Cell Reports Methods

Cell Reports Methods

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A multi-disciplinary, gold #OA journal publishing cutting-edge methodological advances. @cellpress.bsky.social

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Cell Reports Methods
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Standardizing spatial transcriptomic analysis for infectious diseases with STID

dlvr.itStandardizing spatial transcriptomic analysis for infectious diseases with STIDQin et al. present STID, a standardized framework for analyzing spatial transcriptomic data in infectious diseases. STID integrates pathogen detection with spatial characterization of host responses, enabling systematic identification and comparison of infection-associated spatial niches across diverse datasets.
Cell Reports Methods
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mChIP-seq for multiplex epigenomic profiling uncovers cancer-specific histone features in cellular and circulating nucleosomes

dlvr.itmChIP-seq for multiplex epigenomic profiling uncovers cancer-specific histone features in cellular and circulating nucleosomesSun et al. develop mChIP-seq, an epigenomic profiling technology that enables multiplexed and multifactorial ChIP for both cellular and cell-free samples. They demonstrate the technology by profiling cancer-specific features of histone marks in cancer cells and in plasma cell-free nucleosomes from breast cancer patients.
Cell Reports Methods
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Apus enables automated end-to-end analysis and quality control of large-cohort proteomics data

dlvr.itApus enables automated end-to-end analysis and quality control of large-cohort proteomics dataLarge-cohort proteomics is hindered by fragmented workflows that separate data acquisition, analysis, and quality control. Cai et al. present Apus, an end-to-end solution that integrates these processes, enabling proactive quality management and automated analysis from raw mass spectrometry data to biological interpretation.
Cell Reports Methods
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Acute in vivo proximity labeling for membrane-targeted proteomics in neuronal circuits

dlvr.itAcute in vivo proximity labeling for membrane-targeted proteomics in neuronal circuitsThere are limited tools for capturing subcellularly defined proteomes in the brains of awake animals at behaviorally relevant timescales. Anguiano et al. engineered a membrane-targeted TurboID and optimized a labeling strategy allowing a 1- to 2-h protein-tagging window in neuronal cell bodies and in axon terminals to identify proteins enriched in each compartment.
Cell Reports Methods
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Automated cross-session ROI tracking for multicellular calcium imaging with OPTIC

dlvr.itAutomated cross-session ROI tracking for multicellular calcium imaging with OPTICTracking the same cells across imaging sessions is a major bottleneck in longitudinal calcium imaging. Fukatsu et al. develop OPTIC, an accessible, no-code toolbox that combines image registration with optimal-transport matching to track neurons, astrocytes, boutons, and microglia across sessions with higher accuracy than existing tools.
Cell Reports Methods
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Mycobacterium tuberculosis gene expression dynamics in host environments with single-cell resolution

dlvr.itMycobacterium tuberculosis gene expression dynamics in host environments with single-cell resolutionAylan et al. develop a reporter system for Mycobacterium tuberculosis (Mtb) that enables visualization of bacterial gene expression. Their results show that Mtb exhibits diverse gene expression patterns within immune cells during infection and that these patterns are influenced by the intracellular environments to which the bacteria are exposed.
Cell Reports Methods
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High-throughput, amplification-free detection of endogenous gene expression perturbations via fluorescence anisotropy

dlvr.itHigh-throughput, amplification-free detection of endogenous gene expression perturbations via fluorescence anisotropyHigh-throughput gene expression detection assays involve high costs and technological barriers, while gene reporter assays measure only promoter activity. Here, Wei et al. describe CFAR, an accessible, amplification-free, high-throughput method for endogenous gene expression detection. CFAR chemical screening reveals FDA-approved drugs targeting oncogene MYC expression in colorectal cancer cells.
Cell Reports Methods
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In vivo electrophysiology in head-fixed and freely moving mole-rats

