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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 03 November 2015, Vol.112(44), pp.13615-20
    Description: The protein-coding exome of a patient with a monogenic disease contains about 20,000 variants, only one or two of which are disease causing. We found that 58% of rare variants in the protein-coding exome of the general population are located in only 2% of the genes. Prompted by this observation, we aimed to develop a gene-level approach for predicting whether a given human protein-coding gene is likely to harbor disease-causing mutations. To this end, we derived the gene damage index (GDI): a genome-wide, gene-level metric of the mutational damage that has accumulated in the general population. We found that the GDI was correlated with selective evolutionary pressure, protein complexity, coding sequence length, and the number of paralogs. We compared GDI with the leading gene-level approaches, genic intolerance, and de novo excess, and demonstrated that GDI performed best for the detection of false positives (i.e., removing exome variants in genes irrelevant to disease), whereas genic intolerance and de novo excess performed better for the detection of true positives (i.e., assessing de novo mutations in genes likely to be disease causing). The GDI server, data, and software are freely available to noncommercial users from lab.rockefeller.edu/casanova/GDI.
    Keywords: Gene Prioritization ; Gene-Level ; Mutational Damage ; Next Generation Sequencing ; Variant Prioritization ; Exome ; Genetic Diseases, Inborn -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Science, Sept 28, 2012, Vol.337(6102), p.1684(5)
    Description: ISG15 is an interferon (IFN)-[alpha]/beta]-inducible, ubiquitin-like intracellular protein. Its conjugation to various proteins (ISGylation) contributes to antiviral immunity in mice. Here, we describe human patients with inherited ISG15 deficiency and mycobacterial, but not viral, diseases. The lack of intraceilular ISG15 production and protein ISGylation was not associated with cellular susceptibility to any viruses that we tested, consistent with the lack of viral diseases in these patients. By contrast, the lack of mycobacterium-induced ISG15 secretion by leukocytes--granulocyte, in particular--reduced the production of IFN-[gamma] by lymphocytes, including natural killer cells, probably accounting for the enhanced susceptibility to mycobacterial disease. This experiment of nature shows that human ISGylation is largely redundant for antiviral immunity, but that ISG15 plays an essential role as an IFN-[gamma]--inducing secreted molecule for optimal antimycobacterial immunity. 10.1126/science.1224026
    Keywords: Protein Deficiency -- Observations ; Disease Susceptibility -- Research ; Interferon -- Properties
    ISSN: 0036-8075
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  • 3
    Language: English
    In: Gene, 25 July 2013, Vol.524(2), pp.401-402
    Description: We report here the case of a 32-year-old Chinese Han woman who presented with frequent severe abdominal pain, convulsion, numbness and confusion. She also had hypertension, hyponatremia, chronic renal failure, anemia and a high urinary δ-aminolevulinic acid concentration. We identified a heterozygous splicing mutation in intron 11 (IVS11-2A → G) of the porphobilinogen (PBG) deaminase gene ( ) in her genomic DNA. This mutation had previously been reported in a North American patient, but was absent from 50 healthy Chinese controls.
    Keywords: Acute Intermittent Porphyria ; Porphobilinogen (Pbg) Deaminase ; Engineering ; Biology ; Anatomy & Physiology
    ISSN: 0378-1119
    E-ISSN: 1879-0038
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  • 4
    In: The New England Journal of Medicine, 2011, Vol.365(2), pp.127-138
    Description: Background The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette–Guérin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained. Methods We evaluated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, who required hematopoietic stem-cell transplantation. We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease. Results We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA. The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells. Conclusions These findings define a class of human primary immunodeficiencies that affect the differentiation of mononuclear phagocytes. They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity. (Funded by the Medical Research Council and others.) Monocytes and dendritic cells regulate adaptive and innate immunity. This study uncovers an association between mutations in the gene encoding interferon regulatory factor 8 and deficiency of dendritic cells and monocytes in the context of disseminated bacille Calmette–Guérin disease. The discovery of human primary immunodeficiencies that affect the development of granulocytes, B cells, and T cells has been instrumental in defining the contribution of these cell types to protective immunity.1,2 Monocytes, macrophages, and dendritic cells — all mononuclear phagocytes — have essential functions in both innate and acquired immunity. These cells initially recognize and engulf invading microbes, produce proinflammatory cytokines (e.g., interleukin-12), and process antigens for presentation to naive T cells, which consequently secrete various lymphokines (e.g., interferon-γ).3,4 On activation by cytokines secreted by T cells, mononuclear phagocytes destroy ingested microorganisms. There are no known genetic causes . . .
