Mi-2
Dendrite arborization patterns are critical determinants of neuronal function. To explore the basis of transcriptional regulation in dendrite pattern formation, RNA interference (RNAi) was used to screen 730 transcriptional regulators and 78 genes involved in patterning the stereotyped dendritic arbors of class I da neurons were identified in Drosophila. Most of these transcriptional regulators affect dendrite morphology without altering the number of class I dendrite arborization (da) neurons and fall primarily into three groups. Group A genes control both primary dendrite extension and lateral branching, hence the overall dendritic field. Nineteen genes within group A act to increase arborization, whereas 20 other genes restrict dendritic coverage. Group B genes appear to balance dendritic outgrowth and branching. Nineteen group B genes function to promote branching rather than outgrowth, and two others have the opposite effects. Finally, 10 group C genes are critical for the routing of the dendritic arbors of individual class I da neurons. Thus, multiple genetic programs operate to calibrate dendritic coverage, to coordinate the elaboration of primary versus secondary branches, and to lay out these dendritic branches in the proper orientation (Parrish, 2006; Full text of article).
To assay for the stereotyped dendrite arborization pattern of class I da neurons (hereafter referred to as class I neurons) in RNAi-based analysis of dendrite development, a Gal4 enhancer trap line (Gal4221) was used that is highly expressed in class I neurons and weakly expressed in class IV neurons during embryogenesis. Because of the simple and stereotyped dendritic arborization patterns of the dorsally located ddaD and ddaE, the studies of dendrite development focused on these two dorsally located class I neurons (Parrish, 2006).
To establish that RNAi is an efficient method to systematically study dendrite development in the Drosophila embryonic PNS, it was demonstrated that injecting embryos with double-stranded RNA (dsRNA) for green fluorescent protein (gfp) is sufficient to attenuate Gal-4221-driven expression of an mCD8::GFP fusion protein as measured by confocal microscopy. Next whether RNAi could efficiently phenocopy loss-of-function mutants known to affect dendrite development was tested. Similar to the mutant phenotype of short stop (shot), which encodes an actin/microtubule cross-linking protein, shot(RNAi) caused routing defects, dorsal overextension, and a reduction in lateral branching of dorsally extended primary dendrites. Likewise, RNAi of sequoia or flamingo resulted in overextension of ddaD and ddaE, RNAi of hamlet resulted in supernumerary class I neurons, and RNAi of tumbleweed resulted in supernumerary class I neurons and a range of arborization defects, consistent with the reported mutant phenotypes. Thus, RNAi is effective in generating reduction of function phenotypes in embryonic class I dendrites (Parrish, 2006).
In contrast to the genes that coordinately affect dorsal dendrite outgrowth and lateral branching/outgrowth, a group of 21 genes (group B) were identified that have opposing effects on dendrite outgrowth and branching, suggesting that dendrite outgrowth and branching might partially antagonize one another. RNAi of 19 of these genes resulted in dorsal overextension of primary dendrites and a reduction in lateral branching/lateral branch extension. In the most severe cases, such as RNAi of the transcriptional repressor snail, dorsal overextension of almost completely unbranched dendrites was found. Like snail(RNAi), RNAi of the nuclear hormone receptor knirps, the transcriptional repressor l(3)mbt, as well as 15 other genes, all caused dorsal overextension of primary dendrites. As in the case of genes that normally limit arborization, RNAi of these genes rarely caused dendrites to cross the dorsal midline (Parrish, 2006).