dlvr.itIn vivo electrophysiology in head-fixed and freely moving mole-ratsShirdhankar et al. establish a method to record from single neurons in the brain of African mole-rats while they are head-fixed or freely moving, performing natural behaviors. The method allows the study of sensory perception and neural adaptations of these strictly subterranean rodents, well known for their longevity, cancer resistance, and magnetic sense.
Cell Reports Methods
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stFormer integrates spatial ligand signaling into a foundation model for spatial transcriptomics

dlvr.itstFormer integrates spatial ligand signaling into a foundation model for spatial transcriptomicsCao et al. present stFormer, a spatial transcriptomic foundation model that integrates intracellular context with spatial ligand signaling. stFormer improves cell- and gene-level analyses compared with a single-cell foundation model and enables in silico perturbation to investigate spatial ligand signaling responses.
Cell Reports Methods
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SurpHer: A genetically encoded ratiometric biosensor for dynamic extracellular pH imaging

dlvr.itSurpHer: A genetically encoded ratiometric biosensor for dynamic extracellular pH imagingHolste, Dos Santos, et al. develop SurpHer, a genetically encoded ratiometric biosensor for imaging extracellular pH at the surface of living cells. Through modular screening, they develop a membrane-localized SEpHluorin-mKate2 sensor that reports dynamic pH changes across physiological ranges. Stable SurpHer expression enables longitudinal visualization of extracellular pH gradients in a microfluidic pH gradient.
Cell Reports Methods
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A single ROSA26 mouse line for robust tdTomato labeling with Cre, FLP, Dre, Vika, SCre, and VCre recombinases

dlvr.itA single ROSA26 mouse line for robust tdTomato labeling with Cre, FLP, Dre, Vika, SCre, and VCre recombinasesNakashiba et al. engineer a multi-recombinase reporter mouse line, ROSA26-6R, consolidating responsiveness to six recombinases into a single locus. This platform minimizes colony management effort while providing robust tdTomato labeling for antibody-free 3D whole-embryo imaging and fine neural structure visualization.
Cell Reports Methods
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Self-supervised missing-wedge correction enables accurate cellular morphology and volume reconstruction in soft X-ray tomography

dlvr.itSelf-supervised missing-wedge correction enables accurate cellular morphology and volume reconstruction in soft X-ray tomographyChueh et al. present a self-supervised sinogram inpainting framework to correct missing-wedge artifacts in soft X-ray tomography. By recovering unrecorded projection angles without ground-truth data, the model effectively restores cellular morphology and improves the volumetric quantification of complex structures like malaria hemozoin crystals.
Cell Reports Methods
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Intravital 3-photon microscopy of leukocyte dynamics in the splenic white pulp

dlvr.itIntravital 3-photon microscopy of leukocyte dynamics in the splenic white pulpSchienstock et al. present a technical framework using surgical preparation of the mouse spleen, intravital 3-photon microscopy, and quantitative image analysis to interrogate in vivo leukocyte dynamics in the splenic white pulp. This method facilitates the investigation of cellular behaviors that underpin spleen biology in health and disease.
Cell Reports Methods
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A knockin Ntsr1Flp driver enables intersectional and systemic targeting of heterogeneous midbrain dopamine circuits

dlvr.itA knockin Ntsr1Flp driver enables intersectional and systemic targeting of heterogeneous midbrain dopamine circuitsGarcia et al. develop intersectional viral-genetic approaches to access molecularly overlapping dopamine and non-dopaminergic neuron subtypes in the mouse midbrain. Their strategy enables selective targeting of dopaminergic populations and reveals a previously unrecognized non-dopaminergic cell type distributed within the substantia nigra and ventral tegmental area.
Cell Reports Methods
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HisTrader identifies nucleosome-free regions within ChIP-based profiling of histone post-translational modifications

