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1.
Front Mol Biosci ; 7: 31, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32219099

RESUMO

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative monogenetic disorder affecting carriers of premutation (PM) forms of the FMR1 gene, resulting in a progressive development of tremors, ataxia, and neuropsychological problems. This highly disabling disease is quite common in the general population with an estimation of about 20 million PM carriers worldwide. The chances of developing FXTAS increase dramatically with age, with about 45% of male carriers over the age of 50 being affected. Both the gene and pathogenic trigger, a mutant expansion of CGG RNA, causing FXTAS are known. This makes it an interesting disease to develop targeted therapeutic interventions for. Yet, no such interventions are available at this moment. Here we discuss in silico, in vitro, and in vivo approaches and how they have been used to identify the molecular determinants of FXTAS pathology. These approaches have yielded substantial information about FXTAS pathology and, consequently, many markers have emerged to play a key role in understanding the disease mechanism. Integration of the different approaches is expected to provide crucial information about the value of these markers as either therapeutic target or biomarker, essential to monitor therapeutic interventions in the future.

2.
EMBO Rep ; 21(3): e46734, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017402

RESUMO

The mechanisms that regulate the switch between epidermal progenitor state and differentiation are not fully understood. Recent findings indicate that the chromatin remodelling BAF complex (Brg1-associated factor complex or SWI/SNF complex) and the transcription factor p63 mutually recruit one another to open chromatin during epidermal differentiation. Here, we identify a long non-coding transcript that includes an ultraconserved element, uc.291, which physically interacts with ACTL6A and modulates chromatin remodelling to allow differentiation. Loss of uc.291 expression, both in primary keratinocytes and in three-dimensional skin equivalents, inhibits differentiation as indicated by epidermal differentiation complex genes down-regulation. ChIP experiments reveal that upon uc.291 depletion, ACTL6A is bound to the differentiation gene promoters and inhibits BAF complex targeting to induce terminal differentiation genes. In the presence of uc.291, the ACTL6A inhibitory effect is released, allowing chromatin changes to promote the expression of differentiation genes. Thus, uc.291 interacts with ACTL6A to modulate chromatin remodelling activity, allowing the transcription of late differentiation genes.

3.
Proc Natl Acad Sci U S A ; 117(2): 1015-1020, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31892536

RESUMO

To function effectively proteins must avoid aberrant aggregation, and hence they are expected to be expressed at concentrations safely below their solubility limits. By analyzing proteome-wide mass spectrometry data of Caenorhabditis elegans, however, we show that the levels of about three-quarters of the nearly 4,000 proteins analyzed in adult animals are close to their intrinsic solubility limits, indeed exceeding them by about 10% on average. We next asked how aging and functional self-assembly influence these solubility limits. We found that despite the fact that the total quantity of proteins within the cellular environment remains approximately constant during aging, protein aggregation sharply increases between days 6 and 12 of adulthood, after the worms have reproduced, as individual proteins lose their stoichiometric balances and the cellular machinery that maintains solubility undergoes functional decline. These findings reveal that these proteins are highly prone to undergoing concentration-dependent phase separation, which on aging is rationalized in a decrease of their effective solubilities, in particular for proteins associated with translation, growth, reproduction, and the chaperone system.


Assuntos
Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Proteoma/química , Proteoma/metabolismo , Envelhecimento/fisiologia , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Homeostase , Espectrometria de Massas , Chaperonas Moleculares/metabolismo , Agregados Proteicos/fisiologia , Dobramento de Proteína , Solubilidade
4.
Bioinformatics ; 36(3): 940-941, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504168

RESUMO

MOTIVATION: RNA structure is difficult to predict in vivo due to interactions with enzymes and other molecules. Here we introduce CROSSalive, an algorithm to predict the single- and double-stranded regions of RNAs in vivo using predictions of protein interactions. RESULTS: Trained on icSHAPE data in presence (m6a+) and absence of N6 methyladenosine modification (m6a-), CROSSalive achieves cross-validation accuracies between 0.70 and 0.88 in identifying high-confidence single- and double-stranded regions. The algorithm was applied to the long non-coding RNA Xist (17 900 nt, not present in the training) and shows an Area under the ROC curve of 0.83 in predicting structured regions. AVAILABILITY AND IMPLEMENTATION: CROSSalive webserver is freely accessible at http://service.tartaglialab.com/new_submission/crossalive. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

