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| Open AccessDefective N-glycosylation of IL6 induces metastasis and tyrosine kinase inhibitor resistance in lung cancer
Post-translational modifications regulate tumorigenesis and cancer therapy sensitivity. Here, the authors show that N-glycosylation defective Interleukin-6 (deNG-IL6) switches downstream signalling pathway from JAK-STAT3 to SRC-YAP axis and lung cancer cells secrete deNG-IL6 to promote metastasis and tyrosine kinase inhibitor resistance.
- Chun-Hua Hung
- , Shang-Yin Wu
- & Wu-Chou Su
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Article
| Open AccessHuman milk oligosaccharides are associated with maternal genetics and respiratory health of human milk-fed children
This study of nearly 1000 mother-breastmilk-infant triads identifies new genetic polymorphisms linked to human milk oligosaccharide profiles in mothers, which in turn are associated with the long-term respiratory health of their breastfed children.
- Amirthagowri Ambalavanan
- , Le Chang
- & Qingling Duan
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Article
| Open AccessSpecific 3-O-sulfated heparan sulfate domains regulate salivary gland basement membrane metabolism and epithelial differentiation
The use of heparan sulfate mimetics is an attractive target for organ regeneration. Here, the authors identify how highly 3-O-sulfated heparan sulfate domains regulate FGFR signaling and basement membrane metabolism to control epithelial differentiation.
- Vaishali N. Patel
- , Marit H. Aure
- & Matthew P. Hoffman
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Article
| Open AccessGalectins induced from hemocytes bridge phosphatidylserine and N-glycosylated Drpr/CED-1 receptor during dendrite pruning
How Draper activates phagocytosis is not well understood. Here, the authors show that two Drosophila galectins, Hdg and Ctg, are secreted from hemocytes after dendrite injury and bridge phosphatidylserine and Draper to active phagocytosis.
- Hsin-Ho Sung
- , Hsun Li
- & Cheng-Ting Chien
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Article
| Open AccessStructure, biosynthesis and regulation of the T1 antigen, a phase-variable surface polysaccharide conserved in many Salmonella serovars
Some Salmonella isolates produce an enigmatic, transient antigen known as T1. Here, Kelly et al. show that T1 is a complex linear glycan linked to lipid A–core, like a typical O antigen, and is expressed in a phase-variable manner regulated by recombinational inversion of a promoter upstream of the T1 genetic locus.
- Steven D. Kelly
- , Mikel Jason Allas
- & Chris Whitfield
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Article
| Open AccessPerturbed N-glycosylation of Halobacterium salinarum archaellum filaments leads to filament bundling and compromised cell motility
The archaellum, or archaeal ‘flagellum’, includes asparagine-linked glycans that are important for efficient cell motility in archaea through unclear mechanisms. Here, the authors show that glycan truncation leads to clustering of filaments and alterations in cell motility, suggesting that the glycans minimize archaellum filament aggregation that compromises cell motility.
- Shahar Sofer
- , Zlata Vershinin
- & Iris Grossman-Haham
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Article
| Open AccessStructural and mechanistic insights into a lysosomal membrane enzyme HGSNAT involved in Sanfilippo syndrome
HGSNAT is a critical lysosomal membrane enzyme involved in the devastating lysosomal storage disease Sanfilippo syndrome. Here, Zhao et. al. reveal the mechanism for transmembrane acetylation catalyzed by HGSNAT with a series of cryo-EM structures.
- Boyang Zhao
- , Zhongzheng Cao
- & Fei Li
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Article
| Open AccessSingle missense mutations in Vi capsule synthesis genes confer hypervirulence to Salmonella Typhi
Here, Lee and Song describe missense mutations in the viaB locus in clinical isolates of Salmonella Typhi that result in hypo- and hyper-virulent phenotypes due to changes in the capsule.
- Gi Young Lee
- & Jeongmin Song
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Article
| Open AccessRft1 catalyzes lipid-linked oligosaccharide translocation across the ER membrane
Whether Rft1 plays a role during M5GN2-PP-Dol translocation has been controversial for over two decades. In this work, a reconstituted in vitro assay demonstrates that purified Rft1 is sufficient to flip M5GN2-PP-Dol across the lipid bilayer.
- Shuai Chen
- , Cai-Xia Pei
- & Xiao-Dong Gao
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Article
| Open AccessHuman gut microbes express functionally distinct endoglycosidases to metabolize the same N-glycan substrate
The human gut microbiome has a substantial impact on human health. Here, the authors find that prominent human gut microbes express functionally distinct surface endo-β-N-acetylglucosaminidases encoded by different polysaccharide utilization loci to optimally metabolize the same oligomannose N-glycan substrate in the gastrointestinal tract.
