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Article
| Open AccesstgCRISPRi: efficient gene knock-down using truncated gRNAs and catalytically active Cas9
CRISPRi is used for gene silencing in mammalian cells. Here the authors report a gene-suppression/activation strategy using active Cas9 complexed with truncated gRNAs (tgCRISPRi/a) without causing DNA cleavage: they use this to repress or activate expression of several target genes throughout somatic tissues in Drosophila melanogaster.
- Ankush Auradkar
- , Annabel Guichard
- & Ethan Bier
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Article
| Open AccessA split and inducible adenine base editor for precise in vivo base editing
TadA deaminases widely used in many base editors lack post-translational control in cells. Here the authors report a split adenine base editor (sABE) using chemically induced dimerisation (CID) to control the catalytic activity of TadA8e and show this can be used for PCSK9 gene editing in the mouse liver.
- Hongzhi Zeng
- , Qichen Yuan
- & Xue Gao
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Article
| Open AccessA strategy for Cas13 miniaturization based on the structure and AlphaFold
Small Cas enzymes are required for therapeutic use. Here the authors report an Interaction, Dynamics and Conservation (IDC) strategy for protein miniaturisation and use this to generate five compact variants of Cas13 based on a combination of IDC strategy and AlphaFold2.
- Feiyu Zhao
- , Tao Zhang
- & Zhanjun Li
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Article
| Open AccessHeterogeneity in M. tuberculosis β-lactamase inhibition by Sulbactam
Here, the reaction of the suicide inhibitor sulbactam with the M. tuberculosis β-lactamase (BlaC) is investigated with time-resolved crystallography. Singular Value Decomposition is implemented to extract kinetic information despite changes in unit cell parameters during the time-course of the reaction.
- Tek Narsingh Malla
- , Kara Zielinski
- & Marius Schmidt
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Article
| Open AccessEpigenome-wide association analysis of infant bronchiolitis severity: a multicenter prospective cohort study
DNA methylation patterns that are associated with disease can reveal genes involved in disease etiology. Here, the authors identify blood DNA methylation signatures that are associated with bronchiolitis severity and play important roles in tissues, cells, and pathways.
- Zhaozhong Zhu
- , Yijun Li
- & Kohei Hasegawa
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Article
| Open AccessVisualizing the membrane disruption action of antimicrobial peptides by cryo-electron tomography
Antimicrobial peptide mechanism of membrane disruption have not been fully characterized at the cellular level. Here, authors use cryo-electron tomography and AFM to directly visualize the disruption of the outer and inner membranes of Escherichia coli by a de novo-designed peptide.
- Eric H.-L. Chen
- , Chun-Hsiung Wang
- & Rita P.-Y. Chen
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Article
| Open AccessA Type II-B Cas9 nuclease with minimized off-targets and reduced chromosomal translocations in vivo
SpCas9 unintended editing is a major concern. Here the authors report an off-target method using Duplex Sequencing with increased sensitivity for Cas9 mutation detection; they also identify a Cas9 variant of the II-B subfamily with intrinsic high fidelity (PsCas9) and see improved specificity.
- Burcu Bestas
- , Sandra Wimberger
- & Marcello Maresca
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Article
| Open AccessOptogenetic engineering of STING signaling allows remote immunomodulation to enhance cancer immunotherapy
Optogenetics makes use of light-sensitive proteins to control biological processes using light. Here, the authors present an optogenetic system that regulates the cGAS/STING pathway remotely and demonstrate its efficacy in murine tumour models.
- Yaling Dou
- , Rui Chen
- & Yun Huang
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Article
| Open AccessSingle cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A
The mechanism and disease-relevance of pancreatic b-cell heterogeneity remains elusive. Here the authors show that variable HNF1A-FXYD2 activity drives single b-cell heterogeneity at transcriptomic, epigenomic, and electro-physiological levels, which strongly mark the progression of type 2 diabetes.
- Chen Weng
- , Anniya Gu
- & Yan Li
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Article
| Open AccessA deep learning-based stripe self-correction method for stitched microscopic images
Image stitching in fluorescence microscopy can be a hindrance to image quality and to downstream quantitative analyses. Here, the authors propose a deep learning-based stripe self-correction method that corrects diverse stripes and artifacts for stitched microscopic images.
