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| Open AccessDistributed genotyping and clustering of Neisseria strains reveal continual emergence of epidemic meningococcus over a century
Core genome multilocus sequence typing (cgMLST) is used to classify bacterial strains for epidemiological applications. Here, the authors describe a distributed cgMLST scheme that does not require a central database of allelic sequences, and apply it to study evolutionary patterns of epidemic and endemic strains of the genus Neisseria.
- Ling Zhong
- , Menghan Zhang
- & Zhemin Zhou
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Article
| Open AccessBioE3 identifies specific substrates of ubiquitin E3 ligases
Here, the authors describe BioE3, a biotin-based method to discriminate direct substrates of ubiquitin E3 ligases of interest from mere interactors using proximity proteomics. BioE3 responds to chemical treatments, and works with RING- and HECT-type E3s, as well as ubiquitin-likes (e.g., SUMO).
- Orhi Barroso-Gomila
- , Laura Merino-Cacho
- & James D. Sutherland
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Article
| Open Access3D reconstructions of parasite development and the intracellular niche of the microsporidian pathogen Encephalitozoon intestinalis
Microsporidia are obligate intracellular parasitic fungi that can cause opportunistic infections in humans. Here, Antao et al. investigate the intracellular life cycle of human-infecting Encephalitozoon intestinalis using serial block-face scanning electron microscopy to characterize parasite organelle development and host-cell mitochondrial remodeling.
- Noelle V. Antao
- , Cherry Lam
- & Gira Bhabha
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Article
| Open AccessSPACEL: deep learning-based characterization of spatial transcriptome architectures
Spatial transcriptomics (ST) technologies detect transcript distribution in space. Here, authors present a deep learning based method SPACEL for cell type deconvolution, spatial domain identification and 3D alignment, showcasing it as a valuable toolkit for ST data analysis
- Hao Xu
- , Shuyan Wang
- & Kun Qu
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Article
| Open AccessTargetable lesions and proteomes predict therapy sensitivity through disease evolution in pediatric acute lymphoblastic leukemia
The role of clonal evolution on the actionable proteome and response to therapy in childhood acute lymphoblastic leukemia (ALL) remains unknown. Here, targeted sequencing and proteomic analysis of paired ALL diagnosis and relapsed samples revealed PARP1 as a potential therapeutic target.
- Amanda C. Lorentzian
- , Jenna Rever
- & Philipp F. Lange
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Article
| Open AccessQuantification of ligand and mutation-induced bias in EGFR phosphorylation in direct response to ligand binding
The authors show that the oncogenic L834R EGFR mutation induces bias in EGFR signal transduction across the plasma membrane. While EGFR signalling is biased toward Y1068 phosphorylation, the mutation switches the preference to Y1173 phosphorylation.
- Daniel Wirth
- , Ece Özdemir
- & Kalina Hristova
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Article
| Open AccessThe structure of the teleost Immunoglobulin M core provides insights on polymeric antibody evolution, assembly, and function
The formation of polymeric Ig complexes is important for the function of IgM and can vary between species. Here the authors structurally analyse IgM from a teleost species that doesn’t encode a joining chain, which results in a different 3D structure compared to mammalian IgM where other parts of the protein associate to form polymeric complexes.
- Mengfan Lyu
- , Andrey G. Malyutin
- & Beth M. Stadtmueller
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Article
| Open AccessSETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer
SET domain–containing 2 (SETD2) is reported as an immunosuppressor in clear cell renal cell carcinoma (ccRCC). Here the authors show that SETD2 loss enhances de novo sphingomyelin biosynthesis during the transition from polycystic kidney disease to ccRCC.
- Hanyu Rao
- , Changwei Liu
- & Xianting Ding
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Article
| Open AccessCRISPR-based gene drives generate super-Mendelian inheritance in the disease vector Culex quinquefasciatus
Culex mosquitoes are carriers of major diseases like West Nile virus and are a public health concern. Here the authors present a CRISPR-Cas9 gene drive as a control technology in the Culex quinquefasciatus mosquito species.
- Tim Harvey-Samuel
- , Xuechun Feng
- & Valentino M. Gantz
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Article
| Open AccessInferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution
Studying metabolism in distinct subcellular compartments typically involves isolating organelles. Here, the authors demonstrate a quantitative approach to infer cytosolic and mitochondrial metabolic activities based on experiments with intact cells, maintaining physiological conditions.
