Publications
330 results found
Varki A, Cummings RD, Aebi M, et al., 2015, Symbol Nomenclature for Graphical Representations of Glycans, GLYCOBIOLOGY, Vol: 25, Pages: 1323-1324, ISSN: 0959-6658
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- Citations: 636
Dell A, Morris HR, Panico M, et al., 2015, N- and O-glycosylation of gp120 isolated from HIV virions, Glycobiology: accelerating impact across the biomedical sciences, Publisher: Oxford University Press (OUP), Pages: 1230-1230, ISSN: 1460-2423
Dewal MB, DiChiara AS, Antonopoulos A, et al., 2015, XBP1s Links the Unfolded Protein Response to the Molecular Architecture of Mature N-Glycans, CHEMISTRY & BIOLOGY, Vol: 22, Pages: 1301-1312, ISSN: 1074-5521
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- Citations: 29
Nita-Lazar M, Mancini J, Feng C, et al., 2015, The zebrafish galectins Drgal1-L2 and Drgal3-L1 bind in vitro to the infectious hematopoietic necrosis virus (IHNV) glycoprotein and reduce viral adhesion to fish epithelial cells, Developmental and Comparative Immunology, Vol: 55, Pages: 241-252, ISSN: 1879-0089
The infectious hematopoietic necrosis virus (IHNV; Rhabdoviridae, Novirhabdovirus) infects teleost fish, such as salmon and trout, and is responsible for significant losses in the aquaculture industry and in wild fish populations. Although IHNV enters the host through the skin at the base of the fins, the viral adhesion and entry mechanisms are not fully understood. In recent years, evidence has accumulated in support of the key roles played by protein-carbohydrate interactions between host lectins secreted to the extracellular space and virion envelope glycoproteins in modulating viral adhesion and infectivity. In this study, we assessed in vitro the potential role(s) of zebrafish (Danio rerio) proto type galectin-1 (Drgal1-L2) and a chimera galectin-3 (Drgal3-L1) in IHNV adhesion to epithelial cells. Our results suggest that the extracellular Drgal1-L2 and Drgal3-L1 interact directly and in a carbohydrate-dependent manner with the IHNV glycosylated envelope and glycans on the epithelial cell surface, significantly reducing viral adhesion.
Murray AN, Chen W, Antonopoulos A, et al., 2015, Enhanced Aromatic Sequons Increase Oligosaccharyltransferase Glycosylation Efficiency and Glycan Homogeneity, CHEMISTRY & BIOLOGY, Vol: 22, Pages: 1052-1062, ISSN: 1074-5521
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- Citations: 33
Shang C, Chen Q, Dell A, et al., 2015, The Cytotoxicity of Elderberry Ribosome-Inactivating Proteins Is Not Solely Determined by Their Protein Translation Inhibition Activity., PLOS One, Vol: 10, ISSN: 1932-6203
Although the protein translation inhibition activity of ribosome inactivating proteins (RIPs) is well documented, little is known about the contribution of the lectin chain to the biological activity of these proteins. In this study, we compared the in vitro and intracellular activity of several S. nigra (elderberry) RIPs and non-RIP lectins. Our data demonstrate that RIPs from elderberry are much more toxic to HeLa cells than to primary fibroblasts. Differences in the cytotoxicity between the elderberry proteins correlated with differences in glycan specificity of their lectin domain, cellular uptake efficiency and intracellular destination. Despite the fact that the bulk of the RIPs accumulated in the lysosomes and partly in the Golgi apparatus, we could demonstrate effective inhibition of protein synthesis in cellula. As we also observed cytotoxicity for non-RIP lectins, it is clear that the lectin chain triggers additional pathways heralding cell death. Our data suggest that one of these pathways involves the induction of autophagy.
