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| Open AccessSingle-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology
The authors developed a framework for joint protein-metabolite profiling at the single-cell level in human tissue combining targeted multiplexed protein imaging and untargeted spatial metabolomics in a single pipeline.
- Thomas Hu
- , Mayar Allam
- & Ahmet F. Coskun
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Article
| Open AccessGNTD: reconstructing spatial transcriptomes with graph-guided neural tensor decomposition informed by spatial and functional relations
Reconstructing transcriptome-wide spatially-resolved gene expressions requires modelling nonlinear patterns and spatial structures in RNA profiling data. Here, authors introduce a graph-guided neural hierarchical tensor decomposition model that incorporates spatial and functional relations for the task.
- Tianci Song
- , Charles Broadbent
- & Rui Kuang
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Article
| Open AccessSingle-photon microscopy to study biomolecular condensates
The wide variety of cellular processes involving biomolecular condensation makes their quantification a challenging task. Here, the authors present an integrated platform based on single-photon microscopy to study complex biomolecular processes.
- Eleonora Perego
- , Sabrina Zappone
- & Giuseppe Vicidomini
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Comment
| Open AccessIs Protein BLAST a thing of the past?
Will protein structure search tools like AlphaFold replace protein sequence search with BLAST? We discuss the promises, using structure search for remote homology detection, and why protein BLAST, as the leading sequence search tool, should strive to incorporate structural information
- Ali Al-Fatlawi
- , Martin Menzel
- & Michael Schroeder
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Article
| Open AccessElucidation of the structural basis for ligand binding and translocation in conserved insect odorant receptor co-receptors
Insects rely on olfaction for behavior control. Recent structural studies of receptors provide insight into ligand binding. Here, the authors identify dynamic binding mechanism to Orco, explaining its high selectivity with insights in compound screening.
- Jody Pacalon
- , Guillaume Audic
- & Jérémie Topin
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Article
| Open AccessDeepRTAlign: toward accurate retention time alignment for large cohort mass spectrometry data analysis
Retention time (RT) alignment is a crucial step in large cohort proteomics and metabolomics studies. Here, the authors introduce DeepRTAlign, a deep learning tool for RT alignment that shows high identification sensitivity and quantitative accuracy.
- Yi Liu
- , Yun Yang
- & Cheng Chang
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Article
| Open AccessA minority of final stacks yields superior amplitude in single-particle cryo-EM
Here the authors develop an iterative particle sieving method called CryoSieve, demonstrating this method outperforms other cryo-EM particle sorting algorithms to reveal that most particles are unnecessary in final stacks.
- Jianying Zhu
- , Qi Zhang
- & Chenglong Bao
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Article
| Open AccessAmplified fluorogenic immunoassay for early diagnosis and monitoring of Alzheimer’s disease from tear fluid
Accurate diagnosis of Alzheimer’s disease in its earliest stage can prevent the disease and delay the symptoms. Here the authors identify a potential Alzheimer’s biomarker from tear fluid, and develop a nanoparticle-based immunoassay for its detection, demonstrating potential in Alzheimer’s diagnosis.
- Sojeong Lee
- , Eunjung Kim
- & Seungjoo Haam
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Article
| Open AccessThe separation pin distinguishes the pro– and anti–recombinogenic functions of Saccharomyces cerevisiae Srs2
Here the authors report that the main role of the protein Srs2 in homologous recombination is to remove Rad51 from single stranded DNA, rather than to drive synthesis-dependent strand annealing.
- Aviv Meir
- , Vivek B. Raina
- & Eric C. Greene
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Article
| Open AccessShuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo
Gene editing strategies for cystic fibrosis are challenging. Here the authors improve on their previously reported shuttle peptide noncovalently combined with Cas ribonucleoprotein (RNP), and derive the S315 peptide for delivery: they show base editing in the respiratory tract of the rhesus macaques.
- Katarina Kulhankova
- , Soumba Traore
- & Paul B. McCray Jr.
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Article
| Open AccessBlazed oblique plane microscopy reveals scale-invariant inference of brain-wide population activity
Recording neuronal activity at cellular resolution across an entire adult vertebrate brain is challenging. Here, the authors develop a blazed oblique plane microscope to perform brain-wide activity measurements in an adult vertebrate at high cellular resolution.
