12 results on '"Davies, Leela R. L."'
Search Results
2. Why Is N-Glycolylneuraminic Acid Rare in the Vertebrate Brain?
- Author
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Davies, Leela R. L., Varki, Ajit, Bayley, Hagan, Series editor, Houk, Kendall N., Series editor, Hughes, Greg, Series editor, Hunter, Christopher A., Series editor, Ishihara, Kazuaki, Series editor, Krische, Michael J, Series editor, Lehn, J.-M., Series editor, Luque, Rafael, Series editor, Olivucci, Massimo, Series editor, Siegel, Jay S., Series editor, Thiem, Joachim, Series editor, Venturi, Margherita, Series editor, Wong, Chi-Huey, Series editor, Wong, Henry N.C., Series editor, You, Shu-Li, Series editor, Wing-Wah Yam, Vivian, Series editor, Gerardy-Schahn, Rita, Delannoy, Philippe, and von Itzstein, Mark
- Published
- 2015
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3. Polysaccharide and conjugate vaccines to Streptococcus pneumoniae generate distinct humoral responses
- Author
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Davies, Leela R. L., primary, Cizmeci, Deniz, additional, Guo, Wenyue, additional, Luedemann, Corinne, additional, Alexander-Parrish, Ronika, additional, Grant, Lindsay, additional, Isturiz, Raul, additional, Theilacker, Christian, additional, Jodar, Luis, additional, Gessner, Bradford D., additional, and Alter, Galit, additional
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- 2022
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4. Three Functional Variants of IFN Regulatory Factor 5 (IRF5) Define Risk and Protective Haplotypes for Human Lupus
- Author
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Graham, Robert R., Kyogoku, Chieko, Sigurdsson, Snaevar, Vlasova, Irina A., Davies, Leela R. L., Baechler, Emily C., Plenge, Robert M., Koeuth, Thearith, Ortmann, Ward A., Hom, Geoffrey, Bauer, Jason W., Gillett, Clarence, Burtt, Noel, Graham, Deborah S. Cunninghame, Onofrio, Robert, Petri, Michelle, Gunnarsson, Iva, Svenungsson, Elisabet, Rönnblom, Lars, Nordmark, Gunnel, Gregersen, Peter K., Moser, Kathy, Gaffney, Patrick M., Criswell, Lindsey A., Vyse, Timothy J., Syvänen, Ann-Christine, Bohjanen, Paul R., Daly, Mark J., Behrens, Timothy W., and Altshuler, David
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- 2007
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5. TRAF1-C5 as a risk locus for rheumatoid arthritis- a genomewide study
- Author
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Plenge, Robert M., Seielstad, Mark, Padyukov, Leonid, Lee, Annette, T., Remmers, Elaine F., Seldin, Michael F., Bo Ding, Liew, Anthony, Khalili, Houman, Chandrasekaran, Alamelu, Davies, Leela R. L., Kastner, Daniel L., Wentian Li, Tan, Andrian K. S., Bonnard, Carine, Ong, Rick T. H., Thalamuthu, Anbupalam, Klareskog, Lars, Pettersson, Sven, Chunyu Liu, Chao Tian, Wei V. Chen, Carulli, John P., Gregerson, Peter K., Beckman, Evan M., Evan M., Altshuler, David, Alfredsson, Lars, Criswell, Lindsey A., and Amos, Christopher I.
- Subjects
Tumor necrosis factor -- Research ,Tumor necrosis factor -- Physiological aspects ,Rheumatoid arthritis -- Risk factors ,Rheumatoid arthritis -- Research ,Rheumatoid arthritis -- Genetic aspects ,Quantitative trait loci -- Research ,Quantitative trait loci -- Physiological aspects - Abstract
The article discusses a study that helps in the identification of several genetic loci, including TRAF1 (encoding tumor necrosis factor-receptor associated factor 1) and C5 (encoding complement component 5) that increase the risk for rheumatoid arthritis considerably.
- Published
- 2007
6. Why Is N-Glycolylneuraminic Acid Rare in the Vertebrate Brain?
- Author
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Davies, Leela R. L., primary and Varki, Ajit, additional
- Published
- 2013
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- View/download PDF
7. Physiological Exploration of the Long Term Evolutionary Selection against Expression of N-Glycolylneuraminic Acid in the Brain.