5.
Nucleic Acids Res ; 48(D1): D511-D516, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31665505

RESUMO

Bacterial infections have been on the rise world-wide in recent years and have a considerable impact on human well-being in terms of attributable deaths and disability-adjusted life years. Yet many mechanisms underlying bacterial pathogenesis are still poorly understood. Here, we introduce the BacFITBase database for the systematic characterization of bacterial proteins relevant for host infection aimed to enable the identification of new antibiotic targets. BacFITBase is manually curated and contains more than 90 000 entries with information on the contribution of individual genes to bacterial fitness under in vivo infection conditions in a range of host species. The data were collected from 15 different studies in which transposon mutagenesis was performed, including top-priority pathogens such as Acinetobacter baumannii and Campylobacter jejuni, for both of which increasing antibiotic resistance has been reported. Overall, BacFITBase includes information on 15 pathogenic bacteria and 5 host vertebrates across 10 different tissues. It is freely available at www.tartaglialab.com/bacfitbase.

6.
Acta Neuropathol Commun ; 7(1): 197, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796104

RESUMO

Protein aggregation is a pathological feature of neurodegenerative disorders. We previously demonstrated that protein inclusions in the brain are composed of supersaturated proteins, which are abundant and aggregation-prone, and form a metastable subproteome. It is not yet clear, however, whether this phenomenon is also associated with non-neuronal protein conformational disorders. To respond to this question, we analyzed proteomic datasets from biopsies of patients with genetic and acquired protein aggregate myopathy (PAM) by quantifying the changes in composition, concentration and aggregation propensity of proteins in the fibers containing inclusions and those surrounding them. We found that a metastable subproteome is present in skeletal muscle from healthy patients. The expression of this subproteome escalate as proteomic samples are taken more proximal to the pathologic inclusion, eventually exceeding its solubility limits and aggregating. While most supersaturated proteins decrease or maintain steady abundance across healthy fibers and inclusion-containing fibers, proteins within the metastable subproteome rise in abundance, suggesting that they escape regulation. Taken together, our results show in the context of a human conformational disorder that the supersaturation of a metastable subproteome underlies widespread aggregation and correlates with the histopathological state of the tissue.

7.
Methods ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31563541

RESUMO

Given their central role in translation, splicing, localization and stability of transcripts, RNA binding proteins (RBPs) are key regulators of several cellular processes. While experimental efforts have been put to study how RBPs bind to transcripts, very little is known about the RNA contributions to the interaction. Here, we review the most common RNA-centric methods to reveal interactions with RBPs: both in vitro (SELEX, SEQR, RNA-compete and RBNS) and in silico (MEME, SeAMotE, GLAM2, iDeep, MEMERIS, RNA context, RCK, RNApromo and GraphProt). We emphasize the main advantages and disadvantages of each technique and highlight the key physico-chemical features contributing to the identification of RNA motifs involved in RBP recognition. We discuss extrinsic determinants influencing protein-RNA binding, such as post-transcriptional and post-translational modifications as well as expression and location of transcripts.

8.
Nat Commun ; 10(1): 4162, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519910

RESUMO

Insoluble protein aggregates are the hallmarks of many neurodegenerative diseases. For example, aggregates of TDP-43 occur in nearly all cases of amyotrophic lateral sclerosis (ALS). However, whether aggregates cause cellular toxicity is still not clear, even in simpler cellular systems. We reasoned that deep mutagenesis might be a powerful approach to disentangle the relationship between aggregation and toxicity. We generated >50,000 mutations in the prion-like domain (PRD) of TDP-43 and quantified their toxicity in yeast cells. Surprisingly, mutations that increase hydrophobicity and aggregation strongly decrease toxicity. In contrast, toxic variants promote the formation of dynamic liquid-like condensates. Mutations have their strongest effects in a hotspot that genetic interactions reveal to be structured in vivo, illustrating how mutagenesis can probe the in vivo structures of unstructured proteins. Our results show that aggregation of TDP-43 is not harmful but protects cells, most likely by titrating the protein away from a toxic liquid-like phase.


