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Genomics: Protein fossils live on as RNA.
Author: Rajkumar Sasidharan & Mark Gerstein
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"GENOMICS Protein fossils live on as RNA Rajkumar Sasidharan and Mark Gerstein Pseudogenes constitute many of the non-coding DNA sequences that make up large parts of genomes. Once considered merely protein fossils, it now emerges that some of them have active regulatory roles. A central challenge in genome annotation is determining the function of sequences that do not encode proteins, but make up the over- whelming bulk of large genomes ? some 99% in humans. A significant fraction of these sequences are pseudogenes, or fossils of ancient proteins, and although many of them are transcribed into RNA, they have hitherto been deemed ?junk?. However, given the abun- dance of pseudogenes, it is unlikely that they are useless. One function suggested for them is gene regulation, and RNA interference (RNAi) has been proposed as the mechanism for carrying this out. Six papers 1?6 , including three in this issue (pages 793, 798 and 803), significantly expand the known scope of RNAi by describing the discovery of natural small interfering RNA (siRNA) sequences in mice and fruitflies, some of which are potentially transcribed from pseudogenes. The textbook definition of a pseudogene is an inheritable genetic element that is similar to a functioning gene, yet is non-functional. But what is meant by non-functional is debat- able ? not transcribed, not translated, or not under control of a promoter sequence? Pseudogenes are similar to protein-coding genes because they are usually copied from a parent gene, either through unsuccessful duplication or by retrotransposition (whereby a gene is transcribed into RNA, which is then ?reverse-transcribed? back into DNA and inserted somewhere different in the genome). Because all this copying does not yield a nor- mal, functioning protein, pseudogenes are usu- ally identified by obvious ?disablements? in their sequence, such as frameshifts or premature stops. They have been of interest because they provide records of ancient molecules encoded by the genome. Although pseudogenes have generally been considered as evolutionary ?dead-ends?, one of the surprises of genome sequencing has been how abundant they are: tens of thousands of pseudogenes are found in mammalian genomes (roughly the same number as pro- tein-coding genes in all mammals sequenced so far) 7 . In addition, a large proportion of these sequences seem to be under some form of puri- fying selection 8 ? whereby natural selection eliminates deleterious mutations from the population ? and genetic elements under selection have some use. Finally, several large- scale genomic studies probing non-gene parts of the genome for biochemical activity have found many pseudogenes being transcribed and regulatory factors binding upstream of them. One such investigation, the ENCODE pilot project 9 , which looked at a representa- tive 1% of the sequence of the human genome, found strong evidence for at least one-fifth of pseudogenes being actively transcribed. These observations indicate that pseudo- genes might not be purely dead relics of past genes but could be resurrected for new biochemical activities. Indeed, functioning pseudogenes have been reported previously. For instance, in snails, a pseudogene is involved in translational control of the gene that codes for nitric oxide synthase 10 . And transcripts of the mouse pseudogene makorin1-p1 have been proposed to inhibit degradation of their parent gene?s mRNA, effectively enhancing its expression 11 , although this observation has been debated. Nevertheless, a clear mechanism for the functioning of pseudogenes has been lacking. The six studies ? four in flies 1?4 and two in mice 5,6 ? provide such a direct pathway, Figure 1 | Pseudogene-mediated production of endogenous small interfering RNAs (endo-siRNAs). Pseudogenes can arise through the copying of a parent gene (by duplication or by retrotransposition). a, An antisense transcript of the pseudogene and an mRNA transcript of its parent gene can then form a double-stranded RNA. b, Pseudogenic endo-siRNAs can also arise through copying of the parent gene as in a and then nearby duplication and inversion of this copy. The subsequent transcription of both copies results in a long RNA, which folds into a hairpin, as one half of it is complementary to its other half. In both a and b, the double-stranded RNA is cut by Dicer into 21-nucleotide endo-siRNAs, which are guided by the RISC complex to interact with, and degrade, the parent gene?s remaining mRNA transcripts. The mRNA from genes is in red and that from pseudogenes is in blue. Green arrows indicate DNA rearrangements. 