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| 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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Article
| Open AccessIDH1 mutation impairs antiviral response and potentiates oncolytic virotherapy in glioma
The role of human glioma IDH1 mutations in regulation of antiviral response is unclear. Here, the authors show that D2HG produced by mutant IDH1 inhibits IFN antiviral responses in glioma cells, which confers sensitivity to oncolytic virotherapy.
- Xueqin Chen
- , Jun Liu
- & Haipeng Zhang
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Article
| Open AccessVisualization of accessible cholesterol using a GRAM domain-based biosensor
Regulated cholesterol transport is essential for the maintenance of cellular cholesterol distribution and homeostasis, but tools to monitor this process are limited. Here, the authors develop a genetically encoded cholesterol biosensor and demonstrate its use for visualising cellular cholesterol distribution in various live cells in real time.
- Dylan Hong Zheng Koh
- , Tomoki Naito
- & Yasunori Saheki
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Article
| Open AccessAn interferon-integrated mucosal vaccine provides pan-sarbecovirus protection in small animal models
Here, the authors report the generation of a live but defective SARS-CoV-2 virus that is envelope-deficient and expresses human interferon beta. They show that nasal vaccination enhances mucosal and lung T cell response and provides pan-sarbecovirus protection in small animals.
- Chun-Kit Yuen
- , Wan-Man Wong
- & Kin-Hang Kok
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Article
| Open AccessHierarchical organization and assembly of the archaeal cell sheath from an amyloid-like protein
Cellular cryoET reveals how an amyloid-like protein of the prototypical archaeon, Methanospirillum hungatei, oligomerizes into a ring containing a giant 2700-strand β sheet, and how rings stack into hoops and into the cylindrical sheath of the cell.
- Hui Wang
- , Jiayan Zhang
- & Z. Hong Zhou
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Article
| Open AccessMass production of lumenogenic human embryoid bodies and functional cardiospheres using in-air-generated microcapsules
Current methods to generate spheroids are associated with low production throughputs, limiting clinical and industrial translation. Here the authors present a clean ultra-high-throughput in-air microfluidic platform for mass production of lumenogenic embryoid bodies and functional cardiospheres.
- Bas van Loo
- , Simone A. ten Den
- & Jeroen Leijten
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Article
| Open AccessRepurposing conformational changes in ANL superfamily enzymes to rapidly generate biosensors for organic and amino acids
Biosensors have a wide number of potential applications, but rapidly constructing genetically encoded biosensors remains challenging. Here, authors report a method for rapidly converting ANL superfamily enzymes into biosensors for organic acids, based on their conformational changes upon binding.
- Jin Wang
- , Ning Xue
- & Meng Wang
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Article
| Open AccessSingle virus fingerprinting by widefield interferometric defocus-enhanced mid-infrared photothermal microscopy
The study of viruses relies on the detection of viral proteins or viral nucleic acids. Here, the authors present a widefield interferometric defocus-enhanced mid-infrared photothermal (WIDE-MIP) microscope for high-throughput fingerprinting of single viruses.
- Qing Xia
- , Zhongyue Guo
- & Ji-Xin Cheng
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Article
| Open AccessDeveloping mitochondrial base editors with diverse context compatibility and high fidelity via saturated spacer library
Ddd-Aderived cytosine base editors (DdCBEs) are important for research of mitochondrial DNA mutation diseases. Here the authors report a strategy for screening and characterising dsDNA cytidine deaminases, and identify 7 DddA homologs which they optimise to minimise nuclear and mitochondrial off-target editing.
- Haifeng Sun
- , Zhaojun Wang
- & Bin Shen
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Article
| Open AccessSonogenetic control of multiplexed genome regulation and base editing
Exogenous control of genes in vivo is important. Here the authors report a system that can be inducibly activated through thermal energy produced by ultrasound absorption and use this to control induction of gene activation and base editing: they apply this in cell lines and in a mouse model.
- Pei Liu
- , Josquin Foiret
- & Lei S. Qi
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Article
| Open AccessA spatial sequencing atlas of age-induced changes in the lung during influenza infection
Ageing is known to impair the immune response against infectious pathogens. Here, Kasmani et al. present a spatial and transcriptomic atlas of immune changes in the lungs of young and aged mice in response to influenza virus infection.
