Featured
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Article
| Open AccessMultiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer
Intratumoral heterogeneity has been documented in multiple cancer types, and can be linked to treatment resistance. Here, the authors analyse multiregional samples from colorectal cancers and show gene expression subtypes which are less vulnerable to heterogeneity and may partly contribute to differential patient survival.
- Jonas Langerud
- , Ina A. Eilertsen
- & Anita Sveen
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Article
| Open AccessCell of origin epigenetic priming determines susceptibility to Tet2 mutation
HSC mutations lead to diverse clonal hematopoiesis outcomes. This study shows how epigenetic traits can predispose clones for dominance. Sox4 increases sensitivity to Tet2 KO, offering insights into variable phenotypes despite identical mutations.
- Giulia Schiroli
- , Vinay Kartha
- & David T. Scadden
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Article
| Open AccessProdrug-conjugated tumor-seeking commensals for targeted cancer therapy
The chemotherapeutic efficacy of prodrug is limited by its cancer-targeting ability. Here this group reports an engineered commensal Lactobacillus plantarum strain with anticancer prodrugs loading on the surface for nasopharyngeal carcinoma cell-targeting and growth inhibition.
- Haosheng Shen
- , Changyu Zhang
- & Matthew Wook Chang
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Article
| Open AccessSelf-organization of modular activity in immature cortical networks
How the cortex forms spatially structured modules during development is poorly understood. Here, the authors show that activity in early developing cortex is self-organized though local-excitation and lateral inhibition.
- Haleigh N. Mulholland
- , Matthias Kaschube
- & Gordon B. Smith
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Article
| Open AccessAstrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice
The regulatory mechanism and function of astrocytic epigenetic effects on depression remain to be explored. Here, the authors show astrocytic ALKBH5 contributes to depressive-like behaviors via the m6A RNA methylation of GLT-1.
- Fang Guo
- , Jun Fan
- & Xiong Cao
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Article
| Open AccessHeliorhodopsin-mediated light-modulation of ABC transporter
Here, authors classify genes flanking the Heliorhodopsin (HeR)-encoding genes and identify highly conserved residues for protein–protein interactions, revealing a function of HeR as regulatory rhodopsin for multidrug resistance.
- Shin-Gyu Cho
- , Ji-Hyun Kim
- & Kwang-Hwan Jung
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Article
| Open AccessFluorescent fatty acid conjugates for live cell imaging of peroxisomes
The array of tools to image peroxisome regulation is still limited. Here, the authors develop improved fatty acid-based probes with high peroxisome specificity and bright fluorescence in the red/far-red spectrum, which makes them ideal to study peroxisomes in live cells and whole organisms.
- Daria Korotkova
- , Anya Borisyuk
- & Triana Amen
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Article
| Open AccessDeep learning of left atrial structure and function provides link to atrial fibrillation risk
In this study, a deep learning-based model of left atrial size in UK Biobank enabled genome-wide association studies in 35,049 healthy participants. Several lines of evidence, including the PITX2 locus, linked left atrial dysfunction to atrial fibrillation risk.
- James P. Pirruccello
- , Paolo Di Achille
- & Patrick T. Ellinor
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Article
| Open AccessVentral tegmental area dopamine projections to the hippocampus trigger long-term potentiation and contextual learning
How the hippocampus selects relevant events that are worth remembering is debated. Here, authors show midbrain dopamine neurons projecting to the hippocampus provide a teaching signal triggering NeoHebbian LTP and contextual learning.
- Fares J. P. Sayegh
- , Lionel Mouledous
- & Lionel Dahan
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Article
| Open AccessActive transcription and epigenetic reactions synergistically regulate meso-scale genomic organization
Chromatin within interphase nuclei forms compacted nanoscale DNA domains of uniform size. By integrating theory and imaging, here the authors show how the interplay between transcription and epigenetic mechanisms determine this size, independent of cell type.