- Alon Stern
- , Mariam Fokra
- & Tomer Shlomi
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Article
| Open AccessRegulation of species metabolism in synthetic community systems by environmental pH oscillations
Most synthetic communities are unidirectional or two-way interaction without dynamic feedback. Here, the authors report a dynamic feedback system involving artificial cell species, biological cell species, and their environment using pH-sensitive molecule that phase-shift between fluid and gel phases.
- Shubin Li
- , Yingming Zhao
- & Xiaojun Han
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Article
| Open AccessSimultaneous selection of nanobodies for accessible epitopes on immune cells in the tumor microenvironment
INSPIREseq discovers accessible epitopes in complex environments and leads to nanobodies targeting thousands of epitopes. This in vivo diversity selection identifies selective nanobodies, potentially expediting target discovery and drug development.
- Thillai V. Sekar
- , Eslam A. Elghonaimy
- & Todd A. Aguilera
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Article
| Open AccessTOFIMS mass spectrometry-based immunopeptidomics refines tumor antigen identification
MS-based immunopeptidomics provides direct evidence for HLA peptide-antigen presentation, which is indispensable for therapeutic use. Here the authors present an ion mobility MS-based immunopeptidome workflow, largely expand benign reference databases and enables next generation tumor antigen discovery.
- Naomi Hoenisch Gravel
- , Annika Nelde
- & Juliane S. Walz
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Article
| Open AccessSequence-based prediction of the intrinsic solubility of peptides containing non-natural amino acids
Posttranslationally modified amino acids are crucial in physiology and drug development as they alter physicochemical properties such as the solubility of proteins. Here the authors describe CamSolPTM, a software that accurately predicts the solubility of proteins containing these residues.
- Marc Oeller
- , Ryan J. D. Kang
- & Michele Vendruscolo
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Article
| Open AccessTarget-dependent RNA polymerase as universal platform for gene expression control in response to intracellular molecules
Controlling gene expression in response to the intracellular molecule of interest is challenging. Here, the authors repurposed antibody variable regions to control gene expression in an inducible manner by combining them with a split RNA polymerase.
- Shodai Komatsu
- , Hirohisa Ohno
- & Hirohide Saito
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Article
| Open AccessA toolbox of astrocyte-specific, serotype-independent adeno-associated viral vectors using microRNA targeting sequences
Astrocytes, highly prevalent cells in the central nervous system, have been difficult to specifically target with adeno-associated viruses (AAVs). Here, the authors present a microRNA targeting cassette that de-targets other cells, increasing astrocyte specificity of AAVs to over 99%.
- Amy J. Gleichman
- , Riki Kawaguchi
- & S. Thomas Carmichael
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Article
| Open AccessHigh-sensitive spatially resolved T cell receptor sequencing with SPTCR-seq
Understanding T cell behaviour in cancers is vital for improving immunotherapies. Here, the authors present spatially resolved T cell receptor sequencing (SPTCR-seq), a technology that annotates T cell receptors within the tumour ecosystem.
- Jasim Kada Benotmane
- , Jan Kueckelhaus
- & Dieter Henrik Heiland
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Article
| Open AccessJoint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape
The genetic architecture of normal-range cranial vault shape in humans is poorly understood. Here, the authors extract cranial vault shape from MRI and conduct a multi-ancestry GWAS, identifying 30 independently associated genomic loci of which 29 are novel.
- Seppe Goovaerts
- , Hanne Hoskens
- & Peter Claes
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Article
| Open AccessMucosal-associated invariant T cells contribute to suppression of inflammatory myeloid cells in immune-mediated kidney disease
Mucosal associated invariant T (MAIT) cells reside in barrier organs, but their contribution to inflammatory processes in the kidneys is not fully known. Here authors find by single cell RNA sequencing that among the different MAIT cell subtypes found at steady state, a population with MAIT17 signature is expanded in both human crescentic glomerulonephritis and its mouse model, and these cells may play protective role in the disease.
- Ann-Christin Gnirck
- , Marie-Sophie Philipp
- & Jan-Eric Turner
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Article
| Open AccessDimension-agnostic and granularity-based spatially variable gene identification using BSP
Identifying spatially variable genes (SVGs) is essential for linking molecular cell functions with tissue phenotypes. Here, authors introduce a non-parametric model that detects SVGs from two or three-dimensional spatial transcriptomics data by comparing gene expression patterns at granularities.