- Moujtaba Y. Kasmani
- , Paytsar Topchyan
- & Weiguo Cui
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Article
| Open AccessDirect regulation of the voltage sensor of HCN channels by membrane lipid compartmentalization
Voltage sensing of ion channels relies on charged transmembrane helices. Here authors use live-cell FLIM-FRET and nonsense suppression-mediated fluorescence labeling to reveal that voltage sensors undergo direct modulation by compartmentalized membrane domains.
- Lucas J. Handlin
- & Gucan Dai
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Article
| Open AccessIdentification of errors in draft genome assemblies at single-nucleotide resolution for quality assessment and improvement
A high-quality genome assembly is essential for various genomic studies in life sciences. Here the authors develop CRAQ, a reference-free method that facilitates the evaluation and improvement of any de novo genome assembly with single nucleotide resolution.
- Kunpeng Li
- , Peng Xu
- & Yuannian Jiao
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Article
| Open AccessDeep-LASI: deep-learning assisted, single-molecule imaging analysis of multi-color DNA origami structures
Analysis of single-molecule experiments remains time-consuming and prone to human bias. Here, the authors propose Deep-Learning Assisted Single-molecule Imaging analysis, a tool to rapidly analyse single-, two- and three-color single-molecule FRET data.
- Simon Wanninger
- , Pooyeh Asadiatouei
- & Don C. Lamb
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Article
| Open AccessAn automated single-molecule FRET platform for high-content, multiwell plate screening of biomolecular conformations and dynamics
Single-molecule FRET (smFRET) studies often struggle with large parameter spaces. Here, the authors introduce an automated smFRET platform for multiwell plate screening of biomolecular conformations and dynamics.
- Andreas Hartmann
- , Koushik Sreenivasa
- & Michael Schlierf
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Article
| Open AccessA human lung alveolus-on-a-chip model of acute radiation-induced lung injury
Acute exposure to radiation can lead to acute pneumonitis, fibrosis or death. Here the authors develop an alveolus-on chip model to study the molecular characteristics of radiation induced lung injury, better understand radiation induced lung disease and facilitate drug screening.
- Queeny Dasgupta
- , Amanda Jiang
- & Donald E. Ingber
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Article
| Open AccessMolecular landscape and functional characterization of centrosome amplification in ovarian cancer
The prevalence of centrosome amplification (CA) and the genomic landscape of chromosomal instability in high-grade serous ovarian carcinoma (HGSOC) remain to be explored. Here the authors suggest CA as a potential driver of tumour evolution and a biomarker for treatment response in HGSOC.
- Carolin M. Sauer
- , James A. Hall
- & James D. Brenton
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Article
| Open AccessAutomated imaging and identification of proteoforms directly from ovarian cancer tissue
Identification of tissue proteoforms by top-down mass spectrometry remains challenging. Here, the authors present AutoPiMS, a semi-automated multiplexed tandem mass spectrometry workflow for proteoform identification directly from tissue contexts.
- John P. McGee
- , Pei Su
- & Neil L. Kelleher
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Article
| Open AccessMitigating a TDP-43 proteinopathy by targeting ataxin-2 using RNA-targeting CRISPR effector proteins
TDP43 proteinopathies are a devastating group of neurodegenerative disorders. Here the authors show that RNA-targeting CRISPR effector proteins can be used to mitigate TDP-43 pathology when targeting ataxin-2, a modifier of TDP-43-associated toxicity, and apply this to a mouse model.
- M. Alejandra Zeballos C.
- , Hayden J. Moore
- & Thomas Gaj
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Article
| Open AccessChromatin organization drives the search mechanism of nuclear factors
Nuclear factors rapidly scan the genome for targets, but the role of nuclear organization in such search is uncharted. Here, by combining single molecule tracking of nuclear proteins with high resolution imaging of the nucleus, the authors investigate the search mechanism used by factors such as p53.
