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  • 1
    Online Resource
    Online Resource
    Cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human
    Proceedings of the National Academy of Sciences ; 2005
    In:  Proceedings of the National Academy of Sciences Vol. 102, No. 7 ( 2005-02-15), p. 2430-2435
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 7 ( 2005-02-15), p. 2430-2435
    Abstract: The genomic sequences of severe acute respiratory syndrome coronaviruses from human and palm civet of the 2003/2004 outbreak in the city of Guangzhou, China, were nearly identical. Phylogenetic analysis suggested an independent viral invasion from animal to human in this new episode. Combining all existing data but excluding singletons, we identified 202 single-nucleotide variations. Among them, 17 are polymorphic in palm civets only. The ratio of nonsynonymous/synonymous nucleotide substitution in palm civets collected 1 yr apart from different geographic locations is very high, suggesting a rapid evolving process of viral proteins in civet as well, much like their adaptation in the human host in the early 2002–2003 epidemic. Major genetic variations in some critical genes, particularly the Spike gene, seemed essential for the transition from animal-to-human transmission to human-to-human transmission, which eventually caused the first severe acute respiratory syndrome outbreak of 2002/2003.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0409608102
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2005
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 2
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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
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 3
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    Online Resource
    Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 379, No. 6637 ( 2023-03-17)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6637 ( 2023-03-17)
    Abstract: Autoimmune diseases such as ankylosing spondylitis (AS) can be caused by emerging neoantigens that break immune tolerance in humans. Posttranslational modifications (PTMs) have been shown to be a critical mechanism that alters protein structure and function to generate neoantigens and induce subsequent autoimmune responses. Previous studies have confirmed that citrulline-modified peptides are a critical source of neoantigens in rheumatoid arthritis. However, the molecular mechanisms underlying neoantigen formation and pathogenic autoreactive responses for AS are largely unknown. There is an urgent need to develop a systematic approach to profiling the possible PTMs in patients with AS and identifying AS-associated PTMs responsible for autoreactive neoantigen production to better understand the etiology of autoimmune diseases. RATIONALE AS has been suggested to be an autoimmune disease because of its clear correlation with certain major histocompatibility complex (MHC) alleles, including HLA-B27. Neoantigens have been hypothesized to induce an aberrant immune response, leading to pathogenic autoreactive T cell responses and autoantibody generation in AS. Here, we developed a systematic open search approach to identify any possible amino acid residues and derivatives in the proteins that are different from the genomic coding sequences. We then applied this information to identify AS-related neoantigens with PTMs within a possible pool of PTM autoantigens and elucidate the pathogenesis of AS. RESULTS An open search approach was applied to identify any possible amino acid derivatives across the proteome of patients with AS. This approach generated a large set of noncoded amino acids representing the mass differences between the coded amino acids and actual residues. Among these, an amino acid derivative with a delta mass of 72.021 showed the greatest increase in patients with AS and resulted from a PTM called cysteine carboxyethylation. In vitro and in vivo experiments demonstrated that carboxyethylation at a cysteine residue of integrin αIIb [ITGA2B (CD41)] was catalyzed by cystathionine beta synthase (CBS) in a process that required 3-hydroxypropionic acid (3-HPA), a metabolite commonly released from gut microbes. Cysteine carboxyethylation induced the lysosomal degradation of ITGA2B and produced neoantigens that triggered MHC-II–dependent CD4 + T cell responses. Fluorescence polarization and enzyme-linked immunosorbent assay (ELISA) demonstrated that the identified carboxyethylated peptide (ITGA2B-ceC96) specifically interacted with HLA-DRA*01/HLA-DRB1*04 and was associated with autoantibody production and T cell responses in HLA-DRB1*04 patients. Additional in vitro assays showed that the neoantigen ITGA2B-ceC96 correlated with 3-HPA levels but was independent of CBS expression. HLA-DRB1 haplotype, the carboxyethylated peptide, specific autoantibodies, and 3-HPA levels in patients with AS all correlated with one another. 3-HPA–treated and ITGA2B-ceC96–immunized HLA-DR4 transgenic mice developed colitis and vertebral bone erosion. Thus, cysteine carboxyethylation induced by the metabolite 3-HPA generates a neoantigen that appears to be critical for autoimmune responses in patients with AS. CONCLUSION Cysteine carboxyethylation is an in vivo protein modification induced by the metabolite 3-HPA, which is commonly released from gut microbes. Carboxyethylated ITGA2B then induces autoantibody production and autoimmune response in AS. Our work provides a systematic workflow to identify differentially modified proteins that are important for neoantigen production in immune disorders. This approach furthers our understanding of AS pathogenesis and may aid in the development of neoantigen-based diagnosis and treatment for AS and other autoimmune diseases. Metabolite-induced cysteine carboxyethylation provokes HLA-restricted autoimmune responses in ankylosing spondylitis. 3-HPA, which is commonly obtained from food and gut microbes, induces carboxyethylation of cysteine residues in integrin αIIb (ITGA2B). Cysteine carboxyethylation requires CBS, and carboxyethylated ITGA2B (ITGA2B-ceC96) peptides are recruited to the HLA-DR4 complex and thereby stimulate CD4 + T cell responses closely related to AS.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abg2482