As an indication of the hypomorphic nature of many of the alleles and maternal rescue of gene function in mutant embryos, focus was place on dendrite defects that were first apparent during larval stages. For example, a mutant allele of Drosophila Mi-2, which encodes a Hunchback-interacting ATP-dependant chromatin remodeling factor, shows only minor defects in late embryonic stages, but shows an obvious reduction in arborization by 72 h after egg laying. Since Mi-2(RNAi) demonstrates that Mi-2 is required for embryonic dendrite arborization, these findings suggest that Mi-2 is continuously required for class I neurons to maintain proper dendrite arborization patterns. Similarly, the dendritic overbranching associated with a P-element insertion allele of Adf1 was first apparent after embryonic stages, although Adf1(RNAi) caused overbranching in embryos. Class I dendritic arbors of Adf1 mutants are indistinguishable from wild-type neurons until 96 h AEL. By 144 h AEL, ddaE arbors of Adf1 mutants showed a greater than twofold increase in branch number when compared with time-matched wild-type controls. Interestingly, ddaD showed only very minor branching defects in Adf1 mutants, suggesting that ddaD and ddaE might have distinct requirements for Adf1. Similarly, mutant alleles of either E(bx) or Elongin C showed dendrite branching defects only at late larval stages. These findings indicate that Adf1, E(bx), and Elongin C are continuously required to inhibit branching in class I neurons, demonstrating that although class I neurons have very little new branching after embryogenesis, they still retain the capacity to branch (Parrish, 2006).
Chromosome condensation during During cell division, chromosomes undergo morphological changes from a cloud-like interphase morphology into rod-like structures. This transformation is referred to as chromosome condensation. Chromosome condensation is important for faithful chromosome segregation during cell division. The organisation of condensed metaphase chromosomes has been a focus of debate for a long time, and various models have been proposed. One model is that there is a hierarchical organisation, starting from nucleosomes folded into a 30-nm fibre, which form larger and larger loops. Another long-standing, and not mutually exclusive, model is that there is a chromosome scaffold, which has been observed after removal of DNA and most of the chromosome proteins from the metaphase chromosomes. However, the existence and the biological role of this scaffold are subjects of continuous discussion. The most recently proposed model is a polymer model based on data from a chromosome conformation capture method. This proposes that there is a compressed linear array of loops without hierarchical organisation (Nikalayevich, 2014).
Among thousands of proteins found in metaphase chromosomes, condensin complexes and topoisomerase II have been studied most extensively for their involvement in chromosome condensation during cell division. The condensin complex was originally found as the main chromosome condensation factor in Xenopus extract. The involvement of condensin complexes in this process has been demonstrated in many systems. Higher eukaryotes have two condensin complexes, condensin I and II. The two complexes appear to have different localisations and functions. The exact molecular mechanism by which condensin functions has not been established, but it has an ability to positively supercoil DNA (Nikalayevich, 2014).
It has been demonstrated in several systems that topoisomerase II is required for chromosome structure as well as correct chromosome segregation in mitosis and meiosis. Topoisomerase II is present on chromosomes in mitosis and meiosis and is also enriched on centromeres and pericentromeric regions during meiosis. Topoisomerase II decatenates supercoiled DNA by introducing temporary double-strand DNA breaks, and it has been suggested and demonstrated that topoisomerase II acts in opposition to condensin and KIF4A. Both condensin and topoisomerase II are required for the correct chromatin structure of the centromere (Nikalayevich, 2014).
Despite extensive research on the roles of condensin and topoisomerase II in chromosome condensation, some evidence casts doubts on whether these proteins are the only major factors involved in chromosome condensation. In some systems, chromosomes are still able to condense, with various abnormalities, after depletion of condensin subunits. Depletion of condensin does not prevent condensation of chromosomes until the initiation of anaphase, but causes chromosomes to decondense prematurely during anaphase. This has led to a proposal that there is a 'regulator of chromosome architecture' (RCA), an as yet unidentified factor, which acts redundantly with condensin to condense metaphase chromosomes (Nikalayevich, 2014).
