Featured
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| Open AccessIntegrating single cell expression quantitative trait loci summary statistics to understand complex trait risk genes
The authors describe a new transcriptome-wide association study (TWAS) method that integrates single cell eQTL summary statistics with GWAS data to identify cell type-specific risk genes, together with a cell type-aware drug repurposing pipeline.
- Lida Wang
- , Chachrit Khunsriraksakul
- & Bibo Jiang
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Article
| Open AccessCEBPA restricts alveolar type 2 cell plasticity during development and injury-repair
Cell plasticity underlies development and regeneration. Here, the authors show that mouse lung alveolar type 2 cells undergo maturation postnatally and their plasticity is restricted by CEBPA and increases upon viral infection.
- Dalia Hassan
- & Jichao Chen
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Article
| Open AccessCorrelative single molecule lattice light sheet imaging reveals the dynamic relationship between nucleosomes and the local chromatin environment
This study combines lattice light sheet microscopy and single molecule imaging to study protein dynamics and chromatin structure in live cells. The authors describe how nucleosomes and proteins move and are organised in relation to chromatin density.
- Timothy A. Daugird
- , Yu Shi
- & Wesley R. Legant
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| Open AccessRegulation of Myc transcription by an enhancer cluster dedicated to pluripotency and early embryonic expression
MYC regulates numerous genes involved in cell growth and proliferation. Here, Li-Bao et al. study the DNA regions that regulate Myc transcription in early mouse embryos and pluripotent stem cells. They report a specific region with independent modules dedicated to discrete temporal and spatial phases of Myc expression.
- Lin Li-Bao
- , Covadonga Díaz-Díaz
- & Miguel Torres
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| Open AccessA time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues
The mechanisms underlying high-altitude acclimatization remain unclear. Here authors use the sheep model to reveal multi-tissue temporal dynamics of gene transcription and regulation during acclimatization, and provide resources for hypoxia-related studies.
- Ze Yan
- , Ji Yang
- & Meng-Hua Li
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| Open AccessDisentangling genetic effects on transcriptional and post-transcriptional gene regulation through integrating exon and intron expression QTLs
Expression quantitative trait loci (eQTL) studies typically only consider exon expression levels and discard intronic RNA sequencing reads. Here, the authors show that analyzing eQTLs together with QTLs for intron levels and exon-intron ratios expands the number and functional understanding of genetic effects on gene regulatory processes.
- Anneke Brümmer
- & Sven Bergmann
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| Open AccessInvestigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment
The effect of noncoding genetic variation on acute lymphoblastic leukemia treatment response is not fully understood. Here, the authors functionally evaluated variants associated with pharmacological traits and validate the role of rs1247117 in gene regulation impacting therapeutic response.
- Kashi Raj Bhattarai
- , Robert J. Mobley
- & Daniel Savic
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Article
| Open AccessDeep learning the cis-regulatory code for gene expression in selected model plants
This study explores the variation in gene regulation across plant species and genotypes using interpretable deep learning on DNA sequence and RNA-seq data, demonstrating the models’ utility in functional genomics and phenotypic trait prediction.
- Fritz Forbang Peleke
- , Simon Maria Zumkeller
- & Jędrzej Szymański
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Article
| Open AccessEmergence of enhancers at late DNA replicating regions
Here the authors report that enhancers appear more often in late-replicating DNA regions and are enriched for mutations affecting TF binding. This relationship with DNA replication time is seen in species evolution and cancer, suggesting a fundamental principle of genome evolution.
- Paola Cornejo-Páramo
- , Veronika Petrova
- & Emily S. Wong
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Article
| Open AccessMassively parallel screen uncovers many rare 3′ UTR variants regulating mRNA abundance of cancer driver genes
The function of rare non-coding variants remains challenging to decipher. Here, the authors developed MapUTR to uncover 10,524 functional rare 3’ UTR variants regulating mRNA abundance, many of which reside in cancer driver genes.