- Aayush Kant
- , Zixian Guo
- & Vivek B. Shenoy
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Article
| Open AccessGraded decisions in the human brain
Whether decisions are made in a graded or all-or-none fashion remains unclear. Here, the authors provide evidence to suggest that decisions conclude in a graded, rather than a binary, manner, thus providing an analog framework for flexible choice behavior.
- Tao Xie
- , Markus Adamek
- & Jan Kubanek
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Article
| Open AccessSpatiotemporal brain hierarchies of auditory memory recognition and predictive coding
The brain networks orchestrating conscious recognition of auditory sequences are not well understood. Here, the authors reveal hierarchical processing from auditory cortices to hippocampus and cingulate gyrus, enhancing our understanding of predictive coding in memory.
- L. Bonetti
- , G. Fernández-Rubio
- & M. L. Kringelbach
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Article
| Open AccessDisruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis
Macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is implicated in a range of immunopathology. Here the authors show TIGAR drives inflammation and sepsis via activation of TAK1 and that disruption of TIGAR-TAK1 interaction in a murine model of sepsis reduces immunopathology.
- Dongdong Wang
- , Yanxia Li
- & Jingjing Ben
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Article
| Open AccessDiscovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining
Tang et al. describe the development of a fungal genome mining tool which can be used to identify biosynthetic gene clusters from fungal genomes that lack detectable protein domains and demonstrate its functionality.
- Jia Tang
- & Yudai Matsuda
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Article
| Open AccessPriming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells
Phenotypic changes in exhausted T cells are linked to chromatin remodeling. Here the authors show that pharmacological inhibition of the H3K4me1/2 demethylase LSD1 promotes the persistence and enhances the therapeutic activity of adoptively transferred T cells for cancer therapy.
- Fengqi Qiu
- , Peishan Jiang
- & Wanqiang Sheng
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Article
| Open AccessIn vivo neutralization of coral snake venoms with an oligoclonal nanobody mixture in a murine challenge model
Oligoclonal mixtures of neutralising antibodies can target multiple antigen components and represent a potential therapeutic solution for the treatment of envenomation. Here, the authors generate mixtures of nanobodies against coral snake venom toxins and demonstrate they can prevent lethality of coral snake venoms in pre-clinical animal models.
- Melisa Benard-Valle
- , Yessica Wouters
- & Andreas Hougaard Laustsen
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Article
| Open AccessCell-free biosynthesis and engineering of ribosomally synthesized lanthipeptides
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of natural products with potent biological activities but a vast majority of RiPP gene clusters remain unexplored in microbial genomes. Here, the authors report a unified biocatalysis (UniBioCat) system based on cell-free gene expression for rapid biosynthesis and engineering of RiPPs.
- Wan-Qiu Liu
- , Xiangyang Ji
- & Jian Li
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Article
| Open Access3D ocean assessments reveal that fisheries reach deep but marine protection remains shallow
The first three-dimensional spatial analysis of global marine conservation achievements and fisheries footprint reveals 3D conservation gaps and an underrepresentation of high protection levels across all depths while the 3D footprint of fisheries covers all depths.
- Juliette Jacquemont
- , Charles Loiseau
- & Joachim Claudet
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Article
| Open AccessBRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis
Here the authors identify PCNA, a master regulator of DNA replication, as a ubiquitin substrate for the BRCA1/BARD1 heterodimer. This modification is crucial to avoid the appearance of unreplicated DNA gaps in the genome after replication.
- Daniel Salas-Lloret
- , Néstor García-Rodríguez
- & Román González-Prieto
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Article
| Open AccessMitoribosome structure with cofactors and modifications reveals mechanism of ligand binding and interactions with L1 stalk
This study uses cryo-EM, biochemical, and computational approaches to shed light on the fundamental mechanisms underlying the human mitoribosome function, including ligand binding, modifications, Fe-S clusters, and aging-related polyamines.
- Vivek Singh
- , Yuzuru Itoh
- & Alexey Amunts
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Article
| Open AccessThe sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
Antifungal triazoles inhibit biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Here, Xie et al. show that Erg6, the enzyme that catalyzes a previous step in ergosterol biosynthesis, is essential for the viability of Aspergillus fumigatus, and its repression reduces the virulence of this fungal pathogen in an animal model of infection.
