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| Open AccessDetecting m6A at single-molecular resolution via direct RNA sequencing and realistic training data
Direct RNA-seq offers the possibility to identify RNA modifications on single molecules. Here, the authors report on the synthesis of biologically realistic training data and the development of mAFiA that accurately detects m6A on single read level.
- Adrian Chan
- , Isabel S. Naarmann-de Vries
- & Christoph Dieterich
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Article
| Open AccessStructural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A
SV2A is a receptor for botulinum neurotoxin (BoNT) and new generation antiepileptic drugs (AEDs). Here the authors report cryo-EM structures of SV2A in complex with BoNT receptor binding domain and AEDs highlighting the difference in the binding affinity between AEDs.
- Atsushi Yamagata
- , Kaori Ito
- & Mikako Shirouzu
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Article
| Open AccessIlluminating the complete ß-cell mass of the human pancreas- signifying a new view on the islets of Langerhans
The pancreatic islets of Langerhans play a pivotal role in regulating blood glucose homeostasis through the regulated secretion of the hormones insulin and glucagon. Here, the authors use deep tissue 3D imaging to re-construct the entire human pancreas at microscopic resolution and display previously unrecognized heterogeneities in the islet’s cellularity with pre-clinical and clinical implications.
- Joakim Lehrstrand
- , Wayne I. L. Davies
- & Ulf Ahlgren
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Article
| Open AccessTowards establishing a fungal economics spectrum in soil saprobic fungi
Challenges in obtaining empirical trait data hinder the development of trait-based frameworks for soil microbes. Here, the authors analyse traits of saprobic fungal isolates from a grassland site to propose a fungal economics spectrum, suggesting a general trait framework for soil fungi.
- Tessa Camenzind
- , Carlos A. Aguilar-Trigueros
- & Matthias C. Rillig
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Article
| Open AccessMechanoelectronic stimulation of autologous extracellular vesicle biosynthesis implant for gut microbiota modulation
Pathogenic gut microbiota is responsible for a few debilitating gastrointestinal Diseases. Here, the authors develop a wireless mechanoelectronic device designed to manufacture of functional vesicles in vivo to regulate microbiome.
- Shuangshuang Wan
- , Kepeng Wang
- & Lianhui Wang
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Article
| Open AccessImpact of PEG sensitization on the efficacy of PEG hydrogel-mediated tissue engineering
Concerns over the immunogenicity of poly(ethylene glycol) (PEG) are growing, and the implications for tissue engineering are unknown. Here the authors evaluate the impact of anti-PEG antibodies and PEG immunogenicity on the efficacy of a PEG hydrogel-based tissue engineering therapy.
- Alisa H. Isaac
- , Sarea Y. Recalde Phillips
- & Daniel L. Alge
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Article
| Open AccessLate-stage meta-C–H alkylation of pharmaceuticals to modulate biological properties and expedite molecular optimisation in a single step
Installation of small aliphatic motifs within pharmaceuticals provides a medicinally relevant tool in drug discovery programmes. Here, the authors report a late-stage meta-C–H alkylation method facilitating the biological properties modulation of therapeutic agents.
- Lucas Guillemard
- , Lutz Ackermann
- & Magnus J. Johansson
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Matters Arising
| Open AccessThe wheat stripe rust resistance gene YrNAM is Yr10
- Katherine Dibley
- , Matthias Jost
- & Peng Zhang
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Article
| Open AccessImprovement of immune dysregulation in individuals with long COVID at 24-months following SARS-CoV-2 infection
Post-acute sequelae of COVID (PASC) or long-COVID can affect a proportion of those infected but this is not well understood. Here the authors perform a single cell transcriptomics analysis of immune cells from long-COVID patients at 24 months and find that cell changes observed at 3 and 8 months do not persist to 24 months.
- Chansavath Phetsouphanh
- , Brendan Jacka
- & Gail V. Matthews
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Article
| Open AccessInflammation and cytomegalovirus viremia during pregnancy drive sex-differentiated differences in mortality and immune development in HIV-exposed infants
HIV exposed but uninfected infants may face an increased risk of serious infection and mortality. In this work, the authors utilise a cohort from rural Zimbabwe to explore the biological mechanisms underlying infant mortality.