dlvr.itHisTrader identifies nucleosome-free regions within ChIP-based profiling of histone post-translational modificationsKirbizakis et al. develop HisTrader, a tool that pinpoints the short stretches of accessible DNA, where regulatory proteins bind, from widely available histone modification data. HisTrader enables the identification of the active transcription factors and prioritization of disease-associated genetic variants without additional experiments to map open chromatin.
Cell Reports Methods
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Revealing therapeutic single-cell transcriptomic signatures using a simple classifier

dlvr.itRevealing therapeutic single-cell transcriptomic signatures using a simple classifierGene-expression-based drug screening usually requires at least 50–100 copies of the same clone or cells treated in the same way. Ma et al. describe a single-cell analysis platform that enables the detection of therapeutically relevant transcriptomic signatures at a single-replicate level. This supports highly multiplexed single-cell drug discovery.
Cell Reports Methods
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Development and application of nbLIBRA-seq for high-throughput discovery of antigen-specific nanobodies

dlvr.itDevelopment and application of nbLIBRA-seq for high-throughput discovery of antigen-specific nanobodiesLeonard et al. present LIBRA-seq for nanobody discovery (nbLIBRA-seq), a method for rapidly screening and discovering antigen-specific nanobodies in alpaca. The approach increases the throughput and efficiency of nanobody discovery by screening for multiple antigens in the same library. With a single blood sample from a vaccinated alpaca, hundreds to thousands of antigen-specific heavy-chain-expressing B cells can be recovered and analyzed for B cell receptor sequences.
Cell Reports Methods
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Moving beyond linear summation to infer interaction order from neural and biological dynamics

dlvr.itMoving beyond linear summation to infer interaction order from neural and biological dynamicsBiological networks can involve interactions among more than two components, but detecting them from dynamics is difficult. Altshuler et al. introduce a recurrent network framework that compares models at matched capacity to infer whether observed trajectories are best explained by pairwise, three-body, or mixed interactions across biological systems.
Cell Reports Methods
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Self-amplifying RNA enables rapid, durable, integration-free programming of hiPSCs

dlvr.itSelf-amplifying RNA enables rapid, durable, integration-free programming of hiPSCsSelf-amplifying RNAs (saRNAs) have the potential for rapid, durable, non-integrating delivery of transgenes in human induced pluripotent stem cells. Della Santina et al. show that transcription factors and reporters expressed from saRNA are present for multiple weeks, supporting forward programming to neurons and tracking electrophysiological properties in 3D cardiac spheroids.
Cell Reports Methods
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Parallelized bright-field and fluorescence imaging platform for organoids

dlvr.itParallelized bright-field and fluorescence imaging platform for organoidsKim et al. present a multi-camera array scanner (MCAS) that uses 48 parallel lenses to image organoids. The MCAS reduces acquisition time by 98% compared to commercial systems. The platform enables rapid, automated phenotyping of growth, drug response, and viral transduction in 2D and 3D neural cultures.
Cell Reports Methods
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highSpaClone enables copy number alteration inference and tumor subclone analysis for high-resolution spatial transcriptomics

dlvr.ithighSpaClone enables copy number alteration inference and tumor subclone analysis for high-resolution spatial transcriptomicsZang et al. present highSpaClone, a computational framework for inferring copy number alterations (CNAs) and tumor subclones from high-resolution spatially resolved transcriptomics (SRT) data. By integrating gene expression with spatial information, highSpaClone enables the study of tumor evolution and uncovers early genomic changes in surrounding tissues.
Cell Reports Methods
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Cryoprotectants-assisted plunge freezing of thick brain tissue specimens for targeted physiologically relevant cryo-imaging in situ

dlvr.itCryoprotectants-assisted plunge freezing of thick brain tissue specimens for targeted physiologically relevant cryo-imaging in situWeier et al. demonstrate applicability of plunge-freezing for mammalian brain tissue vitrification in the presence of physiologically appropriate cryoprotectant-containing solutions. Subsequent fluorescence-guided cryoelectron tomography and cryo-volume electron microscopy imaging reveal unperturbed tissue morphology and present plunge-freezing as a viable vitrification approach for thicker brain specimens.
Cell Reports Methods
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A morphology-driven workflow to decipher 3D electron microscopy segmentation in diatoms