- Maximilian Hoffmann
- , Jörg Henninger
- & Benjamin Judkewitz
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Article
| Open AccessInteraction dynamics between innate and adaptive immune cells responding to SARS-CoV-2 vaccination in non-human primates
Innate immune responses to mRNA vaccines are less well understood than adaptive immunity. Here, the authors comprehensively characterize the innate and adaptive immune responses to mRNA-1273 vaccinations in rhesus macaques and show how the vaccine activates interactions among components of the two systems.
- Chaim A. Schramm
- , Damee Moon
- & Daniel C. Douek
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Article
| Open AccessAccurate de novo peptide sequencing using fully convolutional neural networks
De novo peptide sequencing allows the identification of peptides without requiring target databases. Here, the authors present PepNet, a convolutional neural network model for accurate de novo peptide sequencing that is capable of analysing large-scale proteomics data.
- Kaiyuan Liu
- , Yuzhen Ye
- & Haixu Tang
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Article
| Open AccessA multi-reservoir extruder for time-resolved serial protein crystallography and compound screening at X-ray free-electron lasers
Protein serial crystallography at X-ray free-electron lasers (XFELs) is a powerful technique for structure determination. Here, authors present a device for sample delivery designed to abate challenges to non-specialists allowing for compound screening.
- Maximilian Wranik
- , Michal W. Kepa
- & Jörg Standfuss
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Article
| Open AccessSpatial transcriptomics deconvolution at single-cell resolution using Redeconve
Computational deconvolution with single-cell RNA sequencing data as a reference is pivotal for interpreting spatial transcriptomics data. Here, authors present Redeconve, which improves the resolution by more than 100-fold with higher accuracy and speed.
- Zixiang Zhou
- , Yunshan Zhong
- & Xianwen Ren
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Article
| Open AccessDefining a core configuration for human centromeres during mitosis
The detailed 3D organization of human centromere components is unknown. Here, the authors use super-resolution microscopy to present a working model for a common core centromere structure.
- Ayantika Sen Gupta
- , Chris Seidel
- & Jennifer L. Gerton
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Article
| Open AccessA fungal plant pathogen discovered in the Devonian Rhynie Chert
Here, the authors describe a pathogenic fungus from a 400-million-year-old fossil plant from the Devonian Rhynie Chert in Scotland. They use advanced imaging methods to determine that the fungus belongs to the sac fungi, the most diverse group of Fungi today.
- Christine Strullu-Derrien
- , Tomasz Goral
- & David L. Hawksworth
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Article
| Open AccessCommon origin of sterol biosynthesis points to a feeding strategy shift in Neoproterozoic animals
Sterane molecular fossils are used to compliment evidence from the fossil record. Here, the authors use a molecular clock to explore the origins of the smt gene, tracing the loss of sterol synthesis to dietary shifts in animals at the end-Neoproterozoic.
- T. Brunoir
- , C. Mulligan
- & D. A. Gold
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Article
| Open AccessEngineered immunogens to elicit antibodies against conserved coronavirus epitopes
A pan-betacoronavirus vaccine will likely require the elicitation of antibodies against spike regions conserved across diverse coronaviruses. Here, authors computationally engineer and experimentally validate immunogens to elicit antibodies against two such spike regions.
- A. Brenda Kapingidza
- , Daniel J. Marston
- & Mihai L. Azoitei
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Article
| Open AccessiU-ExM: nanoscopy of organelles and tissues with iterative ultrastructure expansion microscopy
Current expansion microscopy approaches need further optimization to achieve the precision of nanoscopy techniques. Here, the authors develop an iterative ultrastructure expansion microscopy (iU-ExM) approach that achieves SMLM-level resolution.
- Vincent Louvel
- , Romuald Haase
- & Paul Guichard
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Article
| Open AccessIntegrating spatial and single-cell transcriptomics data using deep generative models with SpatialScope
Spatial transcriptomics (ST) is transforming tissue analysis but has limitations. Here, authors introduce SpatialScope, an integrated approach combining scRNA-seq and ST data using deep generative models, enabling comprehensive spatial characterisation at transcriptome-wide single-cell resolution.
- Xiaomeng Wan
- , Jiashun Xiao
- & Can Yang
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Article
| Open AccessPhenoSV: interpretable phenotype-aware model for the prioritization of genes affected by structural variants
Here, authors present PhenoSV, a phenotype-aware machine-learning model for the functional interpretation of various types of structural variants (SVs) and genes within or outside SVs, facilitating the extraction of biological insights from coding and noncoding SVs.
