IF 6.4 1区生物学

eLife Pub Date : 2024-09-03 DOI: 10.7554/eLife.92707

Brennan J Wadsworth, Marina Leiwe, Eleanor A Minogue, Pedro P Cunha, Viktor Engman, Carolin Brombach, Christos Asvestis, Shiv K Sah-Teli, Emilia Marklund, Peppi Karppinen, Jorge L Ruas, Helene Rundqvist, Johanna T Lanner, Randall S Johnson

{"title":"A 2-hydroxybutyrate-mediated feedback loop regulates muscular fatigue.","authors":"Brennan J Wadsworth, Marina Leiwe, Eleanor A Minogue, Pedro P Cunha, Viktor Engman, Carolin Brombach, Christos Asvestis, Shiv K Sah-Teli, Emilia Marklund, Peppi Karppinen, Jorge L Ruas, Helene Rundqvist, Johanna T Lanner, Randall S Johnson","doi":"10.7554/eLife.92707","DOIUrl":"10.7554/eLife.92707","url":null,"abstract":"Several metabolites have been shown to have independent and at times unexpected biological effects outside of their metabolic pathways. These include succinate, lactate, fumarate, and 2-hydroxyglutarate. 2-Hydroxybutyrate (2HB) is a byproduct of endogenous cysteine synthesis, produced during periods of cellular stress. 2HB rises acutely after exercise; it also rises during infection and is also chronically increased in a number of metabolic disorders. We show here that 2HB inhibits branched-chain aminotransferase enzymes, which in turn triggers a SIRT4-dependent shift in the compartmental abundance of protein ADP-ribosylation. The 2HB-induced decrease in nuclear protein ADP-ribosylation leads to a C/EBPβ-mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity in vitro. We found that repeated injection with 2HB can replicate the improvement to oxidative capacity that occurs following exercise training. Together, we show that 2-HB regulates fundamental aspects of skeletal muscle metabolism.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Differential regulation of the proteome and phosphosproteome along the dorso-ventral axis of the early Drosophila embryo. 果蝇早期胚胎背腹轴蛋白质组和磷酸蛋白组的差异调控。

IF 6.4 1区生物学

eLife Pub Date : 2024-09-02 DOI: 10.7554/eLife.99263

Juan Manuel Gomez, Hendrik Nolte, Elisabeth Vogelsang, Bipasha Dey, Michiko Takeda, Girolamo Giudice, Miriam Faxel, Theresa Haunold, Alina Cepraga, Robert P Zinzen, Marcus Krüger, Evangelia Petsalaki, Yu-Chiun Wang, Maria Leptin

{"title":"Differential regulation of the proteome and phosphosproteome along the dorso-ventral axis of the early Drosophila embryo.","authors":"Juan Manuel Gomez, Hendrik Nolte, Elisabeth Vogelsang, Bipasha Dey, Michiko Takeda, Girolamo Giudice, Miriam Faxel, Theresa Haunold, Alina Cepraga, Robert P Zinzen, Marcus Krüger, Evangelia Petsalaki, Yu-Chiun Wang, Maria Leptin","doi":"10.7554/eLife.99263","DOIUrl":"https://doi.org/10.7554/eLife.99263","url":null,"abstract":"The initially homogeneous epithelium of the early Drosophila embryo differentiates into regional subpopulations with different behaviours and physical properties that are needed for morphogenesis. The factors at top of the genetic hierarchy that control these behaviours are known, but many of their targets are not. To understand how proteins work together to mediate differential cellular activities, we studied in an unbiased manner the proteomes and phosphoproteomes of the three main cell populations along the dorso-ventral axis during gastrulation using mutant embryos that represent the different populations. We detected 6111 protein groups and 6259 phosphosites of which 3398 and 3433 respectively, were differentially regulated. The changes in phosphosite abundance did not correlate with changes in host protein abundance, showing phosphorylation to be a regulatory step during gastrulation. Hierarchical clustering of protein groups and phosphosites identified clusters that contain known fate determinants such as Doc1, Sog, Snail and Twist. The recovery of the appropriate known marker proteins in each of the different mutants we used validated the approach, but also revealed that two mutations that both interfere with the dorsal fate pathway, Toll10B and serpin27aex do this in very different manners. Diffused network analyses within each cluster point to microtubule components as one of the main groups of regulated proteins. Functional studies on the role of microtubules provide the proof of principle that microtubules have different functions in different domains along the DV axis of the embryo.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Arthropoda-specific Tramtrack group BTB protein domains use previously unknown interface to form hexamers. 节肢动物特有的 Tramtrack 组 BTB 蛋白结构域利用以前未知的界面形成六聚体。