- Shu Wang
- , Xiaoxiang Liu
- & Jianxin Chen
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Article
| Open AccessSystematic transcriptional analysis of human cell lines for gene expression landscape and tumor representation
During preclinical drug development, the ability of cancer cell lines to faithfully model human disease is important for identifying potential therapeutic strategies. Here, using transcriptomic datasets of over 1000 cell lines, the authors evaluate how representative each line is of its cancer type and present their cell line selection tool.
- Han Jin
- , Cheng Zhang
- & Adil Mardinoglu
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Article
| Open AccessLocating causal hubs of memory consolidation in spontaneous brain network in male mice
How long-lasting memory is formed remains incompletely understood. Here, using fMRI and hub silencing, the authors discovered causal network hubs that are instrumental in consolidating memory and contributing to network reorganization.
- Zengmin Li
- , Dilsher Athwal
- & Kai-Hsiang Chuang
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Article
| Open AccessProgrammable RNA detection with CRISPR-Cas12a
Cas12a is widely used in diagnostic platforms. Here the authors show that Cas12a can be programmed to directly detect RNA substrates, this is due to the 3’-end of the crRNA tolerating both RNA and DNA substrates: they use this to report a method, SAHARA, to detect RNA sequences.
- Santosh R. Rananaware
- , Emma K. Vesco
- & Piyush K. Jain
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Article
| Open AccessDemonstrating paths for unlocking the value of cloud genomics through cross cohort analysis
The emergence of large-scale genomics projects has led to genetic studies across cohorts. Here, the authors conduct genome-wide association studies meta-analyzing in trusted research environments or pooling together and find similar, but not identical results.
- Nicole Deflaux
- , Margaret Sunitha Selvaraj
- & Alexander G. Bick
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Article
| Open AccessCRUSTY: a versatile web platform for the rapid analysis and visualization of high-dimensional flow cytometry data
CRUSTY is an interactive webtool for flow cytometry data analysis, offering popular algorithms and visualizations, and generating publication-quality figures in minutes. It enables users without bioinformatics expertize to mine complex datasets, supports real-time exploration, and is freely available online.
- Simone Puccio
- , Giorgio Grillo
- & Enrico Lugli
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Article
| Open AccessLrig1-expression confers suppressive function to CD4+ cells and is essential for averting autoimmunity via the Smad2/3/Foxp3 axis
Regulatory T cells, and to certain extent other T cell subsets, limit the immune response to avoid harmful inflammation and tissue damage. Here authors identify a surface molecule, Lrig1, that is directly responsible for the suppressive function in regulatory T cells and in Il-17-producing helper T cells.
- Jae-Seung Moon
- , Chun-Chang Ho
- & Sang-Kyou Lee
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Article
| Open AccessEnhancing photosynthetic CO2 fixation by assembling metal-organic frameworks on Chlorella pyrenoidosa
Concentrating CO2 around Rubisco is critical to improve photosynthetic efficiency for biomass yield. Here, the authors report the self-assembly of metal-organic frameworks (MOFs) on the surface of green alga Chlorella pyrenoidosa to enhance the photosynthetic carbon fixation.
- Dingyi Li
- , Hong Dong
- & Can Li
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Article
| Open AccessTranscranial focused ultrasound-mediated neurochemical and functional connectivity changes in deep cortical regions in humans
The neural mechanisms underlying transcranial ultrasound stimulation (TUS) in humans are not well understood. Here, the authors show that theta-burst stimulation reduces gamma-aminobutyric acid (GABA) levels in the posterior cingulate cortex, as well as increasing functional connectivity in the anterior and posterior cingulate cortex.
- Siti N. Yaakub
- , Tristan A. White
- & Elsa F. Fouragnan
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Article
| Open AccessNext generation synthetic memory via intercepting recombinase function
Memory is a basic tenet of intelligent biological systems. Here the authors engineered a programmable and expandable iteration of recombinase-based synthetic memory (interception) that functions post-translation, resulting in faster recombination.