729 NEWS & VIEWS Vol 453|5 June 2008 showing that pseudogene transcripts can act as natural siRNAs. Broadly speaking, RNAi involves various types of small ?guide? RNA sequence regulat- ing protein levels by targeting mRNA for deg- radation. Pseudogenic siRNAs provide two of the four categories posited by the six stud- ies to organize the natural, or ?endo?, siRNAs (Box 1). Endo-siRNAs in the first category mediate transposon silencing, which is typically a fea- ture of Piwi-interacting RNAs (piRNAs). The studies were therefore careful to distinguish between endo-siRNAs associated with trans- posons and piRNAs on the basis of size (21?22 nucleotides versus 24?30) and Argonaute effec- tor-protein partner (Ago2 versus Piwi). The second category of endo-siRNAs arise from bidirectional transcription of partially overlap- ping loci on opposite DNA strands 1,12 . Studies in mice 5,6 identify a few examples of these, and around 1,000 have been reported in flies 1 , with their target genes consisting mainly of those with nucleic-acid functions, such as nuclease activity and transcription-factor binding 12 . The third category of siRNAs, which have been identified only in mice 5,6 , are products of the interaction between a spliced mRNA tran- script from a protein-coding parent gene and an antisense transcript from its pseudogene, which can be located far away from its parent gene, on the same or a different chromosome (Fig. 1a). Endo-siRNAs of the fourth category are closely related to those in the third. They arise from hairpin-shaped sequences, which in mice 5,6 can come from inverted-repeat structures of pseudogenes (Fig. 1b). Here, the pseudogene also regulates its parent gene, but the double-stranded RNA precursor of the endo-siRNA comes from transcription of an inverted-repeat sequence, producing a hair- pin. The reports show that mouse proteins affected by the third and fourth categories of endo-siRNAs are disproportionately involved in particular functions ? such as regulating cytoskeletal dynamics ? which indicates that their underlying pseudogene-mediated regu- lation has been explicitly selected for and is not simply caused by random pairing of tran- scribed genes and pseudogenes. Hairpin precursors of endo-siRNAs have also been found in flies, but the evidence links them only weakly with inverted repeats of pseudogenes. Thus, most of the new data for pseudogenic siRNAs come from mouse rather than fly studies. One possible reason for this is that the mouse genome contains many more pseudogenes than the fly genome 13 . In fact, even compared with other metazoan organ- isms such as worms, flies are particularly poor in pseudogenes, possibly owing to pronounced genomic deletion processes known to occur in this organism 14 . The scarcity of pseudogenes in flies makes their detection particularly difficult. Nev- ertheless, there is suggestive evidence for fly pseudogenes functioning as endo-siRNAs. First, an appreciable number (~30) have an inverted-repeat structure, associated with the formation of hairpins. Second, many of the sequences obtained by ultra-high-throughput sequencing of small RNAs in the fly coincide with DNA regions containing pseudogenes. In particular, a small but significant number of the ?reads? found using the Solexa sequencing technology 1,4 can be intersected with some 70 pseudogenes, for an average of roughly 12 reads each. Finally, there is strong evidence that for several genes ? particularly the ?-esterase gene and its pseudogene ? a duplicated pseu- dogene forms a functional complex with its parent gene, with regulatory consequences 15 . Of course, to demonstrate the activity of pseudogenes conclusively, further experiments are needed. Deleting a pseudogene and dem- onstrating an effect on its potentially regulated parent gene would be most definitive. Also of great value would be studying the expression patterns of a potential endo-siRNA-produc- ing pseudogene and its regulated parent gene across various tissues ? data which should be generated by the ENCODE and modENCODE projects. In addition to connecting RNAi with pseudogenes, the new studies 1?6 also blur the distinctions between the three ?traditional? classes of small RNA ? siRNAs, piRNAs and Box 1 | Small but significant There are three main classes of small RNA, which