wengen: Biological Overview | References
Gene name - wengen
Cytological map position - 17C5-17C6
Function - receptor
Symbol - wgn
FlyBase ID: FBgn0030941
Genetic map position - X:18,518,082..18,528,936 [-]
Classification - TNFR/NGFR cysteine-rich region
Cellular location - surface transmembrane
|Recent literature||Palmerini, V., Monzani, S., Laurichesse, Q., Loudhaief, R., Mari, S., Cecatiello, V., Olieric, V., Pasqualato, S., Colombani, J., Andersen, D. S. and Mapelli, M. (2021). Drosophila TNFRs Grindelwald and Wengen bind Eiger with different affinities and promote distinct cellular functions. Nat Commun 12(1): 2070. PubMed ID: 33824334
The Drosophila tumour necrosis factor (TNF) ligand-receptor system consists of a unique ligand, Eiger (Egr), and two receptors, Grindelwald (Grnd) and Wengen (Wgn), and therefore provides a simple system for exploring the interplay between ligand and receptors, and the requirement for Grnd and Wgn in TNF/Egr-mediated processes. This study reports the crystallographic structure of the extracellular domain (ECD) of Grnd in complex with Egr, a high-affinity hetero-hexameric assembly reminiscent of human TNF:TNFR complexes. WEctopic expression of Egr results in internalisation of Egr:Grnd complexes in vesicles, a step preceding and strictly required for Egr-induced apoptosis. It was further demonstrated that Wgn binds Egr with much reduced affinity and is localised in intracellular vesicles that are distinct from those containing Egr:Grnd complexes. Altogether, these data provide insight into ligand-mediated activation of Grnd and suggest that distinct affinities of TNF ligands for their receptors promote different and non-redundant cellular functions.
Wengen has been identified as the first member of the Drosophila tumor necrosis factor receptor (TNFR) superfamily. Wengen mRNA is expressed at all stages of Drosophila development. The small-eye phenotype caused by an eye-specific overexpression of a Drosophila TNF superfamily ligand, Eiger, is dramatically suppressed by downregulation of Wengen using RNA interference. In addition, Wengen and Eiger physically interact with each other through their TNFR homology domain and TNF homology domain, respectively. These results suggest that Wengen can act as a component of a functional receptor for Eiger. This identification of Wengen and further genetic analysis should provide increased understanding of the evolutionarily conserved roles of TNF/TNFR superfamily proteins in normal development, as well as in some pathophysiological conditions (Kanda, 2002).
In a Drosophila dominant-modifier screen using the chromosomal deficiency lines that covered more than 70% of the genome, several lines were obtained that suppress the small-eye phenotype caused by Eiger overexpression (GMR>eigerregg1). Through the analysis of these deficiency lines, a line, Df(1)E128/FM7c, was identified in which the deficiency spans the coding region of a predicted gene, CG6531. CG6531 encodes a protein with a cysteine-rich domain (TNFR
To assess whether Wengen is required for Eiger to induce the small-eye phenotype, RNA interference (RNAi) was used to down-regulate the endogenous expression of Wengen. A head-to-head inverted repeat construct for wengen, pUAS-wengen-IR, was generated, and its ability to knock down the wengen expression was examined. Co-transfection of pUAS-HA-wengen together with pUAS-wengen-IR into S2 cells dramatically reduces Wengen expression but has no effect on the expression of HA-CARD, suggesting that wengen-IR works as a specific inhibitor of Wengen expression. To assess the biological functions of Wengen in Drosophila, transgenic flies were generated that misexpress wengen-IR in the developing retina. The small-eye phenotype induced by the eye-specific ectopic expression of Eiger (GMR>eigerregg1) was suppressed by the coexpression of wengen-IR. These results strongly suggest that Wengen is required as a functional transducer of Eiger signaling (Kanda, 2002).
The physical interactions between Wengen and Eiger were assessed using various deletion mutants. Immunoprecipitation assays revealed that full-length Wengen and Eiger physically interact with each other. Eiger interacts with WengenDeltacyt (lacking the cytoplasmic domain) but not with WengenDeltaTNFR (lacking the homology TNFR domain). In addition, full-length Wengen could not interact with Eiger DeltaTNF. These results suggest that Wengen can interact with Eiger, and this interaction is mediated through the TNFR homology domain of Wengen and the TNF homology domain of Eiger (Kanda, 2002).