IF 6.4 1区生物学

eLife Pub Date : 2024-09-02 DOI: 10.7554/eLife.96832

Artem N Bonchuk, Konstantin I Balagurov, Rozbeh Baradaran, Konstantin M Boyko, Nikolai N Sluchanko, Anastasia M Khrustaleva, Anna D Burtseva, Olga V Arkova, Karina K Khalisova, Vladimir O Popov, Andreas Naschberger, Pavel G Georgiev

{"title":"The Arthropoda-specific Tramtrack group BTB protein domains use previously unknown interface to form hexamers.","authors":"Artem N Bonchuk, Konstantin I Balagurov, Rozbeh Baradaran, Konstantin M Boyko, Nikolai N Sluchanko, Anastasia M Khrustaleva, Anna D Burtseva, Olga V Arkova, Karina K Khalisova, Vladimir O Popov, Andreas Naschberger, Pavel G Georgiev","doi":"10.7554/eLife.96832","DOIUrl":"https://doi.org/10.7554/eLife.96832","url":null,"abstract":"BTB (Bric-a-brack, Tramtrack and Broad Complex) is a diverse group of protein-protein interaction domains found within metazoan proteins. Transcription factors contain a dimerizing BTB subtype with a characteristic N-terminal extension. The Tramtrack group (TTK) is a distinct type of BTB domain, which can multimerize. Single-particle cryo-EM microscopy revealed that the TTK-type BTB domains assemble into a hexameric structure consisting of three canonical BTB dimers connected through a previously uncharacterized interface. We demonstrated that the TTK-type BTB domains are found only in Arthropods and have undergone lineage-specific expansion in modern insects. The Drosophila genome encodes 24 transcription factors with TTK-type BTB domains, whereas only four have non‑TTK‑type BTB domains. Yeast two-hybrid analysis revealed that the TTK-type BTB domains have an unusually broad potential for heteromeric associations presumably through dimer-dimer interaction interface. Thus, the TTK-type BTB domains are a structurally and functionally distinct group of protein domains specific to Arthropodan transcription factors.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The genetic architecture of the load linked to dominant and recessive self-incompatibility alleles in Arabidopsis halleri and Arabidopsis lyrata. 拟南芥 Halleri 和拟南芥 lyrata 中与显性和隐性自交不亲和等位基因相关的负载遗传结构。

IF 6.4 1区生物学

eLife Pub Date : 2024-09-02 DOI: 10.7554/eLife.94972

Audrey Le Veve, Mathieu Genete, Christelle Lepers-Blassiau, Chloé Ponitzki, Céline Poux, Xavier Vekemans, Eleonore Durand, Vincent Castric

{"title":"The genetic architecture of the load linked to dominant and recessive self-incompatibility alleles in Arabidopsis halleri and Arabidopsis lyrata.","authors":"Audrey Le Veve, Mathieu Genete, Christelle Lepers-Blassiau, Chloé Ponitzki, Céline Poux, Xavier Vekemans, Eleonore Durand, Vincent Castric","doi":"10.7554/eLife.94972","DOIUrl":"10.7554/eLife.94972","url":null,"abstract":"The long-term balancing selection acting on mating types or sex-determining genes is expected to lead to the accumulation of deleterious mutations in the tightly linked chromosomal segments that are locally 'sheltered' from purifying selection. However, the factors determining the extent of this accumulation are poorly understood. Here, we took advantage of variations in the intensity of balancing selection along a dominance hierarchy formed by alleles at the sporophytic self-incompatibility system of the Brassicaceae to compare the pace at which linked deleterious mutations accumulate among them. We first experimentally measured the phenotypic manifestation of the linked load at three different levels of the dominance hierarchy. We then sequenced and phased polymorphisms in the chromosomal regions linked to 126 distinct copies of S-alleles in two populations of Arabidopsis halleri and three populations of Arabidopsis lyrata. We find that linkage to the S-locus locally distorts phylogenies over about 10-30 kb along the chromosome. The more intense balancing selection on dominant S-alleles results in greater fixation of linked deleterious mutations, while recessive S-alleles accumulate more linked deleterious mutations that are segregating. Hence, the structure rather than the overall magnitude of the linked genetic load differs between dominant and recessive S-alleles. Our results have consequences for the long-term evolution of new S-alleles, the evolution of dominance modifiers between them, and raise the question of why the non-recombining regions of some sex and mating type chromosomes expand over evolutionary times while others, such as the S-locus of the Brassicaceae, remain restricted to small chromosomal regions.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Additional feedforward mechanism of Parkin activation via binding of phospho-UBL and RING0 in trans. 通过磷酸化UBL 和 RING0 的反式结合激活 Parkin 的额外前馈机制。