- Ting Fu
- , Kofi Amoah
- & Xinshu Xiao
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| Open AccessCombined and differential roles of ADD domains of DNMT3A and DNMT3L on DNA methylation landscapes in mouse germ cells
DNMT3A and DNMT3L form a complex to deposit DNA methylation in mammalian germ cells. Here, the authors report that loss-of-function of ADD domains of DNMT3A and/or DNMT3L has various impacts on DNA methylation landscapes in mouse oocytes and sperm.
- Naoki Kubo
- , Ryuji Uehara
- & Hiroyuki Sasaki
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| Open AccessDNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues
Analysis of 92 human homeodomain mutants, including disease-associated variants and variants of uncertain significance, reveals variants with altered DNA binding affinity and/or specificity and specificity-determining positions.
- Kian Hong Kock
- , Patrick K. Kimes
- & Martha L. Bulyk
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Article
| Open AccessAn Intricate Network Involving the Argonaute ALG-1 Modulates Organismal Resistance to Oxidative Stress
In this study, Vergani-Junior et al. show that increased expression of the argonaute ALG-1 in long-lived worms improves oxidative stress resistance through the modulation of microRNAs that downregulate the protein disulfide isomerase pathway.
- Carlos A. Vergani-Junior
- , Raíssa De P. Moro
- & Marcelo A. Mori
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Article
| Open AccessSOXC are critical regulators of adult bone mass
Angelozzi et al. uncover key mechanisms involved in physiological and pathological bone mass remodeling by showing that SOXC transcription factors regulate the bone formation and resorption balance via critical roles in LepR+ mesenchymal stem cells.
- Marco Angelozzi
- , Anirudha Karvande
- & Véronique Lefebvre
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Article
| Open AccessA distal enhancer guides the negative selection of toxic glycoalkaloids during tomato domestication
This study identified a distal enhancer GE1, which acts as the key regulator controlling steroidal glycoalkaloids metabolism by modulating the GAME gene cluster and guides negative selection of steroidal glycoalkaloids production during tomato domestication.
- Feng Bai
- , Peng Shu
- & Mingchun Liu
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Article
| Open AccessExtended stop codon context predicts nonsense codon readthrough efficiency in human cells
Stop codon readthrough, the ribosomal bypass of mRNA nonsense codons, has therapeutic potential for diseases caused by nonsense mutations. Here, the authors used machine learning to define readthrough-conducive mRNA sequences and predict specific CFTR alleles likely amenable to readthrough therapy.
- Kotchaphorn Mangkalaphiban
- , Lianwu Fu
- & Allan Jacobson
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Article
| Open AccessGenetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets
Genetic mechanisms of blood pressure regulation remain poorly defined. Here, the authors perform a kidney multi-omics study to identify 399 kidney effector genes, 11 miRNAs and 97 proteins for blood pressure and hypertension.
- Xiaoguang Xu
- , Chachrit Khunsriraksakul
- & Maciej Tomaszewski
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| Open AccessThe chromatin factors SET-26 and HCF-1 oppose the histone deacetylase HDA-1 in longevity and gene regulation in C. elegans
SET-26, HCF-1, HDA-1 are factors that help package DNA and regulate gene expression. Here, the authors find that SET-26 recruits HCF-1 to specific locations along the genome, where they antagonize the activity of HDA-1. Together, they maintain balanced gene expression and longevity in C. elegans.
- Felicity J. Emerson
- , Caitlin Chiu
- & Siu Sylvia Lee
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Article
| Open AccessA transposon insertion in the promoter of OsUBC12 enhances cold tolerance during japonica rice germination
Japonica rice generally has greater capacity for low temperatures germination (LTG) than indica rice. Here, the authors report an E2 ubiquitin-conjugating enzyme-encoding gene OsUBC12 can increase LTG in japonica rice by negatively regulate ABA signaling via promoting the proteasomal degradation of OsSnRK1.1.
- Chuanzhong Zhang
- , Hongru Wang
- & Jun Fang
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| Open AccessN-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration
Here, Ma et al. investigate the translational profile of cardiac regeneration, pointing to Nat10 as a key regulator of cardiomyocyte proliferative potential, and describing how it regulates cardiac gene expression.