- Juexin Wang
- , Jinpu Li
- & Dong Xu
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Article
| Open AccessImaging cellular forces with photonic crystals
Current techniques for visualizing cell generated forces suffer from throughput limitations. Here, Gu et al. introduced photonic crystal cellular force microscopy, inspired by chameleons, enabling visualization and quantification of vertically directed cell forces, well-suited for drug screening.
- Qiwei Li
- , Zaozao Chen
- & Zhongze Gu
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Article
| Open AccessCryo-EM structures of the plant anion channel SLAC1 from Arabidopsis thaliana suggest a combined activation model
Phosphorylation-mediated activation of SLAC1 anion channel is crucial in plant responses for abiotic stresses including drought. Here, authors determine the open and closed structures of SLAC1, revealing how phosphorylation can activate SLAC1.
- Yeongmok Lee
- , Hyeon Seong Jeong
- & Sangho Lee
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Article
| Open AccessCHEX-seq detects single-cell genomic single-stranded DNA with catalytical potential
The in situ single-stranded open chromatin landscape is dynamically regulated in single cells. In their efforts to understand brain cells’ functional dynamics and to complement the other single-cell chromatin approaches, the authors present a method named CHEX-seq (CHromatin EXposed).
- Youtao Lu
- , Jaehee Lee
- & James Eberwine
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Article
| Open AccessLong-term cargo tracking reveals intricate trafficking through active cytoskeletal networks in the crowded cellular environment
Leveraging a label-free interferometric scattering microscope, scientists tracked numerous cargos within a crowded cellular environment. Intriguingly, cells employ effective strategies echoing human transportation systems to manage such transportation hurdles.
- Jin-Sung Park
- , Il-Buem Lee
- & Minhaeng Cho
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Article
| Open AccessCLOOME: contrastive learning unlocks bioimaging databases for queries with chemical structures
Artificial intelligence can assist in obtaining knowledge from bioimaging data, but need human annotation. Here the authors use multimodal contrastive learning to link chemical structures and cell phenotypes, which can lead to foundation models for microscopy images.
- Ana Sanchez-Fernandez
- , Elisabeth Rumetshofer
- & Günter Klambauer
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Article
| Open AccessCombinatorial quantification of distinct neural projections from retrograde tracing
Comprehensive quantification of neural architectures underlying brain circuitry remains challenging. Here, the authors present a practical method to quantitatively identify nerve cells with specific axonal projections from retrograde anatomical injections.
- Siva Venkadesh
- , Anthony Santarelli
- & Giorgio A. Ascoli
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Article
| Open AccessSpatial-linked alignment tool (SLAT) for aligning heterogenous slices
Spatial omics technologies reveal the organisation of cells in various biological systems. Here, authors propose SLAT, a graph-based algorithm for aligning heterogenous data across technologies, modalities and timepoints, enabling spatiotemporal reconstruction of complex developmental processes.
- Chen-Rui Xia
- , Zhi-Jie Cao
- & Ge Gao
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Article
| Open AccessCamoTSS: analysis of alternative transcription start sites for cellular phenotypes and regulatory patterns from 5' scRNA-seq data
Five-prime single-cell RNA-seq, especially the read 1, has precise capture of transcription start sites (TSS), but such information is often overlooked. Here, authors present a computational method suite, CamoTSS, to precisely identify TSS and quantify its expression, enabling effective detection of alternative TSS usage in different biological processes.
- Ruiyan Hou
- , Chung-Chau Hon
- & Yuanhua Huang
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Article
| Open AccessProgesterone activation of β1-containing BK channels involves two binding sites
Progesterone is used in recovery of cerebral ischemia however the mechanism of action is unknown. Authors report here that micromolar progesterone activates mouse cerebrovascular myocyte BK channels, involving two steroid binding sites.
- Kelsey C. North
- , Andrew A. Shaw
- & Alex M. Dopico
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Article
| Open AccesstrRosettaRNA: automated prediction of RNA 3D structure with transformer network
Here, authors develop trRosettaRNA, a deep learning-based approach for predicting RNA 3D structures. Blind tests demonstrate that the automated predictions compete effectively with top human predictions on natural RNAs.
