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  • 1
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    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
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    Stroke genetics informs drug discovery and risk prediction across ancestries
    Springer Science and Business Media LLC ; 2022
    In:  Nature Vol. 611, No. 7934 ( 2022-11-03), p. 115-123
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 611, No. 7934 ( 2022-11-03), p. 115-123
    Abstract: Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated ( P   〈  0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN ) and variants (such as at GRK5 and NOS3 ). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-022-05165-3
    RVK:
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    RVK:
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    RVK:
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 3
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    Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries
    Springer Science and Business Media LLC ; 2022
    In:  Nature Vol. 612, No. 7938 ( 2022-12-01), p. E7-E7
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 612, No. 7938 ( 2022-12-01), p. E7-E7
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-022-05492-5
    RVK:
    TA 1000
    RVK:
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    RVK:
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 4
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    Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 23 ( 2015-06-09), p. 7243-7248
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 23 ( 2015-06-09), p. 7243-7248
    Abstract: Signal transducer and activator of transcription 3 (STAT3) had been involved in liver fibrogenesis. We aimed to explore the antifibrotic activities of sorafenib and its derivative SC-1 (devoid of Raf kinase inhibition activity) both in vivo and in vitro with special focus on the STAT3 pathway in hepatic stellate cells (HSCs). The clinical role of STAT3 in chronic hepatitis B (CHB) was also investigated. Experimental fibrosis mouse models were established by thioacetamide injection and bile duct ligation in Balb/C mice and treated with sorafenib and SC-1. Rat and human HSCs were used for mechanistic investigations. Forty CHB patients were enrolled to quantify the hepatic phospho-STAT3 (p-STAT3) levels and correlated with liver fibrosis. Both sorafenib and SC-1 ameliorated liver fibrosis in vivo and promoted HSC apoptosis in vitro. p-STAT3 and downstream signals were down-regulated after sorafenib and SC-1 treatment in HSC. STAT3 overexpression in HSC enhanced cell proliferation and undermined the apoptotic effects of sorafenib and SC-1, whereas STAT3-specific inhibition promoted HSC apoptosis. Sorafenib and SC-1 activated Src-homology protein tyrosine phosphatase-1 (SHP-1) and STAT3 inhibition followed. Of particular interest, in CHB patients with advanced liver fibrosis, p-STAT3 in HSC was significantly overexpressed and positively correlated with the severity of liver fibrosis and plasma IL-6 levels. In conclusion, sorafenib and SC-1 ameliorate liver fibrosis through STAT3 inhibition in HSC and STAT3 may potentially serve as a promising fibrotic biomarker and target in liver fibrosis. SHP-1 phosphatase-directed STAT3 inhibition may represent a previously unidentified strategy for antifibrotic drug discovery.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1507499112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
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  • 5
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    Glycoxidative stress–induced mitophagy modulates mitochondrial fates
    Wiley ; 2010
    In:  Annals of the New York Academy of Sciences Vol. 1201, No. 1 ( 2010-07), p. 1-7
    Details
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 1201, No. 1 ( 2010-07), p. 1-7
    Abstract: Diabetes mellitus (DM), a state of chronic hyperglycemia, is associated with a variety of serious complications. Hyperglycemia‐induced advanced glycation end products (AGEs) play an important role in the development of diabetic complications. In vivo , we demonstrated that disrupted mitochondria and autophagy was elevated in type II DM db/db mice. Mitophagy was evidenced by increased autophagosome formation in the β‐islet cells. The adducts of N ɛ ‐(carboxymethyl) lysine (CML), a major AGE, and bovine serum albumin (CML‐BSA) stimulated the conversion of microtubule‐associated protein 1 light chain 3‐I (LC3‐I) to LC3‐II in rat insulinoma cells (RIN‐m5F). CML‐BSA increased ROS generation as demonstrated in a time‐dependent manner. Experiments with mitochondrial targeted enhanced yellow fluorescent protein transfected RIN‐m5F cells, massive fragmented mitochondria were visualized in the CML‐BSA treated cells. Taken together, these data suggested that AGEs may cause mitochondrial dysfunction and mitophagosome formation, and AGEs‐induced glycoxidative stress may trigger mitophagic process to modulate mitochondrial fates leading to either cell survival or cell death.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Issue
    URL: Article
    DOI: 10.1111/nyas.2010.1201.issue-1
    DOI: 10.1111/j.1749-6632.2010.05630.x
    RVK:
    TD 7650
    Language: English
    Publisher: Wiley
    Publication Date: 2010
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  • 6
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    Complement C1q mediates the expansion of periportal hepatic progenitor cells in senescence-associated inflammatory liver
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 12 ( 2020-03-24), p. 6717-6725
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 12 ( 2020-03-24), p. 6717-6725