- Wenya Ma
- , Yanan Tian
- & Benzhi Cai
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| Open AccessMulti-omics analysis in human retina uncovers ultraconserved cis-regulatory elements at rare eye disease loci
Ultraconserved non-coding elements (UCNEs) can regulate developmental gene expression. Retinal multi-omics data integration revealed UCNEs to be candidate cis-regulatory elements during retinal development, which may be implicated in rare eye diseases.
- Victor Lopez Soriano
- , Alfredo Dueñas Rey
- & Elfride De Baere
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Article
| Open AccessGenetic control of thermomorphogenesis in tomato inflorescences
Mechanisms underlying changes in inflorescence development in response to high ambient temperature remain unclear. Here, the authors report the cloning of the MIB2, encoding a homology of SPATULA, and its activation of CONSTANS-Like1 for determining tomato inflorescence branching at high ambient temperature.
- Shuai Sun
- , Zhiqiang Liu
- & Xia Cui
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| Open AccessA landscape of gene expression regulation for synovium in arthritis
Hundreds of arthritis-associated genetic variants have been identified but in most cases their functions remain unknown. Here the authors develop a resource to reveal the effects of variants on gene expression in human synovium, and identify arthritis-related genes.
- Feng Jiang
- , Shou-Ye Hu
- & Tie-Lin Yang
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Article
| Open AccessPredicting proximal tubule failed repair drivers through regularized regression analysis of single cell multiomic sequencing
A profibrotic, proinflammatory kidney cell population has been identified as a driver of chronic kidney disease. Here, authors generate a human kidney single cell multiomic dataset and apply a regularised regression approach to identify transcription factors underpinning this cell population.
- Nicolas Ledru
- , Parker C. Wilson
- & Benjamin D. Humphreys
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| Open AccessLogical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes
Descriptive data in biomedical research are expanding rapidly, but functional validation methods lag behind. Here, authors present Logical Synthetic cis-regulatory DNA, a framework to design reporters that mark cellular states and pathways, showcasing its applicability to complex phenotypic states.
- Carlos Company
- , Matthias Jürgen Schmitt
- & Gaetano Gargiulo
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Article
| Open AccessShort-term hypercaloric carbohydrate loading increases surgical stress resilience by inducing FGF21
Surgery poses significant risks for patients, with attempts to mitigate these risks using multimodal perioperative care pathways. Here, the authors show that preoperative hypercaloric carbohydrate drinks not only alleviate surgical stress but also demonstrates the replicability of this protection using FGF21 treatment alone.
- Thomas Agius
- , Raffaella Emsley
- & Alban Longchamp
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Article
| Open AccessGWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region
Here, the authors identify six risk SNPs for systemic sclerosis by performing GWAS on Japanese patients and meta-analyzing Japanese and European GWAS datasets. Downstream analyses indicate that B cells contribute to pathogenesis.
- Yuki Ishikawa
- , Nao Tanaka
- & Chikashi Terao
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Article
| Open AccessTransposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer
It has been suggested that transposable elements (TE) play a role in tumourigenesis, but the associated mechanisms remain unclear. Here, the authors show, using colorectal cancer data and Bayesian Networks, that TEs can mediate the effect of expression quantitative trait loci and contribute to the regulation of cancer-related genes.
- Nikolaos M. R. Lykoskoufis
- , Evarist Planet
- & Emmanouil T. Dermitzakis
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Article
| Open AccessThe UBP5 histone H2A deubiquitinase counteracts PRCs-mediated repression to regulate Arabidopsis development
The authors demonstrate that UBIQUITIN SPECIFIC PROTEASE 5 (UBP5) is a major H2Aub deubiquitinase that antagonises H3K27me3, leading to transcriptional de-repression and controlling development in Arabidopsis.
