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Genetics and Acquired Hearing Loss [chapter]

Moza Al-Kowari, Meritxell Espino-Guarch
2019 Geriatric Medicine and Gerontology [Working Title]  
Acknowledgements Meritxell Espino-Guarch received funding from Qatar Foundation Grant ID: JSREP07-03-3-006.  ...  Due to DOI: http://dx.doi.org/10.5772/intechopen.86664 Author details Moza Al-Kowari* and Meritxell Espino-Guarch Translational Medicine, Sidra Medicine Hospital, Doha, Qatar *Address all correspondence  ... 
doi:10.5772/intechopen.86664 fatcat:dtjvvaqx7ndf3l57reduy4a7hu

Digenic Inheritance in Cystinuria Mouse Model

Meritxell Espino, Mariona Font-Llitjós, Clara Vilches, Eduardo Salido, Esther Prat, Miguel López de Heredia, Manuel Palacín, Virginia Nunes, Yann Herault
2015 PLoS ONE  
Cystinuria is an aminoaciduria caused by mutations in the genes that encode the two subunits of the amino acid transport system b 0,+ , responsible for the renal reabsorption of cystine and dibasic amino acids. The clinical symptoms of cystinuria relate to nephrolithiasis, due to the precipitation of cystine in urine. Mutations in SLC3A1, which codes for the heavy subunit rBAT, cause cystinuria type A, whereas mutations in SLC7A9, which encodes the light subunit b 0,+ AT, cause cystinuria type
more » ... . By crossing Slc3a1 -/with Slc7a9 -/mice we generated a type AB cystinuria mouse model to test digenic inheritance of cystinuria. The 9 genotypes obtained have been analyzed at early (2-and 5-months) and late stage (8months) of the disease. Monitoring the lithiasic phenotype by X-ray, urine amino acid content analysis and protein expression studies have shown that double heterozygous mice (Slc7a9 +/-Slc3a1 +/-) present lower expression of system b 0,+ and higher hyperexcretion of cystine than single heterozygotes (Slc7a9 +/-Slc3a1 +/+ and Slc7a9 +/+ Slc3a1 +/-) and give rise to lithiasis in 4% of the mice, demonstrating that cystinuria has a digenic inheritance in this mouse model. Moreover in this study it has been demonstrated a genotype/phenotype correlation in type AB cystinuria mouse model providing new insights for further molecular and genetic studies of cystinuria patients.
doi:10.1371/journal.pone.0137277 pmid:26359869 pmcid:PMC4567282 fatcat:nbxpgpt4znaazft3xbzzubipby

Antioxidant Supplementation Reduces Genomic Aberrations in Human Induced Pluripotent Stem Cells

Junfeng Ji, Vivek Sharma, Suxia Qi, Meritxell Espino Guarch, Ping Zhao, Zhiwei Luo, Wenxia Fan, Yu Wang, Faridah Mbabaali, Dante Neculai, Miguel Angel Esteban, John D. McPherson (+1 others)
2014 Stem Cell Reports  
Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) using oncogenic transcription factors. However, this method leads to genetic aberrations in iPSCs via unknown mechanisms, which may limit their clinical use. Here, we demonstrate that the supplementation of growth media with antioxidants reduces the genome instability of cells transduced with the reprogramming factors. Antioxidant supplementation did not affect transgene expression level or silencing kinetics.
more » ... y, iPSCs made with antioxidants had significantly fewer de novo copy number variations, but not fewer coding point mutations, than iPSCs made without antioxidants. Our results suggest that the quality and safety of human iPSCs might be enhanced by using antioxidants in the growth media during the generation and maintenance of iPSCs.
doi:10.1016/j.stemcr.2013.11.004 pmid:24511469 pmcid:PMC3916753 fatcat:k334yk3mgffl7kpeaihymrwuoe

L amino acid transporter structure and molecular bases for the asymmetry of substrate interaction