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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  • 4
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    Online Resource
    Membrane protein MHZ3 stabilizes OsEIN2 in rice by interacting with its Nramp-like domain
    Proceedings of the National Academy of Sciences ; 2018
    In:  Proceedings of the National Academy of Sciences Vol. 115, No. 10 ( 2018-03-06), p. 2520-2525
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 10 ( 2018-03-06), p. 2520-2525
    Abstract: The phytohormone ethylene regulates many aspects of plant growth and development. EIN2 is the central regulator of ethylene signaling, and its turnover is crucial for triggering ethylene responses. Here, we identified a stabilizer of OsEIN2 through analysis of the rice ethylene-response mutant mhz3. Loss-of-function mutations lead to ethylene insensitivity in etiolated rice seedlings. MHZ3 encodes a previously uncharacterized membrane protein localized to the endoplasmic reticulum. Ethylene induces MHZ3 gene and protein expression. Genetically, MHZ3 acts at the OsEIN2 level in the signaling pathway. MHZ3 physically interacts with OsEIN2, and both the N- and C-termini of MHZ3 specifically associate with the OsEIN2 Nramp-like domain. Loss of mhz3 function reduces OsEIN2 abundance and attenuates ethylene-induced OsEIN2 accumulation, whereas MHZ3 overexpression elevates the abundance of both wild-type and mutated OsEIN2 proteins, suggesting that MHZ3 is required for proper accumulation of OsEIN2 protein. The association of MHZ3 with the Nramp-like domain is crucial for OsEIN2 accumulation, demonstrating the significance of the OsEIN2 transmembrane domains in ethylene signaling. Moreover, MHZ3 negatively modulates OsEIN2 ubiquitination, protecting OsEIN2 from proteasome-mediated degradation. Together, these results suggest that ethylene-induced MHZ3 stabilizes OsEIN2 likely by binding to its Nramp-like domain and impeding protein ubiquitination to facilitate ethylene signal transduction. Our findings provide insight into the mechanisms of ethylene signaling.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1718377115
    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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  • 5
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    Online Resource
    PSAP variants in Parkinson’s disease: a large cohort study in Chinese mainland population
    Oxford University Press (OUP) ; 2021
    In:  Brain Vol. 144, No. 3 ( 2021-04-12), p. e25-e25
    Details
    In: Brain, Oxford University Press (OUP), Vol. 144, No. 3 ( 2021-04-12), p. e25-e25
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awaa391
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 6
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    Online Resource
    UQCRC1 variants in Parkinson’s disease: a large cohort study in Chinese mainland population
    Oxford University Press (OUP) ; 2021
    In:  Brain Vol. 144, No. 6 ( 2021-07-28), p. e54-e54
    Details
    In: Brain, Oxford University Press (OUP), Vol. 144, No. 6 ( 2021-07-28), p. e54-e54
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awab137
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 7
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    Online Resource
    Endogenous nitric oxide regulates the recovery of the radiation-resistant bacterium Deinococcus radiodurans from exposure to UV light
    Proceedings of the National Academy of Sciences ; 2009
    In:  Proceedings of the National Academy of Sciences Vol. 106, No. 43 ( 2009-10-27), p. 18183-18188
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 43 ( 2009-10-27), p. 18183-18188
    Abstract: Deinococcus radiodurans (Dr) withstands desiccation, reactive oxygen species, and doses of radiation that would be lethal to most organisms. Deletion of a gene encoding a homolog of mammalian nitric oxide synthase (NOS) severely compromises the recovery of Dr from ultraviolet (UV) radiation damage. The Δ nos defect can be complemented with recombinant NOS, rescued by exogenous nitric oxide (NO) and mimicked in the wild-type strain with an NO scavenging compound. UV radiation induces both upregulation of the nos gene and cellular NO production on similar time scales. Growth recovery does not depend on NO being present during UV irradiation, but rather can be manifested by NO addition hours after exposure. Surprisingly, nos deletion does not increase sensitivity to oxidative damage, and hydrogen peroxide does not induce nos expression. However, NOS-derived NO upregulates transcription of obgE , a gene involved in bacterial growth proliferation and stress response. Overexpression of the ObgE GTPase in the Δ nos background substantially alleviates the growth defect after radiation damage. Thus, NO acts as a signal for the transcriptional regulation of growth in D. radiodurans .
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0907262106
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2009
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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