Assuntos
Biologia Computacional/métodos , Genômica/métodos , Biologia de Sistemas/métodos , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Mutação/genética , Príons/genética , Príons/metabolismo
9.
Nat Commun ; 10(1): 3246, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324771

RESUMO

The combination of high-throughput sequencing and in vivo crosslinking approaches leads to the progressive uncovering of the complex interdependence between cellular transcriptome and proteome. Yet, the molecular determinants governing interactions in protein-RNA networks are not well understood. Here we investigated the relationship between the structure of an RNA and its ability to interact with proteins. Analysing in silico, in vitro and in vivo experiments, we find that the amount of double-stranded regions in an RNA correlates with the number of protein contacts. This relationship -which we call structure-driven protein interactivity- allows classification of RNA types, plays a role in gene regulation and could have implications for the formation of phase-separated ribonucleoprotein assemblies. We validate our hypothesis by showing that a highly structured RNA can rearrange the composition of a protein aggregate. We report that the tendency of proteins to phase-separate is reduced by interactions with specific RNAs.


Assuntos
Conformação de Ácido Nucleico , Domínios Proteicos , Proteínas de Ligação a RNA/química , RNA/química , Algoritmos , Sítios de Ligação , Ontologia Genética , Células HeLa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Moleculares , Ligação Proteica , Proteoma/química , Proteoma/metabolismo , RNA/genética , RNA/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transcriptoma
11.
Sci Rep ; 9(1): 4302, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30867517

RESUMO

The coordination of the synthesis of functionally-related proteins can be achieved at the post-transcriptional level by the action of common regulatory molecules, such as RNA-binding proteins (RBPs). Despite advances in the genome-wide identification of RBPs and their binding transcripts, the protein-RNA interaction space is still largely unexplored, thus hindering a broader understanding of the extent of the post-transcriptional regulation of related coding RNAs. Here, we propose a computational approach that combines protein-mRNA interaction networks and statistical analyses to provide an inferred regulatory landscape for more than 800 human RBPs and identify the cellular processes that can be regulated at the post-transcriptional level. We show that 10% of the tested sets of functionally-related mRNAs can be post-transcriptionally regulated. Moreover, we propose a classification of (i) the RBPs and (ii) the functionally-related mRNAs, based on their distinct behaviors in the functional landscape, hinting towards mechanistic regulatory hypotheses. In addition, we demonstrate the usefulness of the inferred functional landscape to investigate the cellular role of both well-characterized and novel RBPs in the context of human diseases.

12.
J Mol Biol ; 431(8): 1671-1688, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30742796

RESUMO

Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are incurable motor neuron diseases associated with muscle weakness, paralysis and respiratory failure. Accumulation of TAR DNA-binding protein 43 (TDP-43) as toxic cytoplasmic inclusions is one of the hallmarks of these pathologies. TDP-43 is an RNA-binding protein responsible for regulating RNA transcription, splicing, transport and translation. Aggregated TDP-43 does not retain its physiological function. Here, we exploit the ability of TDP-43 to bind specific RNA sequences to validate our hypothesis that the native partners of a protein can be used to interfere with its ability to self-assemble into aggregates. We propose that binding of TDP-43 to specific RNA can compete with protein aggregation. This study provides a solid proof of concept to the hypothesis that natural interactions can be exploited to increase protein solubility and could be adopted as a more general rational therapeutic strategy.

13.
Bioinformatics ; 35(15): 2569-2577, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535291

RESUMO

MOTIVATION: Understanding the molecular mechanisms of thermal stability is a challenge in protein biology. Indeed, knowing the temperature at which proteins are stable has important theoretical implications, which are intimately linked with properties of the native fold, and a wide range of potential applications from drug design to the optimization of enzyme activity. RESULTS: Here, we present a novel graph-theoretical framework to assess thermal stability based on the structure without any a priori information. In this approach we describe proteins as energy-weighted graphs and compare them using ensembles of interaction networks. Investigating the position of specific interactions within the 3D native structure, we developed a parameter-free network descriptor that permits to distinguish thermostable and mesostable proteins with an accuracy of 76% and area under the receiver operating characteristic curve of 78%. AVAILABILITY AND IMPLEMENTATION: Code is available upon request to edoardo.milanetti@uniroma1.it. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

14.
Cell Rep ; 25(12): 3422-3434.e7, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30566867

RESUMO

Recent evidence indicates that specific RNAs promote the formation of ribonucleoprotein condensates by acting as scaffolds for RNA-binding proteins (RBPs). We systematically investigated RNA-RBP interaction networks to understand ribonucleoprotein assembly. We found that highly contacted RNAs are structured, have long UTRs, and contain nucleotide repeat expansions. Among the RNAs with such properties, we identified the FMR1 3' UTR that harbors CGG expansions implicated in fragile X-associated tremor/ataxia syndrome (FXTAS). We studied FMR1 binding partners in silico and in vitro and prioritized the splicing regulator TRA2A for further characterization. In a FXTAS cellular model, we validated the TRA2A-FMR1 interaction and investigated implications of its sequestration at both transcriptomic and post-transcriptomic levels. We found that TRA2A co-aggregates with FMR1 in a FXTAS mouse model and in post-mortem human samples. Our integrative study identifies key components of ribonucleoprotein aggregates, providing links to neurodegenerative disease and allowing the discovery of therapeutic targets.


