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| Open AccessA lineage-resolved cartography of microRNA promoter activity in C. elegans empowers multidimensional developmental analysis
By tracing promoter expression in lineage-mapped single cells, Xu et al. present a whole-body cartography of microRNA transcriptional activities during C. elegans embryogenesis and demonstrate its broad utility in multifaceted functional analyses.
- Weina Xu
- , Jinyi Liu
- & Zhuo Du
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Article
| Open AccessTime-integrated BMP signaling determines fate in a stem cell model for early human development
The interpretation of the key developmental signal BMP remains poorly understood. Here, the authors show that the total time-integrated signaling controls differentiation in a stem cell embryo model and provide a possible mechanism.
- Seth Teague
- , Gillian Primavera
- & Idse Heemskerk
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Article
| Open AccessEffect of aging on the human myometrium at single-cell resolution
Age-associated myometrial dysfunction can cause complications during pregnancy and labor. Here, the authors report that aging myometrium is characterized by diminished contractile capillary cells, altered gene expression, and disrupted cellular communication leading to impaired angiogenesis, increased fibrosis and inflammation.
- Paula Punzon-Jimenez
- , Alba Machado-Lopez
- & Aymara Mas
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| Open AccessMAPS: pathologist-level cell type annotation from tissue images through machine learning
Current cell annotation methods using high-plex spatial proteomics data are resource intensive and demand iterative expert input. Here, the authors present MAPS (Machine learning for Analysis of Proteomics in Spatial biology), an approach that facilitates rapid and precise cell type identification with human-level accuracy from spatial proteomics data.
- Muhammad Shaban
- , Yunhao Bai
- & Faisal Mahmood
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Article
| 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 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 AccessStochastic gene expression and environmental stressors trigger variable somite segmentation phenotypes
Mutations of several genes cause variable phenotypes. Here, the authors show stochastic her1 and her7 gene expression, which is affected by environmental conditions, underlies variability of somite segmentation defects.
- Kemal Keseroglu
- , Oriana Q. H. Zinani
- & Ertuğrul M. Özbudak
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Article
| Open AccessProteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis
Myelofibrosis is a form of myeloproliferative neoplasm with few treatment options available. Here, the authors profiled drug responses and proteomics ex vivo and identify molecularly-guided treatment strategies, including HDAC and BET inhibitors for CALR mutant myelofibrosis patients.
- Mattheus H. E. Wildschut
- , Julien Mena
- & Berend Snijder
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| 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 AccessThe intensities of canonical senescence biomarkers integrate the duration of cell-cycle withdrawal
Senescence and quiescence are considered different cell states but are hard to distinguish. Here, single-cell imaging followed by immunostaining reveals that the intensities of senescence biomarkers are graded rather than binary, reflecting the duration of cell-cycle withdrawal rather than irreversible cell-cycle arrest.
- Humza M. Ashraf
- , Brianna Fernandez
- & Sabrina L. Spencer
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Article
| Open AccessCellular state landscape and herpes simplex virus type 1 infection progression are connected
The heterogeneity of single cell responses during infection have been reported to influence disease outcome. Here, Pietilä et al characterize cellular heterogeneity during Herpes Simplex Virus 1 infection using a multimodal approach that resolves gene expression, proteomic and spatial details at the single cell level.
- Maija K. Pietilä
- , Jana J. Bachmann
- & Cornel Fraefel
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| Open AccessMacrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease
Chronic intestinal inflammatory diseases including ulcerative colitis and Crohn’s disease display extensive heterogeneity in the immunopathology, disease manifestation and response to treatment. Here the authors apply single cell transcriptomic and spatial molecular imaging, and characterise macrophage and neutrophils in samples from patients with inflammatory bowel diseases.
- Alba Garrido-Trigo
- , Ana M. Corraliza
- & Azucena Salas
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| Open AccessCellSighter: a neural network to classify cells in highly multiplexed images
Identification and classification of cells in multiplexed microscopy remain challenging. Here, the authors propose CellSighter, which uses neural networks to perform cell classification directly on multiplexed images, thus leveraging the spatial expression characteristics of proteins.