- Jinhong Xie
- , Jeffrey M. Rybak
- & Jarrod R. Fortwendel
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Article
| Open AccessSOS1 tonoplast neo-localization and the RGG protein SALTY are important in the extreme salinity tolerance of Salicornia bigelovii
The authors show that in the halophyte Salicornia the sodium transporter SOS1 localizes to the tonoplast, likely storing sodium in the vacuole. The intrinsically disordered protein SALTY, increases yeast salt tolerance possibly stabilizing ribosomes in the ER.
- Octavio R. Salazar
- , Ke Chen
- & Sandra M. Schmöckel
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Article
| Open AccessCytomegalovirus drives Vδ1+ γδ T cell expansion and clonality in common variable immunodeficiency
Common variable immunodeficiency (CVID) is an inborn error of immunity, characterized clinically by low immunoglobulin levels, poor vaccine responses and recurrent sinopulmonary infections. Here authors show that the proportion of Vδ1+ γδ T cells in CVID is higher than in healthy controls and these cells respond to persistent cytomegalovirus viremia with expansion and phenotypic alterations.
- Samantha Chan
- , Benjamin Morgan
- & Lauren J. Howson
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Article
| Open AccessDesigning meaningful continuous representations of T cell receptor sequences with deep generative models
Relating T cell receptor (TCR) sequencing to antigen specificity is a challenge especially when TCR specificity is unclear. Here the authors use a low dimensional generative approach to model TCR sequence similarity and to associate TCR sequences with the same specificity.
- Allen Y. Leary
- , Darius Scott
- & Peter G. Hawkins
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Article
| Open AccessTwo telomere-to-telomere gapless genomes reveal insights into Capsicum evolution and capsaicinoid biosynthesis
Chili pepper (Capsicum) is an important vegetables known for fruit pungency given by capsaicinoids. Here, the authors assemble the telomere-to-telomere genomes of a pungent pepper C. annuum and its non-pungent wild relative C. rhomboideum and reveal insights into Capsicum evolution and capsaicinoid biosynthesis.
- Weikai Chen
- , Xiangfeng Wang
- & Li Guo
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Article
| Open AccessAn antifouling membrane-fusogenic liposome for effective intracellular delivery in vivo
Protein corona formation on the surface of liposome nanocarriers can decrease the efficiency of intracellular delivery. Here, the authors develop antifouling membrane-fusogenic liposomes for effective intracellular delivery in vivo.
- Huimin Kong
- , Chunxiong Zheng
- & Mingqiang Li
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Article
| Open AccessInformation-based TMS to mid-lateral prefrontal cortex disrupts action goals during emotional processing
The lateral prefrontal cortex (LPFC) is thought to maintain goal-relevant representations that promote cognitive control, but causal evidence has been limited. By targeting action-goal representations in LPFC with transcranial magnetic stimulation and fMRI, the authors found that LPFC promotes goal oriented behaviour during emotional processing. Reviewer recognition:
- R. C. Lapate
- , M. K. Heckner
- & M. D’Esposito
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Article
| Open AccessSex-specific developmental gene expression atlas unveils dimorphic gene networks in C. elegans
Genetic sex introduces variation in phenotypic traits in sexually reproducing organisms. Here, the authors report a developmental gene expression atlas for C. elegans males and hermaphrodites, highlighting the key role of the insulin-like peptide INS-39 in male development and suggesting genetic underpinnings of sexual dimorphism.
- Rizwanul Haque
- , Sonu Peedikayil Kurien
- & Meital Oren-Suissa
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Article
| Open AccessThe actin cytoskeleton plays multiple roles in structural colour formation in butterfly wing scales
NCOMMS-23-44446C Vivid structural colours in butterflies are caused by photonic nanostructures scattering light, however insight into the development of such structures in vivo remains scarce. Here the authors show that actin plays a vital and direct templating role during structural colour formation in butterfly scales, providing ridge patterning mechanisms that are likely universal across lepidoptera.