- James Godwin
- , Mohan Govindasamy
- & Sara Farrona
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| Open AccessHaplotype-aware modeling of cis-regulatory effects highlights the gaps remaining in eQTL data
Genetic variants that influence gene expression play a major role in human phenotypic variability and disease susceptibility. Here, the authors introduce a computational method to estimate the regulatory effect size in genes with multiple conditionally independent regulatory variants.
- Nava Ehsan
- , Bence M. Kotis
- & Pejman Mohammadi
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| Open AccessIntegrative single-cell characterization of a frugivorous and an insectivorous bat kidney and pancreas
Frugivory evolved multiple times in mammals, including bats. Here, the authors use integrative single-cell sequencing on fruit and insect bat kidneys and pancreases and identify cell population, gene expression and regulatory differences associated with frugivory that also relate to diabetes.
- Wei E. Gordon
- , Seungbyn Baek
- & Nadav Ahituv
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| Open AccessA full-body transcription factor expression atlas with completely resolved cell identities in C. elegans
Invariant cell lineage in C. elegans enables the analysis of transcriptional regulatory mechanisms controlling the fate of each cell at spatiotemporal resolution. Here, the authors develop a tool automating C. elegans cell identification and create an expression atlas of 620 transcription factors.
- Yongbin Li
- , Siyu Chen
- & Xiao Liu
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Article
| Open AccessA distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development
The authors discovered cluster of regulatory sequences that controls HOXA over large genomic distances and across topological domains. This cluster is required for normal craniofacial development in both humans and mice.
- Andrea Wilderman
- , Eva D’haene
- & Justin Cotney
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Article
| Open AccessCell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions
Here, the authors show how the histone methyltransferase SETDB1 is involved in cell-type specific regulation of chromatin landscape by catalyzing H3K9me3, which antagonizes CTCF binding. They further define the subsequent transcriptomic impact.
- Phoebe Lut Fei Tam
- , Ming Fung Cheung
- & Danny Leung
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Article
| Open AccessA unique sigma/anti-sigma system in the actinomycete Actinoplanes missouriensis
Bacteria of the genus Actinoplanes form sporangia which, upon contact with water, release motile spores. Here, the authors study the mechanisms behind sporangium dehiscence and discover a sigma/anti-sigma system with unique features.
- Takeaki Tezuka
- , Kyota Mitsuyama
- & Yasuo Ohnishi
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Article
| Open AccessBRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state
BRD9 is a core non-canonical BAF component. Here the authors show that BRD9 plays a pivotal role in regulating the disease-related cell fate of hematopoietic stem cells. Its loss promotes myeloid skewing while impairing B cell development by altering CTCF-mediated chromatin states.
- Muran Xiao
- , Shinji Kondo
- & Daichi Inoue
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| Open AccessImmune-response 3′UTR alternative polyadenylation quantitative trait loci contribute to variation in human complex traits and diseases
Alternative polyadenylation (APA) has a key role in the post-transcriptional regulation of most human genes but is understudied in cells of the immune system. Here, the authors construct an atlas of cell type-specific APA events in various immune cell-types and stimulation conditions, providing evidence of widespread stimulation-responsiveness and association with immune-related traits.
- Lei Li
- , Xuelian Ma
- & Wei Li
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| Open AccessOutward-oriented sites within clustered CTCF boundaries are key for intra-TAD chromatin interactions and gene regulation
The TAD boundaries comprise clustered arrays of CTCF sites with complex orientations. Here the authors show that the outward-oriented CTCF sites within clustered TAD boundaries are central for intra-TAD chromatin spatial contacts and gene regulation.
- Xiao Ge
- , Haiyan Huang
- & Qiang Wu
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Article
| Open AccessIn vivo RNA interactome profiling reveals 3’UTR-processed small RNA targeting a central regulatory hub
Here the authors report a new approach to profile RNA-RNA interactions in live bacterial cells. The charted RNA interaction networks unveil a key mRNA regulatory hub targeted by twelve small RNAs, including a novel RNA involved in fatty acid metabolism.
