Featured
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Article
| Open AccessPre-mRNA processing factors differentially impact coordination between co-transcriptional cleavage and transcription termination
This study reveals how pre-mRNA processing factors in Arabidopsis distinctly coordinate cleavage and transcription termination, highlighting complex roles of CPSF, CstF, PAPS1, BORDER proteins, and FPA in efficient mRNA maturation.
- Xianhao Jin
- , Juzuo Li
- & Jixian Zhai
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Article
| Open AccessPAL-AI reveals genetic determinants that control poly(A)-tail length during oocyte maturation, with relevance to human fertility
Gene regulation in oocytes relies heavily on poly(A) tail-length changes. Here, the authors develop PAL-AI, a neural network model that predicts tail-length changes, identifies regulatory motifs, and links disruptive genetic variants to negative selection in humans, implicating tail-length control in female fertility.
- Kehui Xiang
- & David P. Bartel
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Article
| Open AccessQueuosine is incorporated into precursor tRNA before splicing
tRNA modifications are essential for function, yet their timing relative to processing is unclear. Here, the authors show that queuosine and derivative modifications occur before splicing of pre-tRNA^Tyr, with cryo-EM confirming direct recognition by the QTRT1/2 complex.
- Wei Guo
- , Igor Kaczmarczyk
- & Francesca Tuorto
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Article
| Open AccessGFP-on mouse model for interrogation of in vivo gene editing
In vivo gene editing hinges on identifying an ideal delivery vehicle from numerous candidates. Here, authors establish the GFP-on mouse model capable of translating successful adenine base editing to a fluorescent readout thus enabling the rapid evaluation of genome editing delivery vehicles.
- Carla Dib
- , Jack A. Queenan
- & Agnieszka D. Czechowicz
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Article
| Open AccessmRNA trafficking directs cell-size-scaling of mitochondria distribution and function
How mitochondria positioning dynamically adapts to changes in cell shape is poorly understood. Here, Bradbury et al. show that cell-size-dependent trafficking of TRAK2 mRNA underpins the cell-size-scaling of mitochondria distribution and activity.
- Joshua J. Bradbury
- , Georgia E. Hulmes
- & Shane P. Herbert
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Article
| Open AccessMitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects
The authors uncover a mechano-metabolic adaptation where confinement induces rapid mitochondrial relocalization to the nuclear periphery, generating localized nuclear ATP surges that support chromatin remodeling, DNA repair, and cell cycle progression.
- Ritobrata Ghose
- , Fabio Pezzano
- & Sara Sdelci
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Article
| Open AccessCas13d-mediated isoform-specific RNA knockdown with a unified computational and experimental toolbox
The majority of human genes can produce multiple isoforms, but studying their functional relevance requires tools to target specific isoforms. Here, the authors develop a CRISPR-based exon-exon junction-targeting strategy to achieve isoform-specific RNA knockdown.
- Megan D. Schertzer
- , Andrew Stirn
- & David A. Knowles
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Article
| Open AccessAutocrine interferon poisoning mediates ADAR1-dependent synthetic lethality in BRCA1/2-mutant cancers
The RNA editing enzyme ADAR1 blocks interferon responses triggered by cytosolic RNA sensors, and has been proposed as a potential target in immuno-oncology. Here, the authors report that BRCA1/2 and ADAR1 are synthetic lethal, showing that ADAR1 depletion in BRCA1-mutant cells causes autocrine interferon poisoning
- Roman M. Chabanon
- , Liudmila Shcherbakova
- & Sophie Postel-Vinay
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Article
| Open AccessRemoval of promoter CpG methylation by epigenome editing reverses HBG silencing
DNA methylation is a critical component for repression of fetal haemoglobin in adult blood cells. Removing DNA methylation from the fetal haemoglobin promoter effectively upregulates the gene, opening avenues for the treatment of blood disorders.
- Henry W. Bell
- , Ruopeng Feng
- & Merlin Crossley
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Article
| Open AccessSingle-cell transcriptomics of ventral forebrain progenitors identifies Evf2 enhancer lncRNA-enhancer gene guidance through direct RNA binding and RNP recruitment domains
Enhancer-gene selectivity establishes gene expression networks during development. Here, the authors link Evf2 enhancer-gene guidance and seizure gene regulation, Evf2 RNA binding sites and chromosomal RNP recruitment domains, and homeodomain motif recognition to support multilayered mechanisms.