- Author
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Yuko Naito-Matsui, Davies, Leela R. L., Hiromu Takematsu, Hsun-Hua Chou, Pam Tangvoranuntakul, Carlin, Aaron F., Verhagen, Andrea, Heyser, Charles J., Seung-Wan Yoo, Choudhury, Biswa, Paton, James C., Paton, Adrienne W., Varki, Nissi M., Schnaar, Ronald L., and Varki, Ajit
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SIALIC acids , *GENETIC overexpression , *GLYCANS , *HYDROXYLASES , *BRAIN , *LABORATORY mice - Abstract
All vertebrate cell surfaces display a dense glycan layer often terminated with sialic acids, which have multiple functions due to their location and diverse modifications. The major sialic acids in most mammalian tissues are N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), the latter being derived from Neu5Ac via addition of one oxygen atom at the sugar nucleotide level by CMP-Neu5Ac hydroxylase (Cmah). Contrasting with other organs that express various ratios of Neu5Ac and Neu5Gc depending on the variable expression of Cmah, Neu5Gc expression in the brain is extremely low in all vertebrates studied to date, suggesting that neural expression is detrimental to animals. However, physiological exploration of the reasons for this long term evolutionary selection has been lacking. To explore the consequences of forced expression of Neu5Gc in the brain, we have established brain-specificCmah transgenic mice. Such Neu5Gc overexpression in the brain resulted in abnormal locomotor activity, impaired object recognition memory, and abnormal axon myelination. Brain-specific Cmah transgenic mice were also lethally sensitive to a Neu5Gcpreferring bacterial toxin, even though Neu5Gc was overexpressed only in the brain and other organs maintained endogenous Neu5Gc expression, as in wild-type mice. Therefore, the unusually strict evolutionary suppression of Neu5Gc expression in the vertebrate brain may be explained by evasion of negative effects on neural functions and by selection against pathogens. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
8. Polysaccharide and conjugate vaccines to Streptococcus pneumoniaegenerate distinct humoral responses
- Author
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Davies, Leela R. L., Cizmeci, Deniz, Guo, Wenyue, Luedemann, Corinne, Alexander-Parrish, Ronika, Grant, Lindsay, Isturiz, Raul, Theilacker, Christian, Jodar, Luis, Gessner, Bradford D., and Alter, Galit
- Abstract
Streptococcus pneumoniaeis a major cause of community-acquired pneumonia, bacteremia, and meningitis in older adults worldwide. Two pneumococcal vaccines containing S. pneumoniaecapsular polysaccharides are in current use: the polysaccharide vaccine PPSV23 and the glycoconjugate vaccine PCV13. In clinical trials, both vaccines elicit similar opsonophagocytic killing activity. In contrast to polysaccharide vaccines, conjugate vaccines have shown consistent efficacy against nasopharyngeal carriage and noninvasive pneumonia overall and for some prevalent individual serotypes. Given these different clinical profiles, it is crucial to understand the differential immunological responses induced by these two vaccines. Here, we used a high-throughput systems serology approach to profile the biophysical and functional features of serum antibodies induced by PCV13 and PPSV23 at 1 month and 1 year. In comparison with PPSV23, PCV13 induced higher titers across antibody isotypes; more durable antibody responses across immunoglobulin G (IgG), IgA, and IgM isotypes; and increased antigenic breadth. Although titers measured in opsonophagocytic activity (OPA) assays were similar between the two groups, confirming what was observed in clinical studies, serum samples from PCV13 vaccinees could induce additional non-OPA antibody-dependent functions, including monocyte phagocytosis and natural killer cell activation. In a multivariate modeling approach, distinct humoral profiles were demonstrated in each arm. Together, these results demonstrate that the glycoconjugate PCV13 vaccine induces an antigenically broader, more durable, polyfunctional antibody response. These findings may help explain the increased protection against S. pneumoniaecolonization and noninvasive pneumonia and the longer duration of protection against invasive pneumococcal disease, mediated by PCV13.
- Published
- 2022
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9. Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups RESISTANCE OFα2-8-LINKED N-GLYCOLYLNEURAMINIC ACID TO ENZYMATIC CLEAVAGE.