Evidence suggests that there are crucial chromosome condensation factors other than condensin and topoisomerase II. Recently, attempts have been made to find new chromosome condensation factors. For example, a chromosome condensation assay allowed high-throughput analysis of genes required for chromosome condensation in fission yeast. In that study, eight new conditional condensin alleles were discovered, together with a new role for DNA polymerase ε (pol ε) and F-box DNA helicase I in chromosome condensation. In addition, a very recent study has identified mutations in several genes that cause chromosome segregation defects similar to those induced by depletion of condensin. Four out of five of these genes encode components of the nucleosome-remodelling complexes (Nikalayevich, 2014)
This report describes the first use of Drosophila oocytes to study chromosome condensation. RNA interference (RNAi)-mediated depletion of a set of chromosomal proteins revealed that depletion of the nucleosome-remodelling protein Mi-2 and the protein kinase NHK-1 (Nucleosomal histone kinase-1, also known as Ballchen in Drosophila) resulted in much more severe defects than depletion of well-known chromosome condensation factors. The condensation defects of Mi-2 and NHK-1 depletion were distinct from each other, suggesting that these proteins function in different pathways. This study found that the main NHK-1 action in chromosome condensation is to suppress Barrier-to-autointergration factor (BAF) activity, which functions to link nuclear envelope proteins to chromosomes (Nikalayevich, 2014)
Therefore, knockdown of potential chromosomal proteins or regulators by RNAi in oocytes has identified new factors promoting chromosome condensation (the NuRD complex and NHK-1) as well as known factors (condensin I, topoisomerase II and Aurora B). Depletion of the protein kinase NHK-1 and the NuRD nucleosome remodelling complex containing Mi-2 caused severe chromosome condensation defects that were distinct from each other. Further study revealed that BAF is the main substrate of NHK-1 for its chromosome condensation function and that NHK-1 promotes chromosome condensation by suppressing the linker activity of BAF between nuclear envelope proteins and DNA. Finally, it was shown that NHK-1 is also important for chromosome condensation in mitosis (Nikalayevich, 2014)
The Drosophila oocyte combined with RNAi is an excellent system for research of chromosome condensation, which complements commonly used mitotic systems. Firstly, Drosophila oocytes grow enormously in volume between completion of pre-meiotic mitosis and recombination and chromosome condensation. Small hairpin RNA (shRNA) expression can be induced after the protein executes its role in the previous mitosis and/or recombination but prior to oocyte growth. Even if the target protein is stable, it becomes sufficiently diluted before chromosome condensation in oocytes. This is in contrast to mitotic cycles where cells only double in size between divisions. Secondly, Drosophila oocytes arrest in metaphase of the first meiotic division. This allows chromosome defects to be studied in the first division after the target protein is depleted, rather than as a mixture of defects accumulated through multiple divisions caused by a gradual decrease of the protein. Finally, as oocytes are large, the condensation state of chromosomes can be clearly observed without mechanical treatment such as squashing or spreading. Therefore, RNAi in Drosophila oocytes could be a powerful system to study chromosome condensation, although negative results should be interpreted with caution as they might be caused by insufficient depletion, genetic redundancy or cell-type-specific function (Nikalayevich, 2014)
Indeed, in this study, a small-scale survey of chromosomal proteins, new chromosome condensation factors were identified in addition to well-known ones, demonstrating the effectiveness of Drosophila oocytes as a research system. Well-known factors, including condensin I subunits, topoisomerase II and Aurora B, showed milder chromosome condensation defects. Knockdown of topoisomerase II or condensin I showed similar condensation defects, and appeared to affect mainly centromeric and/or pericentromeric regions. The previous reports in mitosis are consistent with these result, suggesting that these two factors are not the main condensation factors in mitosis or in meiosis (Nikalayevich, 2014)