- Andrew E. Short
- , Dowan Kim
- & Corey J. Wilson
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Article
| Open AccessFeasibility of an implantable bioreactor for renal cell therapy using silicon nanopore membranes
An implantable bioartificial kidney with a cell-containing bioreactor could be used to treat end-stage renal disease. Here the authors demonstrate the feasibility of an implantable bioreactor by maintaining human cell viability and functionality after implantation in a xenograft model.
- Eun Jung Kim
- , Caressa Chen
- & Shuvo Roy
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Article
| Open AccessFunctionalization and higher-order organization of liposomes with DNA nanostructures
Liposomes are indispensable model membranes and drug carriers. Here, the authors use DNA nanostructures to coat, cluster, and pattern sub-100-nm liposomes, enabling attachment of proteins and temporal control of membrane fusion.
- Zhao Zhang
- , Zhaomeng Feng
- & Edwin R. Chapman
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Article
| Open AccessQTG-Miner aids rapid dissection of the genetic base of tassel branch number in maize
The lack of large-scale QTL cloning method hampers systematic dissection of genetic base of quantitative traits. Here, the authors develop a multi-omics data-based technique for large-scale and rapid cloning of quantitative genes of tassel branch number and discovery of selection signatures in maize breeding.
- Xi Wang
- , Juan Li
- & Lin Li
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Article
| Open AccessSingle-cell lipidomics enabled by dual-polarity ionization and ion mobility-mass spectrometry imaging
Single-cell analysis provides unique insight into individual cell dynamics and cell-to-cell heterogeneity. Here, the authors utilize trapped ion mobility separation coupled with dual-polarity ionization mass spectrometry imaging to enable high-throughput in situ profiling of single-cell lipidome.
- Hua Zhang
- , Yuan Liu
- & Lingjun Li
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Article
| Open AccessProjecting RNA measurements onto single cell atlases to extract cell type-specific expression profiles using scProjection
Many expression deconvolution approaches have been developed to estimate % RNA contributions of diverse cell types to mixed RNA measurements. Here, the authors have developed a complementary approach called scProjection to recover cell type-specific expression profiles from mixed RNA measurements.
- Nelson Johansen
- , Hongru Hu
- & Gerald Quon
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Article
| Open AccessAn IgM-like inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2 variants
In this study, the authors report the development of an inhalable IgM-like ACE2 and show that it broadly neutralizes SARS-CoV-2 variants, lowers viral loads and lung pathology in hamsters when administered early, and has good safety profiles in rats and monkeys.
- Juan Liu
- , Fengfeng Mao
- & Wenhui Li
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Article
| Open AccessWhole genomic analysis reveals atypical non-homologous off-target large structural variants induced by CRISPR-Cas9-mediated genome editing
The safety of CRISPR-Cas9 editing is a concern. Here the authors use whole genomic analysis by 10x linked-read sequencing and optical genome mapping to interrogate the genome integrity after editing: they see large structural variants at on-target sites and unexpected large chromosomal deletions.
- Hsiu-Hui Tsai
- , Hsiao-Jung Kao
- & John Yu
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Article
| Open AccessA photo-triggered self-accelerated nanoplatform for multifunctional image-guided combination cancer immunotherapy
Aggregation-induced emission luminogens (AIEgens) have shown high-performance as photosensitizers. Here the authors combine an AIEgen with paclitaxel-based hypoxia-responsive prodrug into nanoparticles for multifunctional image-guided photodynamic and immunotherapy in preclinical cancer models.
- Xiaoying Kang
- , Yuan Zhang
- & Ben Zhong Tang
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Article
| Open AccessA qPCR technology for direct quantification of methylation in untreated DNA
Analysis of DNA methylation usually requires a chemical or an enzymatic pretreatment step. Here, the authors report a PCR-based technology for the detection of DNA methylation in untreated DNA, and present analytical and clinical results from methylation analysis of the MGMT promoter.
- Kamilla Kolding Bendixen
- , Maria Mindegaard
- & Rasmus Koefoed Petersen
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Article
| Open AccessNext-generation proteomics for quantitative Jumbophage-bacteria interaction mapping
In this study Fossati et al. demonstrate how co-fractionation mass spectrometry can be applied to systematically investigate pathogen proteome organization and host interactome plasticity upon Jumbophage infection of Pseudomonas aeruginosa.