- Author
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Davies, Leela R. L., Pearce, Oliver M. T., Tessier, Matthew B., Assar, Siavash, Smutova, Victoria, Pajunen, Maria, Sumida, Mizuki, Sato, Chihiro, Kitajima, Ken, Finne, Jukka, Gagneux, Pascal, Pshezhetsky, Alexey, Woods, Robert, and Varki, Ajit
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SIALIC acids , *HYDROXYLATION , *OXYGEN , *ATOMS , *PROTEIN synthesis , *AMINO sugars - Abstract
The sialic acid (Sia)N-acetylneuraminic acid (Neu5Ac) and its hydroxylated derivative N-glycolylneuraminic acid (Neu5Gc) differ by one oxygen atom. CMP-Neu5Gc is synthesized from CMP-Neu5Ac, with Neu5Gc representing a highly variable fraction of total Sias in various tissues and among different species. The exception may be the brain, where Neu5Ac is abundant and Neu5Gc is reported to be rare. Here, we confirm this unusual pattern and its evolutionary conservation in additional samples from various species, concluding that brain Neu5Gc expression has been maintained at extremely low levels over hundreds of millions of years of vertebrate evolution. Most explanations for this pattern do not require maintaining neural Neu5Gc at such low levels. We hypothesized that resistance of α2-8-linked Neu5Gc to vertebrate sialidases is the detrimental effect requiring the relative absence of Neu5Gc from brain. This linkage is prominent in polysialic acid (polySia), a molecule with critical roles in vertebrate neural development.Weshow that Neu5Gc is incorporated into neural polySia and does not cause in vitro toxicity. Synthetic polymers of Neu5Ac and Neu5Gc showed that mammalian and bacterial sialidases are much less able to hydrolyze α2-8-linked Neu5Gc at the nonreducing terminus. Notably, this difference was not seen with acid-catalyzed hydrolysis of polySias. Molecular dynamics modeling indicates that differences in the three-dimensional conformation of terminal saccharides may partly explain reduced enzymatic activity. In keeping with this, polymers of N-propionylneuraminic acid are sensitive to sialidases. Resistance of Neu5Gc-containing polySia to sialidases provides a potential explanation for the rarity of Neu5Gc in the vertebrate brain. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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- View/download PDF
10. IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners.
- Author
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Davies LRL, Smith MT, Cizmeci D, Fischinger S, Shih-Lu Lee J, Lu LL, Layton ED, Grant AD, Fielding K, Stein CM, Boom WH, Hawn TR, Fortune SM, Wallis RS, Churchyard GJ, Alter G, and Seshadri C
- Subjects
- Male, Humans, South Africa epidemiology, Antigens, Bacterial, Interferon-gamma, Tuberculin Test, Mycobacterium tuberculosis, Tuberculosis diagnosis, Tuberculosis epidemiology
- Abstract
Background: The prevalence of tuberculosis among men who work in the gold mines of South Africa is among the highest in the world, but a fraction of miners demonstrate consistently negative results upon tuberculin skin test (TST) and IFN-γ release assay (IGRA). We hypothesized that these "resisters" (RSTRs) may display unconventional immune signatures of exposure to M. tuberculosis (M.tb)., Methods: In a cohort of RSTRs and matched controls with latent TB infection (LTBI), we profiled the functional breadth of M.tb antigen-specific T cell and antibody responses using multi-parameter flow cytometry and systems serology, respectively., Findings: RSTRs and LTBI controls both exhibited IFN-γ independent T-cell and IgG antibody responses to M.tb-specific antigens ESAT-6 and CFP-10. Antigen-specific antibody Fc galactosylation and sialylation were higher among RSTRs. In a combined T-cell and antibody analysis, M.tb lysate-stimulated TNF secretion by T cells correlated positively with levels of purified protein derivative-specific IgG. A multivariate model of the combined data was able to differentiate RSTR and LTBI subjects., Interpretation: IFN-γ independent immune signatures of exposure to M.tb, which are not detected by approved clinical diagnostics, are readily detectable in an occupational cohort uniquely characterized by intense and long-term infection pressure. Further, TNF may mediate a coordinated response between M.tb-specific T-cells and B-cells., Funding: This work was supported by the US National Institutes of Health (R01-AI124348 to Boom, Stein, and Hawn; R01-AI125189 and R01-AI146072 to Seshadri; and 75N93019C00071 to Fortune, Alter, Seshadri, and Boom), the Doris Duke Charitable Foundation (Davies), the Bill & Melinda Gates Foundation (OPP1151836 and OPP1109001 to Hawn; and OPP1151840 to Alter), Mass Life Science Foundation (Fortune), and Good Ventures Fund (Fortune)., Competing Interests: Declaration of interests Galit Alter became an employee of Moderna Therapeutics after completion of the work described here and holds equity in Leyden Labs and Systems Seromyx., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