- Fang Liu
- , Ziying Chen
- & Yanjie Chao
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Article
| Open AccessDynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry
Off-target toxicity of antisense oligonucleotides (ASOs) poses a challenge for their clinical use. Here, authors develop a toehold-bearing ASO architecture that mitigates a broad spectrum of off-target interactions, significantly enhancing the safety profile of ASO drugs.
- Chisato Terada
- , Kaho Oh
- & Tsuyoshi Yamamoto
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Article
| Open AccessACS-20/FATP4 mediates the anti-ageing effect of dietary restriction in C. elegans
Dietary restriction is one of the most effective ways to delay ageing. Here, the authors discover a highly conserved lipid metabolism gene functions through transcriptional regulation mechanisms to regulate proteostasis, lifespan and healthspan in response to low nutrients in C. elegans.
- Zi Wang
- , Lina Zou
- & Di Chen
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Article
| Open AccessFear extinction is regulated by the activity of long noncoding RNAs at the synapse
Synaptic activity controls the extinction of conditioned fear. Here the authors discovered a new way that the brain controls memories of fear: a long noncoding RNA called Gas5 that coordinates the activity of RNA granules in the synaptic compartment.
- Wei-Siang Liau
- , Qiongyi Zhao
- & Timothy W. Bredy
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Article
| Open AccessTranscriptome-wide association analyses reveal the impact of regulatory variants on rice panicle architecture and causal gene regulatory networks
Panicle architecture significantly determines rice grain yield. Here, the authors investigate the transcriptome of young panicles from 275 rice varieties and propose a method to identify causal genes for panicle traits and construct regulatory networks.
- Luchang Ming
- , Debao Fu
- & Weibo Xie
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Article
| Open Accessc-di-GMP inhibits the DNA binding activity of H-NS in Salmonella
H-NS is a global regulatory protein that represses expression of many genes in bacteria. Here, Li et al. show that a second messenger, cyclic di-GMP, binds to H-NS and inhibits its binding to DNA, thus relieving H-NS-mediated transcriptional silencing.
- Shuyu Li
- , Qinmeng Liu
- & Lei Zhang
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Article
| Open AccessDeep learning of human polyadenylation sites at nucleotide resolution reveals molecular determinants of site usage and relevance in disease
The authors develop deep learning models to identify genome-wide polyA sites at nucleotide resolution and calculate site strength. They further examine genomic parameters regulating site usage and reveal genetic variants altering polyA activity.
- Emily Kunce Stroup
- & Zhe Ji
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Article
| Open AccessPRO-IP-seq tracks molecular modifications of engaged Pol II complexes at nucleotide resolution
Tracking molecular modifications of engaged Pol II complexes is important for studying transcriptional regulation. Here, the authors combine run-on sequencing (PRO-seq) and immunoprecipitation, revealing dynamics of Pol II CTD phosphorylation at nucleotide-resolution.
- Anniina Vihervaara
- , Philip Versluis
- & John T. Lis
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Article
| Open AccesseQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk
Fetal development plays an important role in defining adult diabetes risk. Here, authors identified a genetic link between fetal pancreatic gene expression, obesity, and diabetes risk through eQTL mapping of iPSC-derived pancreatic progenitor cells.
- Jennifer P. Nguyen
- , Timothy D. Arthur
- & Kelly A. Frazer
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Article
| Open AccessRNA-based translation activators for targeted gene upregulation
Many diseases are driven by the insufficient expression of critical genes, but few technologies are capable of rescuing these endogenous protein levels. Here, Cao et al. present an RNA-based technology that boosts protein production from endogenous mRNAs by upregulating their translation.
- Yang Cao
- , Huachun Liu
- & Bryan C. Dickinson
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Article
| Open AccessCircular single-stranded DNA as switchable vector for gene expression in mammalian cells
Synthetic gene networks in mammalian cells are currently limited to either transcription factors or RNA regulators. Here, the authors develop a regulatory approach based on circular single-stranded DNA, which can be used as a conformationally switchable genetic vector in mammalian cells.
- Linlin Tang
- , Zhijin Tian
- & Jie Song