IF 6.4 1区生物学

eLife Pub Date : 2024-09-02 DOI: 10.7554/eLife.96699

Dipti Ranjan Lenka, Shakti Virendra Dahe, Odetta Antico, Pritiranjan Sahoo, Alan R Prescott, Miratul M K Muqit, Atul Kumar

引用次数: 0

Future movement plans interact in sequential arm movements. 未来的运动计划在连续的手臂运动中相互作用。

IF 6.4 1区生物学

eLife Pub Date : 2024-09-02 DOI: 10.7554/eLife.94485

Mehrdad Kashefi, Sasha Reschechtko, Giacomo Ariani, Mahdiyar Shahbazi, Alice Tan, Jörn Diedrichsen, J Andrew Pruszynski

{"title":"Future movement plans interact in sequential arm movements.","authors":"Mehrdad Kashefi, Sasha Reschechtko, Giacomo Ariani, Mahdiyar Shahbazi, Alice Tan, Jörn Diedrichsen, J Andrew Pruszynski","doi":"10.7554/eLife.94485","DOIUrl":"10.7554/eLife.94485","url":null,"abstract":"Real-world actions often comprise a series of movements that cannot be entirely planned before initiation. When these actions are executed rapidly, the planning of multiple future movements needs to occur simultaneously with the ongoing action. How the brain solves this task remains unknown. Here, we address this question with a new sequential arm reaching paradigm that manipulates how many future reaches are available for planning while controlling execution of the ongoing reach. We show that participants plan at least two future reaches simultaneously with an ongoing reach. Further, the planning processes of the two future reaches are not independent of one another. Evidence that the planning processes interact is twofold. First, correcting for a visual perturbation of the ongoing reach target is slower when more future reaches are planned. Second, the curvature of the current reach is modified based on the next reach only when their planning processes temporally overlap. These interactions between future planning processes may enable smooth production of sequential actions by linking individual segments of a long sequence at the level of motor planning.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CyAbrB2 is a nucleoid-associated protein in Synechocystis controlling hydrogenase expression during fermentation. CyAbrB2 是 Synechocystis 中的一种核团相关蛋白，在发酵过程中控制氢化酶的表达。

IF 6.4 1区生物学

eLife Pub Date : 2024-09-02 DOI: 10.7554/eLife.94245

Ryo Kariyazono, Takashi Osanai

{"title":"CyAbrB2 is a nucleoid-associated protein in Synechocystis controlling hydrogenase expression during fermentation.","authors":"Ryo Kariyazono, Takashi Osanai","doi":"10.7554/eLife.94245","DOIUrl":"10.7554/eLife.94245","url":null,"abstract":"The hox operon in Synechocystis sp. PCC 6803, encoding bidirectional hydrogenase responsible for H2 production, is transcriptionally upregulated under microoxic conditions. Although several regulators for hox transcription have been identified, their dynamics and higher-order DNA structure of hox region in microoxic conditions remain elusive. We focused on key regulators for the hox operon: cyAbrB2, a conserved regulator in cyanobacteria, and SigE, an alternative sigma factor. Chromatin immunoprecipitation sequencing revealed that cyAbrB2 binds to the hox promoter region under aerobic conditions, with its binding being flattened in microoxic conditions. Concurrently, SigE exhibited increased localization to the hox promoter under microoxic conditions. Genome-wide analysis revealed that cyAbrB2 binds broadly to AT-rich genome regions and represses gene expression. Moreover, we demonstrated the physical interactions of the hox promoter region with its distal genomic loci. Both the transition to microoxic conditions and the absence of cyAbrB2 influenced the chromosomal interaction. From these results, we propose that cyAbrB2 is a cyanobacterial nucleoid-associated protein (NAP), modulating chromosomal conformation, which blocks RNA polymerase from the hox promoter in aerobic conditions. We further infer that cyAbrB2, with altered localization pattern upon microoxic conditions, modifies chromosomal conformation in microoxic conditions, which allows SigE-containing RNA polymerase to access the hox promoter. The coordinated actions of this NAP and the alternative sigma factor are crucial for the proper hox expression in microoxic conditions. Our results highlight the impact of cyanobacterial chromosome conformation and NAPs on transcription, which have been insufficiently investigated.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reaching into the future. 走向未来。

IF 6.4 1区生物学

eLife Pub Date : 2024-09-02 DOI: 10.7554/eLife.101739

Raeed H Chowdhury

引用次数: 0

Inhibition of ULK1/2 and KRAS^G12C controls tumor growth in preclinical models of lung cancer. 抑制 ULK1/2 和 KRASG12C 可控制肺癌临床前模型中的肿瘤生长。