Ekaitz Errasti-Murugarren, Joana Fort, Paola Bartoccioni, Lucía Díaz, Els Pardon, Xavier Carpena, Meritxell Espino-Guarch, Antonio Zorzano, Christine Ziegler, Jan Steyaert, Juan Fernández-Recio, Ignacio Fita (+1 others)
2019 Nature Communications  
L-amino acid transporters (LATs) play key roles in human physiology and are implicated in several human pathologies. LATs are asymmetric amino acid exchangers where the low apparent affinity cytoplasmic side controls the exchange of substrates with high apparent affinity on the extracellular side. Here, we report the crystal structures of an LAT, the bacterial alanine-serine-cysteine exchanger (BasC), in a non-occluded inward-facing conformation in both apo and substrate-bound states. We
more » ... lized BasC in complex with a nanobody, which blocks the transporter from the intracellular side, thus unveiling the sidedness of the substrate interaction of BasC. Two conserved residues in human LATs, Tyr 236 and Lys 154, are located in equivalent positions to the Na1 and Na2 sites of sodium-dependent APC superfamily transporters. Functional studies and molecular dynamics (MD) calculations reveal that these residues are key for the asymmetric substrate interaction of BasC and in the homologous human transporter Asc-1.
doi:10.1038/s41467-019-09837-z pmid:31000719 pmcid:PMC6472337 fatcat:sryi23v3e5e6fkq76vex5ag4a4

Slc7a9 knockout mouse is a good cystinuria model for antilithiasic pharmacological studies

Mariona Font-Llitjós, Lídia Feliubadaló, Meritxell Espino, Ramon Clèries, Sandra Mañas, Isabelle M. Frey, Sara Puertas, Guillem Colell, Sergio Palomo, Jessica Aranda, Joana Visa, Manuel Palacín (+1 others)
2007 AJP - Renal Physiology  
Cystinuria is a hereditary disorder caused by a defect in the apical membrane transport system for cystine and dibasic amino acids in renal proximal tubules and intestine, resulting in recurrent urolithiasis. Mutations in SLC3A1 and SLC7A9 genes, that codify for rBAT/b 0,ϩ AT transporter subunits, cause type A and B cystinuria, respectively. In humans, cystinuria treatment is based on the prevention of calculi formation and its dissolution or breakage. Persistent calculi are treated with thiols
more » ... [i.e., D-penicillamine (DP) and mercaptopropionylglycine (MPG)] for cystine solubilization. We have developed a new protocol with DP to validate our Slc7a9 knockout mouse model for the study of the therapeutic effect of drugs in the treatment of cystine lithiasis. We performed a 5-wk treatment of individually caged lithiasic mutant mice with a previously tested DP dose. To appraise the evolution of lithiasis throughout the treatment a noninvasive indirect method of calculi quantification was developed: calculi mass was quantified by densitometry of X-ray images from cystinuric mice before and after treatment. Urine was collected in metabolic cage experiments to quantify amino acids in DP-treated and nontreated, nonlithiasic mutant mice. We found significant differences between DP-treated and nontreated knockout mice in calculi size and in urinary cystine excretion. Histopathological analysis showed that globally nontreated mutant mice had more severe and diffuse urinary system damage than DP-treated mice. Our results validate the use of this mouse model for testing the efficacy of potential new drugs against cystinuria. D-Penicillamine treatment; cystinuria model; calculi; noninvasive imaging system CYSTINURIA (OMIM 220100) IS an autosomal disease of renal reabsorption and intestinal absorption of cystine and dibasic amino acids, caused by defects in the amino acid transporter rBAT/ b 0,ϩ AT. Cystine precipitates in the urinary system to form calculi that can cause obstruction, infection and, ultimately, renal failure (33). Cystinuria is classified into three types according to the urine phenotype in heterozygotes: phenotype * M. Font-Llitjós and L. Feliubadaló contributed equally to this work.
doi:10.1152/ajprenal.00121.2007 pmid:17596531 fatcat:pvp3te6uijfnrb67mpz2iirqhu

BootstRatio: A web-based statistical analysis of fold-change in qPCR and RT-qPCR data using resampling methods