- Ceri Evans
- , Kuda Mutasa
- & Andrew J. Prendergast
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Article
| Open AccessMmcA is an electron conduit that facilitates both intracellular and extracellular electron transport in Methanosarcina acetivorans
Methanogens conserve energy through methane generation, however the biochemical details of anaerobic respiration in methanogens remain unclear. Here, authors show a multiheme c-type cytochrome, MmcA, plays a critical role in methanogenesis and anaerobic respiration.
- Dinesh Gupta
- , Keying Chen
- & Dipti D. Nayak
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Article
| Open AccessCross-link assisted spatial proteomics to map sub-organelle proteomes and membrane protein topologies
The spatial mapping of proteins can give important functional insights. Here, Zhu et al. develop a cross-linking mass spectrometry-based spatial proteomics method that does not require protein engineering, affords sub-organelle resolution, and elucidates both protein locations and membrane topologies.
- Ying Zhu
- , Kerem Can Akkaya
- & Fan Liu
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Article
| Open AccessAn pair of an atypical NLR encoding genes confer Asian soybean rust resistance in soybean
Asian soybean rust (ASR) is a devastating disease of soybean. Here, the author report the identification of an atypical pair of nucleotide-binding leucine-rich repeat (NLR) encoding genes and how they function together to confer broad-spectrum resistance to ASR.
- Qingnan Hao
- , Hongli Yang
- & Xinan Zhou
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Article
| Open AccessPhylogenomic profiles of whole-genome duplications in Poaceae and landscape of differential duplicate retention and losses among major Poaceae lineages
Grasses share a whole-genome duplication called rho, but the adaptive implications are unclear. Here, the authors conduct phylogenomic and phylotranscriptomic analyses of 363 grasses, identifying additional whole-genome duplications and finding that duplicates are implicated in environmental adaptations or morphogenesis.
- Taikui Zhang
- , Weichen Huang
- & Hong Ma
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Article
| Open AccessData-driven recombination detection in viral genomes
Here, the authors present RecombinHunt, a computational method based on big data analysis, that enhances community-based detection of recombinant viral lineages.
- Tommaso Alfonsi
- , Anna Bernasconi
- & Stefano Ceri
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Article
| Open AccessThe DEAD-box ATPase Dbp10/DDX54 initiates peptidyl transferase center formation during 60S ribosome biogenesis
Cruz et al. describe the role of Dbp10/DDX54 in remodeling rRNA structure within the immature eukaryotic peptidyl transferase center of the ribosome, coupling energy-dependent catalysis to a post-catalytic role in factor exchange during 60S ribosomal subunit assembly.
- Victor E. Cruz
- , Christine S. Weirich
- & Jan P. Erzberger
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Article
| Open AccessPhysiological DNA damage promotes functional endoreplication of mammary gland alveolar cells during lactation
Breastfeeding confers lifelong benefits to both mother and child, yet women worldwide experience lactation insufficiency. Here, the authors show that DNA damage occurring in the breast during pregnancy drives the generation of milk-producing cells.
- Rut Molinuevo
- , Julien Menendez
- & Lindsay Hinck
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Article
| Open AccessEngineering a synthetic gene circuit for high-performance inducible expression in mammalian systems
Inducible gene expression systems can be used to control the expression of a gene of interest by means of small molecules. Here the authors present CASwitch, a synthetic gene circuit platform enhancing inducible gene expression systems by reducing leakiness and boosting fold induction, for real world applications like gene therapy vector production and biosensors.
- Giuliano De Carluccio
- , Virginia Fusco
- & Diego di Bernardo
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Article
| Open AccessReconstruction of macroglia and adult neurogenesis evolution through cross-species single-cell transcriptomic analyses
Macroglia are neural cells that have garnered less interest than neurons despite their crucial functions including neurogenesis. Here the authors use sequencing from several species to investigate the evolution of macroglia and of adult neurogenesis.