IF 6.4 1区生物学

eLife Pub Date : 2024-08-30 DOI: 10.7554/eLife.96992

Phaedra C Ghazi, Kayla T O'Toole, Sanjana Srinivas Boggaram, Michael T Scherzer, Mark R Silvis, Yun Zhang, Madhumita Bogdan, Bryan D Smith, Guillermina Lozano, Daniel L Flynn, Eric L Snyder, Conan G Kinsey, Martin McMahon

{"title":"Inhibition of ULK1/2 and KRASG12C controls tumor growth in preclinical models of lung cancer.","authors":"Phaedra C Ghazi, Kayla T O'Toole, Sanjana Srinivas Boggaram, Michael T Scherzer, Mark R Silvis, Yun Zhang, Madhumita Bogdan, Bryan D Smith, Guillermina Lozano, Daniel L Flynn, Eric L Snyder, Conan G Kinsey, Martin McMahon","doi":"10.7554/eLife.96992","DOIUrl":"10.7554/eLife.96992","url":null,"abstract":"Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent U.S. Food and Drug Administration approval of covalent inhibitors of KRASG12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRASG12C-driven NSCLCs respond to these inhibitors, and the emergence of drug resistance in those patients who do respond can be rapid and pleiotropic. Hence, based on a backbone of covalent inhibition of KRASG12C, efforts are underway to develop effective combination therapies. Here, we report that the inhibition of KRASG12C signaling increases autophagy in KRASG12C-expressing lung cancer cells. Moreover, the combination of DCC-3116, a selective ULK1/2 inhibitor, plus sotorasib displays cooperative/synergistic suppression of human KRASG12C-driven lung cancer cell proliferation in vitro and superior tumor control in vivo. Additionally, in genetically engineered mouse models of KRASG12C-driven NSCLC, inhibition of either KRASG12C or ULK1/2 decreases tumor burden and increases mouse survival. Consequently, these data suggest that ULK1/2-mediated autophagy is a pharmacologically actionable cytoprotective stress response to inhibition of KRASG12C in lung cancer.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11364435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Defining cell type-specific immune responses in a mouse model of allergic contact dermatitis by single-cell transcriptomics. 通过单细胞转录组学确定过敏性接触性皮炎小鼠模型中细胞类型特异性免疫反应。

IF 6.4 1区生物学

eLife Pub Date : 2024-08-30 DOI: 10.7554/eLife.94698

Youxi Liu, Meimei Yin, Xiaoting Mao, Shuai Wu, Shuangping Wei, Shujun Heng, Yichun Yang, Jinwen Huang, Zhuolin Guo, Chuan Li, Chao Ji, Liu Hu, Wenjie Liu, Ling-Juan Zhang

{"title":"Defining cell type-specific immune responses in a mouse model of allergic contact dermatitis by single-cell transcriptomics.","authors":"Youxi Liu, Meimei Yin, Xiaoting Mao, Shuai Wu, Shuangping Wei, Shujun Heng, Yichun Yang, Jinwen Huang, Zhuolin Guo, Chuan Li, Chao Ji, Liu Hu, Wenjie Liu, Ling-Juan Zhang","doi":"10.7554/eLife.94698","DOIUrl":"10.7554/eLife.94698","url":null,"abstract":"Allergic contact dermatitis (ACD), a prevalent inflammatory skin disease, is elicited upon repeated skin contact with protein-reactive chemicals through a complex and poorly characterized cellular network between immune cells and skin resident cells. Here, single-cell transcriptomic analysis of the murine hapten-elicited model of ACD reveals that upon elicitation of ACD, infiltrated CD4+ or CD8+ lymphocytes were primarily the IFNγ-producing type 1 central memory phenotype. In contrast, type 2 cytokines (IL4 and IL13) were dominantly expressed by basophils, IL17A was primarily expressed by δγ T cells, and IL1β was identified as the primary cytokine expressed by activated neutrophils/monocytes and macrophages. Furthermore, analysis of skin resident cells identified a sub-cluster of dermal fibroblasts with preadipocyte signature as a prominent target for IFNγ+ lymphocytes and dermal source for key T cell chemokines CXCL9/10. IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism. Furthermore, targeted deletion of Ifngr1 in dermal fibroblasts in mice reduced Cxcl9/10 expression, dermal infiltration of CD8+ T cell, and alleviated ACD inflammation in mice. Finally, we showed that IFNγ+ CD8+ T cells and CXCL10-producing dermal fibroblasts co-enriched in the dermis of human ACD skin. Together, our results define the cell type-specific immune responses in ACD, and recognize an indispensable role of dermal fibroblasts in shaping the development of type-1 skin inflammation through the IFNGR-CXCR3 signaling circuit during ACD pathogenesis.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11364439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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