Ramon Clèries, Jordi Galvez, Meritxell Espino, Josepa Ribes, Virginia Nunes, Miguel López de Heredia
2012 Computers in Biology and Medicine  
Real-time quantitative polymerase chain reaction (qPCR) is widely used in biomedical sciences quantifying its results through the relative expression (RE) of a target gene versus a reference one. Obtaining significance levels for RE assuming an underlying probability distribution of the data may be difficult to assess. We have developed the web-based application BootstRatio, which tackles the statistical significance of the RE and the probability that RE4 1 through resampling methods without
more » ... assumption on the underlying probability distribution for the data analyzed. BootstRatio perform these statistical analyses of gene expression ratios in two settings: (1) when data have been already normalized against a control sample and (2) when the data control samples are provided. Since the estimation of the probability that RE 4 1 is an important feature for this type of analysis, as it is used to assign statistical significance and it can be also computed under the Bayesian framework, a simulation study has been carried out comparing the performance of BootstRatio versus a Bayesian approach in the estimation of that probability. In addition, two analyses, one for each setting, carried out with data from real experiments are presented showing the performance of BootstRatio. Our simulation study suggests that Bootstratio approach performs better than the Bayesian one excepting in certain situations of very small sample size (Nr 12). The web application BootstRatio is accessible through http://regstattools. net/br and developed for the purpose of these intensive computation statistical analyses.
doi:10.1016/j.compbiomed.2011.12.012 pmid:22270228 fatcat:psabee2x4rbjvciosflqjr7tei

Novel SLC7A7 large rearrangements in lysinuric protein intolerance patients involving the same AluY repeat

Mariona Font-Llitjós, Benjamín Rodríguez-Santiago, Meritxell Espino, Ruth Sillué, Sandra Mañas, Laia Gómez, Luis A Pérez-Jurado, Manuel Palacín, Virginia Nunes
2008 European Journal of Human Genetics  
Lysinuric protein intolerance (LPI) is a rare autosomal inherited disease caused by defective cationic aminoacid transport 4F2hc/y þ LAT-1 at the basolateral membrane of epithelial cells in the intestine and kidney. LPI is a multisystemic disease with a variety of clinical symptoms such as hepatosplenomegaly, osteoporosis, hypotonia, developmental delay, pulmonary insufficiency or end-stage renal disease. The SLC7A7 gene, which encodes the y þ LAT-1 protein, is mutated in LPI patients. Mutation
more » ... analysis of the promoter localized in intron 1 and all exons of the SLC7A7 gene was performed in 11 patients from 9 unrelated LPI families. Point mutation screening was performed by exon direct sequencing and a new multiplex ligation probe amplification (MLPA) assay was set up for large rearrangement analysis. Eleven SLC7A7-specific mutations were identified, seven of them were novel: p.L124P, p.C425R, p.R468X, p.Y274fsX21, c.625 þ 1G4C, DelE4-E11 and DelE6-E11. The novel large deletions originated by the recombination of Alu repeats at introns 3 and 5, respectively, with the same AluY sequence localized at the SLC7A7 3 0 region. The novel MLPA assay is robust and valuable for LPI molecular diagnosis. Our results suggest that genomic rearrangements of SLC7A7 play a more important role in LPI than has been reported, increasing the detection rate from 5.1 to 21.4%. Moreover, the 3 0 region AluY repeat could be a recombination hot spot as it is involved in 38% of all SLC7A7 rearranged chromosomes described so far.
doi:10.1038/ejhg.2008.145 pmid:18716612 pmcid:PMC2985956 fatcat:6dkl7gvlu5fjzecnezjbgtvf6m

Intestinal spirochetosis and chronic watery diarrhea: Clinical and histological response to treatment and long-term follow up