- Zhuoran Xu
- , Quan Li
- & Kai Wang
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Article
| Open AccessTemporal morphogen gradient-driven neural induction shapes single expanded neuroepithelium brain organoids with enhanced cortical identity
PSC-brain organoids are typically formed by static medium switches. Here, authors show that a temporal morphogen gradient during neural induction allows the formation of well-specified cortical organoids with a self-organized single neuroepithelium.
- Anna Pagliaro
- , Roxy Finger
- & Benedetta Artegiani
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Article
| Open AccessLabel-free identification of protein aggregates using deep learning
The authors use deep learning to detect and segment unlabeled and unaltered protein aggregates in living cells from transmitted-light images. The method provides a way to quantitatively study protein aggregation dynamics in a simple, fast and accurate way.
- Khalid A. Ibrahim
- , Kristin S. Grußmayer
- & Aleksandra Radenovic
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Article
| Open AccessAncient diversity in host-parasite interaction genes in a model parasitic nematode
Host-parasite interactions can lead to negative frequency-dependent selection. Here, the authors sequence the genomes of H. bakeri and H. polygyrus, parasites of house and wood mice, respectively, and find that proteins that interact with the host immune response are often highly diverse.
- Lewis Stevens
- , Isaac Martínez-Ugalde
- & Mark Blaxter
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Article
| Open AccessDiscovery and remodeling of Vibrio natriegens as a microbial platform for efficient formic acid biorefinery
Formic acid (FA) is a promising CO2-equivalent feedstock for onecarbon biorefinery, but microbial host that can efficiently utilize FA is unavailable. Here, the authors engineer a non-native closed loop in Vibrio natriegens and demonstrate its application in promoting FA utilization.
- Jinzhong Tian
- , Wangshuying Deng
- & Yang Gu
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Article
| Open AccessSis2 regulates yeast replicative lifespan in a dose-dependent manner
Using a microfluidic single-cell aging platform, the authors report how single-cell lifespan varies across more than 300 yeast strains, each missing a single gene. Their top hit, Sis2, was found to regulate yeast lifespan in a dose-dependent fashion.
- Tolga T. Ölmez
- , David F. Moreno
- & Murat Acar
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Article
| Open AccessFragment-sequencing unveils local tissue microenvironments at single-cell resolution
Experimentally preserving tissue microenvironments remains challenging for single-cell sequencing methods. Here, the authors introduce fragment-sequencing, a method that can preserve three-dimensional microenvironments in single-cell RNA-seq, thus allowing the reconstruction of spatial tissue niches.
- Kristina Handler
- , Karsten Bach
- & Andreas E. Moor
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Article
| Open AccessThree-dimensional surface motion capture of multiple freely moving pigs using MAMMAL
3D social movement capture of large-size mammals is essential for agriculture and life science yet challenging. Here, the authors introduce MAMMAL, an algorithm to enable surface motion captures of multiple freely moving animals and quantitative behaviour measurement in a non-invasive manner.
- Liang An
- , Jilong Ren
- & Yebin Liu
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Article
| Open AccessParabacteroides distasonis ameliorates insulin resistance via activation of intestinal GPR109a
Here, the authors show that the gut commensal Parabacteroides distasonis alleviates insulin resistance via nicotinic acid-intestinal GPR109a axis activation, a process promoted by Dendrobium officinale polysaccharide.
- Yonggan Sun
- , Qixing Nie
- & Shaoping Nie
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Article
| Open AccessImproved in situ characterization of protein complex dynamics at scale with thermal proximity co-aggregation
Vast majority of cellular activities are carried out by protein complexes that assembled dynamically in response to cellular needs and environmental cues. Here, the authors present Slim-TPCA, an effective and readily deployable strategy to unravel the functional roles of protein complexes en masse across various cellular processes.
- Siyuan Sun
- , Zhenxiang Zheng
- & Chris Soon Heng Tan
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Article
| Open AccessDeep topographic proteomics of a human brain tumour
Ultrasensitive, spatially-resolved proteomics techniques allow mapping the organisation of healthy and diseased tissues. Here, the authors develop a workflow for spatially-resolved, quantitative tissue proteomics with spatially aware statistics and clustering, with which they characterise a human atypical teratoid-rhabdoid tumour at different spatial resolutions.
- Simon Davis
- , Connor Scott
- & Roman Fischer
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Article
| 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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