Cell Reports Methods

AAV vectors for specific and efficient gene expression in microglia Aoki et al. develop an AAV vector for highly specific and efficient gene expression in cortical microglia. By flanking WPRE with microRNA target sequences, they achieve >90% specificity and enable functional imaging of microglial Ca2+ dynamics. This vector also permits systemic delivery, facilitating broad access to microglia in vivo.

AAV vectors for specific and efficient gene expression in microglia

3D-printed plugs enhance cell usage efficiency for single-cell migration and neuron axon guidance assays Cheng et al. present a 3D-printed plug that significantly advances cell enrichment at microfluidic interfaces. By minimizing sample loss, the plug enables highly efficient low-input migration and axon guidance assays. Its versatile design supports both manual and automated workflows, offering a robust and scalable solution to improve experimental throughput and precision.

3D-printed plugs enhance cell usage efficiency for single-cell migration and neuron axon guidance assays

Genetic analyses of eight complex diseases using predicted continuous representations of disease Chen et al. demonstrate that machine learning-derived continuous disease phenotypes from electronic health records improve genetic discovery, drug target identification, and polygenic risk prediction for complex diseases. These phenotypes complement traditional case-control definitions and, when integrated using multi-trait analysis, uncover additional replicable genetic associations.

Genetic analyses of eight complex diseases using predicted continuous representations of disease

Recent advances and future prospects for blockchain in biomedicine In this review, Ni et al. discuss recent advancements in blockchain technology for biomedical data management, highlighting its potential for enhancing data privacy and security. They explore emerging solutions that could redefine data sharing and computation in healthcare, addressing current implementation challenges and future opportunities.

Recent advances and future prospects for blockchain in biomedicine

Volumetric imaging and computation to explore contractile function in zebrafish hearts Saberigarakani et al. introduce a technical framework that includes light-field microscopy, deconvolution-based reconstruction, deep-learning-based single-cell tracking, and an intuitive VR pipeline for the imaging and analysis of cardiac contractility at up to 200 vol/s with cellular resolution in live zebrafish larvae, enabling real-time 4D visualization and quantification of cardiomyocyte and blood cell dynamics.

Volumetric imaging and computation to explore contractile function in zebrafish hearts

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Combining panel-based and whole-transcriptome-based gene fusion detection by long-read sequencing Rybacki et al. present a combined targeted and whole-transcriptome long-read sequencing strategy, with a computational pipeline to detect gene fusions in clinical cancer samples. By adapting a short-read panel and analyzing panel-negative gliomas, they reveal both known and candidate novel fusions, highlighting the strengths of long-read technology for fusion discovery.

Combining panel-based and whole-transcriptome-based gene fusion detection by long-read sequencing

High-throughput measurement of Drosophila feeding behavior Zheng et al. present a microplate platform combining automated tracking and protein-based quantification that enables high-throughput, single-fly feeding assays in Drosophila. FlyPlate-BCA facilitates metabolic phenotyping, uncovering mating-state-specific protein responses and conserved lipid-driven satiety.

High-throughput measurement of Drosophila feeding behavior

An integrative assay for measuring social aversion and motivation in freely behaving mice Grammer et al. present SAUSI, a behavioral assay that measures social motivation, fear, and hesitancy in freely interacting mice. Using this assay, they show that prolonged social isolation induces social aversion and find distinct forms of social aversion induced by social vs. non-social stressors.

An integrative assay for measuring social aversion and motivation in freely behaving mice

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CUT&Tag and DiBioCUT&Tag enable investigation of the AT-rich epigenome of Plasmodium falciparum from low-input samples Gockel et al. present a version of the epigenomic profiling technique CUT&Tag adapted to the AT-rich genome of the deadly parasite Plasmodium falciparum. This low-input epigenomic profiling protocol enables studies of scarce sample types such as field isolates. Technical advances in coupling CUT&Tag with prior proximity biotinylation further increase the signal for (temporal) chromatin-associated factors.

CUT&Tag and DiBioCUT&Tag enable investigation of the AT-rich epigenome of Plasmodium falciparum from low-input samples

Joint processing of long- and short-read sequencing data with deep learning improves variant calling Gambardella shows that shallow short- and long-read sequencing combined with a retrained DeepVariant model improves small variant detection. This hybrid strategy offers a cost-effective alternative to deep single-tech sequencing and enables unified variant calling instead of post hoc merging across platforms.

Joint processing of long- and short-read sequencing data with deep learning improves variant calling

A fluorescent STING ligand sensor for high-throughput screening of compounds that can enhance tumor immunotherapy High-throughput screening of STING agonists remains challenging due to a lack of suitable tools. Sun et al. develop FiSL, a fluorescent STING ligand sensor, and discover honokiol as an orally available agonist for human and mouse STING. Honokiol demonstrates potent antitumor activity and enhances anti-PD-(L)1 efficacy.

A fluorescent STING ligand sensor for high-throughput screening of compounds that can enhance tumor immunotherapy

Dynamic stimulation promotes functional tissue-like organization of a 3D human lymphoid microenvironment model in vitro Three-dimensional (3D) in vitro modeling is opening the doors to high-quality ex vivo systems for the study of blood cancers and their interaction with the tissue microenvironment. Barozzi et al. develop a dynamic lymphoid-like model to study CLL physiopathology and show the advantages of the perfusion on 3D cell cultures.

Dynamic stimulation promotes functional tissue-like organization of a 3D human lymphoid microenvironment model in vitro

Deuterium labeling enables proteome-wide turnover kinetics analysis in cell culture Alamillo et al. present a D2O labeling mass spectrometry method to measure protein turnover rates that is compatible with multiple cell cultures and medium formulations. The method reveals a parsimonious protein turnover landscape in human induced pluripotent stem cells and identifies hyperdynamic proteins that are unique to self-renewal states.