- Matteo Mazzocca
- , Alessia Loffreda
- & Davide Mazza
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Article
| Open AccessWidefield imaging of rapid pan-cortical voltage dynamics with an indicator evolved for one-photon microscopy
Genetically encoded voltage indicators need fast and large signals to allow widefield imaging of rapid neuronal activity. Here, the authors develop the indicator JEDI-1P and demonstrate pan-cortical voltage imaging and gamma-frequency tracking in awake mice in single trials.
- Xiaoyu Lu
- , Yunmiao Wang
- & François St-Pierre
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Article
| Open AccessShadow imaging for panoptical visualization of brain tissue in vivo
Brain morphology is complex, heterogenous and miniaturized—and notoriously difficult to visualize. Dembitskaya et al. show how fluorescence ‘shadow imaging’ gives detailed and comprehensive access to the cellular architecture of the mouse brain in vivo.
- Yulia Dembitskaya
- , Andrew K. J. Boyce
- & U. Valentin Nägerl
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Article
| Open AccessLarge-scale recording of neuronal activity in freely-moving mice at cellular resolution
Single-cell resolution recording from behaving mice requires either head fixation or attachment of a miniaturized device which may alter behavior. Here, the authors present a new recording method without mechanical restrictions on mouse movement.
- Aniruddha Das
- , Sarah Holden
- & Hod Dana
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Article
| Open AccessAsymmetric gating of a human hetero-pentameric glycine receptor
Despite essential roles in adult nervous systems, how heteromeric Cys-loop receptors work is unclear in the absence of an open state structure. Here, the authors report closed/open state structures and functional experiments, detailing an asymmetric gating mechanism driven by differing contributions from each subunit type.
- Xiaofen Liu
- & Weiwei Wang
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Article
| Open AccessCreating resistance to avian influenza infection through genome editing of the ANP32 gene family
In chickens, influenza A virus relies on host protein ANP32A. Here the authors use CRISPR/Cas9 to generate homozygous gene edited chickens containing two ANP32A amino acid substitutions that prevent viral polymerase interaction.
- Alewo Idoko-Akoh
- , Daniel H. Goldhill
- & Mike J. McGrew
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Article
| Open AccessDeep flanking sequence engineering for efficient promoter design using DeepSEED
Designing promoters with desired properties is crucial in synthetic biology. Here, authors introduce DeepSEED, an AI-aided flanking sequence optimisation framework which combines expert knowledge with deep learning techniques to efficiently design promoters in both eukaryotic and prokaryotic cells.
- Pengcheng Zhang
- , Haochen Wang
- & Xiaowo Wang
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Article
| Open AccessBone disease imaging through the near-infrared-II window
Skeletal disorders are commonly diagnosed by X-ray imaging, but the radiation limits its use. Here, the authors show that intravital NIR-II bone imaging is effective in diagnosis of a series of common bone diseases non-invasively in mice.
- Chao Mi
- , Xun Zhang
- & Dayong Jin
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Article
| Open AccessGLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics
Agonists of the glucagon-like peptide-1 receptor are used to treat diabetes and obesity. Here, Wright et al. investigate the subcellular location of the receptor’s signaling events and uncover associations between signaling profiles and adverse drug reactions.
- Shane C. Wright
- , Aikaterini Motso
- & Volker M. Lauschke
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Article
| Open AccessReversible photoregulation of cell-cell adhesions with opto-E-cadherin
Tools for high spatiotemporal control of cell-cell adhesions are lacking. Here, authors propose an optogenetic tool, opto-E-cadherin, that allows reversible control of E-cadherin-mediated cell-cell adhesions with blue light.
- Brice Nzigou Mombo
- , Brent M. Bijonowski
- & Seraphine V. Wegner
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Article
| Open AccessFluorescent sensors for imaging of interstitial calcium
The study of interstitial calcium remains challenging due to scarce methodology. Here, authors present ultra-low affinity genetically encoded fluorescent biosensors for monitoring calcium in intercellular spaces in living tissues.