Ersek A, Xu K, Antonopoulos A, et al., 2015, Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease, Journal of Clinical Investigation, Vol: 125, Pages: 2279-2292, ISSN: 1558-8238
Glycosphingolipids (GSLs) are essential constituents of cell membranes and lipid rafts and can modulate signal transduction events. The contribution of GSLs in osteoclast (OC) activation and osteolytic bone diseases in malignancies such as the plasma cell dyscrasia multiple myeloma (MM) is not known. Here, we tested the hypothesis that pathological activation of OCs in MM requires de novo GSL synthesis and is further enhanced by myeloma cell–derived GSLs. Glucosylceramide synthase (GCS) inhibitors, including the clinically approved agent N-butyl-deoxynojirimycin (NB-DNJ), prevented OC development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of transcriptional activator NFATc1. GM3 was the prevailing GSL produced by patient-derived myeloma cells and MM cell lines, and exogenous addition of GM3 synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and insulin-like growth factor 1 (IGF-1) to induce osteoclastogenesis in precursors. In WT mice, administration of GM3 increased OC numbers and activity, an effect that was reversed by treatment with NB-DNJ. In a murine MM model, treatment with NB-DNJ markedly improved osteolytic bone disease symptoms. Together, these data demonstrate that both tumor-derived and de novo synthesized GSLs influence osteoclastogenesis and suggest that NB-DNJ may reduce pathological OC activation and bone destruction associated with MM.
Stansell A, 2015, Gp120 on HIV-1 Virions Lacks O-Linked Carbohydrate, PLOS ONE, Vol: 10, Pages: 1-15
As HIV-1-encoded envelope protein traverses the secretory pathway, it may be modified with N- and O-linked carbohydrate. When the gp120s of HIV-1 NL4-3, HIV-1 YU2, HIV-1 Bal, HIV-1 JRFL, and HIV-1 JRCSF were expressed as secreted proteins, the threonine at consensus position 499 was found to be O-glycosylated. For SIVmac239, the corresponding threonine was also glycosylated when gp120 was recombinantly expressed. Similarly-positioned, highly-conserved threonines in the influenza A virus H1N1 HA1 and H5N1 HA1 envelope proteins were also found to carry O-glycans when expressed as secreted proteins. In all cases, the threonines were modified predominantly with disialylated core 1 glycans, together with related core 1 and core 2 structures. Secreted HIV-1 gp140 was modified to a lesser extent with mainly monosialylated core 1 O-glycans, suggesting that the ectodomain of the gp41 transmembrane component may limit the accessibility of Thr499 to glycosyltransferases. In striking contrast to these findings, gp120 on purified virions of HIV-1 Bal and SIV CP-MAC lacked any detectable O-glycosylation of the C-terminal threonine. Our results indicate the absence of O-linked carbohydrates on Thr499 as it exists on the surface of virions and suggest caution in the interpretation of analyses of post-translational modifications that utilize recombinant forms of envelope protein.
Czajkowsky DM, Andersen JT, Fuchs A, et al., 2015, Developing the IVIG biomimetic, Hexa-Fc, for drug and vaccine applications, SCIENTIFIC REPORTS, Vol: 5, ISSN: 2045-2322
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- Citations: 28
Nataraj A, 2015, MKAN27435 Is Required for the Biosynthesis of Higher Subclasses of Lipooligosaccharides in Mycobacterium kansasii, PLoS ONE, Vol: 10, ISSN: 1932-6203
Lipooligosaccharides are glycolipids found in the cell wall of many mycobacterial species including the opportunistic pathogen Mycobacterium kansasii. The genome of M. kansasii ATCC12478 contains a cluster with genes orthologous to Mycobacterium marinum LOS biosynthesis genes. To initiate a genetic dissection of this cluster and demonstrate its role in LOS biosynthesis in M. kansasii, we chose MKAN27435, a gene encoding a putative glycosyltransferase. Using Specialized Transduction, a phage-based gene knockout tool previously used to generate null mutants in other mycobacteria, we generated a MKAN27435 null mutant. The mutant strain was found to be defective in the biosynthesis of higher LOS subspecies, viz LOS-IV, LOS-V, LOS-VI and LOS-VII. Additionally, a range of low abundance species were detected in the mutant strain and mass spectroscopic analysis indicated that these were shunt products generated from LOS-III by the addition of up to six molecules of a pentose.