- Edward Li
- , Abhijit Chakraborty
- & Jhumku D. Kohtz
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Article
| Open AccessA complex between IF2 and NusA suggests early coupling of transcription-translation
The in vivo dynamics of bacterial translation initiation has remained unexplored. Here, the authors measured ribosome binding kinetics of the key factors directly inside living E. coli cells, using single-molecule tracking techniques, and found novel link between translation and transcription.
- Mikhail Metelev
- & Magnus Johansson
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Article
| Open AccessSMCHD1 maintains heterochromatin, genome compartments and epigenome landscape in human myoblasts
The authors characterize SMCHD1 as a nuclear lamina-associated protein in human myoblasts where it serves as an anchor for heterochromatin. Loss of SMCHD1 leads to B-to-A compartment transitions and numerous changes in 3D chromatin organization.
- Zhijun Huang
- , Wei Cui
- & Gerd P. Pfeifer
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Article
| Open AccessSomites are a source of nephron progenitors in zebrafish
This study reveals that cells of the zebrafish kidney can originate from the somites, structures traditionally held as precursors to the skeletal muscle, challenging a century-old paradigm and prompting a re-evaluation of kidney organogenesis in vertebrates.
- Zhenzhen Peng
- , Thitinee Vanichapol
- & Alan J. Davidson
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Article
| Open AccessMelbournevirus encodes a shorter H2B-H2A doublet histone variant that forms structurally distinct nucleosome structures
Melbournevirus encodes a conserved shorter H2B-H2A doublet variant. Here the authors report a cryo-EM structure of a nucleosome-like particle reconstituted with viral H4-H3 and the identified variant H2B-H2A doublet in Melbournevirus, and demonstrated that it is essential for viral fitness.
- Alejandro Villalta
- , Hugo Bisio
- & Karolin Luger
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Article
| Open AccessLarge-scale RNA-Seq mining reveals ciclopirox olamine induces TDP-43 cryptic exons
TDP-43 nuclear clearance and loss-of-function, a hallmark of ALS-FTD and other neurodegenerative diseases, causes widespread inclusion of harmful cryptic exons. Here, the authors developed SnapMine to analyze cryptic exon inclusion across public RNA-seq datasets and identified that the antifungal ciclopirox olamine (CPX) induces such inclusion via heavy metal toxicity and oxidative stress.
- Irika R. Sinha
- , Parker S. Sandal
- & Jonathan P. Ling
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Article
| Open AccessU-rich elements drive pervasive cryptic splicing in 3’ UTR massively parallel reporter assays
Massively parallel reporter assays (MPRAs) are powerful technologies for measuring the impact of non-coding sequences on gene expression. Here, the authors demonstrate that MPRA reporters often undergo cryptic splicing that is activated by U-rich sequences, which can convolute MPRA measurements.
- Khoa Dao
- , Courtney F. Jungers
- & Anthony M. Mustoe
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Article
| Open AccessRestriction of Ku translocation protects telomere ends
Chromosome ends must be protected from fusion by NHEJ despite Ku binding to telomeres. Here, the authors show that at telomeres yeast Rap1 inhibits Ku’s translocation on DNA, preventing NHEJ and protecting telomeres without displacing Ku.
- Stefano Mattarocci
- , Sonia Baconnais
- & Stéphane Marcand
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Article
| Open AccessArrest Peptide Profiling resolves co-translational folding pathways and chaperone interactions in vivo
Protein folding is facilitated by cellular machinery, but studying folding in the cellular context is challenging. Here, the authors developed Arrest Peptide Profiling to map co-translational folding and chaperone interactions in living cells.
- Xiuqi Chen
- , Vincent J. Hilser
- & Christian M. Kaiser
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Article
| Open AccessStarship giant transposons dominate plastic genomic regions in a fungal plant pathogen and drive virulence evolution
Giant transposons, known as ‘Starships’, mediate horizontal gene transfer between fungal genomes. Here, Sato et al. show that Starships occupy genome regions crucial for infection in a plant pathogenic fungus, show signatures of horizontal transfer between distant fungal species, and may facilitate the formation of new virulence genes.
- Yukiyo Sato
- , Roos Bex
- & Bart P.H.J. Thomma
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Article
| Open AccessPEAK1 maintains tight junctions in intestinal epithelial cells and resists colitis by inhibiting autophagy-mediated ZO-1 degradation
Tight junctions are crucial for maintaining intestinal barrier homeostasis. Here the authors show that PEAK1 sustains Src activity at tight junctions and facilitates its interaction with ZO-1 to preserve tight junction integrity.