generally differ in biogenesis, sorting and function 19 . (1) MicroRNAs (miRNAs) mainly regulate genes involved in developmental processes. Specific miRNA genes encode mRNA-like primary transcripts that form hairpin structures, which are in turn excised by the enzyme Drosha (not shown) to form precursor miRNAs. In flies, further cleavage of these sequences by the Dicer enzyme Dcr1 and its specific co-factor Loqs yields mature miRNAs of ~22 nucleotides (nt). To carry out their function, miRNAs are incorporated into the RISC protein complex, which contains the effector protein Ago1, a member of the Argonaute family. (2) Conventional small- interfering RNAs (siRNAs) of ~21 nucleotides are produced through cleavage of double- stranded RNA (dsRNA) ? in flies, by the Dicer enzyme Dcr2 and its co-factor R2D2 (refs 17, 19). These small RNAs bind to the Argonaute- family effector Ago2 and function in defence against external nucleic acids, such as synthetic dsRNAs or intermediates of viral replication. (3) Discrete genomic loci give rise to single-stranded RNA sequences (ssRNA), which are then processed to ~27 nt Piwi-interacting RNAs (piRNAs). piRNA biosynthesis remains somewhat ambiguous, but is known not to require Dicer. piRNAs bind to Piwi, another member of the Argonaute family that seems to be expressed only in germline cells. It is believed that these small RNAs function as master controllers of mobile genetic sequences called transposable elements 20 . In the figure, grey lines indicate known relationships, whereas red lines indicate new ones reported in the six papers 1?6 . Clearly, the boundaries between the three small-RNA classes have been somewhat blurred by these reports. For details of how endo-siRNAs arise from pseudogenes, see Figure 1. R.S. & M.G. 730 NATURE|Vol 453|5 June 2008NEWS & VIEWS microRNAs (miRNAs) ? which are distinct in their biogenesis and cellular roles (Box 1). The studies 1?6 find that endo-siRNAs regulate transposons as piRNAs do; that, like miRNAs, they can arise from hairpins; and that, in flies, their processing involves a similar co-factor to the processing of miRNAs (Box 1). This blurring of boundaries among dif- ferent types of small RNA, together with the newly established links between siRNAs and pseudogenes, has interesting evolutionary implications. In plants, inverted duplications containing a protein-coding gene have been proposed 16 as a mechanism to create new miRNAs. Thus, one can imagine a gene being copied (either by duplication or retrotrans- cription) and this copy then being duplicated (again) in inverted fashion. Given the ubiqui- tous nature of genomic transcription, the copy and its inverted duplicate could potentially be transcribed to a hairpin precursor of endo- siRNAs to regulate the parent gene. As the function of the hairpin no longer has anything to do with encoding protein, its sequence, still under selection, can acquire frameshifts and stop codons, making it seem pseudogenic. One could even imagine its sequence drifting further and becoming grad- ually transformed into a miRNA gene, the sequence of which is much less similar to the gene encoding its target mRNA. So pseudo- genes encoding endo-siRNAs might provide a crucial intermediate link to understanding the evolution of miRNA-mediated regulation 17 . Although speculative, the plausibility of this theory is bolstered by a recent survey 18 of the genomic context of more than 300 human miRNA loci, which identified two that lie within pseudogenes. ? Rajkumar Sasidharan and Mark Gerstein are in the Departments of Molecular Biophysics and Biochemistry, and Computer Science, Yale University, New Haven, Connecticut 06520, USA. e-mail: mark.gerstein@yale.edu 1. Czech, B. et al. Nature 453, 798?802 (2008). 2. Ghildiyal, M. et al. Science 320, 1077?1081 (2008). 3. Kawamura, Y. et al. Nature 453, 793?797 (2008). 4. Okamura, K. et al. Nature 453, 803?806 (2008). 5. Tam, O. H. et al. Nature 453, 534?538 (2008). 6. Watanabe, T. et al. Nature 453, 539?543 (2008). 7. Zhang, Z., Carriero, N. & Gerstein, M. Trends Genet. 20, 62?67 (2004). 8. Zheng, D. et al. Genome Res. 17, 839?851 (2007). 9. The ENCODE Project Consortium Nature 447, 799?816 (2007). 10. Korneev, S. A., Park, J.-H. & O?Shea, M. J. Neurosci. 19, 7711?7720 (1999). 11. Hirotsune, S. et al. Nature 423, 91?96 (2003). 12. Okamura, K., Balla, S., Martin, R., Liu, N. & Lai, E. C. Nature Struct. Mol. Biol. doi:10.1038/nsmb.1438 (2008). 13. Harrison, P. M., Milburn, D., Zhang, Z., Bertone, P. & Gerstein, M. Nucleic Acids Res. 31, 1033?1037 (2003). 