- Victoria J. Lloyd
- , Stephanie L. Burg
- & Andrew J. Parnell
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Article
| 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 AccessFunctionality of chimeric TssA proteins in the type VI secretion system reveals sheath docking specificity within their N-terminal domains
The bacterium Pseudomonas aeruginosa has three type-VI secretion systems that exhibit differences in the size and domain organization of one of their components, protein TssA. Here, Fecht et al. provide insights into the functions of the different TssA domains and propose a model for the role played by TssA proteins in secretion-system assembly.
- Selina Fecht
- , Patricia Paracuellos
- & Alain Filloux
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Article
| Open AccessTryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis
Amino acids availability is normally a limitation for protein synthesis and can determine cancer progression and therapy response. Here, the authors show that MYC-associated cancer has a dependency on tryptophan not because of translation regulation, but Indole 3-Pyruvate synthesis.
- Niranjan Venkateswaran
- , Roy Garcia
- & Maralice Conacci-Sorrell
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Article
| Open AccessHeuristics in risky decision-making relate to preferential representation of information
Individuals differ in how they weight probability and reward information when making risky choices. Here, the authors use magnetoencephalography to test whether such variation is related to how information is neurally represented during choice evaluation.
- Evan M. Russek
- , Rani Moran
- & Quentin J. M. Huys
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Article
| Open AccessElevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart
Heart failure is characterised by a detrimental rise in the intracellular sodium concentration. Here the authors show that this reversibly reprogrammes energy metabolism in the heart making this a possible therapeutic target for the development of new drugs.
- Yu Jin Chung
- , Zoe Hoare
- & Michael J. Shattock
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Article
| Open AccessFatal COVID-19 pulmonary disease involves ferroptosis
Ferroptosis is a form of cell death that has been associated with different diseases. Here the authors describe an association of ferroptosis with COVID-19 pulmonary pathologies in both patient samples and hamster model and suggest that the dysregulation in iron and lipid metabolism could provide targets to reduce pathology.
- Baiyu Qiu
- , Fereshteh Zandkarimi
- & Brent R. Stockwell
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Article
| Open AccessTargeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer
The ability of anti-cancer therapies such as radiotherapy, chemotherapy and immunotherapy to induce ferroptosis has been linked to their efficacy. Here, the authors demonstrate that SOX13 promotes ferroptosis-resistance via transactivation of SCAF1, identifying SOX13 as a targeted therapeutic vulnerability in gastric cancer.
- Hui Yang
- , Qingqing Li
- & Mingzhe Ma
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Article
| Open AccessDevelopment of a long noncoding RNA-based machine learning model to predict COVID-19 in-hospital mortality
Identifying biomarkers associated with risk of severe COVID-19 disease could inform clinical management. Here, the authors identify a long noncoding RNA associated with severe disease using data from three European countries, and validate their finding in data from Canada.
- Yvan Devaux
- , Lu Zhang
- & Hüseyin Firat
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Article
| Open AccessProduction of deoxycholic acid by low-abundant microbial species is associated with impaired glucose metabolism
Secondary bile acids are microbially produced metabolites linked to metabolic diseases. A challenge in microbiota research is to understand how bacteria collaborate to produce such bioactive molecules. Here, the authors show that adding a single low-abundance bacterial species to a community can significantly affect the metabolic output and host physiology.
- Annika Wahlström
- , Ariel Brumbaugh
- & Fredrik Bäckhed
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Article
| Open AccessEmergent ribozyme behaviors in oxychlorine brines indicate a unique niche for molecular evolution on Mars
Mars, an attractive candidate for potential presence of extraterrestrial life, contains oxychlorine species such as perchlorate at its surface. Here, the authors show perchlorate brines support folding and catalysis of functional RNAs, while inactivating representative protein enzymes, and that perchlorate enables new ribozyme functions, including ribozyme catalyzed chlorination of organic molecules.