- Diego E. Sastre
- , Nazneen Sultana
- & Eric J. Sundberg
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Article
| Open AccessBinding of Akkermansia muciniphila to mucin is O-glycan specific
Intestinal mucus consists of densely O-glycosylated mucins, serving as a nutrient source for bacteria. Elzinga et al. show that mucin-degrading Akkermansia muciniphila selectively binds to O-glycan structures found on human colonic mucins.
- Janneke Elzinga
- , Yoshiki Narimatsu
- & Hanne L. P. Tytgat
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Article
| Open AccessGenetic and functional diversity of β-N-acetylgalactosamine-targeting glycosidases expanded by deep-sea metagenome analysis
Four β-N-acetylgalactosaminidase gene families were identified via deep-sea metagenome analysis. The biochemical and structural characterization of the aforementioned enzymes revealed their functional diversity and monophyletic evolutionary history.
- Tomomi Sumida
- , Satoshi Hiraoka
- & Takuro Nunoura
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Article
| Open AccessA Toxoplasma gondii O-glycosyltransferase that modulates bradyzoite cyst wall rigidity is distinct from host homologues
A Toxoplasma gondii mucin-type O-glycosyltransferase uses a unique catalytic mechanism to modify bradyzoite cyst wall proteins. A second metal coupled to substrate binding is required for catalysis, while an active site glutamate suggests a double-displacement mechanism.
- Pranav Kumar
- , Tadakimi Tomita
- & Nadine L. Samara
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Article
| Open AccessA comprehensive synthetic library of poly-N-acetyl glucosamines enabled vaccine against lethal challenges of Staphylococcus aureus
Poly-β-(1–6)-N-acetylglucosamine (PNAG) is an important vaccine target, but the impact of the number and position of free amine vs N-acetylation on its antigenicity is not well understood. Here, the authors report a divergent strategy to synthesize a comprehensive library of PNAG pentasaccharides, enabling the identification of enhanced epitopes for vaccines against Staphylococcus aureus including drug resistant strains.
- Zibin Tan
- , Weizhun Yang
- & Xuefei Huang
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Article
| Open AccessProbing altered receptor specificities of antigenically drifting human H3N2 viruses by chemoenzymatic synthesis, NMR, and modeling
Binding modes of antigenically drifted hemagglutinins of human influenza A viruses have been determined by NMR using synthetic N-glycans having 13C-labeled monosaccharides to pinpoint which monosaccharides of extended LacNAc chains engage with the HAs.
- Luca Unione
- , Augustinus N. A. Ammerlaan
- & Geert-Jan Boons
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Article
| Open AccessEnzymatic conversion of human blood group A kidneys to universal blood group O
ABO blood group compatibility restrictions limit the availability of organs for patients awaiting transplantation. Here, the authors show the rapid enzymatic removal of blood group A antigens from the vasculature of human kidneys using normothermic and hypothermic machine perfusion technologies to make universal blood group O organs for transplantation.
- Serena MacMillan
- , Sarah A. Hosgood
- & Michael L. Nicholson
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Article
| Open AccessStructure and function of Semaphorin-5A glycosaminoglycan interactions
Semaphorin 5A (Sema5A) forms complexes with heparan and chondroitin sulfate proteoglycans to regulate neuronal migration. Here, the authors show that the thrombospondin-like repeat 4 (TSR4) of Sema5A enables glycosaminoglycan association, multimerization, and neural progenitor cell distribution.
- Gergely N. Nagy
- , Xiao-Feng Zhao
- & E. Yvonne Jones
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Article
| Open AccessPrediction of glycopeptide fragment mass spectra by deep learning
Deep learning has achieved a notable success in proteomics and is now emerging in glycoproteomics. Here, the authors develop a neural network-based method to predict mass spectra of intact glycopeptides and demonstrate its potential in data-dependent and data-independent acquisition glycoproteomics.
- Yi Yang
- & Qun Fang
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Article
| Open AccessLipoarabinomannan mediates localized cell wall integrity during division in mycobacteria
Mycobacteria have a unique cell envelope that includes characteristic lipoglycans, such as lipoarabinomannan. Here, Sparks et al. show that this lipoglycan plays roles in maintenance of local cell envelope integrity and septal placement during cell division.