    Keywords: Medicine;
    ISSN: 0028-4793
    E-ISSN: 1533-4406
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  • 5
    Language: English
    In: Science (New York, N.Y.), 28 September 2012, Vol.337(6102), pp.1684-8
    Description: ISG15 is an interferon (IFN)-α/β-inducible, ubiquitin-like intracellular protein. Its conjugation to various proteins (ISGylation) contributes to antiviral immunity in mice. Here, we describe human patients with inherited ISG15 deficiency and mycobacterial, but not viral, diseases. The lack of intracellular ISG15 production and protein ISGylation was not associated with cellular susceptibility to any viruses that we tested, consistent with the lack of viral diseases in these patients. By contrast, the lack of mycobacterium-induced ISG15 secretion by leukocytes-granulocyte, in particular-reduced the production of IFN-γ by lymphocytes, including natural killer cells, probably accounting for the enhanced susceptibility to mycobacterial disease. This experiment of nature shows that human ISGylation is largely redundant for antiviral immunity, but that ISG15 plays an essential role as an IFN-γ-inducing secreted molecule for optimal antimycobacterial immunity.
    Keywords: Cytokines -- Immunology ; Interferon-Gamma -- Immunology ; Mycobacterium Infections -- Immunology ; Ubiquitins -- Immunology ; Virus Diseases -- Immunology
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 6
    Language: English
    In: Emerging Infectious Diseases, 01 June 2016, Vol.22(6), pp.1124-1126
    Description: Although vitamin C is not produced in the body, it is important for many biochemical and physiological functions. Little is known about the current vitamin C status of Canadians. This study describes the correlates of vitamin C status in a nationally representative sample of adults. Data are from the 2012/2013 Canadian Health Measures Survey. Plasma vitamin C (L-ascorbic acid) concentrations were measured among a fasting subsample of respondents aged 20 to 79 (n = 1,615). Vitamin C status, prevalence of deficiency (plasma vitamin C 〈 11 μmol/L), and use of vitamin C-containing supplements were estimated. Multivariate regression models were used to examine associations between vitamin C status and sociodemographic characteristics, smoking, body mass index, supplement use, and consumption of fruit juice and citrus fruit. The mean plasma vitamin C concentration of adults aged 20 to 79 was 53 μmol/L; fewer than 3% were vitamin C-deficient. Almost 22% took a vitamin C-containing supplement. Concentrations were lower among smokers and people who were obese, and higher among vitamin C supplement users and fruit juice and citrus fruit consumers. Multivariate models showed that supplement use was the strongest and most consistent predictor of vitamin C status; fruit juice and citrus fruit consumption were predictors only among populations with lower vitamin C concentrations (for example, smokers, obese). Few Canadians were vitamin C-deficient. Smokers and people with a higher BMI were most at risk of lower vitamin C concentrations; concentrations were higher among supplement users and consumers of fruit juice and citrus fruit.