Mondal N, Buffone A, Stolfa G, et al., 2015, ST3Gal-4 is the primary sialyltransferase regulating the synthesis of E-, P-, and L-selectin ligands on human myeloid leukocytes, Blood, Vol: 125, Pages: 687-696, ISSN: 0006-4971
The precise glycosyltransferase enzymes that mediate selectin-ligand biosynthesis in human leukocytes are unknown. This knowledge is important because selectin-mediated cell tethering and rolling is a critical component of both normal immune response and various vascular disorders. We evaluated the role of 3 α(2,3)sialyltransferases, ST3Gal-3, -4, and -6, which act on the type II N-Acetyllactosamine structure (Galβ1,4GlcNAc) to create sialyl Lewis-X (sLeX) and related sialofucosylated glycans on human leukocytes of myeloid lineage. These genes were either silenced using lentiviral short hairpin RNA (shRNA) or functionally ablated using the clustered regularly interspaced short palindromic repeat/Cas9 technology. The results show that ST3Gal-4, but not ST3Gal-3 or -6, is the major sialyltransferase regulating the biosynthesis of E-, P-, and L-selectin ligands in humans. Reduction in ST3Gal-4 activity lowered cell-surface HECA-452 epitope expression by 75% to 95%. Glycomics profiling of knockouts demonstrate an almost complete loss of the sLeX epitope on both leukocyte N- and O-glycans. In cell-adhesion studies, ST3Gal-4 knockdown/knockout cells displayed 90% to 100% reduction in tethering and rolling density on all selectins. ST3Gal-4 silencing in neutrophils derived from human CD34+ hematopoietic stem cells also resulted in 80% to 90% reduction in cell adhesion to all selectins. Overall, a single sialyltransferase regulates selectin-ligand biosynthesis in human leukocytes, unlike mice where multiple enzymes contribute to this function.
Haslam SM, Pang PC, Antonopoulos A, et al., 2015, Mass spectrometric analyses of cell and tissue glycomes, Glycoscience: Biology and Medicine, Pages: 69-77, ISBN: 9784431548409
This chapter discusses mass spectrometric (MS) strategies for mammalian cell and tissue glycomics and places the principles underlying them within a historical framework. Ultrahigh-sensitivity MALDI-TOF/TOF glycomic methodologies are based on the analysis of permethylated derivatives of pools of glycans that are released from glycoproteins or glycolipids enzymatically or chemically. Very complex mixtures from biological extracts of cells and tissues can be screened in this way, thereby revealing the types of glycans present and, importantly, providing clues to structures that are likely to be functionally important. Optimal glycomic workflows are illustrated by glycomic data from human cytolytic T lymphocytes. Fragmentation pathways that are central to glycomics are briefly outlined, and the use of the Glyco Work Bench tool to assist fragment ion annotation is briefly explained. Finally, the open-access data repositories of the Consortium for Functional Glycomics, which contain glycomics data for murine and human hematopoietic cell populations, are described.
Damerell D, Ceroni A, Maass K, et al., 2015, Annotation of glycomics MS and MS/MS spectra using the GlycoWorkbench software tool., Methods Mol Biol, Vol: 1273, Pages: 3-15
The GlycoWorkbench software tool allows users to semiautomatically annotate glycomics MS and MS/MS spectra and MS glycoproteomics spectra. The GlycanBuilder software tool is embedded within GlycoWorkbench allowing users to draw glycan structures and export images of the drawn structures. This chapter demonstrates to users how to draw glycan structures within GlycoWorkbench using the GlycanBuilder software tool. This chapter also demonstrates how to use GlycoWorkbench to import MS and MS/MS glycomics spectra and use the cascading annotation feature to annotate both the MS and MS/MS spectra with a single command.