dlvr.itA morphology-driven workflow to decipher 3D electron microscopy segmentation in diatomsUwizeye et al. present an AI framework that segments whole-cell 3D electron microscopy volumes accurately using little training data and ordinary computers. By replacing laborious manual tracing, it makes large-scale comparison of microbial cell architecture faster, more reproducible, and more accessible.
Cell Reports Methods
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Causal assessment of Bayesian gene regulatory networks from single-cell transcriptomics

dlvr.itCausal assessment of Bayesian gene regulatory networks from single-cell transcriptomicsSato et al. present scstruc, an R package for learning and evaluating directed gene regulatory networks from single-cell transcriptomic data. By combining Bayesian network structure learning, causal-structure metrics, reference-free validation, and marker arc analysis, scstruc supports method selection and interpretation of condition-associated regulatory changes.
Cell Reports Methods
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Multimodal alignment improves generalizability of genomic biomarker prediction in computational pathology

dlvr.itMultimodal alignment improves generalizability of genomic biomarker prediction in computational pathologyRedekop et al. present MARBLE, a multimodal contrastive pretraining approach for histology and genetic biomarker alignment. Fine-tuning the image-only module, using a real-world cohort of MSK-IMPACT samples, the authors demonstrate data-efficient biomarker prediction.
Cell Reports Methods
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A deep learning framework for oligopeptide candidate discovery across metabolism-related contexts

dlvr.itA deep learning framework for oligopeptide candidate discovery across metabolism-related contextsXiao et al. present Deepeptide, a deep learning-based pipeline for identifying oligopeptide leads without requiring indication-specific training data. By linking disease-related information, biological processes, and molecular functions, Deepeptide identifies candidate oligopeptides across multiple metabolism-related contexts, supporting broader AI-assisted peptide lead discovery.
Cell Reports Methods
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Engineering lymphatic collecting vessel phenotypes through combined hyaluronic acid cues and oscillatory shear stress

dlvr.itEngineering lymphatic collecting vessel phenotypes through combined hyaluronic acid cues and oscillatory shear stressTo advance lymphatic vessel engineering, Lightsey at el. develop a microfluidic device-based approach that integrates physiologically relevant extracellular matrix cues with oscillatory shear stress. Using human lymphatic endothelial cells cultured on dopamine-modified hyaluronic acid or fibronectin, this approach reveals how the matrix-flow interactions drive mechanotransduction, collecting vessel specification, and lymphatic morphogenesis.
Cell Reports Methods
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Spatially resolved synaptic connectome mapping with FISH-decodable CASS barcodes

dlvr.itSpatially resolved synaptic connectome mapping with FISH-decodable CASS barcodesDissociation-based viral tracing loses neuronal spatial data, while EM and in situ sequencing are costly. Zhu et al. present FISH-detectable CASS barcodes with rabies monosynaptic tracing to capture anatomically intact synaptic connections. Accessible on routine imaging systems, the platform reveals layer-specific visual circuit wiring and works with other spatial profiling assays.
Cell Reports Methods
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Image-guided alignment of consecutive multi-modal tissue slides

dlvr.itImage-guided alignment of consecutive multi-modal tissue slidesManzato et al. develop COAST, a method to physically register images from consecutive tissue sections, enabling reliable downstream multi-modal analysis. Applying COAST to Stereo-seq and MALDI-MSI, the authors map the transcriptional and metabolic changes associated with kidney regeneration in an ischemia-reperfusion injury mouse model.
Cell Reports Methods
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A multiplex genome editing pipeline for rapid combinatorial trait engineering