- Zaikuan Zhang
- , Yajun Xie
- & Qin Zhou
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Article
| Open AccessDetermination of trunk neural crest cell fate and susceptibility to splicing perturbation by the DLC1-SF3B1-PHF5A splicing complex
How neural crest development is specifically regulated by splicing factors and its vulnerability to splicing dysregulation remains unclear. Here, the authors identify neural crest-specific and somite-specific splicing complexes that confer distinct susceptibility to splicing perturbation.
- Zhengfan Zheng
- , Suisui Guo
- & Martin Cheung
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Article
| Open AccessAllosteric activation of the SPRTN protease by ubiquitin maintains genome stability
The DNA-dependent protease SPRTN cleaves toxic DNA-protein crosslinks (DPCs). Here, the authors show that SPRTN is activated by DPC-ubiquitylation through an allosteric ubiquitin binding interface. This regulatory mechanism enables precise control of SPRTN activity during DNA repair.
- Sophie Dürauer
- , Hyun-Seo Kang
- & Julian Stingele
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Article
| Open AccessA new paradigm of islet adaptations in human pregnancy: insights from immunohistochemistry and proteomics
Here the authors show that human pancreatic islets adapt during pregnancy with increased α-cell area and GLP-1 abundance, while key differences from islet adaptations in mouse pregnancy include unchanged β-cell PRLR abundance and absent β-cell 5-HT2B receptor expression.
- Faheem Seedat
- , Katie Holden
- & M. Irina Stefana
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Article
| Open AccessIdentification of a key nucleotide influencing Cas12a crRNA activity for universal photo-controlled CRISPR diagnostics
Existing photo-controlled CRISPR diagnostic methods suffer from limited universality, high cost, and low detection efficiency. Here, the authors develop a photo-caging strategy designed for the direct repeat (DR) region of Cas12a crRNA, enabling a broadly applicable one-pot detection platform
- Tian Tian
- , Hongrui Xiao
- & Xiaoming Zhou
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Article
| Open AccessA UFD1 variant encoding a microprotein modulates UFD1f and IPMK ubiquitination to play pivotal roles in anti-stress responses
Some small mRNA isoforms regulate cellular responses to stress. Here, Li et al. identify UFD1s, a stress responsive micro-RNA that encodes a conserved microprotein that regulates ubiquitination of full length UFD1, promotes autophagy and fatty acid oxidation, and acts to alleviate NASH progression in mice.
- Xiuzhi Li
- , Xiaolin Wang
- & Liang Chen
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Article
| Open AccessStructural insights into the roles of PARP4 and NAD+ binding in the human vault cage
Vaults are massive, cytoplasmic, cage-like ribonucleoprotein assemblies. Here, authors describe cryo-EM structures of human vault encapsulating PARP4 & nucleotide ligands, as well as proteomic data showing that depleting PARP4 alters the vault interactome.
- Jane E. Lodwick
- , Rong Shen
- & Minglei Zhao
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Article
| Open AccessCompasSeq: epitranscriptome-wide percentage assessment of metabolite-capped RNA at the transcript resolution
Certain cellular metabolites can cap RNA molecules, influencing their function. Here, the authors develop CompasSeq, a quantitative method to profile these noncanonical RNA caps across the transcriptome and reveal their dynamic changes with age in mouse liver.
- Yuanbo Liu
- , Dean Li
- & Nan Liu
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Article
| Open AccessSmall RNA in sperm–Paternal contributions to human embryo development
Sperm delivers not only the paternal genome but also regulatory sRNAs. Here they show that sRNAs, including miRNAs and Y-RNAs, correlate with sperm concentration, fertilization, and embryo quality, suggesting their potential as biomarkers to improve IVF outcomes.
- Signe Isacson
- , Kajsa Karlsson
- & Anita Öst
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Article
| Open AccessDe novo designed protein guiding targeted protein degradation
Targeted protein degradation in bacteria typically requires fusion with tags or chemical degraders. Here, authors developed GPlad, a tunable system using designed guide proteins and arginine kinase to degrade diverse proteins in E. coli without the need for exogenous degraders or protein fusions.
- Zhendong Li
- , Gan Qiao
- & Liming Liu
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Article
| Open AccessRegulation of plant immunity through histone H3 β-hydroxybutyrylation-mediated transcriptional control
The function of histone lysine β-hydroxybutyrylation (Kbhb) is unclear in plants. Here, the authors show that H3K9bhb is enriched at transcription start sites in rice and regulates gene expression during immune responses.