This study has identified the first Drosophila member of the TNFR superfamily, Wengen. Most of the genes for the TNFR superfamily encode type I or III membrane proteins with one or more extracellular ligand-binding domains and a cytoplasmic region that activates cell functions. In general, the extracellular domain of this family of proteins shows a relatively low level of sequence conservation, despite sharing a common fundamental structure. The cytoplasmic regions of the receptors show considerably more diversity in sequence and size than the extracellular regions. There are no common intracellular motifs found in all members of the TNFR superfamily except for some domains such as the TRAF2-binding domain [(P/S/A/T)X(Q/E)E or PXQXXD], which is required for both NF-kappaB activation and JNK activation, or a domain of ~80 amino acids called the 'death domain', for caspase activation. However, the amino acid sequence of Wengen reveals that it has neither a TRAF2-binding domain nor a death domain in the cytoplasmic region, suggesting that there should be another mechanism to transduce signals (Kanda, 2002).
Whereas Eiger can stimulate the JNK pathway, the stimulation of the JNK pathway in response to the overexpression of Wengen in S2 cells or the Drosophila compound eye could not be detected. It is possible that because the amount of ligand is limited, overexpression of Wengen is not sufficient to activate the downstream signals. It is also possible that intracellular adapter proteins, which are required for transducing signals, are not expressed or limited in Wengen expressing cells. Otherwise, Wengen may require one or more co-receptors that transduce signals to the cytoplasm. For instance, heteromeric receptor complex is used to transduce Hedgehog signaling. Hedgehog binds to its receptor Patched, and then the inhibitory function of Patched against its binding partner, Smoothened, is cancelled. In this way, Hedgehog signaling is transduced into the cells. Because the heteromeric complex of receptors has never been reported to transduce TNF family signaling, it is possible that Eiger/Wengen may use the novel type of TNF signaling mechanisms. In any case, further genetic and biochemical studies of Eiger/Wengen should help to elucidate the unique signaling mechanisms that include the caspase-independent pathway triggered by Eiger (Kanda, 2002).
In mammals, members of the tumor necrosis factor (TNF) family play an important role in the regulation of cellular proliferation, differentiation and programmed cell death. This study describes isolation and characterization of an orthologous ligand/receptor axis in Drosophila. The ligand, designated Eiger, is a type II membrane glycosylated protein, which can be cleaved at residue 145 and released from the cell surface as a soluble factor, thereby representing the first potential cytokine to be described in Drosophila. Eiger exists in two alternatively spliced isoforms, Eiger long (Eiger-L) and Eiger short (Eiger-s), both of which are expressed throughout development and in the adult. A novel Drosophila member of the TNF receptor family, designated Wengen, is a type I membrane protein that can physically interact with the recently described TRAF2 homolog dTRAF2. Both Eiger and Wengen are expressed in distinctive patterns during embryogenesis and Eiger is responsive to genotoxic stress. Forced expression of Eiger-L, Eiger-s or Wengen, caused apoptotic cell death which could be rescued by caspase inhibitors or the JNK phosphatase Puckered. In addition, Eiger-induced cell killing is attenuated by RNAi-mediated suppression of Wengen. These results illustrate that Eiger and Wengen represent proximal components of an evolutionarily conserved TNF-like signaling pathway in Drosophila (Kauppila, 2003).
The Drosophila genomic database was searched for sequences with homology to the extracellular domain of human TNFR1, and a candidate sequence was identified. This sequence encoded a cDNA of 993 nt and was identical to the sequence of a recently isolated Drosophila receptor, designated Wengen (Kanda, 2002). Sequence analysis revealed that the extracellular domain of Wengen contained a single cysteine-rich pseudorepeat with significant homology to other members of the TNFR family. However, Wengen possessed a unique cytoplasmic domain with no sequence homology to any TNFR family member (Kauppila, 2003).