- Ian L. Sparks
- , Takehiro Kado
- & Yasu S. Morita
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Article
| Open AccessSubstrate binding and catalytic mechanism of the Se-glycosyltransferase SenB in the biosynthesis of selenoneine
SenB is a Se-glycosyltransferase in the microbial biosynthesis pathway of selenoneine. Here, the authors perform the structure-function investigation, providing mechanistic insights into a two-step catalytic reaction of SenB.
- Wei Huang
- , Jun Song
- & Feng Long
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Article
| Open AccessMolecular-level architecture of Chlamydomonas reinhardtii’s glycoprotein-rich cell wall
Chlamydomonas reinhardtii produces a glycoprotein-rich cell wall. Using nuclear magnetic resonance and mass spectrometry approaches, this study reveals unprecedented details on its protein and carbohydrate content, and provide an atomic-level architecture model.
- Alexandre Poulhazan
- , Alexandre A. Arnold
- & Isabelle Marcotte
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Article
| Open AccessN-linked Fc glycosylation is not required for IgG-B-cell receptor function in a GC-derived B-cell line
IgG molecules are glycosylated at a conserved asparagine residue of their constant region, and this modification is essential for the effector functions of their soluble form, such as complement activation and binding to Fcɣ receptors. Here authors show that in a model B-cell line, neither the expression nor the function of the membrane-bound form of IgG depend on glycosylation.
- Theresa Kissel
- , Veerle F. A. M. Derksen
- & René E. M. Toes
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Article
| Open AccessMultiple pathways for glucose phosphate transport and utilization support growth of Cryptosporidium parvum
The parasite Cryptosporidium has a reduced genome and is dependent on glycolysis for energy production. Here, Xu et al demonstrate that multiple pathways and glucose transporters exist in this organism which are essential for growth and facilitate energy acquisition and utilization.
- Rui Xu
- , Wandy L. Beatty
- & L. David Sibley
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Article
| Open AccessMCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation
B cell activation and differentiation entails metabolic remodelling, involving differential utilisation of monocarboxylates such as L-lactate and pyruvate. Here authors show by B-cell-specific genomic deletion of monocarboxylate transporter 1 (MCT1) that the consequential scarcity of pyruvate results in decreased acetylation of Histone H3 at K27, leading to decreased AID transcription and deficient class switching to IgG.
- Wenna Chi
- , Na Kang
- & Ligong Chen
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Article
| Open AccessSelenium-based metabolic oligosaccharide engineering strategy for quantitative glycan detection
Metabolic oligosaccharide engineering (MOE) is a classical strategy for carbohydrate perception but suffers from glycan quantification. Here the authors develop a selenium-based metabolic oligosaccharide engineering strategy (SeMOE), based on elemental analysis, to quantitatively detect and visualize glycans both in vitro and in vivo.
- Xiao Tian
- , Lingna Zheng
- & Ran Xie
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Article
| Open AccessSite-selected in situ polymerization for living cell surface engineering
Constructing polymer-based mimics on the surface of cells has potential to manipulate cell behavior, but precise control of grafting sites is challenging. Here, the authors report a method for site selected radical polymerization on cell surfaces by metabolic labelling.
- Yihong Zhong
- , Lijia Xu
- & Huangxian Ju
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Article
| Open AccessGlycoengineered keratinocyte library reveals essential functions of specific glycans for all stages of HSV-1 infection
Here authors generate a glycoengineered keratinocyte library delineating human glycosylation pathways. The use of this library reveals that each stage of the HSV-1 infectious cycle is sensitive to alterations in the cellular glycan landscape, identifying critical biosynthetic steps that could be exploited for targeting HSV-1.
- Ieva Bagdonaite
- , Irina N. Marinova
- & Hans H. Wandall
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Article
| Open AccessCryo-EM structure of human O-GlcNAcylation enzyme pair OGT-OGA complex
The single pair of enzymes in human, OGT and OGA, mediates protein OGlcNAcylation cycle. Here, authors provide cryo-EM structures of OGT-OGA complex, revealing how OGT selects native substrates and the mutual inhibition mechanism between OGT and OGA.
- Ping Lu
- , Yusong Liu
- & Haishan Gao
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Article
| Open AccessO-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations
The neurofilament cytoskeleton is critical for axon function and can be dysregulated in disease. Here, the authors show that intracellular glycosylation regulates a key neurofilament protein.