    Keywords: Non-Tuberculous Mycobacteria ; Interferon-Gamma ; Interferon-Γ, Antibody, Autoantibodies, Herpesviridae, Monoclonal, Interleukine 12, Immunodeficiency, Antimycobacteria, Mycobacterium, Intracellulare ; Nontuberculous Mycobacteria ; Non-Tuberculous ; Interferon-Γ ; Public Health
    ISSN: 1080-6040
    E-ISSN: 1080-6059
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  • 7
    Language: English
    In: Biosensors and Bioelectronics, 15 May 2012, Vol.35(1), pp.407-412
    Description: ► A simple “post-additional” method for antioxidant capacity determination is developed. ► A cheap and stable artificial enzyme, G-quadruplex DNAzyme, is used instead of natural peroxidases. ► The stabilization of the pre-formed ABTS by ATP makes the large-scale preparation of ABTS possible. ► Using this method, the relative antioxidant capacity of antioxidants can be detected and compared easily. ► This method can be used for high-throughput visual screen of antioxidants. The scavenging of 2,2′-azinobis(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) radical cation (ABTS ) by antioxidants has been widely used in antioxidant capacity assay. Because of ABTS disproportionation, however, this radical cannot be prepared on a large scale and stored long-term, making it unsuitable for high-throughput detection and screening of antioxidants. We developed a modified “post-additional” antioxidant capacity assay. This method possessed two remarkable features: First, instead of natural peroxidases, an artificial enzyme, G-quadruplex DNAzyme, was used for the preparation of ABTS , thus greatly reducing the cost of the assay, and eliminating the strict demand for the storage of enzymes. Second, an ABTS stabilizer, adenosine triphosphate (ATP), was used. In the presence of ATP, the disproportionation of ABTS was effectively inhibited, and the lifetime of this radical cation was prolonged about 6-fold (12 days versus 2 days), making the large-scale preparation of ABTS possible. Utilizing this method, the antioxidant capacities of individual antioxidants and real samples can be quantified and compared easily. In addition, this method can be developed as a high-throughput screening method for antioxidants. The screening results could even be judged by the naked eye, eliminating the need for expensive instruments.
    Keywords: G-Quadruplex Dnazyme ; Antioxidant Capacity ; ATP ; Abts ; Free Radical ; Engineering ; Biology
    ISSN: 0956-5663
    E-ISSN: 1873-4235
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  • 8
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(3), p.e58286
    Description: We report identical twins with intellectual disability, progressive spastic paraplegia and short stature, born to a consanguineous family. Intriguingly, both children presented with lymphadenitis caused by the live Bacillus Calmette-Guérin (BCG) vaccine. Two syndromes - hereditary spastic paraplegia (HSP) and mycobacterial disease - thus occurred simultaneously. Whole-exome sequencing (WES) revealed a homozygous nonsense mutation (p.R1105X) of the AP4E1 gene, which was confirmed by Sanger sequencing. The p.R1105X mutation has no effect on AP4E1 mRNA levels, but results in lower levels of AP-4ε protein and of the other components of the AP-4 complex, as shown by western blotting, immunoprecipitation and immunofluorescence. Thus, the C-terminal part of the AP-4ε subunit plays an important role in maintaining the integrity of the AP-4 complex. No abnormalities of the IL-12/IFN-γ axis or oxidative burst pathways were identified. In conclusion, we identified twins with autosomal recessive AP-4 deficiency associated with HSP and mycobacterial disease, suggesting that AP-4 may play important role in the neurological and immunological systems.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 9
    Language: English
    In: Current Opinion in Immunology, August 2012, Vol.24(4), pp.364-378
    Description: ▶ Autosomal recessive complete loss-of-function STAT1 deficiency predisposes to mycobacterial and viral diseases. ▶ Autosomal recessive partial loss-of-function STAT1 deficiency predisposes to mild mycobacterial and viral diseases. ▶ Autosomal dominant loss-of-function STAT1 deficiency predisposes to mycobacterial disease. ▶ Autosomal dominant gain-of-function STAT1 disorder predisposes to chronic mucocutaneous disease. The genetic dissection of various human infectious diseases has led to the definition of inborn errors of human STAT1 immunity of four types, including (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD gain of STAT1 activity. The two types of AR STAT1 defect give rise to a broad infectious phenotype with susceptibility to intramacrophagic bacteria (mostly mycobacteria) and viruses (herpes viruses at least), due principally to the impairment of IFN-γ-mediated and IFN-α/β-mediated immunity, respectively. Clinical outcome depends on the extent to which the STAT1 defect decreases responsiveness to these cytokines. AD STAT1 deficiency selectively predisposes individuals to mycobacterial disease, owing to the impairment of IFN-γ-mediated immunity, as IFN-α/β-mediated immunity is maintained. Finally, AD gain of STAT1 activity is associated with autoimmunity, probably owing to an enhancement of IFN-α/β-mediated immunity. More surprisingly, it is also associated with chronic mucocutaneous candidiasis, through as yet undetermined mechanisms involving an inhibition of the development of IL-17-producing T cells. Thus, germline mutations in human define four distinct clinical disorders. Various combinations of viral, mycobacterial and fungal infections are therefore allelic at the human locus. These experiments of Nature neatly highlight the clinical and immunological impact of the human genetic dissection of infectious phenotypes.