dlvr.itA multiplex genome editing pipeline for rapid combinatorial trait engineeringChen and Coquelin et al. present a multiplex genome editing workflow capable of generating highly modified mice with complex traits within a single generation. By combining editing modalities, this approach enables up to eleven simultaneous genomic modifications to advance the scale of genetically modified mouse models.
Cell Reports Methods
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CaptureBody enables accurate unmixing for spectral flow cytometry

dlvr.itCaptureBody enables accurate unmixing for spectral flow cytometryTo address challenges associated with single-stain controls for spectral flow cytometry, Zambidis et al. design a bispecific antibody, termed CaptureBody, that binds to all leukocytes and then captures fluorescent-conjugated antibodies. CaptureBodies enable cell-based controls independent of the original antibody’s epitope and produce unmixing comparable to directly labeled cells.
Cell Reports Methods
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Improving computational tumor ploidy estimation in complex cancer genomes through flow-cytometry-guided calibration

dlvr.itImproving computational tumor ploidy estimation in complex cancer genomes through flow-cytometry-guided calibrationButters et al. show that sequencing-based estimates of tumor DNA content can be incorrect in genomically complex cancers, distorting interpretation of genome doubling and cancer-gene copy number. Flow cytometry of archival FFPE tissues provides a practical experimental reference, improving genomic analysis and revealing hidden genome doubling in genomically “quiet” sarcomas.
Cell Reports Methods
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Deep mapping of structural perturbations to energetics enables precise TCR design

dlvr.itDeep mapping of structural perturbations to energetics enables precise TCR designLuo et al. present mpTCRai, a deep learning framework for predicting TCR-antigen specificity. By mapping sequence mutations to structural perturbations and energetic consequences, mpTCRai serves as a computational pre-filtering engine to narrow down vast mutational spaces, guiding and accelerating the rational design of TCRs.
Cell Reports Methods
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Inference of lineage hierarchies, growth, and drug response mechanisms in cancer cell populations without tracking

dlvr.itInference of lineage hierarchies, growth, and drug response mechanisms in cancer cell populations without trackingPiras et al. present a statistical framework to infer lineage hierarchies and phenotypic transition probabilities in heterogeneous cell populations without tracking individual cells. Using multi-type Bienaymé-Galton-Watson branching processes, the method reconstructs growth, plasticity, drug-response mechanisms, and LGR5/KRT20 dynamics in colorectal cancer tumoroids from cell-state abundance data.
Cell Reports Methods
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Calibrated simulations for dynamic focusing of ultrasound through the temporal window

dlvr.itCalibrated simulations for dynamic focusing of ultrasound through the temporal windowFocused ultrasound can target deep brain regions but predicted and delivered pressures often diverge. Dadgar-Kiani et al. introduce a practical calibration framework based on sparse measurements and optimized skull attenuation that reduces this mismatch, enabling safer personalized transcranial ultrasound.
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A sensitive method for profiling cell-type-specific secretomes of rare cells from complex tissues

dlvr.itA sensitive method for profiling cell-type-specific secretomes of rare cells from complex tissuesShipkovenska et al. present an improved method for profiling cell-type-specific secretomes in complex tissues without the use of viral vectors. The authors perform proof-of-principle validation by profiling the secretomes of two rare cell types with innate immune functions: liver Kupffer cells and airway microfold cells.
Cell Reports Methods
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A scalable microarrayed organoid platform for precision modeling of intestinal epithelial damage and recovery

dlvr.itA scalable microarrayed organoid platform for precision modeling of intestinal epithelial damage and recoveryMeyer et al. present a microarrayed human intestinal organoid platform for longitudinal, single-organoid analysis of cytokine-induced epithelial injury and recovery. The study introduces IORS to quantify epithelial restitution and applies the platform to benchmark bioactives that support barrier recovery under controlled inflammatory stress.
Cell Reports Methods
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Deep learning-driven multiplexed mycotoxin detection via color-size encoded microbead imaging