A previous study of Mi-2 in Drosophila suggested that it promotes decondensation of chromosomes because overexpression of wild-type Mi-2 results in chromosome decondensation in polytene or mitotic cells and overexpression of dominant-negative Mi-2 results in overcondensation. In the current study, Mi-2 RNAi in oocytes showed chromosome decondensation, whereas in a preliminary study in neuroblasts Mi-2 RNAi did not show chromosome decondensation. The difference from the previous study might be due to the method of disrupting the Mi-2 function or cell types used for the studies. It is argued that the phenotype caused by RNAi in oocytes is a better reflection of the in vivo function. RNAi of other NuRD subunits indicated that the NuRD complex is important for chromosome condensation (Nikalayevich, 2014)
How does the NuRD complex promote chromosome condensation? It is possible that nucleosome remodelling is directly required during chromosome condensation. For example, proper positioning of nucleosomes might be important for full chromosome condensation. Indeed, other nucleosome remodelling complexes have been suggested to be involved in chromosome condensation in fission yeast. Alternatively, histone deacetylase acivity of the NuRD complex might be important for chromosome condensation, as histone modifications are a major way to regulate chromosome structure. The possibility that NuRD acts through transcription of other chromosome condensation factors cannot be excluded, as it is known to regulate gene transcription. Further studies using more sophisticated mutations would help to distinguish these possibilities (Nikalayevich, 2014)
Knockdown of NHK-1 resulted in severe chromosome condensation defects in nearly all oocytes. Previously, involvement of NHK-1 or its orthologues in metaphase chromosome condensation has not been reported, although overexpression of the human orthologue disrupts chromatin organisation in interphase. None of the three female sterile nhk-1 mutants showed chromosome condensation defects in metaphase I in oocytes. This might be because the minimal NHK-1 activity required for producing viable adults is sufficient to allow chromosome condensation in oocytes. Female-germline-specific RNAi is likely to have achieved greater depletion of NHK-1 in oocytes. This study showed that phosphorylation of BAF, thus inactivating its linking of DNA to LEM-domain-containing inner nuclear membrane proteins, is the major role of NHK-1 in chromosome condensation in oocytes. However, NHK-1 might regulate multiple pathways during condensation, for example, it has been shown that it is required for histone 2A phosphorylation and condensin recruitment in prophase I oocytes (Nikalayevich, 2014)
A crucial question is whether the chromosome condensation defect is a direct consequence of NHK-1 loss or a secondary consequence of a karyosome defect in prophase I oocytes. Evidence indicates that the compact karyosome in the prophase I nucleus and chromosome condensation in metaphase I are at least partly independent. In female-sterile hypomophic nhk-1 mutants, chromatin organisation in prophase I oocytes is defective, but metaphase I chromosomes are properly condensed in mature oocytes. By contrast, in Mi-2 RNAi oocytes, the karyosome is normal in prophase I, but chromosomes become undercondensed after nuclear envelope breakdown in some metaphase I oocytes. Furthermore, as chromosome condensation in mitosis is also defective in nhk-1 mutants, the role for NHK-1 in chromosome condensation must be at least partly independent from meiosis-specific chromatin organisation. Therefore, release of LEM-containing nuclear envelope proteins from chromosomes might be a prerequisite for proper chromosome condensation (Nikalayevich, 2014)
In conclusion, this targeted survey using RNAi in Drosophila oocytes has already identified new factors required for chromosome condensation. Further analysis provided new insights into the molecular mechanism of condensation including the release of nuclear envelope proteins from chromosomes and nucleosome remodelling and/or histone deacetylation as essential steps for condensation. In future, a larger scale screen of putative chromosomal proteins might prove to be fruitful (Nikalayevich, 2014)