- David Morizet
- , Isabelle Foucher
- & Laure Bally-Cuif
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Article
| Open AccessSurvival and rapid resuscitation permit limited productivity in desert microbial communities
Prompt physiological reactivation after rainfall pulses may be key for microbial survival in arid ecosystems. Here, the authors use stable isotope tracers, single-cell NanoSIMS and metatranscriptomics to shed light on how desert biocrust microbial communities respond to rewetting.
- Stefanie Imminger
- , Dimitri V. Meier
- & Dagmar Woebken
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Article
| Open AccessA cfDNA methylation-based tissue-of-origin classifier for cancers of unknown primary
Cancer of unknown primary is difficult to treat due to high heterogeneity in treatment response depending on the original site. Here, the authors use DNA methylation data to develop a machine learning classifier to predict the tissue of origin from a single blood draw, allowing potential treatment changes to improve efficacy.
- Alicia-Marie Conway
- , Simon P. Pearce
- & Dominic G. Rothwell
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Matters Arising
| Open AccessPopulation genetic considerations regarding the interpretation of within-patient SARS-CoV-2 polymorphism data
- Vivak Soni
- , John W. Terbot II
- & Jeffrey D. Jensen
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Article
| Open AccessSynergistic effect of two human-like monoclonal antibodies confers protection against orthopoxvirus infection
In this study, the authors show that a single dose of a combination of two human-like monoclonal antibodies protect mice in therapeutic treatment against challenges with ectromelia virus and monkeypox virus. Combination treatment provided more effective viral clearance than single antibody treatment.
- Hadas Tamir
- , Tal Noy-Porat
- & Tomer Israely
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Article
| Open AccessUnexpectedly uneven distribution of functional trade-offs explains cranial morphological diversity in carnivores
Functional trade-offs can affect phenotypic variation. Here, the authors examine trade-offs between bite force and speed in 132 carnivore species, finding that optimising for velocity can be obtained in more ways than optimising for force, and this may impact morphological variability.
- Gabriele Sansalone
- , Stephen Wroe
- & Carmelo Fruciano
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Article
| 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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Article
| Open AccessMechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2
The biogenesis of iron-sulfur proteins in eukaryotes is initiated by the mitochondrial core ISC complex. Here, the authors provide structural, biochemical and spectroscopic data to characterize sulfur transfer intermediates in the core ISC complex.
- Vinzent Schulz
- , Ralf Steinhilper
- & Roland Lill
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Article
| Open AccessCryo-EM structures of adenosine receptor A3AR bound to selective agonists
Adenosine A3 receptor (A3AR) holds promise for treating inflammatory and cancer conditions. Here, Cai et al. present cryo-EM structures of A3AR bound to agonists CF101 and CF102, offering insights into its activation and ligand interaction, crucial for developing targeted therapies.
- Hongmin Cai
- , Shimeng Guo
- & H. Eric Xu
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Matters Arising
| Open AccessReply to: Population genetic considerations regarding the interpretation of within-patient SARS-CoV-2 polymorphism data
- Chase W. Nelson
- , Leo L. M. Poon
- & Haogao Gu
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Article
| Open AccessHost response during unresolved urinary tract infection alters female mammary tissue homeostasis through collagen deposition and TIMP1
Urinary tract infections (UTIs) can elicit systemic host-responses. Here the authors report that, in a mouse model, unresolved UTI is associated with alterations of the mammary tissue, including collagen deposition and hyperplasia.
- Samantha Henry
- , Steven Macauley Lewis
- & Camila Oresco dos Santos
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Article
| Open AccessExposing the molecular heterogeneity of glycosylated biotherapeutics
The molecular heterogeneity of glycosylated biotherapeutics often complicates analysis by intact mass spectrometry. Here, the authors propose a simplified procedure for characterization that employs proton transfer charge reduction. Integration with glycomic and glycopeptide datasets can further provide glycoform-level information.
- Luis F. Schachner
- , Christopher Mullen
- & Wendy Sandoval
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Article
| Open AccessUveal melanoma immunogenomics predict immunotherapy resistance and susceptibility
Metastatic uveal melanoma is poorly responsive to immune checkpoint inhibition. Here, the authors analyse 100 uveal melanoma metastases using bulk and single cell RNA-seq, TCR analysis, and immune reactivity to show potent, yet, quiescent tumour infiltrating lymphocytes that can be harnessed by adoptive transfer to confer tumour immunity.