- Andrea Fossati
- , Deepto Mozumdar
- & Danielle L. Swaney
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Article
| Open AccessDroplet-based high-throughput single microbe RNA sequencing by smRandom-seq
Population level transcriptomics measurements miss bacterial heterogeneity. Here the authors report smRandom-seq, a droplet-based high-throughput single-microbe RNA-seq assay, using random primers for in situ cDNA generation, droplets for single-microbe barcoding, and CRISPR-based rRNA depletion.
- Ziye Xu
- , Yuting Wang
- & Yongcheng Wang
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Article
| Open AccessCell type-specific delivery by modular envelope design
Targetable delivery vectors for genetic cargo are needed. Here the authors report a modular platform with separate fusion and targeting components—Delivery to Intended REcipient Cells Through Envelope Design (DIRECTED)—and show cell type-specific delivery.
- Daniel Strebinger
- , Chris J. Frangieh
- & Feng Zhang
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Comment
| Open AccessEpichaperomics reveals dysfunctional chaperone protein networks
Molecular chaperones establish essential protein-protein interaction networks. Modified versions of these assemblies are generally enriched in certain maladies. A study published in Nature Communications used epichaperomics to identify unique changes occurring in chaperone-formed protein networks during mitosis in cancer cells.
- Mark R. Woodford
- , Dimitra Bourboulia
- & Mehdi Mollapour
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Article
| Open AccessSimultaneous magnetic resonance imaging of pH, perfusion and renal filtration using hyperpolarized 13C-labelled Z-OMPD
pH alterations are a hallmark of many pathologies including cancer and kidney disease. Here the authors describe [1,5- 13 C2]Z-OMPD as a probe for hyperpolarized 13C-MRI with good pH sensitivity and hyperpolarization properties which combined with tailored MRI protocols allow sub-minute imaging of pH, renal perfusion and filtration simultaneously.
- Martin Grashei
- , Pascal Wodtke
- & Franz Schilling
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Article
| Open AccessA mechanistic reinterpretation of fast inactivation in voltage-gated Na+ channels
Here, authors have identified two pairs of large hydrophobic residues in the channel S6 segments that form the inactivation gate of eukaryotic Na+ channels.
- Yichen Liu
- , Carlos A. Z. Bassetto Jr
- & Francisco Bezanilla
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Article
| Open AccessEngineered NIR-II fluorophores with ultralong-distance molecular packing for high-contrast deep lesion identification
To achieve high-contrast in fluorescence imaging of deep tissues is challenging. Here, the authors develop NIR-II fluorescent small molecules with high brightness and emission extending to 1900 nm, enabling in vivo imaging of deep tissues with enhanced signal-to-background ratios.
- Zhe Feng
- , Yuanyuan Li
- & Jun Qian
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Article
| Open AccessEarly-adulthood spike in protein translation drives aging via juvenile hormone/germline signaling
The transient elevation in protein translation during early-adulthood in Drosophila imposes long-lasting negative impacts on future aging trajectories by triggering proteostatic dysfunction at old ages.
- Harper S. Kim
- , Danitra J. Parker
- & Andrew M. Pickering
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Article
| Open AccessTIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation
CD226 provides a co-stimulatory signal to the T cell receptor during activation, and TIGIT is believed to inhibit this process by competing for the CD226 ligand CD155. Here authors show that ligand binding induces dense nanocluster formation by TIGIT which initiates intrinsic, CD226 independent inhibitory signals, proximal to T cell receptor signalling.
- Jonathan D. Worboys
- , Katherine N. Vowell
- & Daniel M. Davis
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Article
| Open AccessA deep learning method for replicate-based analysis of chromosome conformation contacts using Siamese neural networks
Siamese neural networks are a powerful deep learning approach for image analysis. Here, the authors adapt this method to the replicate-based analysis of Hi-C data and find that it successfully discriminates technical noise from biological variation.