Aubry, F., Mattei, M. G. and Galibert, F. (1998). Identification of a human 17p-located cDNA encoding a protein of the Snf2-like helicase family. Eur. J. Biochem. 254(3): 558-64. PubMed Citation: 9688266
Ballestar, E., Pile, L. A., Wassarman, D. A., Wolffe, A. P. and Wade, P. A. (2001). A Drosophila MBD family member is a transcriptional co-repressor associated with specific genes. Eur. J. Biochem. 268,5397 -540. 11606202
Bouazoune, K., et al. (2002). The dMi-2 chromodomains are DNA binding modules important for ATP-dependent nucleosome mobilization. EMBO J. 21: 2430-2440. 12006495
Brehm, A., et al. (1999). The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth. EMBO J. 18(9): 2449-58. PubMed Citation: 10228159
Brehm, A., et al. (2000). dMi-2 and ISWI chromatin remodelling factors have distinct nucleosome binding and mobilization properties. EMBO J. 19(16):4332-41. PubMed Citation: 10944116
Corona, D. F., et al. (1999). ISWI is an ATP-dependent nucleosome remodeling factor. Mol. Cell 3: 239-245. PubMed Citation: 10078206
Fasulo, B., Deuring, R., Murawska, M., Gause, M., Dorighi, K. M., Schaaf, C. A., Dorsett, D., Brehm, A. and Tamkun, J. W. (2012). The Drosophila MI-2 chromatin-remodeling factor regulates higher-order chromatin structure and cohesin dynamics in vivo. PLoS Genet 8: e1002878. Pubmed: 22912596
Feng, Q. and Zhang, Y. (2001). The MeCP1 complex represses transcription through preferential binding, remodeling, and deacetylating methylated nucleosomes. Genes Dev. 15: 827-8324. 11297506
Gong, Z., Brackertz, M. and Renkawitz, R. (2006). SUMO modification enhances p66-mediated transcriptional repression of the Mi-2/NuRD complex. Mol. Cell. Biol. 26(12): 4519-28. 16738318
Guschin, D., et al. (2000). ATP-Dependent histone octamer mobilization and histone deacetylation mediated by the Mi-2 chromatin remodeling complex. Biochemistry 39(18): 5238-45. PubMed Citation: 10819992
Hamiche, A., et al. (1998). ATP-dependent histone octamer sliding mediated by the chromatin remodeling complex NURF. Cell 97(7): 833-42. PubMed Citation: 10399912
Hirose, F., Ohshima, N., Kwon, E.-J., Yoshida, H., Yamaguchi, M. (2002). Drosophila Mi-2 negatively regulates dDREF by inhibiting its DNA-binding activity. Mol. Cell. Biol. 22: 5182-5193. 12077345
Jin, S. G., Jiang, C. L., Rauch, T., Li, H. and Pfeifer, G. P. (2005). MBD3L2 interacts with MBD3 and components of the NuRD complex and can oppose MBD2-MeCP1-mediated methylation silencing. J. Biol. Chem. 280(13): 12700-9. 15701600
Kehle, J., et al. (1998). dMi-2, a Hunchback-interacting protein that functions in Polycomb repression. Science 282(5395): 1897-900. PubMed Citation: 9836641
Kim, J., et al. (1999). Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity 10(3): 345-55. PubMed Citation: 10204490
Kim, J., Lu, C., Srinivasan, S., Awe, S., Brehm, A. and Fuller, M. T. (2017). Blocking promiscuous activation at cryptic promoters directs cell type-specific gene expression. Science 356(6339): 717-721. PubMed ID: 28522526
Kingston, R. E. and Narlikar, G. J. (1999) ATP-dependent remodeling and acetylation as regulators of chromatin fluidity. Genes Dev. 13: 2339-2352. PubMed Citation: 10500090
Koipally, J., et al. (1999). Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes. EMBO J. 18(11): 3090-100. PubMed Citation: 10357820
Kon, C., Cadigan, K. M., da Silva, S. L. and Nusse, R. (2005). Developmental roles of the Mi-2/NURD-associated protein p66 in Drosophila. Genetics 169(4): 2087-100. 15695365
Längst, G., et al. (1999). Nucleosome movement by CHRAC and ISWI without disruption or trans-displacement of the histone octamer. Cell 97: 843-852. PubMed Citation: 10399913
Linder, B., et al. (2007). CHD4/Mi-2β activity is required for the positioning of the mesoderm/neuroectoderm boundary in Xenopus. Genes Dev. 21: 973-983. Medline abstract: 17438000
Marhold, J., Zbylut, M., Lankenau, D. H., Li, M., Gerlich, D., Ballesar, E., Mechler, B. M. and Lyko, F. (2002). Stage-specific chromosomal association of Drosophila dMBD2/3 during genome activation. Chromosoma 111: 13-21. 12068919