Chen Q, Müller JS, Pang P-C, et al., 2015, Global N-linked Glycosylation is Not Significantly Impaired in Myoblasts in Congenital Myasthenic Syndromes Caused by Defective Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1), Biomolecules, Vol: 5, Pages: 2758-2781, ISSN: 2218-273X
Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the first enzyme of the hexosamine biosynthetic pathway. It transfers an amino group from glutamine to fructose-6-phosphate to yield glucosamine-6-phosphate, thus providing the precursor for uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) synthesis. UDP-GlcNAc is an essential substrate for all mammalian glycosylation biosynthetic pathways and N-glycan branching is especially sensitive to alterations in the concentration of this sugar nucleotide. It has been reported that GFPT1 mutations lead to a distinct sub-class of congenital myasthenic syndromes (CMS) termed “limb-girdle CMS with tubular aggregates”. CMS are hereditary neuromuscular transmission disorders in which neuromuscular junctions are impaired. To investigate whether alterations in protein glycosylation at the neuromuscular junction might be involved in this impairment, we have employed mass spectrometric strategies to study the N-glycomes of myoblasts and myotubes derived from two healthy controls, three GFPT1 patients, and four patients with other muscular diseases, namely CMS caused by mutations in DOK7, myopathy caused by mutations in MTND5, limb girdle muscular dystrophy type 2A (LGMD2A), and Pompe disease. A comparison of the relative abundances of bi-, tri-, and tetra-antennary N-glycans in each of the cell preparations revealed that all samples exhibited broadly similar levels of branching. Moreover, although some differences were observed in the relative abundances of some of the N-glycan constituents, these variations were modest and were not confined to the GFPT1 samples. Therefore, GFPT1 mutations in CMS patients do not appear to compromise global N-glycosylation in muscle cells.
Macauley MS, Arlian BM, Rillahan CD, et al., 2014, Systemic blockade of sialylation in mice with a global inhibitor of sialyltransferases, Journal of Biological Chemistry, Vol: 289, Pages: 35149-35158, ISSN: 0021-9258
Sialic acid terminates glycans of glycoproteins and glycolipids that play numerous biological roles in health and disease. While genetic tools are available for interrogating the effects of decreased or abolished sialoside expression in mice, pharmacological inhibition of the sialyltransferase family has to date not been possible. We have recently shown that a sialic acid analog, 3F-NeuAc, added to the media of cultured cells shuts down sialylation by a mechanism involving its intracellular conversion to CMP-3F-NeuAc, a competitive inhibitor of all sialyltransferases. Here we show that administering 3F-NeuAc to mice dramatically decreases sialylated glycans in cells of all tissues tested, including: blood, spleen, liver, brain, lung, heart, kidney, and testes. A single dose results in greatly decreased sialoside expression for over 7 weeks in some tissues. While blockade of sialylation with 3F-NeuAc does not affect viability of cultured cells, its use in vivo has a deleterious 'on-target' effect on liver and kidney function. After administration of 3F-NeuAc, liver enzymes in the blood are dramatically altered, and mice develop proteinuria concomitant with dramatic loss of sialic acid in the glomeruli within 4 days, leading to irreversible kidney dysfunction and failure to thrive. These results confirm a critical role for sialosides in liver and kidney function and document the feasibility of pharmacological inhibition of sialyltransferases for in vivo modulation of sialoside expression.