11. Discrepancy between Mtb-specific IFN-γ and IgG responses in HIV-positive people with low CD4 counts.
- Author
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Mthembu M, Bowman KA, Davies LRL, Khuzwayo S, Mazibuko L, Bassett T, Ramjit D, Mhlane Z, Karim F, Alter G, Ndung'u T, and Wong EB
- Subjects
- Adult, Male, Humans, Interferon-gamma, South Africa epidemiology, Antibodies, CD4 Lymphocyte Count, HIV Infections complications, HIV Infections diagnosis, Tuberculosis diagnosis, Mycobacterium tuberculosis
- Abstract
Background: Tuberculosis (TB) is a leading infectious cause of death worldwide and treating latent TB infection (LTBI) with TB preventative therapy is a global priority. This study aimed to measure interferon gamma (IFN-γ) release assay (IGRA) positivity (the current reference standard for LTBI diagnosis) and Mtb-specific IgG antibodies in otherwise healthy adults without HIV and those living with HIV (PLWH)., Methods: One-hundred and eighteen adults (65 without HIV and 53 antiretroviral-naïve PLWH), from a peri-urban setting in KwaZulu-Natal, South Africa were enrolled. IFN-γ released following stimulation with ESAT-6/CFP-10 peptides and plasma IgG antibodies specific for multiple Mtb antigens were measured using the QuantiFERON-TB Gold Plus (QFT) and customized Luminex assays, respectively. The relationships between QFT status, relative concentrations of anti-Mtb IgG, HIV-status, sex, age and CD4 count were analysed., Findings: Older age, male sex and higher CD4 count were independently associated with QFT positivity (p = 0.045, 0.05 and 0.002 respectively). There was no difference in QFT status between people with and without HIV infection (58% and 65% respectively, p = 0.06), but within CD4 count quartiles, people with HIV had higher QFT positivity than people without HIV (p = 0.008 (2nd quartile), <0.0001 (3rd quartile)). Concentrations of Mtb-specific IFN-γ were lowest, and relative concentrations of Mtb-specific IgGs were highest in PLWH in the lowest CD4 quartile., Interpretation: These results suggest that the QFT assay underestimates LTBI among immunosuppressed people with HIV and Mtb-specific IgG may be a useful alternative biomarker for Mtb infection. Further evaluation of how Mtb-specific antibodies can be leveraged to improve LTBI diagnosis is warranted, particularly in HIV-endemic areas., Fundings: NIH, AHRI, SHIP: SA-MRC and SANTHE., Competing Interests: Declaration of interests All authors declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
12. Physiological Exploration of the Long Term Evolutionary Selection against Expression of N -Glycolylneuraminic Acid in the Brain.
- Author
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Naito-Matsui Y, Davies LR, Takematsu H, Chou HH, Tangvoranuntakul P, Carlin AF, Verhagen A, Heyser CJ, Yoo SW, Choudhury B, Paton JC, Paton AW, Varki NM, Schnaar RL, and Varki A
- Subjects
- Animals, Chromatography, High Pressure Liquid, Endothelium, Vascular metabolism, Locomotion, Mass Spectrometry, Memory Disorders metabolism, Mice, Mice, Transgenic, Biological Evolution, Brain metabolism, Neuraminic Acids metabolism
- Abstract
All vertebrate cell surfaces display a dense glycan layer often terminated with sialic acids, which have multiple functions due to their location and diverse modifications. The major sialic acids in most mammalian tissues are N -acetylneuraminic acid (Neu5Ac) and N -glycolylneuraminic acid (Neu5Gc), the latter being derived from Neu5Ac via addition of one oxygen atom at the sugar nucleotide level by CMP-Neu5Ac hydroxylase (Cmah). Contrasting with other organs that express various ratios of Neu5Ac and Neu5Gc depending on the variable expression of Cmah, Neu5Gc expression in the brain is extremely low in all vertebrates studied to date, suggesting that neural expression is detrimental to animals. However, physiological exploration of the reasons for this long term evolutionary selection has been lacking. To explore the consequences of forced expression of Neu5Gc in the brain, we have established brain-specific Cmah transgenic mice. Such Neu5Gc overexpression in the brain resulted in abnormal locomotor activity, impaired object recognition memory, and abnormal axon myelination. Brain-specific Cmah transgenic mice were also lethally sensitive to a Neu5Gc-preferring bacterial toxin, even though Neu5Gc was overexpressed only in the brain and other organs maintained endogenous Neu5Gc expression, as in wild-type mice. Therefore, the unusually strict evolutionary suppression of Neu5Gc expression in the vertebrate brain may be explained by evasion of negative effects on neural functions and by selection against pathogens., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
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