dlvr.itDeep learning-driven multiplexed mycotoxin detection via color-size encoded microbead imagingLin et al. develop a color-size two-dimensional (2D)-encoded single-microbead imaging platform for the homogeneous analysis of four mycotoxins. By incorporating the YOLOv11 deep learning model to enable rapid data processing, the method offers a strategy for high-throughput food safety screening.
Cell Reports Methods
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Dye-cycling DNA origami rotors for long-term tracking of transcription at base-pair resolution

dlvr.itDye-cycling DNA origami rotors for long-term tracking of transcription at base-pair resolutionWacker et al. present dcORBIT, a single-molecule fluorescence method based on DNA origami rotors that uses dye cycling to enable long-term measurement of DNA rotation at base-pair resolution. dcORBIT extends our toolkit to study molecular rotation and is here used to reveal molecular variability during transcription by E. coli RNAPs.
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Modeling microbiome modulation of tumor metabolic networks to predict synergistic therapies

dlvr.itModeling microbiome modulation of tumor metabolic networks to predict synergistic therapiesBadenoch et al. develop a machine learning and metabolic modeling framework that predicts how gut microbes alter colorectal cancer drug response. The model identifies unintuitive drug-microbe synergies and their mechanisms, generalizing across microbial species and treatment modalities, including immunotherapy, to enable microbiome-informed combination therapy.
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AAV-DJ enables efficient, function-preserving neuronal transduction for circuit interrogation in human cortical and thalamic organoids

dlvr.itAAV-DJ enables efficient, function-preserving neuronal transduction for circuit interrogation in human cortical and thalamic organoidsAdachi et al. systematically benchmark AAV capsids in human cortical and thalamic organoids by integrating gene delivery, cell type tropism, cytotoxicity, and neuronal function. By identifying AAV-DJ as a low-toxicity, function-preserving vector, this study offers a practical platform for imaging, manipulating, and tracing human neural circuits in vitro.
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SwitchClass distinguishes baseline- and perturbation-aligned features across intermediate molecular states

dlvr.itSwitchClass distinguishes baseline- and perturbation-aligned features across intermediate molecular statesXiao et al. present SwitchClass, a label-switch classification framework that scores whether molecular features in intermediate states align with baseline or perturbation. Across proteomic, phosphoproteomic, and single-cell transcriptomic datasets, SwitchClass reveals recovered and persistent molecular programs after cancer treatment, dietary reversal, and COVID-19.
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Mesenchymal stem cell-derived liver-on-a-chip reconstitutes human liver structure and function

dlvr.itMesenchymal stem cell-derived liver-on-a-chip reconstitutes human liver structure and functionBrooks et al. report a human MSC-derived liver-on-a-chip integrating endothelial cells, hepatocytes, and cholangiocytes from a single donor source. The platform reconstructs the sinusoidal, hepatic, and biliary compartments, supports hepatic uptake and biliary excretion, and models ischemic liver injury with therapeutic cell recruitment for personalized therapy and liver research.
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Strategic enhancement of Cas9 nickase-driven gene amplification

dlvr.itStrategic enhancement of Cas9 nickase-driven gene amplificationTakesue et al. enhance the nCas9-based gene amplification method BITREx through the development of (1) a plasmid reporter that predicts gRNA performance and (2) BITREx 2.0, a dual-nicking strategy that exploits synergistic interactions between two gRNAs. These advances broaden the utility of BITREx for gene amplification applications.
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Volumetric denoising enables high-throughput volume electron microscopy and efficient downstream analysis

dlvr.itVolumetric denoising enables high-throughput volume electron microscopy and efficient downstream analysisChen et al. determined the pivotal role of sufficient axial resolution in maintaining data quality of volume electron microscopy despite varying image signal-to-noise ratios and developed a volumetric denoising algorithm. Volumetric denoising enables finer serial block-face cutting and improves organelle and synapse segmentation accuracy.