14. Petrov, D. A., Lozovskaya, E. R. & Hartl, D. L. Nature 384, 346?349 (1996). 15. Balakirev, E. S., Anisimova, M. & Ayala, F. J. J. Mol. Evol. 62, 496?510 (2006). 16. Allen, E. et al. Nature Genet. 36, 1282?1290 (2004). 17. Chapman, E. J. & Carrington, J. C. Nature Rev. Genet. 8, 884?896 (2007). 18. Devor, E. J. J. Hered. 97, 186?190 (2006). 19. Matranga, C. & Zamore, P. D. Curr. Biol. 17, R789?R793 (2007). 20. Brennecke, J. et al. Cell 128, 1089?1103 (2007). ATTOSECOND PHYSICS An easier route to high harmony Mark I. Stockman The generation of ultrashort light pulses by atomic ionization and recombination doesn?t come cheap. But by niftily exploiting the play of light on a nanostructured surface, it can be done on a table-top. Extreme ultraviolet (EUV) radiation has great potential to be extreme not just in name, but in usefulness. It is the band of ultraviolet light with the shortest wavelength ? around 5?50 nanometres, between 100 and 10 times shorter than that of visible light. In applications such as microscopy and lithography it can thus be used to probe and etch at tiny scales. What?s more, this wavelength regime is that of many atomic resonances, making EUV light ide- ally suited for spectroscopic applications. On page 757 of this issue 1 , Kim et al. detail a deft new way to produce EUV radiation ? one that could be considerably more economical that previous approaches. The way in which EUV radiation is cur- rently generated is extremely fiddly. It starts with the amplification of light pulses from an oscillator, a source of laser light. These are used to drive the repeated ionization of noble-gas atoms. The electrons freed during this process are accelerated in the light field and, because the sign of the field reverses after half a cycle, re-collide with their parent atoms 2,3 , releasing the electrons? surplus energy as light. The result is a sequence of ultrashort (attosecond) pulses that are themselves useful tools for high-time- resolution metrology 4,5 . More detailed consid- eration of the process reveals that the spectrum of these pulses consists of a comb of ?high har- monics? ? spectral lines at wavelengths equal to the wavelength of the driving field divided by some integer. (Owing to symmetries of the par- ticular situation, only light corresponding to odd-integer divisors is generated in this case.) The highest-harmonic (shortest-wavelength) component of this spectrum can be selected by filtering to produce a single attosecond pulse at an EUV wavelength. Things would be much simpler if EUV radia- tion could be produced directly from an oscilla- tor ? an ultrashort pulsed laser of relatively low intensity ? without the need for sophisticated, complex and expensive amplifiers to produce a high-intensity optical field. Kim et al. 1 provide a distinct glimmer of an indication that such an approach could be viable. They illuminate an intricate, nanoscale gold antenna structure with light from a standard titanium?sapphire laser, with a wavelength of 800 nm. The inter- action of the light with the antennas produces high harmonics right up to the 17th harmonic ? whose wavelength of 47 nm lies within the EUV range. The optical intensity required to generate this light is, at 10 11 W cm ?2 , about 100 times less than in the traditional approaches. The secret of the authors? success is the nanoscale behaviour of ?quasiparticles? known as surface plasmons. These packets of optical energy represent rapid oscillations of electron density that spring up in the surface regions of metal nanoparticles when bathed in an inci- dent light field. If this incident light is of the right frequency, the surface plasmons can enter resonance, greatly increasing the local field intensity over that of the excitation wave. This phenomenon has a central role in, for example, surface-enhanced Raman scattering 6 , a spec- troscopy and imaging technique that is sensi- tive enough to detect the presence of individual molecules adsorbed on a metal surface. The extent of this field enhancement is determined by the nanoparticles? plasmonic resonance properties, which in turn depend mostly on the resistivity of the metal at the fre- quency of the optical light. Additional mag- nitude comes from geometric effects 7?9 , both in narrow gaps between particles where there is a significant localization of optical energy, leading to the formation of ?gap plasmons?, and also similarly around sharp tips, a phenom- enon known as the lightning-rod effect. Nano- particles have been specifically engineered in Figure 1 | Stripping on the table-top. The bow-tie-shaped gold nanoantennas used by Kim et al. 1 develop electric-field strengths in the gap through interactions with quasiparticles known as surface plasmons. (The field strength E is colour-coded; note that intensity is proportional to the square of the field strength.) When a beam of argon atoms (green) is directed towards the gap, the field strips them of electrons, which subsequently recombine ? a process that results in the generation of high harmonics of the original light, including the sought-after extreme ultraviolet radiation. (Data and calculations courtesy of J. Aizpurua.) 