- Tanner G. Hoog
- , Matthew R. Pawlak
- & Aaron E. Engelhart
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Article
| Open AccessAbsolute dating of the European Neolithic using the 5259 BC rapid 14C excursion
The Neolithic site of Dispilio, Northern Greece, is a pile-dwelling site with 900+ piles excavated. Here, the authors use the 5259 BC Miyake event to date the juniper tree-ring chronology constructed from these piles to 5140 BC, making it the first Neolithic site in the region to be absolutely calendar dated.
- Andrej Maczkowski
- , Charlotte Pearson
- & Albert Hafner
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Article
| Open AccessInflammatory and neurodegenerative serum protein biomarkers increase sensitivity to detect clinical and radiographic disease activity in multiple sclerosis
Inflammatory and degenerative processes are thought to play a role in the pathophysiology of multiple sclerosis. Here, the authors identified twenty serum proteins associated with increased clinical and radiographic disease activity.
- Tanuja Chitnis
- , Ferhan Qureshi
- & Sergio E. Baranzini
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Article
| Open AccessHomozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility
Here the authors show that a homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters the accessibility of variant-distal methylation sites in EPRS1 mRNA, revealing a new RNA-dependent mechanism by which genetic variants can influence gene expression and disease.
- Debjit Khan
- , Iyappan Ramachandiran
- & Paul L. Fox
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Review Article
| Open AccessShaping of microbial phenotypes by trade-offs
Trade-offs play a key role in controlling bacterial growth and shaping microbial phenotypes, which further drives the emergence of ecologically relevant phenomena including co-existence, population heterogeneity and oligotrophic/copiotrophic lifestyles.
- Manlu Zhu
- & Xiongfeng Dai
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Article
| Open AccessVascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation
The molecular basis underlying infection infection-mediated lung pathology is not fully revealed. Here the authors report that SPARCL1 expressed in pulmonary capillary endothelial cells contributes to immune pathology in mouse model via pro-inflammatory macrophage induction, while circulating SPARCL1 levels corelate with COVID-19 lethality.
- Gan Zhao
- , Maria E. Gentile
- & Andrew E. Vaughan
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Article
| Open AccessInvariant γδTCR natural killer-like effector T cells in the naked mole-rat
Naked mole-rats are long-lived rodents known to be resistant to the development of cancer, yet their immune system remains poorly explored. Here, the authors identify natural killer-like effector γδ T cells that express a dominant γδ T cell receptor and may serve a role in tumour immunosurveillance.
- Guillem Sanchez Sanchez
- , Stephan Emmrich
- & David Vermijlen
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Article
| Open AccessMitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC
The relevance of mitochondrial cysteine metabolism to ferroptosis is unknown. Here, Ward et al. show that mitochondrial Fe-S cluster synthesis persists under cysteine limitation via the catabolism of glutathione and at the expense of cell viability.
- Nathan P. Ward
- , Sang Jun Yoon
- & Gina M. DeNicola
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Article
| Open AccessA systematic review and meta-analysis of unimodal and multimodal predation risk assessment in birds
Animal behavioural response to predation risk could depend on the type and number of cues. This global metaanalysis shows that providing multiple cues of predation risk reduces variance in the behavioural responses of birds.
- Kimberley J. Mathot
- , Josue David Arteaga-Torres
- & Shinichi Nakagawa
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Article
| Open AccessPreserving ester-linked modifications reveals glutamate and aspartate mono-ADP-ribosylation by PARP1 and its reversal by PARG
Ester-linked modifications are common but difficult to detect. Here, the authors present methods based on ester preservation and a sensitive antibody to reveal DNA damage-induced mono-ADP-ribosylation on aspartate and glutamate. This signal, part of the first wave of PARP1 signaling, is removed by PARG.
- Edoardo José Longarini
- & Ivan Matić
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Article
| Open AccessHsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation
Hsc70 (heat shock protein family A member 8) is a cytoplasmic chaperone protein involved in endosomal micro-autophagy and chaperone-mediated autophagy. Here the authors report that Hsc70 promotes lysosomal degradation of PD-L1 and that its overexpression promotes anti-tumor immune responses in preclinical cancer models.
- Xiaoyan Xu
- , Tingxue Xie
- & Hongguang Xia
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