- Yael Amitay
- , Yuval Bussi
- & Leeat Keren
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| Open AccessDamage dynamics and the role of chance in the timing of E. coli cell death
To understand why genetically identical cells die at different times the authors measured damage dynamics in individual cells. They report lifespan variation comes not from initial conditions but from stochastic accumulation of damage that saturates repair systems.
- Yifan Yang
- , Omer Karin
- & Uri Alon
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Article
| Open AccessA Glb1-2A-mCherry reporter monitors systemic aging and predicts lifespan in middle-aged mice
Monitoring the aging process in vivo is challenging. Here the authors generate a Glb1+/m‒Glb1-2A-mCherry (GAC) reporter mouse model, where the GAC signal is consistently correlated with established biomarkers of cellular senescence, cardiac hypertrophy and shortened lifespan, which may prove helpful for studies developing anti-aging interventions.
- Jie Sun
- , Ming Wang
- & Baohua Liu
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| Open AccessRevealing β-TrCP activity dynamics in live cells with a genetically encoded biosensor
β-TrCP plays an important role in diverse cellular processes such as the cell cycle and inflammation. Here the authors develop a biosensor for β-TrCP activity and use it to investigate β-TrCP dynamics during the cell cycle, and to screen a small-molecule library for β-TrCP activators and inhibitors.
- Debasish Paul
- , Stephen C. Kales
- & Steven D. Cappell
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Article
| Open AccessIdentifying multicellular spatiotemporal organization of cells with SpaceFlow
A critical task in spatial transcriptomics analysis is to understand inherently spatial relationships among cells. Here, the authors present a deep learning framework to integrate spatial and transcriptional information, spatially extending pseudotime and revealing spatiotemporal organization of cells.
- Honglei Ren
- , Benjamin L. Walker
- & Qing Nie
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Article
| Open AccessFrequency modulation of a bacterial quorum sensing response
Quorum-sensing bacteria produce and secrete autoinducers that trigger a behavioral change in the population when reaching a certain threshold. Here, Bettenworth et al. show that autoinducer synthase gene expression in Sinorhizobium meliloti occurs in asynchronous stochastic pulses, and that physiological cues modulate pulse frequency and, consequently, response behavior dynamics. Frequency-modulated pulsing in autoinducer synthase gene expression thus represents a time-based mechanism for information integration and collective decision-making.
- Vera Bettenworth
- , Simon van Vliet
- & Anke Becker
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Article
| Open AccessDifferential regulation of alternative promoters emerges from unified kinetics of enhancer-promoter interaction
Alternative promoters differ in their expression patterns, whose mechanisms are not well understood. Here the authors show that alternative promoters of a Drosophila embryonic gene hunchback are regulated by different action modes of two enhancers.
- Jingyao Wang
- , Shihe Zhang
- & Heng Xu
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| Open AccessClusterMap for multi-scale clustering analysis of spatial gene expression
In situ transcriptomics maps RNA expression patterns across intact tissues taking our understanding of gene expression to a new level. Here, the authors present a computational method that uncovers gene expression, cell niche, and tissue region patterns from 2D and 3D spatial transcriptomics.
- Yichun He
- , Xin Tang
- & Xiao Wang
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| Open AccessStochastic pausing at latent HIV-1 promoters generates transcriptional bursting
The ability of HIV to alternate between acute and latent forms is thought to rely on a transcriptional feedback loop where polymerase pausing is released by the viral protein Tat. Here, the authors show that viral genome transcription can occur in a burst-like stochastic manner in the absence of Tat.
- Katjana Tantale
- , Encar Garcia-Oliver
- & Edouard Bertrand
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| Open AccessA distinct growth physiology enhances bacterial growth under rapid nutrient fluctuations
Here the authors use microfluidics and single-cell microscopy to quantify the growth dynamics of individual E. coli cells exposed to nutrient fluctuations with periods as short as 30 seconds, finding that nutrient fluctuations reduce growth rates up to 50% compared to a steady nutrient delivery of equal average concentration, implying that temporal variability is an important parameter in bacterial growth.
- Jen Nguyen
- , Vicente Fernandez
- & Roman Stocker
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| Open AccessClump sequencing exposes the spatial expression programs of intestinal secretory cells
Combining scRNA-seq with spatial information to enable the reconstruction of spatially-resolved cell atlases is challenging for rare cell types. Here the authors present ClumpSeq, an approach for sequencing small clumps of tissue attached cells, and apply it to establish spatial atlases for all secretory cell types in the small intestine.
