroscience ; 2021
    In:  The Journal of Neuroscience Vol. 41, No. 50 ( 2021-12-15), p. 10356-10364
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 41, No. 50 ( 2021-12-15), p. 10356-10364
    Abstract: Semantic processing is an amodal process with modality-specific information integrated in supramodal “convergence zones” or “semantic hub” with executive mechanisms that tailor semantic representation in a task-appropriate way. One unsolved question is how frontal control region dynamically interacts with temporal representation region in semantic integration. The present study addressed this issue by using inhibitory double-pulse transcranial magnetic stimulation over the left inferior frontal gyrus (IFG) or left posterior middle temporal gyrus (pMTG) in one of eight 40 ms time windows (TWs) (3 TWs before and 5 TWs after the identification point of speech), when human participants (12 females, 14 males) were presented with semantically congruent or incongruent gesture-speech pairs but merely identified the gender of speech. We found a TW-selective disruption of gesture-speech integration, indexed by the semantic congruency effect (i.e., a cost of reaction time because of semantic conflict), when stimulating the left pMTG in TW1, TW2, and TW7 but when stimulating the left IFG in TW3 and TW6. Based on the timing relationship, we hypothesize a two-stage gesture-speech integration circuit with a pMTG-to-IFG sequential involvement in the prelexical stage for activating gesture semantics and top-down constraining the phonological processing of speech. In the postlexical stage, an IFG-to-pMTG feedback signal might be implicated for the control of goal-directed representations and multimodal semantic unification. Our findings provide new insights into the dynamic brain network of multimodal semantic processing by causally revealing the temporal dynamics of frontal control and temporal representation regions. SIGNIFICANCE STATEMENT Previous research has identified differential functions of left inferior frontal gyrus (IFG) and posterior middle temporal gyrus (pMTG) in semantic control and semantic representation, respectively, and a causal contribution of both regions in gesture-speech integration. However, it remains largely unclear how the two regions dynamically interact in semantic processing. By using double-pulse transcranial magnetic stimulation to disrupt regional activity at specific time, this study for the first time revealed critical time windows when the two areas were causally involved in integrating gesture and speech semantics. Findings suggest a pMTG-IFG-pMTG neurocircuit loop in gesture-speech integration, which deepens current knowledge and inspires future investigation of the temporal dynamics and cognitive processes of the amodal semantic network.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1355-21.2021
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2021
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  • 8
    Online Resource
    Online Resource
    All-optical photon switching, router and amplifier using a passive-active optomechanical system
    IOP Publishing ; 2018
    In:  EPL (Europhysics Letters) Vol. 122, No. 2 ( 2018-06-12), p. 24001-
    Details
    In: EPL (Europhysics Letters), IOP Publishing, Vol. 122, No. 2 ( 2018-06-12), p. 24001-
    Type of Medium: Online Resource
    ISSN: 1286-4854
    URL: Article
    DOI: 10.1209/0295-5075/122/24001
    Language: Unknown
    Publisher: IOP Publishing
    Publication Date: 2018
    detail.hit.zdb_id: 1465366-7
    detail.hit.zdb_id: 165776-8
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  • 9
    Online Resource
    Online Resource
    Structure and dynamics of a glass-forming binary complex plasma with non-reciprocal interaction
    IOP Publishing ; 2018
    In:  EPL (Europhysics Letters) Vol. 123, No. 3 ( 2018-09-10), p. 35001-
    Details
    In: EPL (Europhysics Letters), IOP Publishing, Vol. 123, No. 3 ( 2018-09-10), p. 35001-
    Type of Medium: Online Resource
    ISSN: 1286-4854
    URL: Article
    DOI: 10.1209/0295-5075/123/35001
    Language: Unknown
    Publisher: IOP Publishing
    Publication Date: 2018
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    detail.hit.zdb_id: 165776-8
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  • 10
    Online Resource
    Online Resource
    Broadband H-shaped seismic metamaterial with a rubber coating
    IOP Publishing ; 2019
    In:  EPL (Europhysics Letters) Vol. 127, No. 1 ( 2019-08-12), p. 17002-
    Details
    In: EPL (Europhysics Letters), IOP Publishing, Vol. 127, No. 1 ( 2019-08-12), p. 17002-
    Type of Medium: Online Resource
    ISSN: 1286-4854
    URL: Article
    DOI: 10.1209/0295-5075/127/17002
    Language: Unknown
    Publisher: IOP Publishing
    Publication Date: 2019
    detail.hit.zdb_id: 1465366-7
    detail.hit.zdb_id: 165776-8
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