Ciprian A, Sherine F, Dell AL, 2014, The adhesion-GPCR CELSR3 promotes axonal facisulation in the embryonic zebrafish., ASCB/IFCB Meeting, Publisher: AMER SOC CELL BIOLOGY, ISSN: 1059-1524
Macauley M, Arlian B, Rillahan C, et al., 2014, <i>In vivo</i> blockade of sialylation with a global sialyltransferase inhibitor causes irreversible kidney dysfunction, Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR), Publisher: OXFORD UNIV PRESS INC, Pages: 1089-1089, ISSN: 0959-6658
Jia N, Barclay WS, Roberts K, et al., 2014, Glycomic characterization of respiratory tract tissues of ferrets IMPLICATIONS FOR ITS USE IN INFLUENZA VIRUS INFECTION STUDIES, Journal of Biological Chemistry, Vol: 289, Pages: 28489-28504, ISSN: 0021-9258
The initial recognition between influenza virus and the host cell is mediated by interactions between the viral surface protein hemagglutinin and sialic acid-terminated glycoconjugates on the host cell surface. The sialic acid residues can be linked to the adjacent monosaccharide by α2–3- or α2–6-type glycosidic bonds. It is this linkage difference that primarily defines the species barrier of the influenza virus infection with α2–3 binding being associated with avian influenza viruses and α2–6 binding being associated with human strains. The ferret has been extensively used as an animal model to study the transmission of influenza. To better understand the validity of this model system, we undertook glycomic characterization of respiratory tissues of ferret, which allows a comparison of potential viral receptors to be made between humans and ferrets. To complement the structural analysis, lectin staining experiments were performed to characterize the regional distributions of glycans along the respiratory tract of ferrets. Finally, the binding between the glycans identified and the hemagglutinins of different strains of influenza viruses was assessed by glycan array experiments. Our data indicated that the respiratory tissues of ferret heterogeneously express both α2–3- and α2–6-linked sialic acids. However, the respiratory tissues of ferret also expressed the Sda epitope (NeuAcα2-3(GalNAcβ1–4)Galβ1–4GlcNAc) and sialylated N,N′-diacetyllactosamine (NeuAcα2–6GalNAcβ1–4GlcNAc), which have not been observed in the human respiratory tract surface epithelium. The presence of the Sda epitope reduces potential binding sites for avian viruses and thus may have implications for the usefulness of the ferret in the study of influenza virus infection.
Sassi A, Fliegauf M, Yang L, et al., 2014, Hypomorphic Homozygous Mutations in Phosphoglucomutase3 Impair Immunity and Increase Serum IGE Levels, 16th Biennial Meeting of the European-Society-for-Immunodeficiencies, Publisher: SPRINGER/PLENUM PUBLISHERS, Pages: S161-S162, ISSN: 0271-9142
Boztug K, Jaervinen PM, Salzer E, et al., 2014, Human JAGN1 Deficiency Causes Disturbed Myeloid Cell Homeostasis and Severe Congenital Neutropenia, 16th Biennial Meeting of the European-Society-for-Immunodeficiencies, Publisher: SPRINGER/PLENUM PUBLISHERS, Pages: S151-S152, ISSN: 0271-9142
Faulds-Pain A, Twine SM, Vinogradov E, et al., 2014, The post-translational modification of the <i>Clostridium difficile</i> flagellin affects motility, cell surface properties and virulence, MOLECULAR MICROBIOLOGY, Vol: 94, Pages: 272-289, ISSN: 0950-382X
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- Citations: 35
Boztug K, Jaervinen PM, Salzer E, et al., 2014, JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia, NATURE GENETICS, Vol: 46, Pages: 1021-+, ISSN: 1061-4036
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- Citations: 88
Wohlschlager T, Butschi A, Grassi P, et al., 2014, Methylated glycans as conserved targets of animal and fungal innate defense, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 111, Pages: E2787-E2796, ISSN: 0027-8424
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- Citations: 61
Zhang H, Zhu F, Yang T, et al., 2014, The highly conserved domain of unknown function 1792 has a distinct glycosyltransferase fold, NATURE COMMUNICATIONS, Vol: 5, ISSN: 2041-1723
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- Citations: 52
York WS, Agravat S, Aoki-Kinoshita KF, et al., 2014, MIRAGE: The minimum information required for a glycomics experiment, GLYCOBIOLOGY, Vol: 24, Pages: 402-406, ISSN: 0959-6658
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- Citations: 84