Marhold, J., Kramer, K., Kremmer, E. and Lyko, F. (2004). The Drosophila MBD2/3 protein mediates interactions between the MI-2 chromatin complex and CpT/A-methylated DNA. Development 131: 6033-6039. 15537686
Mathieu, E. L., Finkernagel, F., Murawska, M., Scharfe, M., Jarek, M. and Brehm, A. (2012). Recruitment of the ATP-dependent chromatin remodeler dMi-2 to the transcribed region of active heat shock genes. Nucleic Acids Res 40: 4879-4891. Pubmed: 22362736
Murawsky, C. M., et al. (2001). Tramtrack69 interacts with the dMi-2 subunit of the Drosophila NuRD chromatin remodelling complex. EMBO Reports 2: 1089-1094. 11743021
Murawska, M., Hassler, M., Renkawitz-Pohl, R., Ladurner, A. and Brehm, A. (2011). Stress-induced PARP activation mediates recruitment of Drosophila Mi-2 to promote heat shock gene expression. PLoS Genet 7: e1002206. Pubmed: 21829383
Nikalayevich, E. and Ohkura, H. (2014). The NuRD nucleosome remodelling complex and NHK-1 kinase are required for chromosome condensation in oocytes. J Cell Sci [Epub ahead of print]. PubMed ID: 25501812
O'Neill, D. W., et al. (2000). An ikaros-containing chromatin-remodeling complex in adult-type erythroid cells. Mol. Cell. Biol. 20(20): 7572-82. PubMed Citation: 11003653
Parrish, J. Z., Kim, M. D., Jan, L. Y. and Jan, Y. N. (2006). Genome-wide analyses identify transcription factors required for proper morphogenesis of Drosophila sensory neuron dendrites. Genes Dev. 20(7): 820-35. Medline abstract: 16547170
Polo, S. E., Kaidi, A., Baskcomb, L., Galanty, Y. and Jackson, S. P. (2010). Regulation of DNA-damage responses and cell-cycle progression by the chromatin remodelling factor CHD4. Embo J. 29: 3130-3139. PubMed Citation: 20693977
Scimone, M. L., Meisel, J., Reddien, P. W. (2010). The Mi-2-like Smed-CHD4 gene is required for stem cell differentiation in the planarian Schmidtea mediterranea. Development 137(8): 1231-41. PubMed Citation: 20223763
Solari, F. and Ahringer, J. (2000). NURD-complex genes antagonise Ras-induced vulval development in Caenorhabditis elegans. Curr. Biol. 10(4): 223-6. PubMed Citation: 10704416
Srinivasan, S., et al. (2005). The Drosophila trithorax group protein Kismet facilitates an early step in transcriptional elongation by RNA Polymerase II. Development 132: 1623-1635. 15728673
Tong, J. K., et al. (1998). Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395: 917-921. PubMed Citation: 9804427
Tweedie, S., Ng, H. H., Barlow, A. L., Turner, B. M., Hendrich, B. and Bird, A. (1999). Vestiges of a DNA methylation system in Drosophila melanogaster? Nat. Genet. 23: 389-390. 10581020
Unhavaithaya, Y., et al. (2002). MEP-1 and a homolog of the NURD complex component Mi-2 act together to maintain germline-soma distinctions in C. elegans. Cell 111: 991-1002. 12507426
von Zelewsky, T., et al. (2000). The C. elegans Mi-2 chromatin-remodelling proteins function in vulval cell fate determination. Development 127: 5277-5284. PubMed ID: 11076750
Wade, P. A., et al. (1998). A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. Curr. Biol. 8(14): 843-6. PubMed ID: 9663395
Wade, P. A., et al. (1999). Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat. Genet. 23(1): 62-6. PubMed ID: 10471500
Whitehouse, I., et al. (1999). Nucleosome mobilization catalysed by the yeast SWI/SNF complex. Nature 400: 784-787. PubMed ID: 10466730
Woodage, T., et al. (1997). Characterization of the CHD family of proteins. Proc. Natl Acad. Sci. 94: 11472-11477. PubMed ID: 9326634
Xue, Y., et al. (1998). NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol. Cell 2 851-861. PubMed ID: 9885572
Yamasaki, Y. and Nishida, Y. (2006). Mi-2 chromatin remodeling factor functions in sensory organ development through proneural gene repression in Drosophila. Dev. Growth Differ. 48(7): 411-8. Medline abstract: 16961588
Zhang, Y., et al. (1998). The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell 95(2): 279-89. PubMed ID: 9790534
Zhang, Y., et al. (1999). Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13(15): 1924-35. PubMed ID: 10444591
Yokoyama, H., Nakos, K., Santarella-Mellwig, R., Rybina, S., Krijgsveld, J., Koffa, M. D. and Mattaj, I. W. (2013). CHD4 is a RanGTP-dependent MAP that stabilizes microtubules and regulates bipolar spindle formation. Curr Biol 23: 2443-2451. PubMed ID: 24268414
date revised: 10 April 2015
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