Maria Esteve, Antonio Salas, Fernando Fernandez-Banares, Josep Lloreta, Meritxell Marine, Clara Isabel Gonzalez, Montserrat Forne, Jaume Casalots, Rebeca Santaolalla, Jorge Carlos Espinos, Mohammed Arif Munshi, David John Hampson (+1 others)
2006 Journal of Gastroenterology and Hepatology  
The clinical significance of intestinal spirochetosis is uncertain, therefore the aim of the present paper was to assess the prevalence of histological intestinal spirochetosis in patients with and without chronic watery diarrhea and to evaluate its clinical relevance. Methods: A prospective diagnostic work-up of intestinal spirochetosis was made on biopsy samples taken from patients with chronic watery diarrhea submitted between 1994 and 2004 (1174 colonoscopies with multiple biopsies). Three
more » ... ther positive cases identified from routine endoscopic biopsies also were reviewed. In addition, samples from 100 asymptomatic control patients and a random sample of another 104 colonic specimens were reviewed for intestinal spirochetosis. The diagnosis was established by light and electron microscopy. Polymerase chain reaction (PCR) amplification of the 16S ribosomal RNA and reduced nicotinamide adenine dinucleotide (NADH) oxidase genes of the intestinal spirochetes Brachyspira aalborgi and Brachyspira pilosicoli was performed on tissue biopsies of the 11 positive patients. After diagnosis, treatment with penicillin benzatine (PB) or metronidazole was offered to all symptomatic patients and they were followed for a mean of 45.4 months (range: 37-113 months). Results: Eight patients with chronic watery diarrhea were positive for intestinal spirochetosis. Intestinal spirochetosis was not diagnosed in the controls. Histological resolution of the infection paralleled clinical recovery in six patients (following metronidazole treatment in three). Most patients showed mild, non-specific colonic inflammation. Invasion by the spirochetes was not demonstrated by electron microscopy. Brachyspira aalborgi and B. pilosicoli each were identified by PCR in two cases. Conclusions: Histological intestinal spirochetosis appears to be relatively uncommon in Catalonia (Spain) compared to previous reports from other countries, but was identified in patients (0.7%) with chronic watery diarrhea. Sustained clinical recovery after spontaneous or drug-induced spirochetal disappearance in these individuals suggests that intestinal spirochetosis may play a pathogenic role in chronic watery diarrhea. Treatment with metronidazole is advisable in patients with persistent symptoms.
doi:10.1111/j.1440-1746.2006.04150.x pmid:16872318 fatcat:3czfifllxrayzjxfjkfsw4qgpe

Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss

Meritxell Espino Guarch, Mariona Font-Llitjós, Silvia Murillo-Cuesta, Ekaitz Errasti- Murugarren, Adelaida M Celaya, Giorgia Girotto, Dragana Vuckovic, Massimo Mezzavilla, Clara Vilches, Susanna Bodoy, Ignasi Sahún, Laura González (+7 others)
2018 eLife  
DOI: https://doi.org/10.7554/eLife.31511 Meritxell Espino Guarch, Conceptualization, Resources, Methodology, Writing-original draft, Writing-review and editing, Western Blot, Brain IHC, Stress Response  ...  DOI: https://doi.org/10.7554/eLife.31511.013 Espino Guarch et al. eLife 2018;7:e31511. DOI: https://doi.org/10.7554/eLife.31511 Figure 4 4 Figure 4.  ... 
doi:10.7554/elife.31511 pmid:29355479 pmcid:PMC5811215 fatcat:pbbhgob3mffwplwyn6lk4rde3m

Novel cystine transporter in renal proximal tubule identified as a missing partner of cystinuria-related plasma membrane protein rBAT/SLC3A1