- Qiutao Xu
- , Zhengting Chen
- & Xiaoyang Chen
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Article
| Open AccessLIN-39 is a neuron-specific developmental determinant of longevity in Caenorhabditis elegans with reduced insulin signaling
Kavšek et al. reveal in this C. elegans study that the LIN-39 and DAF-16 transcription factors cooperate to regulate enhancer activity in VC neurons and ensure proper neuron maturation. This in turn is required for longevity under reduced IIS conditions, linking chromatin dynamics to lifespan extension.
- Alan Kavšek
- , Jérôme Salignon
- & Christian G. Riedel
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Article
| Open AccessSubversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma
The EWSR1::FLI1 fusion protein is the oncogenic driver of Ewing sarcoma (EwS). Here, the authors find that EWSR1::FLI1 plays a non-canonical role in mRNA decay via interactions with the CCR4-NOT deadenylation complex and the RNA-binding protein HuR. This role uncovers a new therapeutic vulnerability of EwS to HuR inhibition.
- Bartimée Galvan
- , Loïc Ongena
- & Franck Dequiedt
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Article
| Open AccessATF7IP/SETDB1-mediated epigenetic programming regulates thymic homing and T lymphopoiesis of hematopoietic progenitors during embryogenesis
Here they show that ATF7IP/SETDB1-mediated epigenetic programming governs T lymphoid progenitor trafficking and differentiation, providing important insights into the pathogenesis of human T lymphoid diseases.
- Wenqi Chen
- , Jiaxin Wu
- & Tao P. Zhong
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Article
| Open AccessComprehensive RAD51C ovarian cancer variant analysis uncouples homologous recombination and replicative functions
The tumor suppressor RAD51C is mutated in ovarian cancers. Through variant analysis the authors identify a mutation cluster in the RAD51C Walker B region important for the repair of DNA double-strand breaks and replicative damage. By identifying Walker B separation-of-function alleles, they show that these activities can be uncoupled.
- Hayley L. Rein
- , Yashpal Rawal
- & Kara A. Bernstein
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Article
| Open AccessRefined DNA repair manipulation enables a universal knock-in strategy in mouse embryos
Precise CRISPR-based gene knock-in is often limited by variable efficiency across sgRNAs. Here, the authors develop ChemiCATI, a universal strategy combining Polq knockdown and AZD7648 treatment, enabling efficient and predictable integration across multiple loci in mouse embryos.
- Hongyu Chen
- , Qingtong Tan
- & Zhen Liu
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Article
| Open AccessRetrograde signals control dynamic changes to the chromatin state at photosynthesis-associated loci
Quevedo et al., demonstrate that the epigenome is closely connected to organellar activities through retrograde signals, and that such signals drive specific changes to chromatin availability that permit full activation of photosynthesis genes.
- Marti Quevedo
- , Ivona Kubalová
- & Åsa Strand
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Article
| Open AccessPhase separated condensates of ATRX regulate neural progenitor identity
Tomooka et al. demonstrate that phase-separated ATRX condensates play an essential role in maintaining human neural progenitor identity through chromatin regulation and transcriptional control.
- Ryo Tomooka
- , Tsukasa Sanosaka
- & Jun Kohyama
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Article
| Open AccessForced expression of MSR repeat transcripts above a threshold limit breaks heterochromatin organisation
Transcription of Major Satellite Repeats above a threshold limit reveals that the structural organisation of mouse heterochromatin is dependent on its transcriptional chromatin state and its associated repeat RNA.
- Reagan W. Ching
- , Kalina M. Świst-Rosowska
- & Thomas Jenuwein
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Article
| Open AccessOpposing roles of pseudokinases NRBP1 and NRBP2 in regulating L1 retrotransposition
Gene duplication often leads to paralogs with distinct functions. Here, the authors show that two paralogous proteins NRBP1 and NRBP2 oppositely regulate L1 retrotransposition by modulating L1 mRNA and ORF1p association, with NRBP2 promoting NRBP1 degradation via heterodimerization.
- Wei Yang
- , Shaobo Cong
- & Wenjing Qi
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Article
| Open AccessTRF1 relies on fork reversal to prevent fragility at human telomeres
Telomere replication poses unique challenges. Here, the authors show that TRF1 prevents telomere fragility by promoting replication fork reversal, a process dependent on RNA:DNA hybrids and necessary for TFIIH-mediated restart of leading strand synthesis. When fork reversal is impaired, PrimPol serves as a compensatory mechanism.