- Shravan Leonard-Murali
- , Chetana Bhaskarla
- & Udai S. Kammula
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Article
| Open AccessA fine-scale Arabidopsis chromatin landscape reveals chromatin conformation-associated transcriptional dynamics
Plants utilize transcriptional dynamics to adapt to cold stress. Here, Zhang et al. describe a network of chromatin interactions between gene promoters across the Arabidopsis genome that could facilitate co-regulation of gene expression during cold stress.
- Yueying Zhang
- , Qianli Dong
- & Huakun Zhang
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Article
| Open AccessInsights into the inhibition of protospacer integration via direct interaction between Cas2 and AcrVA5
Here, the authors characterize an anti-CRISPR protein that prevents protospacer integration by Cas1-Cas2, providing structural insights that may benefit CRISPR-Cas systems research.
- Mingfang Bi
- , Wenjing Su
- & Xiaobing Mo
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Article
| Open AccessEmerging variants develop total escape from potent monoclonal antibodies induced by BA.4/5 infection
Many emerging SARS-CoV-2 variants partially escape the humoral immune response. Here, Liu et al. characterize 28 antibodies from BA.4/5 breakthrough infections and find attrition of neutralization and complete loss of function for variants with Spike mutations at positions 455 and 456.
- Chang Liu
- , Raksha Das
- & Gavin R. Screaton
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Article
| Open AccessCXCL5 activates CXCR2 in nociceptive sensory neurons to drive joint pain and inflammation in experimental gouty arthritis
Here, the authors demonstrate that CXCL5 expression is increased in ankle joints of gouty arthritis model mice. CXCL5-neuronal CXCR2-TRPA1 axis contributes to gouty arthritis pain, neutrophil influx and joint inflammation.
- Chengyu Yin
- , Boyu Liu
- & Boyi Liu
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Article
| Open AccessUltrasensitive single-step CRISPR detection of monkeypox virus in minutes with a vest-pocket diagnostic device
The recent monkeypox outbreak highlighted the need for rapid and accurate diagnosis of this disease. Here, authors develop an ultrasensitive and streamlined CRISPR assay using miniaturized device, which can detect monkeypox virus in rash fluid swab, oral swab, saliva, and urine within 15 minutes.
- Yunxiang Wang
- , Hong Chen
- & Shengqi Wang
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Article
| Open AccessTertiary structure and conformational dynamics of the anti-amyloidogenic chaperone DNAJB6b at atomistic resolution
Adupa et al show how the anti-amyloidogenic molecular chaperone DNAJB6 adopts three conformational states that determine the accessibility of its substrate binding domain. In all states, interactions with HSP70 are shielded, suggesting that functional interactions only may occur upon substrate binding.
- Vasista Adupa
- , Elizaveta Ustyantseva
- & Patrick R. Onck
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Article
| Open AccessRobust compression and detection of epileptiform patterns in ECoG using a real-time spiking neural network hardware framework
Costa et al. designed a modular spiking neural network in a neuromorphic device with heterogeneous silicon neurons that remotely detects epileptiform discharges and High Frequency Oscillations in intra-operative EEG during epilepsy surgery in real-time.
- Filippo Costa
- , Eline V. Schaft
- & Johannes Sarnthein
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Article
| Open AccessDistinct information conveyed to the olfactory bulb by feedforward input from the nose and feedback from the cortex
How the feedforward information from the nose and feedback from the cortex interact in the olfactory bulb is not fully understood. Here, by imaging olfactory sensory neurons and cortical projections to the olfactory bulb, the authors show that sensory transformations contained within both streams.
- Joseph D. Zak
- , Gautam Reddy
- & Venkatesh N. Murthy
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Article
| Open AccessATP-free in vitro biotransformation of starch-derived maltodextrin into poly-3-hydroxybutyrate via acetyl-CoA
Several in vitro synthetic enzymatic biosystems (ivSEBs) to produce poly-3-hydroxybutyrate (PHB) via acetyl-coenzyme A (acetyl-CoA) have been reported, but suffer from complicated operation procedures, low yields, and/or dependence on costly ATP. Here, the authors report the design of an ATP-free ivSEB for one-pot, high-yield PHB biosynthesis via acetyl-CoA utilizing starch-derived maltodextrin as the sole substrate.
