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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
    Oxidative Damage and Mitochondrial DNA Mutations with Endometriosis
    Wiley ; 2005
    In:  Annals of the New York Academy of Sciences Vol. 1042, No. 1 ( 2005-05), p. 186-194
    Details
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 1042, No. 1 ( 2005-05), p. 186-194
    Abstract: A bstract : Endometriosis, a frequently encountered disease in gynecology, is a considerable threat to the physical, psychological, and social integrity of women. Moreover, up to 50% of infertile patients have this disease. The etiology and pathogenesis of this important disease are poorly understood; it is defined as an ectopic location for endometrium‐like glandular epithelium and stroma outside of the uterine cavity. It still remains an open question as to what extent the peritoneal environment influences the establishment and/or progression of endometriosis. As a result of such stress, a sterile, inflammatory reaction with the secretion of growth factors, cytokines, and chemokines is generated, which is especially deleterious to successful reproduction. Significantly higher amounts of oxidative damage were detected in endometriotic lesions than in controlled normal endometrium, including mitochondrial DNA (mtDNA) rearrangement, 8‐OH‐deoxyguanosine (8‐OH‐dG), and lipoperoxide contents. There were approximately sixfold increases in 8‐OH‐dG and lipoperoxides in chocolate cysts compared with normal endometrial tissues. A novel 5,335‐bp deletion of mtDNA was identified in endometriotic tissue. According to these results, we propose that oxidative stress and mtDNA mutations might be anticipated in the initiation or progression of endometriosis. Only by understanding the mechanisms involved in the pathogenesis of endometriosis can we develop a basis for new diagnostic and therapeutic approaches.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Article
    DOI: 10.1196/annals.1338.021
    RVK:
    TD 7650
    Language: English
    Publisher: Wiley
    Publication Date: 2005
    detail.hit.zdb_id: 2834079-6
    detail.hit.zdb_id: 211003-9
    detail.hit.zdb_id: 2071584-5
    SSG: 11
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  • 3
    Online Resource
    Online Resource
    Molecular insight and pharmacological approaches targeting mitochondrial dynamics in skeletal muscle during obesity
    Wiley ; 2015
    In:  Annals of the New York Academy of Sciences Vol. 1350, No. 1 ( 2015-09), p. 82-94
    Details
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 1350, No. 1 ( 2015-09), p. 82-94
    Abstract: Obesity‐associated insulin resistance is the major characteristic of the early stage of metabolic syndrome. A decline in mitochondrial function plays a role in the development of insulin resistance in obesity and type 2 diabetes. Accumulating data reveal that mitochondrial dynamics, the balance between mitochondrial fusion and fission, are an important factor in the maintenance of mitochondrial function. Thus, the mechanisms underlying the regulation of mitochondrial dynamics in obesity deserve further investigation. This review describes an overview of mitochondrial fusion and fission machineries, and discusses the mechanistic and functional aspects of mitochondrial dynamics, with a focus on skeletal muscle in obesity. Finally, we discuss current pharmacological approaches of targeting mitochondrial dynamics. Elucidating the role of mitochondrial dynamics in skeletal muscle afflicted by obesity may provide not only important clues in understanding muscle insulin resistance, but also new therapeutic targets.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Issue
    URL: Article
    DOI: 10.1111/nyas.2015.1350.issue-1
    DOI: 10.1111/nyas.12863
    RVK:
    TD 7650
    Language: English
    Publisher: Wiley
    Publication Date: 2015
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    detail.hit.zdb_id: 2071584-5
    SSG: 11
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  • 4
    Online Resource
    Online Resource
    Depletion of β-catenin from mature hepatocytes of mice promotes expansion of hepatic progenitor cells and tumor development
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 45 ( 2011-11-08), p. 18384-18389
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 45 ( 2011-11-08), p. 18384-18389
    Abstract: Depletion of β-catenin impairs regeneration of the rapid turn-over gut epithelial cells, but appears dispensable for that of the slow turn-over mature hepatocytes in mice until 1 y of age. As the life span of mature murine hepatocytes is about 400 d, we studied conditional β-catenin knockout mice ( Alb-Cre ; Ctnnb1 flx/flx ) until 20 mo of age to determine the function of β-catenin in the postnatal liver. β-catenin was absent from the hepatocytes of β-catenin knockout mice 4 wk after delivery. From 9 mo of age, hepatocytes were gradually replaced by newly formed β-catenin-positive hepatocytes, which constituted about 90% of hepatocytes at 18–20 mo of age. This process was accompanied by active proliferation of bile duct/ductule cells. β-catenin-positive hepatocytes exhibited elevated proliferation activity and expression of progenitor cell markers, but lower albumin and Cre. This might explain their intact β-catenin protein, and suggest their origins from hepatic progenitor cells. Liver tumors arose spontaneously from β-catenin-positive cells, and tumorigenesis was accelerated by hepatitis B X protein. These results indicate β-catenin critical for the regeneration of mature hepatocytes. Failure to regenerate mature hepatocytes results in proliferation of hepatic progenitor cells that are able to maintain liver function but are predisposed to form liver tumors.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1116386108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
    detail.hit.zdb_id: 209104-5
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    SSG: 11
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Mammalian Cdk5 is a functional homologue of the budding yeast Pho85 cyclin-dependent protein kinase
    Proceedings of the National Academy of Sciences ; 1999
    In:  Proceedings of the National Academy of Sciences Vol. 96, No. 25 ( 1999-12-07), p. 14445-14450
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 96, No. 25 ( 1999-12-07), p. 14445-14450
    Abstract: Mammalian Cdk5 is a member of the cyclin-dependent kinase family that is activated by a neuron-specific regulator, p35, to regulate neuronal migration and neurite outgrowth. p35/Cdk5 kinase colocalizes with and regulates the activity of the Pak1 kinase in neuronal growth cones and likely impacts on actin cytoskeletal dynamics through Pak1. Here, we describe a functional homologue of Cdk5 in budding yeast, Pho85. Like Cdk5, Pho85 has been implicated in actin cytoskeleton regulation through phosphorylation of an actin-regulatory protein. Overexpression of CDK5 in yeast cells complemented most phenotypes associated with pho85Δ , including defects in the repression of acid phosphatase expression, sensitivity to salt, and a G 1 progression defect. Consistent with the functional complementation, Cdk5 associated with and was activated by the Pho85 cyclins Pho80 and Pcl2 in yeast cells. In a reciprocal series of experiments, we found that Pho85 associated with the Cdk5 activators p35 and p25 to form an active kinase complex in mammalian and insect cells, supporting our hypothesis that Pho85 and Cdk5 are functionally related. Our results suggest the existence of a functionally conserved pathway involving Cdks and actin-regulatory proteins that promotes reorganization of the actin cytoskeleton in response to regulatory signals.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.96.25.14445
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1999
    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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