- Ariel A. Valiente-Gabioud
- , Inés Garteizgogeascoa Suñer
- & Oliver Griesbeck
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Article
| Open AccessEstimating the contribution of CD4 T cell subset proliferation and differentiation to HIV persistence
The authors used mathematical modeling of human data to study how HIV persists despite suppressive antiretroviral therapy. They found that when latently infected CD4+ T cells proliferate or differentiate, they can create HIV DNA and passage it into other subsets. More mature CD4 cell subsets then clear HIV DNA faster.
- Daniel B. Reeves
- , Charline Bacchus-Souffan
- & Peter W. Hunt
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Article
| Open AccessReactivation of a somatic errantivirus and germline invasion in Drosophila ovaries
Yoth et al. report that some mobile retrovirus-like genetic elements, errantiviruses, pose a threat to genome integrity when reactivated in somatic gonadal tissue, showing that they can infect the oocyte and transpose into the germline genome.
- Marianne Yoth
- , Stéphanie Maupetit-Méhouas
- & Emilie Brasset
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Article
| Open AccessEfficient plant genome engineering using a probiotic sourced CRISPR-Cas9 system
In the field of plant genome engineering, new nucleases with improved editing efficiency and alterative PAM requirements are needed. Here, the authors report a probiotic sourced CRISPR-LrCas9 system with similar PAM requirement to Cas12a and show its high efficiencies in various genome editing applications.
- Zhaohui Zhong
- , Guanqing Liu
- & Yong Zhang
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Article
| Open AccessBiomolecular condensates modulate membrane lipid packing and hydration
Nano-environmental probes and advance imaging microscopy provide deep insight into protein phase separation and the interaction of condensates with membranes, revealing that wetting by condensates can modulate membrane lipid packing and hydration.
- Agustín Mangiarotti
- , Macarena Siri
- & Rumiana Dimova
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Article
| Open AccessGlobal mapping of RNA-chromatin contacts reveals a proximity-dominated connectivity model for ncRNA-gene interactions
Many types of RNAs are associated with chromatin. Here the authors identify chromatin-bound RNAs and their binding sites in human embryonic stem cells suggesting that most chromatin-associated RNAs act proximal to their encoding loci and single RNAs are unlikely to alter gene expression.
- Charles Limouse
- , Owen K. Smith
- & Aaron F. Straight
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Article
| Open AccessAll-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ
How ROS diffuse and are cleared between mitochondrial compartments governs oxidative stress and cell signaling. Here, authors map the kinetics of ROS dynamics using optogenetics and discover acute ROS transiently elongates mitochondria.
- Shon A. Koren
- , Nada Ahmed Selim
- & Andrew P. Wojtovich
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Article
| Open AccessFEAST: A flow cytometry-based toolkit for interrogating microglial engulfment of synaptic and myelin proteins
When and how microglia engulf synapses and myelin is still unclear. Here, the authors provide a suite of flow cytometry-based approaches to quantify engulfment, paving the way for high-throughput assessment of microglial function in health and disease.
- Lasse Dissing-Olesen
- , Alec J. Walker
- & Beth Stevens
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Article
| Open AccessPrevious infection with seasonal coronaviruses does not protect male Syrian hamsters from challenge with SARS-CoV-2
Here, the authors analysed immune response to two consecutive coronavirus infections and observed that hamsters infected with seasonal coronaviruses were not protected from COVID-19 despite cross-reactive antibodies. Antiviral and germinal center B cell responses were suppressed but not during SARS-CoV-2 variant infections.
- Magen E. Francis
- , Ethan B. Jansen
- & Alyson A. Kelvin
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Article
| Open AccessTracing immune cells around biomaterials with spatial anchors during large-scale wound regeneration
Skin scarring devoid of dermal appendages has unfavorable effects on aesthetic and physiological functions. Here, the authors present a treatment based on extracellular matrix scaffolds and perform multimodal analysis to highlight the role of Tregs recruited by the biomaterial in mitigating tissue fibrous by suppressing excessive inflammation.
- Yang Yang
- , Chenyu Chu
- & Yili Qu
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Article
| Open AccessDeep learning-enabled realistic virtual histology with ultraviolet photoacoustic remote sensing microscopy
Oncologic tumour resection is not fully accurate. Here the authors report a label-free virtual histological imaging method based on a non-contact, reflection-mode ultraviolet photoacoustic remote sensing and scattering microscope, combined with unsupervised deep learning using a cycle-consistent GAN.