- Wenkai Wang
- , Chenjie Feng
- & Jianyi Yang
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Article
| Open AccessreplicAnt: a pipeline for generating annotated images of animals in complex environments using Unreal Engine
Deep learning-based computer vision tools are transforming animal behavioural research; however, many challenges remain. Here, Plum et al. present replicAnt, a novel tool for generating synthetic data to train computer vision models for animal behaviour studies, reducing the need for manual annotation.
- Fabian Plum
- , René Bulla
- & David Labonte
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Article
| Open AccessMePMe-seq: antibody-free simultaneous m6A and m5C mapping in mRNA by metabolic propargyl labeling and sequencing
Methylation is the dominant modification in mRNA and occurs at a variety of sites. Here, Hartstock et al. show that a clickable analogue of the key cosubstrate S-adenosyl-L-methionine (SAM) can be produced in cells, allowing for identification and mapping of different methylated nucleosides in mRNA.
- Katja Hartstock
- , Nadine A. Kueck
- & Andrea Rentmeister
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Article
| Open AccessNIPMAP: niche-phenotype mapping of multiplex histology data by community ecology
Multiplex histology faces the challenge of integrating tissue architecture with the identification of relevant spatial cellular phenotypes. Using community ecology principles, the authors propose NIPMAP, a tool for niche-phenotype mapping of multiplex histology data.
- Anissa El Marrahi
- , Fabio Lipreri
- & Jean Hausser
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Article
| Open AccessStructural insights into the modulation of coronavirus spike tilting and infectivity by hinge glycans
In this work, the authors combine cryo-electron tomography of vitrified virions, mass spectrometry, modeling, molecular dynamics and infectivity assay and report that a hinge glycan on viral spike protein influences virus infection and immune evasion.
- David Chmielewski
- , Eric A. Wilson
- & Wah Chiu
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Article
| Open AccessLensAge index as a deep learning-based biological age for self-monitoring the risks of age-related diseases and mortality
Age is closely related to health, but chronologically defined age often disagrees with biological age. Here, the authors develop an indicator of biological age - LensAge index - to reveal individuals’ aging level, and it can be implemented with smartphones, showing potential for self-monitoring of aging.
- Ruiyang Li
- , Wenben Chen
- & Haotian Lin
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Article
| Open AccessIL-21R-STAT3 signalling initiates a differentiation program in uterine tissue-resident NK cells to support pregnancy
Uterine natural killer (NK) cells support tissue homeostasis in the uterus during pregnancy, but it is not fully known how they differentiate into potentially cytotoxic effector cells while avoiding tissue damage. Here authors show that Il21 receptor signalling via STAT3 activation governs their differentiation, while an apoptotic cell death program ensures that harm is limited.
- Mengwei Han
- , Luni Hu
- & Chao Zhong
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Article
| Open AccessLipofuscin-like autofluorescence within microglia and its impact on studying microglial engulfment
Microglia are brain macrophages that engulf and clear cellular material and protein aggregates. Here, the authors show that lipofuscin-like autofluorescence can confound microglial engulfment analyses, which they can resolve with a photobleaching protocol.
- Jacob M. Stillman
- , Francisco Mendes Lopes
- & Dorothy P. Schafer
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Article
| Open AccessPRO-IP-seq tracks molecular modifications of engaged Pol II complexes at nucleotide resolution
Tracking molecular modifications of engaged Pol II complexes is important for studying transcriptional regulation. Here, the authors combine run-on sequencing (PRO-seq) and immunoprecipitation, revealing dynamics of Pol II CTD phosphorylation at nucleotide-resolution.
- Anniina Vihervaara
- , Philip Versluis
- & John T. Lis
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Article
| Open AccessEfficient optical plasmonic tweezer-controlled single-molecule SERS characterization of pH-dependent amylin species in aqueous milieus
Studying rare species in mixtures is challenging. Here, authors utilize on-and-off optical plasmonic trapping to control SERS-active nanocavity to analyse pH-dependent amylin species at single-molecule level, unveiling amyloid aggregation mechanisms.
- Wenhao Fu
- , Huanyu Chi
- & Jinqing Huang
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Article
| Open AccessIn situ quantification of osmotic pressure within living embryonic tissues
Osmotic pressure is thought to play a key role in many cellular and developmental processes, but remains challenging to measure it in cells and tissues. Here, the authors present a sensor based on double emulsion droplets that allows quantification of osmotic pressure in situ and in vivo.