- Duc T. Huynh
- , Kalina N. Tsolova
- & Michael Boyce
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Article
| Open AccessMolecular mechanism of decision-making in glycosaminoglycan biosynthesis
Heparan sulfate (HS) and chondroitin sulfate (CS) are different glycosaminoglycan chains that are attached to core proteins via the same linker tetrasaccharide, and it was unclear how core proteins are specifically modified with HS or CS. Here, the authors determine that the CS-initiating glycosyltransferase CSGALNACT2 is promiscuous, whereas the HS-initiating glycosyltransferase EXTL3 selects only certain core proteins for modification.
- Douglas Sammon
- , Anja Krueger
- & Erhard Hohenester
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Article
| Open AccessGlycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE
Mucin glycoproteins are biologically relevant but are challenging to study. Here, the authors characterized the SmE enzyme and used it to glycoproteomic ally map immune checkpoint proteins. This information then drove MD simulations and binding assays to understand how glycosylation controls structure and function.
- Joann Chongsaritsinsuk
- , Alexandra D. Steigmeyer
- & Stacy A. Malaker
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Article
| Open AccessGlyco-engineered MDCK cells display preferred receptors of H3N2 influenza absent in eggs used for vaccines
Evolution of human H3N2 influenza has limited the specificity of hemagglutinin to a subset of glycan receptors, which brings challenges. By glyco-engineering cell lines, authors show the importance of extended glycan receptors for growth of recent H3N2 viruses and relevance to their production for vaccines.
- Chika Kikuchi
- , Aristotelis Antonopoulos
- & James C. Paulson
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Article
| Open AccessIdentification and characterization of endo-α-, exo-α-, and exo-β-d-arabinofuranosidases degrading lipoarabinomannan and arabinogalactan of mycobacteria
Lipoarabinomannan and arabinogalactan in the mycobacterial cell wall contain d-arabinan core. Here, the authors identify and characterize the molecular structures and mechanisms of four bacterial enzymes that synergistically degrade the alpha- and beta-linkages of d-arabinan.
- Michiko Shimokawa
- , Akihiro Ishiwata
- & Kiyotaka Fujita
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Article
| Open AccessChemoenzymatic synthesis of genetically-encoded multivalent liquid N-glycan arrays
Cellular glycosylation is complex and heterogeneous, which is challenging to reproduce synthetically. Here, the authors report on enzymatic remodelling of multivalent glycosylated bacteriophages to produce genetically encoded library of N-glycans which can be used to measure glycan-protein interactions with lectins on the surface of live cells and organs.
- Chih-Lan Lin
- , Mirat Sojitra
- & Ratmir Derda
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Article
| Open AccessMetabolic glycan labeling immobilizes dendritic cell membrane and enhances antitumor efficacy of dendritic cell vaccine
Dendritic cell (DC) vaccines were among the first FDA-approved cancer immunotherapies but have been limited by the modest therapeutic efficacy. Here, authors report a facile metabolic glycan labeling approach to improving the cytotoxic T lymphocyte response and antitumor efficacy of DC vaccines.
- Joonsu Han
- , Rimsha Bhatta
- & Hua Wang
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Article
| Open AccessThe Gram-positive bacterium Romboutsia ilealis harbors a polysaccharide synthase that can produce (1,3;1,4)-β-d-glucans
(1,3;1,4)-β-d-Glucans are widely distributed in many organisms, but little is known about the enzymes responsible for their synthesis outside the grasses. Here, the authors report on the presence of (1,3;1,4)-β-d-glucans in the exopolysaccharides of the Gram-positive bacterium Romboutsia ilealis and identify and characterize the (1,3;1,4)-β-d-glucan synthase RiGT2.
- Shu-Chieh Chang
- , Mu-Rong Kao
- & Yves S. Y. Hsieh
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Article
| Open AccessGlycopeptide database search and de novo sequencing with PEAKS GlycanFinder enable highly sensitive glycoproteomics
Accurate identification of intact glycopeptides from mass spectrometry data is essential for the characterization of glycosylation events in biological samples. Here, the authors propose GlycanFinder, a database search and de novo sequencing tool for the analysis of intact glycopeptides.
- Weiping Sun
- , Qianqiu Zhang
- & Baozhen Shan
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Article
| Open AccessStructural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b
Siglec-15 inhibits T cell function in the tumor microenvironment. Here, the authors solve the crystal structure of antibody-bound Siglec-15, characterize its binding mode to sialic acids, and identify sialylated CD11b as one of its binding partners on T cells.
