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| Open AccessThe bacterial replication origin BUS promotes nucleobase capture
Here, the authors show that a DnaA:origin complex promotes specific nucleobase capture from a single DNA strand. It is proposed that this mechanism may play a key role stimulating opening of bacterial chromosome origins.
- Simone Pelliciari
- , Salomé Bodet-Lefèvre
- & Heath Murray
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Article
| Open AccessRemodeling of the ribosomal quality control and integrated stress response by viral ubiquitin deconjugases
Here, the authors show how the vDUB from the large tegument protein from the human herpes virus can reprogram translation in host cells by modulating the activity of the ribosome quality machinery and activating the integrated stress response.
- Jiangnan Liu
- , Noemi Nagy
- & Maria G. Masucci
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Article
| Open AccessNuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation
Zhen and colleagues show that nuclear cGAS represses L1 retrotransposition to stabilize the genome by enhancing the interaction between ORF2p and the E3 ligase TRIM41 upon DNA damage, which leads to the ubiquitination and degradation of ORF2p.
- Zhengyi Zhen
- , Yu Chen
- & Zhiyong Mao
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Article
| Open Access5mC modification orchestrates choriogenesis and fertilization by preventing prolonged ftz-f1 expression
The mechanism by which DNA methylation regulates female reproduction in insects is largely unknown. Here Zhao et al. demonstrate that the 5mC modification orchestrates timely choriogenesis and proper fertilization by preventing prolonged ftz-f1 expression in the German cockroach.
- Zheng Zhao
- , Liang Li
- & Chonghua Ren
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Article
| Open AccessThe assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination
The role that cellular bioenergetics plays in the early stages of Alzheimer’s disease is poorly understood. Here the authors describe structures of key OXPHOS assembly proteins, providing insights into how these pathways are interlinked and regulated.
- Lindsay McGregor
- , Samira Acajjaoui
- & Montserrat Soler-Lopez
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Article
| Open AccessImmunoproximity biotinylation reveals the axon initial segment proteome
The molecular composition of the axon initial segment (AIS) is not well defined. Here, the authors used a ratiometric immunoproximity labeling strategy on fixed wild-type rat neurons to identify the AIS proteome, including the scaffolding protein SCRIB.
- Wei Zhang
- , Yu Fu
- & Peng Zou
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Article
| Open AccessAn allele-selective inter-chromosomal protein bridge supports monogenic antigen expression in the African trypanosome
Nuclear organization impacts allelic exclusion. Here, the authors describe a self-limiting protein bridge that connects two chromosomes, and two transcription and splicing compartments, to maintain monogenic VSG expression in the African trypanosome.
- Joana R. C. Faria
- , Michele Tinti
- & David Horn
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Article
| Open AccessDissecting the basis for differential substrate specificity of ADAR1 and ADAR2
Human ADAR1 and ADAR2 edit millions of adenosines transcriptome-wide, altering RNA structure. Here the authors show that variations in RNA binding domains influence site-specific editing, enhancing ADAR2-targeted therapeutics.
- Marlon S. Zambrano-Mila
- , Monika Witzenberger
- & Schraga Schwartz
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Article
| Open AccessPhase-separated CCER1 coordinates the histone-to-protamine transition and male fertility
Here the authors reveal that phase‐separated nuclear CCER1 condensates are required for male fertility by mediating chromatin condensation and histone epigenetic modification, while loss‐of‐function variants of human CCER1 are pathogenic in patients with nonobstructive azoospermia (NOA).
- Dongdong Qin
- , Yayun Gu
- & Zhibin Hu
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Article
| Open AccessRIF1 regulates early replication timing in murine B cells
Here the authors show that in activated B cells, RIF1 primarily binds early-replicating active chromatin and promotes early replication. RIF1 and MCM proteins establish early replication timing signatures genome-wide and ensure early replication of highly transcribed genes.
- Daniel Malzl
- , Mihaela Peycheva
- & Rushad Pavri
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Article
| Open AccessThe distinct translational landscapes of gram-negative Salmonella and gram-positive Listeria
In this work, Bryant and Lastovka et al. utilise advanced ribosome profiling and transcriptomics techniques, to reveal distinct translation control mechanisms in Salmonella and Listeria, two highly divergent bacterial species.