- Rita Manco
- , Inna Averbukh
- & Shalev Itzkovitz
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Article
| Open AccessOvercoming the design, build, test bottleneck for synthesis of nonrepetitive protein-RNA cassettes
Phage-coat proteins can be used to build synthetic biology parts. Here the authors use an oligo library and machine learning to predict and verify sequences based on binding scores.
- Noa Katz
- , Eitamar Tripto
- & Roee Amit
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Article
| Open AccessEpigenetic modulation reveals differentiation state specificity of oncogene addiction
Epigenetic mechanisms associated with the differentiation state of cancer cells and their heterogeneity influence tumor responses to oncogene-targeted therapies. In this study, the authors perform an epigenetic compound screen and single-cell analysis in BRAF-mutant melanoma cells to identify compounds that block three distinct drug-tolerant epigenetic states associated with either one of the lysine-specific histone demethylases Kdm1a or Kdm4b, or BET proteins.
- Mehwish Khaliq
- , Mohan Manikkam
- & Mohammad Fallahi-Sichani
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Article
| Open AccessConstruction of intracellular asymmetry and asymmetric division in Escherichia coli
Establishing protein gradients for asymmetric cell division is fundamental across all kingdoms of life. Here the authors construct asymmetric cell division in E. coli by localizing the expression of RNA polymerase using an orthogonal unipolar scaffold, and restricting diffusion of its products.
- Da-Wei Lin
- , Yang Liu
- & Hsiao-Chun Huang
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| Open AccessNanoscopic subcellular imaging enabled by ion beam tomography
Secondary ion beam mass spectrometry (SIMS) is a method to obtain a chemical snapshot of biological tissue, but the spatial resolution is low. Here, the authors develop a computational and technology pipeline to localise a chemical signal in SIMS in 3D and sub-25 nm accuracy, called Ion Beam Tomography
- Ahmet F. Coskun
- , Guojun Han
- & Garry P. Nolan
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| Open AccessEmerging heterogeneous compartments by viruses in single bacterial cells
Here, the authors apply live-cell and in situ fluorescence imaging at the single-molecule level to examine lambda DNA replication in single cells, finding that individual phage DNAs sequester host factors to their own vicinity and confine their replicated DNAs into separate compartments, suggesting that phage decision-making transcripts are spatially organized in separate compartments to allow distinct subcellular decisions to develop.
- Jimmy T. Trinh
- , Qiuyan Shao
- & Lanying Zeng
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Article
| Open AccessSingle-particle imaging of stress-promoters induction reveals the interplay between MAPK signaling, chromatin and transcription factors
Mitogen-Activated Protein Kinases integrate extracellular information in all eukaryotic cells. Using a live mRNA reporter, here the authors monitor transcriptional bursting in Saccharomyces cerevisiae upon hyper-osmotic shock and characterize the influence of MAPK signalling, chromatin and transcription factors on the dynamics of transcription.
- Victoria Wosika
- & Serge Pelet
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| Open AccessLgr5+ telocytes are a signaling source at the intestinal villus tip
Epithelial gene expression has been shown to be zonated along the crypt-villus axis, but mechanisms shaping this spatial variability were unknown. Here, Bahar Halpern et al. uncover zonation of mesenchymal cells, including Lgr5+ telocytes, which regulate epithelial gene expression at the villus tip.
- Keren Bahar Halpern
- , Hassan Massalha
- & Shalev Itzkovitz
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Article
| Open AccessMitochondrial origins of fractional control in regulated cell death
Phenotypic cell-to-cell variability contributes to fractional killing, but the mechanisms are incompletely understood. Here the authors show that mitochondrial density correlates with cell survival in response to TRAIL, and that variable effective concentrations of Bax/Bak contribute to the effect.
- Luís C. Santos
- , Robert Vogel
- & Pablo Meyer
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| Open AccessEscherichia coli can survive stress by noisy growth modulation
Noisy gene expression leading to phenotypic variability can help organisms to survive in changing environments. Here, Patange et al. show that noisy expression of a stress response regulator, RpoS, allows E. coli cells to modulate their growth rates to survive future adverse environments.
