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  • 1
    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:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
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  • 2
    Online Resource
    Online Resource
    Characterization of HPV and host genome interactions in primary head and neck cancers
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 43 ( 2014-10-28), p. 15544-15549
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 43 ( 2014-10-28), p. 15544-15549
    Abstract: Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1416074111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
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    SSG: 11
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Black Americans' perspectives on ally confrontations of racial prejudice
    Elsevier BV ; 2022
    In:  Journal of Experimental Social Psychology Vol. 101 ( 2022-07), p. 104337-
    Details
    In: Journal of Experimental Social Psychology, Elsevier BV, Vol. 101 ( 2022-07), p. 104337-
    Type of Medium: Online Resource
    ISSN: 0022-1031
    URL: Article
    DOI: 10.1016/j.jesp.2022.104337
    RVK:
    CL 1000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 1469604-6
    SSG: 5,2
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  • 4
    Online Resource
    Online Resource
    China: Its People, Its Society, Its Culture.
    SAGE Publications ; 1961
    In:  American Sociological Review Vol. 26, No. 1 ( 1961-02), p. 145-
    Details
    In: American Sociological Review, SAGE Publications, Vol. 26, No. 1 ( 1961-02), p. 145-
    Type of Medium: Online Resource
    ISSN: 0003-1224
    URL: Article
    DOI: 10.2307/2090550
    RVK:
    MN 1000
    Language: Unknown
    Publisher: SAGE Publications
    Publication Date: 1961
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    detail.hit.zdb_id: 2010058-9
    SSG: 2,1
    SSG: 3,4
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  • 5
    Online Resource
    Online Resource
    Suppressing reverberation in cochlear implant stimulus patterns using time-frequency masks based on phoneme groups
    Acoustical Society of America (ASA) ; 2022
    In:  The Journal of the Acoustical Society of America Vol. 152, No. 4_Supplement ( 2022-10-01), p. A91-A91
    Details
    In: The Journal of the Acoustical Society of America, Acoustical Society of America (ASA), Vol. 152, No. 4_Supplement ( 2022-10-01), p. A91-A91
    Abstract: Cochlear implant (CI) users experience considerable difficulty in understanding speech in reverberant listening environments. This issue is commonly addressed with time-frequency masking, where a time-frequency decomposed reverberant signal is multiplied by a matrix of gain values to suppress reverberation. However, mask estimation is challenging in reverberant environments due to the large spectro-temporal variations in the speech signal. To overcome this variability, we previously developed a phoneme-based algorithm that selects a different mask estimation model based on the underlying phoneme. In the ideal case where knowledge of the phoneme was assumed, the phoneme-based approach provided larger benefits than a phoneme-independent approach when tested in normal-hearing listeners using an acoustic model of CI processing. The current work investigates the phoneme-based mask estimation algorithm in the real-time feasible case where the prediction from a phoneme classifier is used to select the phoneme-specific mask. To further ensure real-time feasibility, both the phoneme classifier and mask estimation algorithm use causal features extracted from within the CI processing framework. We conducted experiments in normal-hearing listeners using an acoustic model of CI processing, and the results showed that the phoneme-specific algorithm benefitted the majority of subjects. [Work supported by NIH through Grant No. R01DC014290-05.]
    Type of Medium: Online Resource
    ISSN: 0001-4966 , 1520-8524
    URL: Article
    DOI: 10.1121/10.0015650
    RVK:
    EQ 1000
    Language: English
    Publisher: Acoustical Society of America (ASA)
    Publication Date: 2022
    detail.hit.zdb_id: 1461063-2
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  • 6
    Online Resource
    Online Resource
    Mitigating the effects of reverberation and noise in cochlear implants
    Acoustical Society of America (ASA) ; 2018
    In:  The Journal of the Acoustical Society of America Vol. 143, No. 3_Supplement ( 2018-03-01), p. 1943-1943
    Details
    In: The Journal of the Acoustical Society of America, Acoustical Society of America (ASA), Vol. 143, No. 3_Supplement ( 2018-03-01), p. 1943-1943
    Abstract: In listening environments with room reverberation and background noise, cochlear implant (CI) users experience substantial difficulties in understanding speech. Because everyday environments have different combinations of reverberation and noise, there is a need to develop algorithms that can mitigate both effects to improve speech intelligibility. Desmond et al. (2014) developed a machine learning approach to mitigate the adverse effects of late reverberant reflections of speech signals by using a classifier to detect and remove affected segments in CI pulse trains. In this study, we investigate the robustness of the reverberation mitigation algorithm in environments with both reverberation and noise. We conducted sentence recognition tests in normal hearing listeners using vocoded speech with unmitigated and mitigated reverberant-only or noisy reverberant speech signals, across different reverberation times and noise types. Improvements in speech intelligibility were observed in mitigated reverberant-only conditions. However, mixed results were obtained in the mitigated noisy reverberant conditions as a reduction in speech intelligibility was observed for noise types whose spectra were similar to that of anechoic speech. Based on these results, the focus of future work will be to develop a context-dependent approach that activates different mitigation strategies for different acoustic environments. [Research supported by NIH grant R01DC014290-03.]
    Type of Medium: Online Resource
    ISSN: 0001-4966 , 1520-8524
    URL: Article
    DOI: 10.1121/1.5036363
    RVK:
    EQ 1000
    Language: English
    Publisher: Acoustical Society of America (ASA)
    Publication Date: 2018
    detail.hit.zdb_id: 1461063-2
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  • 7
    Online Resource
    Online Resource
    Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 10 ( 2011-03-08), p. 4006-4011
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 10 ( 2011-03-08), p. 4006-4011
    Abstract: We report that the dominant human missense mutations G303E and G296S in GATA4 , a cardiac-specific transcription factor gene, cause atrioventricular septal defects and valve abnormalities by disrupting a signaling cascade involved in endocardial cushion development. These GATA4 missense mutations, but not a mutation causing secundum atrial septal defects (S52F), demonstrated impaired protein interactions with SMAD4, a transcription factor required for canonical bone morphogenetic protein/transforming growth factor-β ( BMP / TGF-β ) signaling. Gata4 and Smad4 genetically interact in vivo: atrioventricular septal defects result from endothelial-specific Gata4 and Smad4 compound haploinsufficiency. Endothelial-specific knockout of Smad4 caused an absence of valve-forming activity: Smad4 -deficient endocardium was associated with acellular endocardial cushions, absent epithelial-to-mesenchymal transformation, reduced endocardial proliferation, and loss of Id2 expression in valve-forming regions. We show that Gata4 and Smad4 cooperatively activated the Id2 promoter, that human GATA4 mutations abrogated this activity, and that Id2 deficiency in mice could cause atrioventricular septal defects. We suggest that one determinant of the phenotypic spectrum caused by human GATA4 mutations is differential effects on GATA4/SMAD4 interactions required for endocardial cushion development.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1019025108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
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    Location Call Number Limitation Availability
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