Shushi Nagamori, Pattama Wiriyasermkul, Meritxell Espino Guarch, Hirohisa Okuyama, Saya Nakagomi, Kenjiro Tadagaki, Yumiko Nishinaka, Susanna Bodoy, Kazuaki Takafuji, Suguru Okuda, Junko Kurokawa, Ryuichi Ohgaki (+3 others)
2016 Proceedings of the National Academy of Sciences of the United States of America  
Heterodimeric amino acid transporters play crucial roles in epithelial transport, as well as in cellular nutrition. Among them, the heterodimer of a membrane protein b 0,+ AT/SLC7A9 and its auxiliary subunit rBAT/ SLC3A1 is responsible for cystine reabsorption in renal proximal tubules. The mutations in either subunit cause cystinuria, an inherited amino aciduria with impaired renal reabsorption of cystine and dibasic amino acids. However, an unsolved paradox is that rBAT is highly expressed in
more » ... the S3 segment, the late proximal tubules, whereas b 0,+ AT expression is highest in the S1 segment, the early proximal tubules, so that the presence of an unknown partner of rBAT in the S3 segment has been proposed. In this study, by means of coimmunoprecipitation followed by mass spectrometry, we have found that a membrane protein AGT1/SLC7A13 is the second partner of rBAT. AGT1 is localized in the apical membrane of the S3 segment, where it forms a heterodimer with rBAT. Depletion of rBAT in mice eliminates the expression of AGT1 in the renal apical membrane. We have reconstituted the purified AGT1-rBAT heterodimer into proteoliposomes and showed that AGT1 transports cystine, aspartate, and glutamate. In the apical membrane of the S3 segment, AGT1 is suggested to locate itself in close proximity to sodium-dependent acidic amino acid transporter EAAC1 for efficient functional coupling. EAAC1 is proposed to take up aspartate and glutamate released into luminal fluid by AGT1 due to its countertransport so that preventing the urinary loss of aspartate and glutamate. Taken all together, AGT1 is the long-postulated second cystine transporter in the S3 segment of proximal tubules and a possible candidate to be involved in isolated cystinuria. amino acid transporter | cystine reabsorption | cystinuria | kidney T he heteromeric amino acid transporter (HAT) family is one of the major amino acid transporter families responsible for cellular uptake and epithelial transport (1-3). HATs form heterodimers composed of a 12 membrane spanning light chain (SLC7) that catalyzes transport functions and a single membrane spanning heavy chain (SLC3) essential for plasma membrane localization and stabilization of the light chains. Two heavy chains, SLC3A1/ rBAT and SLC3A2/4F2hc/CD98hc, covalently bound to light chains via a disulfide bridge have been identified so far (4-6). 4F2hc interacts with most of the light chains in HATs whereas rBAT has been known to form a heterodimer only with b 0,+ AT/ SLC7A9. Because the rBAT-b 0,+ AT complex is presented on the apical membrane of proximal tubules in the kidney and involved in the reabsorption of cystine and dibasic amino acids, the mutations of either rBAT or b 0,+ AT cause cystinuria, a disorder of renal reabsorption of cystine and dibasic amino acids leading to serious renal lithiasis due to low solubility of cystine (7) . An unsolved paradox on rBAT and b 0,+ AT has been the discrepancy between the distribution of rBAT and that of b 0,+ AT (5, (8) (9) (10) . rBAT is the most abundant in the S3 segment of proximal tubules, and its expression declines toward the S1 segment (11, 12) . In contrast, the expression of b 0,+ AT is highest in the S1 segment and decreases toward the S3 segment (5, 8). Furthermore, even in b 0,+ AT-deficient mice, heterodimers containing rBAT still have been observed (13). Therefore, it has been proposed that unknown partners of rBAT exist in the S3 segment (5, 9, 14, 15) . The HAT family includes two members, AGT1/SLC7A13 and Asc2, whose heavy chains have not been identified (16, 17). Among them, aspartate/glutamate transporter 1 (AGT1) has been identified as an Na + -independent acidic amino acid transporter expressed specifically in the kidney (17). In this study, we have generated new anti-AGT1 antibodies to search for the unknown heavy chain(s), by means of coimmunoprecipitation followed by mass spectrometry, and have revealed that rBAT is a heavy chain of AGT1. AGT1 was detected at the apical membrane of the S3 segment in renal proximal tubules. A transport assay of the AGT1-rBAT heterodimer reconstituted into proteoliposomes revealed that it transports cystine as well as aspartate and glutamate. We Significance Although molecular identification of transporters in mammals seems almost settled, some long-proposed transporters still remain to be revealed. The second cystine transporter in renal cystine reabsorption is one of such transporters. Its genetic defect has been proposed to be responsible for a type of cystinuria distinct from that caused by the mutations of the already known cystine transporter. In this study, we have found a membrane protein SLC7A13 as the second cystine transporter with proposed characteristics, and provided a possible clue to the genetics of previously unidentified cystinuria. Intricate functional coupling of SLC7A13 with the nearby glutamate transporter is also proposed. We have solved long-lasting problems in renal cystine transport physiology and paradoxes regarding the unmatched distribution of cystine transporter components.
doi:10.1073/pnas.1519959113 pmid:26739563 pmcid:PMC4725474 fatcat:yfuoby542bbsxhn2eftbf4oeeq

Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients

Moza Alkowari, Meritxell Espino-Guarch, Sahar Daas, Doua Abdelrahman, Waseem Hasan, Navaneethakrishnan Krishnamoorthy, Abbirami Sathappan, Patrick Sheehan, Nicholas Van Panhuys, The Qatar Genome Program Research Consortium, Xavier Estivill
2022
Hereditary hearing loss (HHL) is a common genetic disorder accounting for at least 60% of pre-lingual deafness in children, of which 70% is inherited in an autosomal recessive pattern. The long tradition of consanguinity among the Qatari population has increased the prevalence of HHL, which negatively impacts the quality of life. Here, we functionally validated the pathogenicity of the c.178G>C, p.E60Q mutation in the MYO6 gene, which was detected previously in a Qatari HHL family, using
more » ... r and animal models. In vitro analysis was conducted in HeLa cells transiently transfected with plasmids carrying MYO6WT or MYO6p.E60Q, and a zebrafish model was generated to characterize the in vivo phenotype. Cells transfected with MYO6WT showed higher expression of MYO6 in the plasma membrane and increased ATPase activity. Modeling the human MYO6 variants in zebrafish resulted in severe otic defects. At 72 h post-injection, MYO6p.E60Q embryos demonstrated alterations in the sizes of the saccule and utricle. Additionally, zebrafish with MYO6p.E60Q displayed super-coiled and bent hair bundles in otic hair cells when compared to control and MYO6WT embryos. In conclusion, our cellular and animal models add support to the in silico prediction that the p.E60Q missense variant is pathogenic and damaging to the protein. Since the c.178G>C MYO6 variant has a 0.5% allele frequency in the Qatari population, about 400 times higher than in other populations, it could contribute to explaining the high prevalence of hearing impairment in Qatar.
doi:10.3390/ijms23063369 pmid:35328790 pmcid:PMC8949016 fatcat:o2vsmunnxvbrtpr5figsyfg2jy

Contextos. Revista Crítica de Literatura. Año 1. N°1. 2010

Claudia Rodríguez M
2011 Estudios filológicos  
Representación de la violencia política en la poesía quechua" (99-112), de Gonzalo Espino Relucé, da cuenta de cómo, a través de la wanka (canto elegíaco), se representa el dolor, el despojo, por parte  ...  "Otra modernidad vanguardista: las propuestas de Gamaliel Churata y Oswald de Andrade" (83-98) de Meritxell Hernando Marsal, es un interesante artículo que propone y permite la articulación de las nociones  ... 
doi:10.4067/s0071-17132011000200010 fatcat:3xuq73o23zf6flihjataiazsne

Transcriptome and Literature Mining Highlight the Differential Expression of ERLIN1 in Immune Cells during Sepsis

Susie S. Y. Huang, Mohammed Toufiq, Luis R. Saraiva, Nicholas Van Panhuys, Damien Chaussabel, Mathieu Garand
2021 Biology  
The authors also thank Sharadambal Ramaseri Sunder and Meritxell Espino Guarch for their expert help and opinions on protein biology.  ... 
doi:10.3390/biology10080755 pmid:34439987 pmcid:PMC8389572 fatcat:64f5syw2gbhrljc3bemkynvm6e

El Departament d'Història de l'Art en el curso 2017-18

Dirección Departament d'Història de l'Art
2019 Ars Longa Cuadernos de arte  
Ferrer, Meritxell; LÓPEZ-BERTRÁN, Mireia, "Perfumes, Make-up and Jewelry: Bodily Care and Gender in the Phoenician and Punic World (8th-4th centuries BC)".  ...  VÁZQUEZ DE ÁGREDOS PASCUAL, Marisa, ha dirigido el Trabajo Final de Máster de Flor Natividad Espino, "Identificación de potenciales patrimoniales en la ciudad de Lima como vía de fortalecimiento en materia  ... 
doi:10.7203/arslonga.27.13965 fatcat:xyouwtnqyjamdccc6frgljdg6m

UNIVERSIDAD NACIONAL MAYOR DE SAN MARCOS FACULTAD DE LETRAS Y CIENCIAS HUMANAS

E De Literatura
unpublished
Asimismo para Meritxell Hernando: "Los muertos no desaparecen, sino que permanecen en la memoria de los vivos" (2014: 44).  ...  Zubristki, Furtonato Jaúgerue, Alison Krögel, Jean-Philippe Husson, Armando Arteaga, Gonzalo Espino, Julio Noriega y Óscar Huamán.  ... 
fatcat:f5t22bnkobgzhjupqqijs52tpa
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