- Om Patange
- , Christian Schwall
- & James C. W. Locke
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| Open AccessSingle-cell barcode analysis provides a rapid readout of cellular signaling pathways in clinical specimens
Diagnostic tests need optimization to avoid invasive and costly repeated biopsies. Here the authors present an antibody-DNA barcoding approach where harvested single cells can be re-stained through custom oligonucleotide-fluorophore conjugates, enabling multiplexed analysis of cancer pathways.
- Randy J. Giedt
- , Divya Pathania
- & Ralph Weissleder
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Article
| Open AccessDeconvolution of subcellular protrusion heterogeneity and the underlying actin regulator dynamics from live cell imaging
Cell protrusion dynamics are heterogeneous at the subcellular level, but current analyses operate at the cellular or ensemble level. Here the authors develop a computational framework to quantify subcellular protrusion phenotypes and reveal the underlying actin regulator dynamics at the leading edge.
- Chuangqi Wang
- , Hee June Choi
- & Kwonmoo Lee
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| Open AccessThe transcription-repair coupling factor Mfd associates with RNA polymerase in the absence of exogenous damage
The bacterial transcription-repair coupling factor Mfd displaces stalled RNA polymerase (RNAP) by promoting transcription termination at sites of DNA lesions. Here the authors find—using single molecule imaging in live Escherichia coli—that RNAP stalls frequently during transcription, and needs to be rescued by Mfd during normal growth.
- Han N. Ho
- , Antoine M. van Oijen
- & Harshad Ghodke
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| Open AccessMonitoring single-cell gene regulation under dynamically controllable conditions with integrated microfluidics and software
How gene regulatory pathways control cell fate decisions in single cells is not fully understood. Here the authors present an integrated dual-input microfluidic chip and a linked analysis software, enabling tracking of gene regulatory responses of single bacterial cells to changing conditions.
- Matthias Kaiser
- , Florian Jug
- & Erik van Nimwegen
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| Open AccessIntelligent image-based in situ single-cell isolation
The isolation of single cells while retaining context is important for quantifying cellular heterogeneity but technically challenging. Here, the authors develop a high-throughput, scalable workflow for microscopy-based single cell isolation using machine-learning, high-throughput microscopy and laser capture microdissection.
- Csilla Brasko
- , Kevin Smith
- & Peter Horvath
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| Open AccessNoise reduction as an emergent property of single-cell aging
Gene expression is a noisy process, but it is not known how noise in gene expression changes during the aging of single cells. Here the authors show that noise decreases during normal aging, and provide support for aging-associated increases in chromatin state transitions governing noise reduction.
- Ping Liu
- , Ruijie Song
- & Murat Acar
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Article
| Open AccessLight-sensing via hydrogen peroxide and a peroxiredoxin
While yeasts lack dedicated photoreceptors, they nonetheless possess metabolic rhythms responsive to light. Here the authors find that light signalling in budding yeast involves the production of H2O2, which in turn regulates protein kinase A through a peroxiredoxin-thioredoxin redox relay.
- Kristofer Bodvard
- , Ken Peeters
- & Mikael Molin
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| Open AccessCell fate decisions emerge as phages cooperate or compete inside their host
The bacteriophage lambda and its hostEscherichia coli provide a model system to study cell-fate decisions. Here, Trinh et al. develop a four-colour fluorescence system at the single-cell/single-virus/single-viral-DNA level and find phages cooperate during lysogenization and compete during lysis.
- Jimmy T. Trinh
- , Tamás Székely
- & Lanying Zeng
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Article
| Open AccessSingle-cell analysis and stochastic modelling unveil large cell-to-cell variability in influenza A virus infection
Cell-to-cell variability in viral infection means that cell population measurements may not be an accurate representation of the process. Using both experimental and modelling approaches the authors confirm this notion showing that influenza virus infections are variable processes affected by intrinsic and extrinsic noise.
- Frank S. Heldt
- , Sascha Y. Kupke
- & Timo Frensing
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| Open AccessHighly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method
Multiplexed single cell measurements provide insight into connections between cell state and phenotype. Here Lin et al.present CycIF, a high throughput, public domain immunofluorescence method for multiplexed single-cell analysis of adherent cells following live-cell imaging.
- Jia-Ren Lin
- , Mohammad Fallahi-Sichani
- & Peter K. Sorger