- Owain J. Bryant
- , Filip Lastovka
- & Betty Y. -W. Chung
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Article
| Open AccessLoss of cohesin regulator PDS5A reveals repressive role of Polycomb loops
Through a genetic screen, the authors find that the cohesin regulator PDS5A is required for Polycomb target gene silencing. Derepression upon cohesin dysregulation is linked to loss of Polycomb loops without change in repressive chromatin domains.
- Daniel Bsteh
- , Hagar F. Moussa
- & Oliver Bell
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Article
| Open AccessThe long non-coding RNA HOTAIR contributes to joint-specific gene expression in rheumatoid arthritis
Although patients with rheumatoid arthritis (RA) usually exhibit symmetrical joint involvement, some can develop alternative patterns of arthritis, often translating into differences in responsiveness to treatment. In this study, the authors propose that the long-noncoding RNA, HOTAIR, might contribute to these differences.
- Muriel Elhai
- , Raphael Micheroli
- & Caroline Ospelt
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Article
| Open AccessSingle cell multi-omics reveal intra-cell-line heterogeneity across human cancer cell lines
Intra-cell line heterogeneity remains to be characterized. Here, the use of single multi-omics on a large panel of human cell lines identifies copy number variation, epigenetic variation and extrachromosomal DNA distribution as the main contributors to intra-cell line heterogeneity.
- Qionghua Zhu
- , Xin Zhao
- & Liang Wu
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Article
| Open AccessStructure of the complete Saccharomyces cerevisiae Rpd3S-nucleosome complex
In this study, the authors present the cryogenic electron microscopy reconstruction of the Rpd3S complex engaged with a nucleosome. The corresponding model describes the interactions that facilitate histone deacetylation within gene bodies by the Rpd3S complex.
- Jonathan W. Markert
- , Seychelle M. Vos
- & Lucas Farnung
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Article
| Open AccessLncRNA MIR200CHG inhibits EMT in gastric cancer by stabilizing miR-200c from target-directed miRNA degradation
The roles of long non-coding RNAs (lncRNAs) in different subtypes of gastric cancer (GC) remain to be characterized. Here, the authors identify lncRNA MIR200CHG as a master regulator of Microsatellite stable (MSS)/epithelial-mesenchymal transition (EMT) GC subtype, which inhibits EMT and metastasis by stabilizing miR-200c.
- Yixiao Zhu
- , Chengmei Huang
- & Xin Wang
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Article
| Open AccessThe separation pin distinguishes the pro– and anti–recombinogenic functions of Saccharomyces cerevisiae Srs2
Here the authors report that the main role of the protein Srs2 in homologous recombination is to remove Rad51 from single stranded DNA, rather than to drive synthesis-dependent strand annealing.
- Aviv Meir
- , Vivek B. Raina
- & Eric C. Greene
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Article
| Open AccessExcess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy
The prion protein PrPC is known to play a role in skeletal muscle development and physiology, including in myopathy. Here, the authors report that excess PrPC binds microRNAs that enhance its aggregation, which inhibits autophagy in muscle cells.
- Jing Tao
- , Yanping Zeng
- & Yi Liang
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Article
| Open AccessCharacterization of nucleolar SUMO isopeptidases unveils a general p53-independent checkpoint of impaired ribosome biogenesis
Ribosome biogenesis is tightly coordinated with cell-cycle progression. By characterizing the SUMO isopeptidases SENP3/SENP5, Doenig et al. identify a long-sought p53-independent impaired ribosome checkpoint that converges on downregulation of CDK6.
- Judith Dönig
- , Hannah Mende
- & Stefan Müller
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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 AccessAcetylation regulates the oligomerization state and activity of RNase J, the Helicobacter pylori major ribonuclease
Here the authors find that RNase J, the major ribonuclease of the gastric pathogen Helicobacter pylori is post-translationally modified by acetylation. They show that acetylation can control RNase J activity.