Deuterium labeling enables proteome-wide turnover kinetics analysis in cell culture

Graft-seq precisely maps RNA modifications via site-specific chemical grafting strategy Li et al. present Graft-seq, a direct and enrichment-free technique for detecting RNA modifications at base resolution through chemical grafting. Graft-seq enables detection of internal and cap RNA modifications, including internal N6-methyladenosine (m6A) and cap N6,2′-O-dimethyladenosine (m6Am) as well as nicotinamide adenine dinucleotide (NAD), establishing a broad platform for profiling epitranscriptomes.

Graft-seq precisely maps RNA modifications via site-specific chemical grafting strategy

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TransTag enables simple and efficient transgene mapping in zebrafish via tagmentation Meng et al. develop a method called TransTag for simple and efficient mapping of Tol2-based transgenes in zebrafish. TransTag robustly identifies transgene insertion sites and offers an alignment-free Shiny app for data analysis, providing a valuable perspective for studies involving transgenic lines.

TransTag enables simple and efficient transgene mapping in zebrafish via tagmentation

Automated denoising of CITE-seq data with ThresholdR Oliaeimotlagh et al. present ThresholdR, a method to denoise ADT expression data from CITE-seq experiments. This approach offers improved cell-type annotation and performance when compared with other widely used methods.

Automated denoising of CITE-seq data with ThresholdR

Self-supervised learning for generalizable particle picking in cryo-EM micrographs Zamanos et al. introduce a self-supervised particle picking method for cryoelectron microscopy (cryo-EM) that overcomes the need for annotations. Leveraging masked autoencoders to learn micrograph features, the pipeline clusters pixels into particle or background classes, allowing for robust and accurate particle picking across diverse cryo-EM experiments.

Self-supervised learning for generalizable particle picking in cryo-EM micrographs

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TAS-seq enables subcellular single-stranded adenosine profiling by signal peptide-assisted adenosine deamination To study RNA structure in the cell, Wang et al. develop TAS-seq using the deaminase TadA-8e localized to subcellular compartments to enzymatically label single-stranded adenosine in RNA. This technique allows for the detection of local structural variations across compartments and RNA heterogeneity at the single-cell level.

TAS-seq enables subcellular single-stranded adenosine profiling by signal peptide-assisted adenosine deamination

Characterization of human CMV-specific CD8+ T cells using multi-layer single-cell omics Gemünd et al. present a multi-omics single-cell workflow that leverages sequencing-based dCODE dextramers to sensitively identify rare, antigen-specific T cells. This approach enables comprehensive characterization of human immune responses and provides a valuable resource for researchers studying T cell specificity and function in complex biological samples.

Characterization of human CMV-specific CD8+ T cells using multi-layer single-cell omics

A single-cell transposable element atlas of human cell identity Reyes-Gopar et al. introduce Stellarscope, a computational approach for quantifying locus-specific transposable element expression in single-cell RNA sequencing data. The authors profile human PBMCs and reveal transposable elements marking specific cell subtypes. Stellarscope is available as an open-source package and promises to enable continued study of “genomic dark matter.”

A single-cell transposable element atlas of human cell identity

Combination of in vivo and in vitro phosphoproteomics determines the PP2A target repertoire on proteome scale Brunner et al. developed an on-bead in vitro phosphatase screen that uses whole-proteome lysates as input. In combination with in vivo phosphoproteomics, they outline the PP2A target repertoire. Focusing on PPP2R5E/B56ε-containing PP2A complexes, they highlight that PP2A negatively affects stress granule formation.

Combination of in vivo and in vitro phosphoproteomics determines the PP2A target repertoire on proteome scale

Fragment dispersity index analysis of cfDNA fragments reveals chromatin accessibility and enables early cancer detection Wang et al. propose the FDI, a new cfDNA fragmentation pattern capturing chromatin accessibility. The identified high-FDI regions are enriched in regulatory elements and hold functional significance. Leveraging the FDI within dispersed regions, the FDI-oncology model achieves accurate diagnosis, subtyping, and prognosis across multiple cancer datasets.

Fragment dispersity index analysis of cfDNA fragments reveals chromatin accessibility and enables early cancer detection

A generalizable and targeted molecular biopsy approach for in situ cryogenic electron tomography of vitreous brain tissue Glynn et al. present a workflow for routine analysis of mammalian brain tissue by cryogenic electron tomography. The combination of robust sample vitrification, correlated cryo-fluorescence microscopy, and plasma focused ion beam milling is utilized to demonstrate a high-throughput and targeted approach for structural investigations in mouse hippocampal tissue.

A generalizable and targeted molecular biopsy approach for in situ cryogenic electron tomography of vitreous brain tissue

CRISPR GENome and epigenome engineering improves loss-of-function genetic-screening approaches Stadager et al. present CRISPRgenee, a dual-action gene-editing system that improves the efficiency and reliability of gene loss-of-function studies by combining gene knockout and epigenetic repression in a single step, enabling faster and more reliable identification of genes controlling cell function and disease mechanisms.

CRISPR GENome and epigenome engineering improves loss-of-function genetic-screening approaches

Engineering high-efficiency matriptase substrates using E. coli display for applications in prodrug activation Mestre Borras et al. develop an E. coli display platform for high-throughput screening of protease substrates. Using this method, they identify matriptase-cleavable sequences that outperform existing substrates and enable efficient prodrug activation.

Engineering high-efficiency matriptase substrates using E. coli display for applications in prodrug activation

Visualizing chromatin communication in living cells through Oligo-LiveFISH