- Matthew T. Martell
- , Nathaniel J. M. Haven
- & Roger J. Zemp
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Article
| Open AccessMaintenance of pluripotency-like signature in the entire ectoderm leads to neural crest stem cell potential
How the neural crest gains its pluripotency-like stem cell potential is unclear. Here, the authors show that the entire post-gastrula ectoderm maintains expression of pluripotency genes, leading to the high stem cell capacity in the neural crest.
- Ceren Pajanoja
- , Jenny Hsin
- & Laura Kerosuo
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Article
| Open AccessEpigenomic analysis of formalin-fixed paraffin-embedded samples by CUT&Tag
Conducting epigenomic studies on FFPE samples is traditionally challenging due to chromatin damage caused due to exposure to formaldehyde. Here, the authors show that an optimisation of their previous CUTAC method allows the production of high-resolution maps of regulatory elements from FFPE samples.
- Steven Henikoff
- , Jorja G. Henikoff
- & Eric C. Holland
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Article
| Open AccessSeasonal pigment fluctuation in diploid and polyploid Arabidopsis revealed by machine learning-based phenotyping method PlantServation
Long-term monitoring of plants in field fluctuating environments remains challenging. Here, the authors develop PlantServation, a machine learning-based phenotyping method, and estimate environmental and genotypic effects on the pigment anthocyanin content of diploid and polyploid Arabidopsis.
- Reiko Akiyama
- , Takao Goto
- & Kentaro K. Shimizu
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Article
| Open AccessmRNA vaccines encoding fusion proteins of monkeypox virus antigens protect mice from vaccinia virus challenge
The authors report mRNA vaccines encoding a fusion protein of MPXV A35R extracellular domain and full-length M1R and observe improved anti-M1R antibody response. The vaccines show enhanced active and passive protection in female mice challenged with a lethal dose of vaccinia virus.
- Fujun Hou
- , Yuntao Zhang
- & Xiaoming Yang
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Article
| Open AccessDistinct sub-second dopamine signaling in dorsolateral striatum measured by a genetically-encoded fluorescent sensor
Genetically encoded dopamine sensors have emerged as an alternative to voltammetry for in vivo dopamine measurements. Here, the authors compare these two methods directly, and document dopamine responses during Pavlovian conditioning across the striatum.
- Armando G. Salinas
- , Jeong Oen Lee
- & David M. Lovinger
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Article
| Open AccessSEPepQuant enhances the detection of possible isoform regulations in shotgun proteomics
Protein isoform quantification in shotgun proteomics is challenging due to the mapping of many peptides to multiple protein isoforms. Here, the authors present a computational method SEPepQuant and demonstrate its utility in revealing protein isoform level regulation in shotgun proteomics.
- Yongchao Dou
- , Yuejia Liu
- & Bing Zhang
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Article
| Open AccessA robust normalized local filter to estimate compositional heterogeneity directly from cryo-EM maps
Heterogeneity in structural biology data includes potentially valuable information about binding and dynamics. Here, the authors devise, validate and demonstrate a method to quantify local heterogeneity in 3D reconstructions.
- Björn O. Forsberg
- , Pranav N. M. Shah
- & Alister Burt
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Article
| Open AccessPlasma metabolomic profiles associated with mortality and longevity in a prospective analysis of 13,512 individuals
The metabolic alterations underpinning aging processes and mortality in humans are not well understood. Here, the authors show that differences in levels of nucleosides, amino acids, and several lipid subclasses can predict mortality and longevity.
- Fenglei Wang
- , Anne-Julie Tessier
- & Marta Guasch-Ferré
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Article
| Open AccessPolyamine detergents tailored for native mass spectrometry studies of membrane proteins
Native mass spectrometry of membrane proteins in commonly used detergents are not ideal for preserving non-covalent interactions. Here, the authors develop new detergents for native MS of intact membrane proteins, opening new opportunities to study membrane proteins in various detergents.
- Yun Zhu
- , Bo-Ji Peng
- & Arthur Laganowsky
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