- Maria Pia Lenza
- , Leire Egia-Mendikute
- & June Ereño-Orbea
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Article
| Open AccessUnraveling the glycosylated immunopeptidome with HLA-Glyco
Protein glycosylation plays a vital role in antigen recognition and immune modulation. Here, the authors present a computational workflow for identifying glycosylated peptides from mass spectrometry-based immunopeptidome data and investigate the properties of glycosylated MHC associated peptides.
- Georges Bedran
- , Daniel A. Polasky
- & Alexey I. Nesvizhskii
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Article
| Open AccessThe divisome but not the elongasome organizes capsule synthesis in Streptococcus pneumoniae
The bacterial cell envelope consists of multiple layers, the synthesis of which is coordinated through unclear mechanisms. Here, Nakamoto et al. reveal a mechanism linking the synthesis of capsular polysaccharides and cell wall peptidoglycan in pneumococci.
- Rei Nakamoto
- , Sarp Bamyaci
- & Lok-To Sham
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Article
| Open AccessSpatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis
Spatial metabolomics are used to describe the location and chemistry of small molecules involved in metabolic phenotypes. Here, Conroy et al. present a bioinformatic pipeline to analyze MALDI data and show that it can be used to identify actionable targets such as glycogen in fibrotic lungs of both human and mice.
- Lindsey R. Conroy
- , Harrison A. Clarke
- & Ramon C. Sun
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Article
| Open AccessSiglec-6 mediates the uptake of extracellular vesicles through a noncanonical glycolipid binding pocket
Siglec-glycolipid interactions are often studied outside the context of a lipid bilayer. Here, the authors combine a variety of chemical biology techniques to demonstrate a unique and physiologically relevant ability of Siglec-6 to recognize glycolipids in a membrane.
- Edward N. Schmidt
- , Dimitra Lamprinaki
- & Matthew S. Macauley
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Article
| Open AccessIdentification of d-arabinan-degrading enzymes in mycobacteria
Bacterial cell growth and division require the coordinated action of enzymes that synthesize and degrade cell wall polymers. Here, the authors identify enzymes that cleave the D-arabinan core of arabinogalactan, an unusual component of the cell wall of Mycobacterium tuberculosis and other mycobacteria.
- Omar Al-Jourani
- , Samuel T. Benedict
- & Patrick J. Moynihan
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Article
| Open AccessVibrio cholerae biofilms use modular adhesins with glycan-targeting and nonspecific surface binding domains for colonization
Bacteria often express multiple adhesive proteins (adhesins) for biofilm formation, but it is often unclear whether adhesins have specialized or redundant roles. Here, the authors show that Vibrio cholerae uses two adhesins with overlapping but distinct functions to achieve robust adhesion to diverse surfaces.
- Xin Huang
- , Thomas Nero
- & Jing Yan
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Article
| Open AccessA cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates
Here, the authors show that cell internalization of Engrailed2 not only relies on its homeodomain, but also involves a cationic region which interacts selectively with cell surface heparan sulfates.
- Sébastien Cardon
- , Yadira P. Hervis
- & Sandrine Sagan
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Article
| Open AccessSingle-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimers as HIV-1 vaccine candidates
Here the authors present an HIV-1 vaccine strategy that combines Env stabilization, nanoparticle display, and glycan trimming, which improves neutralizing antibody responses, frequency of vaccine responders, and germinal center reactions in animal models.
- Yi-Nan Zhang
- , Jennifer Paynter
- & Jiang Zhu
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Article
| Open AccessSialidases and fucosidases of Akkermansia muciniphila are crucial for growth on mucin and nutrient sharing with mucus-associated gut bacteria
This study offers molecular insight into the sialidase and fucosidase decapping apparatus that initiates growth on mucin and promotes nutrient sharing by the dedicated mucolytic symbiont Akkermansia muciniphila with the mucus-associated microbiota.
- Bashar Shuoker
- , Michael J. Pichler
- & Maher Abou Hachem
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Article
| Open AccessTurning universal O into rare Bombay type blood
People with the rare Bombay-type Oh blood group can only be transfused with Oh blood. Here, the authors characterize a bacterial α−1,2-fucosidase that can convert universal O type into rare Bombay type blood.
- Itxaso Anso
- , Andreas Naegeli
- & Marcelo E. Guerin
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Article
| Open AccessIdentification of tagged glycans with a protein nanopore
The structural complexity of glycans seriously challenges the currently available analytical methods. Here, the authors report the identification of glycan isomers, glycans with varying chain lengths, and distinct branched glycans, via a glycan derivatization strategy and nanopore sensing.
- Minmin Li
- , Yuting Xiong
- & Guangyan Qing