- Antoine Vian
- , Marie Pochitaloff
- & Otger Campàs
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Article
| Open AccessDefining neutralization and allostery by antibodies against COVID-19 variants
Here, Tulsian et al. identified the effect of biologically relevant full-length IgG binding on the Spike protein from different SARS-CoV-2 variants to comprehensively understand the mechanisms of antibody evasion, towards the development of better antiviral strategies.
- Nikhil Kumar Tulsian
- , Raghuvamsi Venkata Palur
- & Paul Anthony MacAry
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Article
| Open AccessContinually recruited naïve T cells contribute to the follicular helper and regulatory T cell pools in germinal centers
B cell clonal expansion and affinity maturation takes place in germinal centers (GC) and is orchestrated by follicular T cells. Here authors show that naïve conventional T cells are continuously recruited to the GCs during the GC reaction and develop into follicular helper and regulatory T cells, thus quantitatively contribute to remodelling the GC overtime.
- Julia Merkenschlager
- , Riza-Maria Berz
- & Michel C. Nussenzweig
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Article
| Open AccessOptogenetic control of YAP reveals a dynamic communication code for stem cell fate and proliferation
The transcriptional regulator YAP controls cellular decisions such as proliferation, differentiation, and pluripotency. Here, the authors show a concentration-dependent and temporal communication code for YAP that enables cells to choose between these programs.
- Kirstin Meyer
- , Nicholas C. Lammers
- & Orion D. Weiner
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Article
| Open AccessNear-infrared-II photoacoustic imaging and photo-triggered synergistic treatment of thrombosis via fibrin-specific homopolymer nanoparticles
The near-infrared-II (NIR-II) window has shown great promise for in vivo imaging and therapy. Here, the authors integrate a homopolymer and thermo-sensitive nitric oxide prodrug into nanoparticles for long-wavelength NIR-II photoacoustic imaging and synergistic treatment in preclinical thrombosis models.
- Jianwen Song
- , Xiaoying Kang
- & Ji Qi
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Article
| Open AccessLactate biosensors for spectrally and spatially multiplexed fluorescence imaging
l-Lactate is increasingly recognized as a key metabolite and signalling molecule in mammals, but the methods to investigate it in vivo have been limited. Here, authors report a pair of improved biosensors—one green and one red—for visualizing l-lactate both inside and outside of cells.
- Yusuke Nasu
- , Abhi Aggarwal
- & Robert E. Campbell
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Article
| Open AccessAntibody-directed extracellular proximity biotinylation reveals that Contactin-1 regulates axo-axonic innervation of axon initial segments
Few resident cell surface proteins have been identified at the axon initial segment. Here, Ogawa and colleagues use proximity labeling and proteomics to identify Contactin-1 as a transmembrane axon initial segment protein that regulates brain wiring.
- Yuki Ogawa
- , Brian C. Lim
- & Matthew N. Rasband
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Article
| Open AccessFHL1 promotes chikungunya and o’nyong-nyong virus infection and pathogenesis with implications for alphavirus vaccine design
FHL1A is a crucial host factor for alphavirus infection but its impact on pathogenesis is unclear. Here, the authors use a FHL1−/− knockout mouse model to show that the FHL1 splice variant impacts arthritis and myositis after chikungunya or o’nyong-nyong infections but not Ross River or mayaro virus infection.
- Wern Hann Ng
- , Xiang Liu
- & Suresh Mahalingam
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Article
| Open AccessEnzymatic synthesis and nanopore sequencing of 12-letter supernumerary DNA
Unnatural base pairing xenonucleic acids (XNAs) can be used to expand life’s alphabet beyond ATGC. Here, authors show strategies for enzymatic synthesis and next-generation nanopore sequencing of XNA base pairs for reading and writing 12-letter DNA (ATGCBSPZXKJV).
- Hinako Kawabe
- , Christopher A. Thomas
- & Jorge A. Marchand
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Article
| Open AccessSialic acid O-acetylation patterns and glycosidic linkage type determination by ion mobility-mass spectrometry
O-acetylation is a common modification of sialic acids. Here, a library of synthetic O-acetylated sialosides made it possible to develop an ion mobility mass spectrometry (IM-MS) approach that can elucidate exact O-acetylation patterns and glycosidic linkage types of sialosides isolated from biological samples.
- Gaёl M. Vos
- , Kevin C. Hooijschuur
- & Geert-Jan Boons
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