Assuntos
Ataxia/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , RNA/metabolismo , Ribonucleoproteínas/metabolismo , Tremor/metabolismo , Animais , Encéfalo/patologia , Células COS , Núcleo Celular/metabolismo , Simulação por Computador , Proteína do X Frágil de Retardo Mental/metabolismo , Humanos , Corpos de Inclusão/metabolismo , Camundongos , Mapas de Interação de Proteínas , Processamento de RNA/genética , RNA não Traduzido/metabolismo , Proteínas de Ligação a RNA/metabolismo , Reprodutibilidade dos Testes , Fatores de Processamento de Serina-Arginina/metabolismo
15.
Front Mol Biosci ; 5: 111, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30560136

RESUMO

To compare the secondary structure profiles of RNA molecules we developed the CROSSalign method. CROSSalign is based on the combination of the Computational Recognition Of Secondary Structure (CROSS) algorithm to predict the RNA secondary structure profile at single-nucleotide resolution and the Dynamic Time Warping (DTW) method to align profiles of different lengths. We applied CROSSalign to investigate the structural conservation of long non-coding RNAs such as XIST and HOTAIR as well as ssRNA viruses including HIV. CROSSalign performs pair-wise comparisons and is able to find homologs between thousands of matches identifying the exact regions of similarity between profiles of different lengths. In a pool of sequences with the same secondary structure CROSSalign accurately recognizes repeat A of XIST and domain D2 of HOTAIR and outperforms other methods based on covariance modeling. The algorithm is freely available at the webpage http://service.tartaglialab.com//new_submission/crossalign.

16.
Nat Struct Mol Biol ; 25(11): 1035-1046, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30374086

RESUMO

Synchronization of mitochondrial and cytoplasmic translation rates is critical for the maintenance of cellular fitness, with cancer cells being especially vulnerable to translational uncoupling. Although alterations of cytosolic protein synthesis are common in human cancer, compensating mechanisms in mitochondrial translation remain elusive. Here we show that the malignant long non-coding RNA (lncRNA) SAMMSON promotes a balanced increase in ribosomal RNA (rRNA) maturation and protein synthesis in the cytosol and mitochondria by modulating the localization of CARF, an RNA-binding protein that sequesters the exo-ribonuclease XRN2 in the nucleoplasm, which under normal circumstances limits nucleolar rRNA maturation. SAMMSON interferes with XRN2 binding to CARF in the nucleus by favoring the formation of an aberrant cytoplasmic RNA-protein complex containing CARF and p32, a mitochondrial protein required for the processing of the mitochondrial rRNAs. These data highlight how a single oncogenic lncRNA can simultaneously modulate RNA-protein complex formation in two distinct cellular compartments to promote cell growth.


Assuntos
Neoplasias/genética , Neoplasias/metabolismo , Biossíntese de Proteínas/genética , RNA Longo não Codificante/genética , Proteínas Reguladoras de Apoptose/metabolismo , Sítios de Ligação , Compartimento Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células/genética , Citosol/metabolismo , Exorribonucleases/metabolismo , Células HEK293 , Humanos , Mitocôndrias/metabolismo , Modelos Biológicos , Neoplasias/patologia , Processamento Pós-Transcricional do RNA , RNA Longo não Codificante/metabolismo , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , Proteínas de Ligação a RNA/metabolismo
17.
Nucleic Acids Res ; 46(2): 917-928, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29165713

RESUMO

The human transcriptome contains thousands of long non-coding RNAs (lncRNAs). Characterizing their function is a current challenge. An emerging concept is that lncRNAs serve as protein scaffolds, forming ribonucleoproteins and bringing proteins in proximity. However, only few scaffolding lncRNAs have been characterized and the prevalence of this function is unknown. Here, we propose the first computational approach aimed at predicting scaffolding lncRNAs at large scale. We predicted the largest human lncRNA-protein interaction network to date using the catRAPID omics algorithm. In combination with tissue expression and statistical approaches, we identified 847 lncRNAs (∼5% of the long non-coding transcriptome) predicted to scaffold half of the known protein complexes and network modules. Lastly, we show that the association of certain lncRNAs to disease may involve their scaffolding ability. Overall, our results suggest for the first time that RNA-mediated scaffolding of protein complexes and modules may be a common mechanism in human cells.