- Alejandro Tejada-Arranz
- , Aleksei Lulla
- & Hilde De Reuse
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Article
| Open AccessProgrammable de novo designed coiled coil-mediated phase separation in mammalian cells
Membraneless liquid compartments based on phase-separating biopolymers have been observed in diverse cell types and attributed to weak multivalent interactions predominantly based on intrinsically disordered domains. Here the authors design protein liquid condensates from tunable concatenated coiled-coil dimer modules, unraveling the principles for coexisting condensates, chemical regulation, formation from either one or two polypeptide components in mammalian cells.
- Maruša Ramšak
- , Dominique A. Ramirez
- & Roman Jerala
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Article
| Open AccessQuorum-sensing synthase mutations re-calibrate autoinducer concentrations in clinical isolates of Pseudomonas aeruginosa to enhance pathogenesis
Simanek et al. discovered variants that arise in the protein responsible for synthesizing a molecule required for bacterial communication, which mediates the progression of virulence in the pathogen Pseudomonas aeruginosa.
- Kayla A. Simanek
- , Megan L. Schumacher
- & Jon E. Paczkowski
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Article
| Open AccessStructural insights into the role of GTPBP10 in the RNA maturation of the mitoribosome
The biogenesis of ribosomes is a highly coordinated process. Here, Nguyen et al. uncover how the mitochondria-specific interplay of the GTPases GTPBP10 and GTPBP7 ensures proper maturation of the catalytic RNA center of the human mitoribosome.
- Thu Giang Nguyen
- , Christina Ritter
- & Eva Kummer
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Article
| Open AccessDefining a core configuration for human centromeres during mitosis
The detailed 3D organization of human centromere components is unknown. Here, the authors use super-resolution microscopy to present a working model for a common core centromere structure.
- Ayantika Sen Gupta
- , Chris Seidel
- & Jennifer L. Gerton
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Article
| Open AccessBuilding a eukaryotic chromosome arm by de novo design and synthesis
In Saccharomyces cerevisiae, the left arm of chromosome XII only requires 12 genes to maintain cell viability, whereas 25 genes are needed for robust fitness. Here the authors demonstrate that the entire arm can be replaced by a neochromosome with completely artificial sequences.
- Shuangying Jiang
- , Zhouqing Luo
- & Junbiao Dai
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Article
| Open AccessCaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection
Here the authors show that the calcium-sensing kinase CaMKK2 phosphorylates STN1 in response to replication stress and elevated cytosolic calcium concentration to protect stalled replication forks from aberrant MRE11 degradation. Cancer-associated STN1 mutations abolish STN1 phosphorylation, resulting in fork instability.
- Rishi Kumar Jaiswal
- , Kai-Hang Lei
- & Weihang Chai
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Article
| Open AccessBile proteome reveals biliary regeneration during normothermic preservation of human donor livers
Normothermic machine perfusion (NMP) is increasingly used for preserving and evaluating donor livers before transplantation. Here, the authors demonstrate increased regenerative protein profiles in the bile of perfused livers considered suitable for transplantation, providing insight into the mechanisms linked to recovery of the biliary tree following ischemia-reperfusion injury.
- Adam M. Thorne
- , Justina C. Wolters
- & Vincent E. de Meijer
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Article
| Open AccessThe SPOC proteins DIDO3 and PHF3 co-regulate gene expression and neuronal differentiation
Death-inducer obliterator 3 (DIDO3) and PHD finger protein 3 (PHF3) are paralogue proteins that regulate transcription elongation by docking onto phosphorylated serine-2 in the C-terminal domain (CTD) of Pol II through their SPOC domains. Here the authors characterize the interplay of these proteins and show that they coregulate neuronal target genes.
- Johannes Benedum
- , Vedran Franke
- & Dea Slade
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Article
| Open AccessObservation of coordinated RNA folding events by systematic cotranscriptional RNA structure probing
RNA begins to fold as the nascent transcript emerges from a transcribing RNA polymerase. Here, the authors develop a concise method for mapping RNA folding pathways that couples in vitro transcription with high-throughput RNA chemical probing.