20 40 60 80 100 120 140 E Argon 50 nm 731 NATURE|Vol 453|5 June 2008 NEWS & VIEWS quasi-two-dimensional, Mott?Hubbard charge transfer antiferromagnetic insulators in their undoped ground state. These last three proper- ties are believed to be key to high-temperature superconductivity, and are about the only cri- teria on which you can find (almost) univer- sal agreement among those trying to choose between the bespoke fashions hanging in the high-T c theoretical closet. However, observe in Figure 1 that the Fe ions, although nominally Fe 2+ , analogous to Cu 2+ , are tetrahedrally coordinated rela- tive to the pnictide anions, as opposed to the square-planar symmetry of the copper oxide compounds. In the first-row transi- tion metals ? scandium to zinc ? there are ten d-electron states (five described by orbital momentum), each of which can hold two electrons with one spin up and another down. We can play with these states to build various cationic configurations. A simple yardstick, called Hund?s rule, helps build possible com- binations in isolated atoms and ions. It says we have to start filling from the bottom, first occupying each orbital with an up-spin and then starting over again with spin-down, until all available d-electrons are consumed. Thus Fe 2+ , with six electrons at large, will result in a ground state one electron in excess of a half-filled Hund?s occupation distribution, and Cu 2+ , with nine electrons to spend, will yield one electron fewer (a ?hole? or effective positive charge) than a filled d-orbital shell. Therefore, in a very crude sense, the new FeAs superconductors can be thought of as the electron analogues of the hole-transport- ing CuO complexes, and both measurements and theoretical studies bear this out. The real situation is far more complex than just stated, and simple Hund?s rule arguments are confounded by symmetry, position and overlap of neighbouring anions (O 2? , As ?(3?x) ), and by Coulomb repulsion that tends to sepa- rate spins in otherwise ?Pauli-allowed? cation states from the next nearest cation neighbour. The trade jargon for these effects is ?crystal field splitting?, ?hybridization? and ?Hubbard U?, respectively. You can be assured each of these is currently undergoing intense explo- ration. All this notwithstanding, the simple Hund?s rule picture that the ferrous pnictides and copper oxides are electron?hole ?duals? may not be simply fortuitous. It may be the reason that, after years of intense searching, nickel and cobalt complexes have not yielded high-temperature superconductors (at least not yet). In fact, with T c now at 55 K, are these ferrous pnictides truly ?high-temperature supercon- ductors?? Simply answered, we don?t know at present. But it is useful to remember that the expression ?high-temperature superconductiv- ity? did not originate with Bednorz and M�ller?s paper 1 of 1986. Those who, like myself, are of mature years will recall that this description was coined as a result of studies 7,8 in the 1960s that superconductivity mediated by electron? phonon pairing would top out at around 30 K, and compounds showing anything above this value would be referred to as ?high-tempera- ture materials?. Although the mechanism of high T c in the copper oxide perovskites remains in question, we do have evidence 9 in MgB 2 that electron?phonon coupling can achieve a tran- sition temperature of 40 K. Is 55 K really that much higher? Although most of the theoretical tailoring for the various ferrous pnictides is styled after fashions for the cuprate superconductors, one experimental study harks back to much earlier designs. Chen et al. 10 report direct measurement of the superconducting energy gap and its temperature dependence in poly- crystalline samples of Sm(O 0.85 F 0.15 )FeAs, with T c = 42 K. The technique used is called Andreev spectroscopy. This is a variant of tunnelling spectroscopy whereby, at a contact between