- Ediem Al-jibury
- , James W. D. King
- & Daniel Rueckert
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Article
| Open AccessOne-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids
CRISPR base editing technologies can be used for disease modelling. Here the authors use various base editing tools to generate tumour models in human adult stem cell-derived hepatocyte, endometrial and intestinal organoids.
- Maarten H. Geurts
- , Shashank Gandhi
- & Hans Clevers
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Matters Arising
| Open AccessReply to: Fluid signal suppression characteristics of 3D-FLAIR with a T2 selective inversion pulse in the skull base
- Mehmet Sait Albayram
- , Garrett Smith
- & Onder Albayram
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Article
| Open AccessZwitterionic microgel preservation platform for circulating tumor cells in whole blood specimen
Blood specimen stabilization for the preservation of circulating tumor cells remains challenging. Here, the authors present a zwitterionic microgel platform for long-term hypothermic preservation of circulating tumor cells in the whole blood of cancer patients for noninvasive diagnostics.
- Yiming Ma
- , Jun Zhang
- & Lei Zhang
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Article
| Open AccessAn integrated organoid omics map extends modeling potential of kidney disease
Lassé et al. show that genes involved in kidney organoid proteomic response to TNFα segregate a subset of individuals with poor outcomes in proteinuric kidney disease, demonstrating the relevance of kidney organoid modeling to human kidney disease.
- Moritz Lassé
- , Jamal El Saghir
- & Markus M. Rinschen
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Article
| Open AccessIdentification of gene function based on models capturing natural variability of Arabidopsis thaliana lipid metabolism
The use of automated tools to reconstruct lipid metabolic pathways is not warranted in plants. Here, the authors construct Plant Lipid Module for Arabidopsis rosette using constraint-based modeling, demonstrate its integration in other plant metabolic models, and use it to dissect the genetic architecture of lipid metabolism.
- Sandra Correa Córdoba
- , Hao Tong
- & Zoran Nikoloski
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Article
| Open AccessSnapFISH: a computational pipeline to identify chromatin loops from multiplexed DNA FISH data
Multiplexed DNA FISH technologies are powerful tools to reveal chromatin spatial organisation. Here, the authors developed SnapFISH, a computational pipeline to identify chromatin loops from multiplexed DNA FISH data.
- Lindsay Lee
- , Hongyu Yu
- & Ming Hu
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Article
| Open AccessFluorescent protein lifetimes report densities and phases of nuclear condensates during embryonic stem-cell differentiation
Fluorescent proteins can report on many cellular variables. Here, authors develop a method for reporting high local densities, and use it to show that density distribution of heterochromatin in mouse embryonic stem cells are not in a liquid phase.
- Khalil Joron
- , Juliane Oliveira Viegas
- & Eitan Lerner
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Article
| Open AccessCharacterizing cancer metabolism from bulk and single-cell RNA-seq data using METAFlux
Metabolic reprogramming is a common indicator of the tumour microenvironment. Here the authors develop the METAflux framework to predict metabolic fluxes from single cell RNA-seq data.
- Yuefan Huang
- , Vakul Mohanty
- & Ken Chen
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Article
| Open AccessIdentification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase
TMEM16F is a Ca2+ activated ion channel and lipid scramblase involved in cell fusion. Here authors determine cryo-EM structures of TMEM16F with or without bound blockers, such as the FDA-approved drug niclosamide.
- Shengjie Feng
- , Cristina Puchades
- & Lily Yeh Jan
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Article
| Open AccessIn situ synthesis and dynamic simulation of molecularly imprinted polymeric nanoparticles on a micro-reactor system
Molecularly imprinted polymers are useful elements in sensing and biomedical research but their fabrication is challenging. Here, the authors report a micro-reactor for in situ and continuous production of molecularly imprinted polymers.
- Özgecan Erdem
- , Ismail Eş
- & Fatih Inci
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Article
| Open AccessCell-type-specific co-expression inference from single cell RNA-sequencing data
Inferring co-expressions with scRNA-seq data is challenging, and existing methods suffer from inflated false positives and biases. Here, the authors proposed CS-CORE, which yields unbiased estimates and identifies co-expressions that are more reproducible and biologically relevant for scRNA-seq data.
- Chang Su
- , Zichun Xu
- & Jingfei Zhang
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