- Courtney E. Szyjka
- & Eric J. Strobel
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Article
| Open AccessMechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting
What underlies the synthetic lethality between BRCA1/2 or 53BP1 loss and Polθ loss is unclear. Here, the authors show that RPA-RAD52-MRE11 drive lethality when Polθ is absent in these cells. In BRCA1/2-deficient cells, sensitivity to Polθ inhibition additionally depends on the inhibited protein.
- George E. Ronson
- , Katarzyna Starowicz
- & Joanna R. Morris
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Article
| Open AccessThe protein interactome of the citrus Huanglongbing pathogen Candidatus Liberibacter asiaticus
Research on the biology and pathogenicity of ‘Candidatus Liberibacter asiaticus’ (CLas), the bacterium that causes citrus Huanglongbing disease, is hampered by our inability to cultivate it in artificial media. Here, Carter et al. use a high-throughput yeast-two-hybrid screen to identify thousands of interactions between CLas proteins, thus providing insights into their potential functions.
- Erica W. Carter
- , Orlene Guerra Peraza
- & Nian Wang
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Article
| Open AccessArabidopsis telomerase takes off by uncoupling enzyme activity from telomere length maintenance in space
Telomeres are proposed to be sentinels for stress. Here, the authors report a strong induction of telomerase in space-flown Arabidopsis without telomere length changes. Instead, telomerase activity is inversely correlated with genome oxidation
- Borja Barbero Barcenilla
- , Alexander D. Meyers
- & Dorothy E. Shippen
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Article
| Open AccessNuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity
How nuclear architecture assists the replication stress response is still largely unknown. Here the authors show that nuclear actin polymerization rapidly extends upon mild DNA damage. By limiting Primpol activity, this response mediates fork slowing and reversal, protecting chromosome stability.
- Maria Dilia Palumbieri
- , Chiara Merigliano
- & Massimo Lopes
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Article
| Open AccessMicroRNA-mediated attenuation of branched-chain amino acid catabolism promotes ferroptosis in chronic kidney disease
Cisplatin, a chemotherapy drug, can cause long-lasting kidney injury. The authors explore miRNA:mRNA interactions in cisplatin-injured kidneys and find that such a cisplatin inducible miRNA as miR-429-3p suppresses the catabolism of branched-chain amino acids, leading to stimulation of ferroptotic cell death.
- Hisakatsu Sone
- , Tae Jin Lee
- & Sang-Ho Kwon
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Article
| Open AccessProteomic characterization of epithelial ovarian cancer delineates molecular signatures and therapeutic targets in distinct histological subtypes
The molecular phenotypic features of epithelial ovarian cancer (EOC) remain elusive. Here, the authors perform mass spectrometry-based proteomic profiling for 269 EOC patients and reveal molecularly distinct features and potential therapeutic targets among the histological subtypes of EOC.
- Ting-Ting Gong
- , Shuang Guo
- & Qi-Jun Wu
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Article
| Open AccessMutual modulation of gut microbiota and the immune system in type 1 diabetes models
Type-1 diabetes pathogenesis has been strongly linked with changes in the intestinal microbiota. Here, the authors demonstrate that mice susceptible to type-1 diabetes become resistant when co-housed with resistant mice, an effect that was associated with changes in gut microbiota, gut permeability, and the immune system.
- Estela Rosell-Mases
- , Alba Santiago
- & Chaysavanh Manichanh
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Article
| Open AccessFragment-sequencing unveils local tissue microenvironments at single-cell resolution
Experimentally preserving tissue microenvironments remains challenging for single-cell sequencing methods. Here, the authors introduce fragment-sequencing, a method that can preserve three-dimensional microenvironments in single-cell RNA-seq, thus allowing the reconstruction of spatial tissue niches.
- Kristina Handler
- , Karsten Bach
- & Andreas E. Moor
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Article
| Open AccessGene duplication and deletion caused by over-replication at a fork barrier
Gene duplications and deletions are important drivers of evolution and disease. Here, the authors show that excess DNA generated at a replication fork barrier can be integrated at a new genomic site causing both a gene duplication and a deletion.