    Keywords: Medicine ; Biology
    ISSN: 0952-7915
    E-ISSN: 1879-0372
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  • 10
    In: Journal of the Science of Food and Agriculture, May 2013, Vol.93(7), pp.1584-1590
    Description: Byline: , , Xiao-Fei Zhang, Xiao-Li Yang, Feng Qiu, Zhen Ou-yang, Mei-Hua Yang Keywords: foods and medicinal plants; zearalenone; [alpha]-zearalenol; HPLC-FLD; LC-MS-MS Abstract Background Mycotoxins, which may contaminate many foods and medicinal plants, are poisonous to humans. A high-performance liquid chromatography with fluorescence detection (HPLC-FLD) method was successfully developed for analysing the contamination levels of zearalenone (ZON) and its metabolite [alpha]-zearalenol ([alpha]-ZOL) in 100 widely consumed foods and medicinal plants in China. Samples were extracted with methanol-water (80:20, v/v), and cleaned up by using an immunoaffinity column. Results The limits of detection of this developed method for ZON and [alpha]-ZOL were 4 A[micro]g kg.sub.-1 and 2.5 A[micro]g kg.sub.-1, respectively. Recoveries for the samples spiked with three levels (30, 60 and 300 A[micro]g kg.sub.-1 for ZON and [alpha]-ZOL) ranged from 85.8% to 96.1% with relative standard deviation (RSD) of 2.6-7.1% for ZON, and from 89.9% to 98.7% with RSD of 1.9-9.2% for [alpha]-ZOL. Twelve (12%) of these tested samples were contaminated with ZON at levels ranging from 5.3 to 295.8 A[micro]g kg.sub.-1. The most contaminated samples were Semen coicis, four of them in a concentration level exceeding 60 A[micro]g kg.sub.-1 'maximum level' (range 68.9-119.6 A[micro]g kg.sub.-1). Positive samples were further confirmed by liquid chromatography-tandem mass spectrometry. Conclusion The results suggest that it is necessary to control ZON contamination in medicinal plants, especially Semen coicis. This is a successful study on the analysis of ZON and [alpha]-ZOL in medicinal plants in China by HPLC-FLD. Immunoaffinity clean-up and HPLC-FLD proved to have broad applicability in the field of simultaneously detecting ZON and [alpha]-ZOL in foods and medicinal plants and other complicated matrices.A[c] 2012 Society of Chemical Industry Author Affiliation: Article Note: Wei-Jun Kong and Hong-Hong Shen contributed equally to this work.
    Keywords: Foods And Medicinal Plants ; Zearalenone ; ‐Zearalenol ; Hplc‐Fld ; Lc‐Ms‐Ms
    ISSN: 0022-5142
    E-ISSN: 1097-0010
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