- Xinlei Wei
- , Xue Yang
- & Chun You
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Article
| Open AccessDifferentiation shifts from a reversible to an irreversible heterochromatin state at the DM1 locus
Gene-editing at the DM1 mutant locus revealed a fundamental difference between undifferentiated and differentiated cell states: abnormal epigenetic modifications cannot be repaired after differentiation.
- Tayma Handal
- , Sarah Juster
- & Rachel Eiges
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Article
| Open AccessBacterial peptidoglycan acts as a digestive signal mediating host adaptation to diverse food resources in C. elegans
Here, by using a food digestion model in C. elegans, the authors identify a mechanism by which bacterial peptidoglycan (PGN) interacts with Bacterial Colonization Factor-1 (BCF-1) triggering C. elegans to expand its ability to consume a wide range of foods in their natural environment.
- Fanrui Hao
- , Huimin Liu
- & Bin Qi
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Article
| Open AccessThe physiological interactome of TCR-like antibody therapeutics in human tissues
The use of bispecific antibodies to target tumour-specific epitopes presented by MHC molecules in tumour tissue is a promising avenue for cancer immunotherapy. Here the authors use a mass-spectrometry guided analysis to identify off-target MHC-peptide complexes that bind to TCR-like antibodies next to the target peptide, enabling a novel approach to monitoring of antibody specificity during clinical maturation and development.
- Estelle Marrer-Berger
- , Annalisa Nicastri
- & Nicola Ternette
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Article
| Open AccessSm-like protein Rof inhibits transcription termination factor ρ by binding site obstruction and conformational insulation
Said et al. used cryoEM, biochemistry and bioinformatics to uncover how the Sm-like protein Rof regulates transcription termination. Rof binds termination factor ρ, inhibiting ρ ring closure and its association with RNA or transcription complexes.
- Nelly Said
- , Mark Finazzo
- & Markus C. Wahl
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Article
| Open AccessOptogenetic control of mRNA condensation reveals an intimate link between condensate material properties and functions
Biomolecular condensates play important roles in diverse cellular activities. Here the authors employ optogenetic tool and single-molecule mRNA imaging, showing that sequestering target mRNAs into condensates lead to translation inhibition.
- Min Lee
- , Hyungseok C. Moon
- & Yongdae Shin
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Article
| Open AccessDynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase
Here the authors present the cryo-EM structure of active and inhibited human MTHFR, revealing a dynamic inhibitory mechanism dependent on dual SAM binding. The resulting closed conformation features an autoinhibitory element effectively blocking enzymatic activity.
- Linnea K. M. Blomgren
- , Melanie Huber
- & Thomas J. McCorvie
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Article
| Open AccessConjunctive encoding of exploratory intentions and spatial information in the hippocampus
The hippocampus maps space, but its role in encoding investigatory intentions is unclear. Here the authors show that certain CA1 neurons encode both spatial information and animals’ intention to explore, depending on input from lateral entorhinal cortex.
- Yi-Fan Zeng
- , Ke-Xin Yang
- & Ning Zhou
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Article
| Open AccessDonor regulatory T cells rapidly adapt to recipient tissues to control murine acute graft-versus-host disease
Graft-versus-Host disease is a major complication after allogeneic bone marrow transplantation and is ameliorated by adoptively transferred donor regulatory T cells. Here, the authors apply transcriptomic and TCR profiling to assess regulatory T cell organ-specific adaptation in murine bone marrow transplantation models.
- David J. Dittmar
- , Franziska Pielmeier
- & Michael Rehli
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Article
| Open AccessReciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry
Unveiling the regulation of mitotic protein degradation is crucial for cancer therapy. Here, the authors reveal that a reciprocal inhibition of PIN1-APC/CCDH1 controls the cell cycle and mitotic protein degradation, offering a synergistic anti-tumor strategy.
- Shizhong Ke
- , Fabin Dang
- & Kun Ping Lu
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