a normal metal and a superconduc- tor, an electron from the metal injected into the superconductor at energies lower than the superconducting gap gives rise to a super- conducting pair (Cooper pair of electrons of opposite spin), which are subsequently spin-charge compensated by a ?reflection? of positive polarity (a hole) back into the nor- mal metal. The resulting current?voltage dependence is a direct measurement of the superconducting pairing energy. Astonishingly, Chen et al. 10 find that their results best fit the time-honoured Bardeen? Cooper?Schrieffer (BCS) theory 11 , the break- through in the mid-twentieth century that solved the riddle of superconductivity in all materials available up to that time. Although originally formulated to accommodate the pairing of electrons mediated by lattice vibrations (phonons), in its broadest sense the BCS framework can encompass pairing of fermions in a boson field ? perhaps even the ?flavours? found in neutron stars, quarks and gluons, giving rise to ?colour? supercon- ductivity at the relatively low cosmological temperature of 10 9 (the units don?t matter). So Chen and colleagues? identification of classic BCS behaviour does not rule out the possibil- ity that some more exotic bosonic glue than phonons might be behind superconductivity in these ferrous pnictides. Whenever a new superconductor with a T c higher than 30 K appears on the scene, I inevitably get asked if it will bring applications closer. The question is perhaps more pertinent when the material involves particularly noxious elements such as arsenic. My answer is always ?Just follow the money.? If the pot at the end of the rainbow has enough gold inside (and so far it does not for applied superconductivity), the environmental issues can be overcome. I give you semiconductor manufacture and process- ing, which uses some of the most toxic com- pounds (including arsenides) in creation, yet is tolerated and brought under control because its financial return is in the trillions. Again, the units don?t matter. Will T c in the pnictides continue to go up, and perhaps double or triple as happened in 1987?88? I doubt it. We?ve now been on standby for several months, and to my mind the best hope is that the discovery of pnic- tide high-temperature superconductivity will help us understand better the physics of the cuprates. The iron age has yet to dawn. ? Paul M. Grant is at W2AGZ Technologies, 1147 Mockingbird Hill Lane, San Jose, California 95120, USA. e-mail: w2agz@pacbell.net 1. Bednorz, J. G. & M�ller, K. A. Z. Phys. B 64, 189?193 (1986). 2. Wu, M. K. et al. Phys. Rev. Lett. 58, 908?910 (1987). 3. Kamihara, Y. et al. J. Am. Chem. Soc. 128, 10012?10013 (2006). 4. Kamihara, Y., Watanabe, T., Hirano, M. & Hosono, H. J. Am. Chem. Soc. 130, 3296?3297 (2008). 5. Takahashi, H. et al. Nature 453, 376?378 (2008). 6. Yang, J. et al. Supercond. Sci. Technol. 21, doi:10.1088/0953- 2048/21/8/082001 (2008). 7. McMillan, W. L. Phys Rev. 167, 331?344 (1968). 8. Allen, P. B. & Dynes, R. C. Phys. Rev. B 12, 905?922 (1975). 9. Nagamatsu, J., Nakagawa, N., Muranaka, T., Zenitani, Y. & Akimitsu, J. Nature 410, 63?64 (2001). 10. Chen, T. Y., Tesanovic, Z., Liu, R. H., Chen, X. H. & Chien, C. L. Nature doi:10.1038/nature07081 (2008). 11. Bardeen, J., Cooper, L. N. & Schrieffer, J. R. Phys. Rev. 108, 1175?1204 (1957). Figure 1 | The unit cell of LaOFeP. In this generic example 3 of the family of lanthanum-series oxyfluoride ferrous pnictides, the overall cell charge is neutral but the individual layers are not, implying electron doping of the FeP layer. Note also that the P coordination of Fe is tetrahedral, not square planar as is the case for the high-T c copper oxide perovskites. (Reproduced from ref. 3.) Correction The News & Views article ?Genomics: Protein fossils live on as RNA?, by Rajkumar Sasidharan and Mark Gerstein (Nature 453, 729?731; 2008), contains the following incorrect statement: ???reads? found using the Solexa sequencing technology 1,4 can be intersected with some seven pseudogenes, for an average of roughly two reads each.? In fact, these reads intersected with some 70 pseudogenes, for an average of roughly 12 reads each. Also, in the text of Box 1, ?nt? (nucleotide) was omitted from one passage, which should read ??to ~27 nt Piwi-interacting RNAs (piRNAs).? These corrections have already been made to the online versions of this article. (La 3+ O 2? ) + layer (Fe 2+ P 3? ) ? layer Fe P La O 1001 NATURE|Vol 453|19 June 2008 NEWS & VIEWS "
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