- Mélina Vaurs
- , Eloïse Claude
- & Anabelle Decottignies
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Article
| Open AccessQuantification of transcript isoforms at the single-cell level using SCALPEL
Single-cell RNA-seq facilitates the study of transcriptome diversity in individual cells. Here, authors introduce a tool for isoform quantification at the single-cell level using 3’ scRNA-seq data, contributing to the study of post-transcriptional gene regulation in individual cells.
- Franz Ake
- , Marcel Schilling
- & Mireya Plass
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Article
| Open AccessHP1 loses its chromatin clustering and phase separation function across evolution
Here, the authors compare HP1 from fission yeast, fly and mouse, and find that the propensity of HP1 to phase-separate and to cluster heterochromatin decrease in this order, suggesting an evolutionary adaptation of HP1 function.
- Sanâa Bensaha
- , Dominika Lewandowska
- & Fabian Erdel
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Article
| Open AccessComprehensive resolution and classification of the Epstein Barr virus transcriptome
Here, the authors profile the EBV transcriptome during lytic replication and identify over 1,400 unique EBV transcript isoforms, resolving major isoforms of most lytic open reading frames, alternative and biphasic promoters and an enhancer function for the viral lytic origin of replication.
- Truong D. Nguyen
- , Jia Wang
- & Erik K. Flemington
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Article
| Open AccessRegulating cleavage activity and enabling microRNA detection with split sgRNA in Cas12b
CRISPR-Cas12b diagnostics are limited by sgRNAs length. Here, authors present a split sgRNA approach enabling precise Cas12b activity regulation and direct microRNA detection without reverse transcription, using clinical samples.
- Jiaqi Wang
- , Xiaofang Ye
- & Chaoxing Liu
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Article
| Open AccessChronic cerebral hypoperfusion induces venous dysfunction via EPAS1 regulation in mice
How changes in brain blood vessels lead to a chronic reduction in blood flow and, consequently, to vascular dementia is poorly understood. Here, the authors show that venous endothelial dysfunction driven by EPAS1 promotes abnormal vascular remodeling and contributes to cognitive decline.
- Vanessa Kristina Wazny
- , Aparna Mahadevan
- & Christine Cheung
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Article
| Open AccessHigh-coverage allele-resolved single-cell DNA methylation profiling reveals cell lineage, X-inactivation state, and replication dynamics
Here, the authors describe scDEEP-mC, an improved single-cell whole-genome bisulfite sequencing method for complex libraries and deep genomic coverage, and show advanced analyses of allele-specific methylation, replication dynamics, and X-inactivation.
- Nathan J. Spix
- , Walid Abi Habib
- & Peter W. Laird
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Article
| Open AccessDishevelled-1 regulates global transcriptomic changes and associates with ETS1 transcription factor
Currently, nuclear roles for DVL1 and its involvement in gene regulation remained unclear. Here the authors reveal that altering DVL1 expression significantly reshapes gene expression patterns across the genome and identify ETS1 as a key transcription factor that partners with nuclear DVL1, guiding it to specific genomic targets.
- Dalia Martinez-Marin
- , Monica Sharma
- & Kevin Pruitt
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Article
| Open AccessRNA-binding protein YebC enhances translation of proline-rich amino acid stretches in bacteria
Polyproline motifs induce ribosome stalling during translation. Here, Ignatov et al. identify RNA-binding proteins in the pathogenic bacterium Streptococcus pyogenes, and show that one of these proteins, YebC, acts as a translation factor enhancing translation of proteins with polyproline motifs.
- Dmitriy Ignatov
- , Vivekanandan Shanmuganathan
- & Emmanuelle Charpentier
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Article
| Open AccessNuclear morphometrics coupled with machine learning identifies dynamic states of senescence across age
Aging leads to progressive loss of effective tissue regeneration, which has been linked to the accumulation of senescent cells. Here, the authors use machine learning to identify a stable nuclear morphometric phenotype that detects senescent cells across tissues and age, enabling their quantification and mapping in diverse environments.
- Sahil A. Mapkar
- , Sarah A. Bliss
- & Michael N. Wosczyna
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- Cell division
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- DNA metabolism
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- Post-translational modifications
- Protein folding
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