    Abstract: Most hepatocellular carcinomas (HCCs) develop in patients with chronic hepatitis, which creates a microenvironment for the growth of hepatic progenitor cells (HPCs) at the periportal area and subsequent development of HCCs. We investigated the signal from the inflammatory liver for this pathogenic process in the hepatic conditional β-catenin knockout mouse model. Senescent β-catenin–depleted hepatocytes in aged mice create an inflammatory microenvironment that stimulates periportal HPC expansion but arrests differentiation, which predisposes mice to the development of liver tumors. The release of complement C1q from macrophages in the inflammatory niche was identified as the unorthodox signal that activated the β-catenin pathway in periportal HPCs and was responsible for their expansion and de-differentiation. C1q inhibitors blocked the β-catenin pathway in both the expanding HPCs and the liver tumors but spared its orthodox pathway in pericentral normal hepatocytes. This mechanism has been validated in human liver specimens from patients with chronic hepatitis. Taken together, these results demonstrate that C1q- mediated activation of β-catenin pathway in periportal HPCs is a previously unrecognized mechanism for replenishing hepatocytes in the inflammatory liver and, if unchecked, for promoting hepatocarcinogenesis. C1q may become a new target for blocking carcinogenesis in patients with chronic hepatitis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1918028117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
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    SSG: 11
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  • 7
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    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
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  • 8
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    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
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    SSG: 11
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  • 9
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    Alleviation of Oxidative Damage in Multiple Tissues in Rats with Streptozotocin‐Induced Diabetes by Rice Bran Oil Supplementation
    Wiley ; 2005
    In:  Annals of the New York Academy of Sciences Vol. 1042, No. 1 ( 2005-05), p. 365-371
    Details
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 1042, No. 1 ( 2005-05), p. 365-371
    Abstract: A bstract : The possibility of 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) serving as a sensitive biomarker of oxidative DNA damage and oxidative stress was investigated. Reactive oxygen species (ROS) have been reported to be a cause of diabetes induced by chemicals such as streptozotocin (STZ) in experimental animals. In this study, we examined oxidative DNA damage in multiple tissues in rats with STZ‐induced diabetes by measuring the levels of 8‐OHdG in the liver, kidney, pancreas, brain, and heart. Levels of 8‐OHdG in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) were also determined in multiple tissues of rats treated with rice bran oil. Levels were 0.19 ± 0.07, 0.88 ± 0.30, 1.97 ± 0.05, and 9.79 ± 3.09 (1/10 5 dG) in the liver of nDNA of normal rats, nDNA of STZ‐induced diabetic rats, mtDNA of normal rats, and mtDNA of STZ‐induced diabetic rats, respectively. Levels of mtDNA of 8‐OHdG were 10 times higher than those of nDNA in multiple tissues. Significant reductions in mtDNA 8‐OHdG levels were seen in the liver, kidney, and pancreas of diabetic rats treated with rice bran oil compared with diabetic rats without intervention. Our study demonstrated that oxidative mtDNA damage may occur in multiple tissues of STZ‐induced diabetics rats. Intervention with rice bran oil treatment may reverse the increase in the frequency of 8‐OHdG.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Article
    DOI: 10.1196/annals.1338.061
    RVK:
    TD 7650
    Language: English
    Publisher: Wiley
    Publication Date: 2005
    detail.hit.zdb_id: 2834079-6
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  • 10
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    Cadmium Toxicity toward Caspase‐Independent Apoptosis through the Mitochondria‐Calcium Pathway in mtDNA‐Depleted Cells
    Wiley ; 2005
    In:  Annals of the New York Academy of Sciences Vol. 1042, No. 1 ( 2005-05), p. 497-505
    Details
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 1042, No. 1 ( 2005-05), p. 497-505
    Abstract: A bstract : Mitochondria are believed to be integrators and coordinators of programmed cell death in addition to their respiratory function. Using mitochondrial DNA (mtDNA)‐depleted osteosarcoma cells (ρ 0 cells) as a cell model, we investigated the apoptogenic signaling pathway of cadmium (Cd) under a condition of mitochondrial dysfunction. The apoptotic percentage was determined to be around 58.0% after a 24‐h exposure to 25 μM Cd using flow cytometry staining with propidium iodine (PI). Pretreatment with Z‐VAD‐fmk, a broad‐spectrum caspase inhibitor, failed to prevent apoptosis following Cd exposure. Moreover, Cd was unable to activate caspase 3 using DEVD‐AFC as a substrate, indicating that Cd induced a caspase‐independent apoptotic pathway in ρ 0 cells. JC‐1 staining demonstrated that mitochondrial membrane depolarization was a prelude to apoptosis. On the other hand, the intracellular calcium concentration increased 12.5‐fold after a 2‐h exposure to Cd. More importantly, the apoptogenic activity of Cd was almost abolished by ruthenium red, a mitochondrial calcium uniporter blocker. This led us to conclude that mtDNA‐depleted cells provide an alternative pathway for Cd to conduct caspase‐independent apoptosis through a mitochondria‐calcium mechanism.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Article
    DOI: 10.1196/annals.1338.043
    RVK:
    TD 7650
    Language: English
    Publisher: Wiley
    Publication Date: 2005
    detail.hit.zdb_id: 2834079-6
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    detail.hit.zdb_id: 2071584-5
    SSG: 11
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