Sassi A, Lazaroski S, Wu G, et al., 2014, Hypomorphic homozygous mutations in phosphoglucomutase 3 (<i>PGM3</i>) impair immunity and increase serum IgE levels, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 133, Pages: 1410-U681, ISSN: 0091-6749
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- Citations: 132
Peng W, Nycholat CM, Mcbride R, et al., 2014, Synthesis of biologically active <i>N</i>- and <i>O</i>-linked glycans with multi-sialylated poly-<i>N</i>-acetyllactosamine extensions using P. damsela a2-6 sialyltransferase, 247th National Spring Meeting of the American-Chemical-Society (ACS), Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727
Jedrzejewski PM, Jimenez del Val I, Constantinou A, et al., 2014, Towards controlling the glycoform: a model framework linking extracellular metabolites to antibody glycosylation, International Journal of Molecular Sciences, Vol: 15, Pages: 4492-4522, ISSN: 1422-0067
Glycoproteins represent the largest group of the growing number of biologically-derived medicines. The associated glycan structures and their distribution are known to have a large impact on pharmacokinetics. A modelling framework was developed to provide a link from the extracellular environment and its effect on intracellular metabolites to the distribution of glycans on the constant region of an antibody product. The main focus of this work is the mechanistic in silico reconstruction of the nucleotide sugar donor (NSD) metabolic network by means of 34 species mass balances and the saturation kinetics rates of the 60 metabolic reactions involved. NSDs are the co-substrates of the glycosylation process in the Golgi apparatus and their simulated dynamic intracellular concentration profiles were linked to an existing model describing the distribution of N-linked glycan structures of the antibody constant region. The modelling framework also describes the growth dynamics of the cell population by means of modified Monod kinetics. Simulation results match well to experimental data from a murine hybridoma cell line. The result is a modelling platform which is able to describe the product glycoform based on extracellular conditions. It represents a first step towards the in silico prediction of the glycoform of a biotherapeutic and provides a platform for the optimisation of bioprocess conditions with respect to product quality.
Murugaesu N, Iravani M, Van Weverwijk A, et al., 2014, An In Vivo Functional Screen Identifies ST6GalNAc2 Sialyltransferase as a Breast Cancer Metastasis Suppressor, CANCER DISCOVERY, Vol: 4, Pages: 304-317, ISSN: 2159-8274
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- Citations: 70
Halder S, Cotmore S, Heimburg-Molinaro J, et al., 2014, Profiling of Glycan Receptors for Minute Virus of Mice in Permissive Cell Lines Towards Understanding the Mechanism of Cell Recognition, PLOS One, Vol: 9, ISSN: 1932-6203
The recognition of sialic acids by two strains of minute virus of mice (MVM), MVMp (prototype) and MVMi (immunosuppressive), is an essential requirement for successful infection. To understand the potential for recognition of different modifications of sialic acid by MVM, three types of capsids, virus-like particles, wild type empty (no DNA) capsids, and DNA packaged virions, were screened on a sialylated glycan microarray (SGM). Both viruses demonstrated a preference for binding to 9-O-methylated sialic acid derivatives, while MVMp showed additional binding to 9-O-acetylated and 9-O-lactoylated sialic acid derivatives, indicating recognition differences. The glycans recognized contained a type-2 Galβ1-4GlcNAc motif (Neu5Acα2-3Galβ1-4GlcNAc or 3′SIA-LN) and were biantennary complex-type N-glycans with the exception of one. To correlate the recognition of the 3′SIA-LN glycan motif as well as the biantennary structures to their natural expression in cell lines permissive for MVMp, MVMi, or both strains, the N- and O-glycans, and polar glycolipids present in three cell lines used for in vitro studies, A9 fibroblasts, EL4 T lymphocytes, and the SV40 transformed NB324K cells, were analyzed by MALDI-TOF/TOF mass spectrometry. The cells showed an abundance of the sialylated glycan motifs recognized by the viruses in the SGM and previous glycan microarrays supporting their role in cellular recognition by MVM. Significantly, the NB324K showed fucosylation at the non-reducing end of their biantennary glycans, suggesting that recognition of these cells is possibly mediated by the Lewis X motif as in 3′SIA-LeX identified in a previous glycan microarray screen.
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