- Judith Oehler
- , Carl A. Morrow
- & Matthew C. Whitby
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Article
| Open AccessModulation of insulin secretion by RBFOX2-mediated alternative splicing
Insulin secretion from the pancreatic beta cell is a tightly regulated process that is vital for maintaining blood glucose homeostasis. Here, the authors show that the RNA binding protein RBFOX2 is a regulator of insulin secretion through the alternative splicing of genes required for insulin granule docking and exocytosis.
- Nicole D. Moss
- , Kristen L. Wells
- & Lori Sussel
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Article
| Open AccessThe rate of epigenetic drift scales with maximum lifespan across mammals
Epigenetic drift has been hypothesized to contribute to epigenetic clock signals and variation in lifespan across species. Here, the authors show that an empirical measure of epigenetic drift scales with maximum lifespan across four mammal species and accumulates in non-random genomic locations.
- Emily M. Bertucci-Richter
- & Benjamin B. Parrott
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Article
| Open AccessID1 expressing macrophages support cancer cell stemness and limit CD8+ T cell infiltration in colorectal cancer
Inhibitor of differentiation 1 (ID1) has been described as a cancer-promoting factor and also involved in the formation of an immunosuppressive tumor microenvironment. Here the authors report that ID1-expressing tumor associated macrophages favor colorectal cancer progression by promoting cancer cell stemness and CD8+ T cell exclusion.
- Shuang Shang
- , Chen Yang
- & Fang Hua
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Article
| Open AccessVector-borne Trypanosoma brucei parasites develop in artificial human skin and persist as skin tissue forms
Here, authors show that tsetse-fly transmitted trypanosomes rapidly differentiate within human skin equivalents, eventually entering a reversible quiescent stage and conclude that these skin tissue forms may contribute to long-term parasite infections in asymptomatic individuals.
- Christian Reuter
- , Laura Hauf
- & Markus Engstler
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Article
| Open AccessA dual role of RBM42 in modulating splicing and translation of CDKN1A/p21 during DNA damage response
Here the authors show a function of RBM42 in regulating splicing and translation of the p53-target gene CDKN1A/p21. This makes RBM42 an RNA-binding protein that links splicing and translation to fine-tune gene expression during DNA damage.
- Bella M. Ben-Oz
- , Feras E. Machour
- & Nabieh Ayoub
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Article
| Open AccessThe heat shock protein LarA activates the Lon protease in response to proteotoxic stress
The Lon protease is an important protein degradation machine and is conserved across the three domains of life. Here, the authors describe a small proteotoxic stress-induced protein that functions as an allosteric activator of Lon.
- Deike J. Omnus
- , Matthias J. Fink
- & Kristina Jonas
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Article
| Open AccessDistinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection
Although type-1 diabetes has a clear genetic component, not all children who are at risk eventually develop autoimmunity, suggesting the existence of environmental triggers. In this longitudinal transcriptomic study, the authors find that children who later develop autoimmunity have a distinct profile before the appearance of autoantibodies and may have impaired responses to enterovirus infection.
- Jake Lin
- , Elaheh Moradi
- & Matti Nykter
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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 AccessReduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension
It is unknown whether unrepaired DNA damage in lung endothelial cells causes persistent pulmonary arterial hypertension. Here, the authors combine oxidative stress with impaired BMPR2 signaling to link a reduction in FOXF1 to unrepaired DNA damage and impaired regeneration of normal endothelium.
- Sarasa Isobe
- , Ramesh V. Nair
- & Marlene Rabinovitch
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Article
| Open AccessTargetable lesions and proteomes predict therapy sensitivity through disease evolution in pediatric acute lymphoblastic leukemia
The role of clonal evolution on the actionable proteome and response to therapy in childhood acute lymphoblastic leukemia (ALL) remains unknown. Here, targeted sequencing and proteomic analysis of paired ALL diagnosis and relapsed samples revealed PARP1 as a potential therapeutic target.
- Amanda C. Lorentzian
- , Jenna Rever
- & Philipp F. Lange
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- Post-translational modifications
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