Assuntos
Biologia Computacional/métodos , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ribonucleoproteínas/metabolismo , Algoritmos , Predisposição Genética para Doença/genética , Humanos , Ligação Proteica , Mapas de Interação de Proteínas , Proteoma/genética , Proteoma/metabolismo , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Ribonucleoproteínas/genética , Transcriptoma
18.
Nucleic Acids Res ; 45(22): 12888-12903, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-29149290

RESUMO

Recent evidence indicates a link between Parkinson's Disease (PD) and the expression of a-synuclein (SNCA) isoforms with different 3' untranslated regions (3'UTRs). Yet, the post-transcriptional mechanisms regulating SNCA expression are unknown. Using a large-scale in vitro /in silico screening we identified RNA-binding proteins (RBPs) that interact with SNCA 3' UTRs. We identified two RBPs, ELAVL1 and TIAR, that bind with high affinity to the most abundant and translationally active 3' UTR isoform (575 nt). Knockdown and overexpression experiments indicate that both ELAVL1 and TIAR positively regulate endogenous SNCA in vivo. The mechanism of regulation implies mRNA stabilization as well as enhancement of translation in the case of TIAR. We observed significant alteration of both TIAR and ELAVL1 expression in motor cortex of post-mortem brain donors and primary cultured fibroblast from patients affected by PD and Multiple System Atrophy (MSA). Moreover, trans expression quantitative trait loci (trans-eQTLs) analysis revealed that a group of single nucleotide polymorphisms (SNPs) in TIAR genomic locus influences SNCA expression in two different brain areas, nucleus accumbens and hippocampus. Our study sheds light on the 3' UTR-mediated regulation of SNCA and its link with PD pathogenesis, thus opening up new avenues for investigation of post-transcriptional mechanisms in neurodegeneration.


Assuntos
Regiões 3' não Traduzidas/genética , Regulação da Expressão Gênica , Doença de Parkinson/genética , alfa-Sinucleína/genética , Linhagem Celular Tumoral , Células Cultivadas , Proteína Semelhante a ELAV 1/genética , Proteína Semelhante a ELAV 1/metabolismo , Células HeLa , Hipocampo/metabolismo , Humanos , Núcleo Accumbens/metabolismo , Doença de Parkinson/metabolismo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , alfa-Sinucleína/metabolismo
20.
Proc Natl Acad Sci U S A ; 114(20): E3935-E3943, 2017 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-28396410

RESUMO

Amyotrophic lateral sclerosis (ALS) is a heterogeneous degenerative motor neuron disease linked to numerous genetic mutations in apparently unrelated proteins. These proteins, including SOD1, TDP-43, and FUS, are highly aggregation-prone and form a variety of intracellular inclusion bodies that are characteristic of different neuropathological subtypes of the disease. Contained within these inclusions are a variety of proteins that do not share obvious characteristics other than coaggregation. However, recent evidence from other neurodegenerative disorders suggests that disease-affected biochemical pathways can be characterized by the presence of proteins that are supersaturated, with cellular concentrations significantly greater than their solubilities. Here, we show that the proteins that form inclusions of mutant SOD1, TDP-43, and FUS are not merely a subset of the native interaction partners of these three proteins, which are themselves supersaturated. To explain the presence of coaggregating proteins in inclusions in the brain and spinal cord, we observe that they have an average supersaturation even greater than the average supersaturation of the native interaction partners in motor neurons, but not when scores are generated from an average of other human tissues. These results suggest that inclusion bodies in various forms of ALS result from a set of proteins that are metastable in motor neurons, and thus prone to aggregation upon a disease-related progressive collapse of protein homeostasis in this specific setting.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Agregação Patológica de Proteínas/fisiopatologia , Nervos Espinhais/fisiopatologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Encéfalo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/fisiologia , Neurônios Motores/metabolismo , Mutação , Agregados Proteicos/fisiologia , Agregação Patológica de Proteínas/metabolismo , Dobramento de Proteína , Proteína FUS de Ligação a RNA/metabolismo , Medula Espinal/metabolismo , Nervos Espinhais/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/genética
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