It was reported that Wengen is a type III membrane protein with a single hydrophobic transmembrane domain (Kanda, 2002). However, sequence analysis revealed that, in addition to the transmembrane domain between residues 202 and 222, Wengen cDNA also encoded for a hydrophobic stretch of amino acids between residues 54 and 59, which could potentially represent a signal peptide. Such a topology is characteristic of type I membrane proteins, including most mammalian receptors of the TNFR family. In order to determine whether Wengen is a type I or type III membrane protein, several constructs were generated with a Flag epitope tag placed at different locations in the deduced open reading frame. Construct Wengen-A positions the Flag epitope tag at the N-terminus of the full-length Wengen protein-coding region. The construct designated Wengen-B encoded a murine Igkappa chain signal peptide followed by the Flag epitope tag and amino acids 14-343 of Wengen. Construct C resembled construct B in topology except that it included the Wengen protein-coding region downstream of the hydrophobic stretch of amino acids representing the putative signal peptide (i.e. amino-acid residues 60-343). A construct was generated encoding amino acids 1-318 of human XEDAR fused to the murine Igkappa chain signal peptide and the Flag epitope. XEDAR is a recently isolated receptor of the TNFR family and a well-characterized type III membrane protein. The above constructs were transfected into 293 T cells along with a GFP reporter construct, and the expression of the Flag epitope tag was analysed on the surface of GFP-expressing cells using FACS analysis. If Wengen corresponds to a type I membrane protein, the epitope tag will be absent from the mature proteins predicted from constructs A and B since it is positioned upstream of the signal peptide cleavage site in these plasmids and, as such, the Flag tag would not be detected on the surface of the cells expressing these constructs (Wengen-A and Wengen-B). In contrast, the Flag epitope tag will be expected to be expressed on the surface of cells expressing the construct C since, in this construct, the Flag epitope is located downstream of the heterologous signal peptide. The cell surface expression of the Flag epitope was not detected in the case of cells transfected with constructs A and B, but readily detected Flag-positive cells in the construct C transfectants. Hence, the epitope was found on the surface of cells only if it was positioned on the C-terminal side of the predicted Wengen signal peptide. In parallel studies with a known type 1 receptor, cell surface expression of the Flag tag was also detected in the case of cells transfected with the comparable Flag-XEDAR construct. Collectively, the above results lend strong support for the hypothesis that Wengen is a type I membrane protein (Kauppila, 2003).
To begin a functional characterization of Eiger and Wengen, the embryonic expression patterns of these genes were examined by in situ hybridization. Eiger mRNA was detected in early embryonic stages in a pattern that was highly localized to the dorsal surface of pregastrulating embryos. Localization of mRNAs to the dorsal side probably reflects maternally derived transcripts that become positioned during oogenesis and could reflect an important role in early pattern formation. By contrast, expression of Wengen appears to be very low or undetectable in pregastrulating embryos. During gastrulation, Wengen-positive cells are detected in the inner layer of embryonic tissue corresponding to the presumptive mesoderm while, at the same stage, Eiger expression occurs in the epidermal layer of the embryo and is most prominent at the surface of dorsal folds that will later form the amnioserosa. At germ band extended stages, Wengen transcripts continue to accumulate in the mesodermal segments of the embryo while its ligand, Eiger, is prominent in the adjacent neurogenic region. In later-staged embryos (stages 15/16) both Eiger and Wengen are detected in subsets of cells within the condensing nerve cord (Kauppila, 2003).
Since TNF and its receptors are implicated in some vertebrate models of damage-induced cell death, tests were performed to see whether Eiger or Wengen might be responsive during genotoxic stress. Eiger RNAs were consistently induced by gamma radiation between two- and fourfold while, in these same samples, levels of Wengen transcripts were unchanged. These findings were confirmed using RT-PCR methods and also it was also determined that both Eiger-s and Eiger-L isoforms are radiation responsive (Kauppila, 2003).
Using transient transfection assays, Wengen and Eiger were tested for apoptosis induction in Drosophila S2 cells. Both the long and short isoforms of Eiger ligand are equally effective at promoting cell death (~40% survival). Similar levels of cell death are provoked by the receptor, Wengen. No overt synergistic effects were detected in cotransfections of Eiger together with Wengen, but cell death induced by both isoforms of the ligand -- as well as the receptor -- were partially reversed by caspase inhibitor peptides, zDEVD and zVAD (Kauppila, 2003).
To test the hypothesis that Wengen is a receptor for Eiger, the effects of dsRNA-mediated silencing of Wengen upon Eiger-induced cell killing were tested. Silencing of Wengen effectively attenuates cell killing triggered by either of the Eiger isoforms. Moreover, these effects are clearly target specific since dsRNA-mediated silencing of either hid or rpr had no influence upon Eiger-induced cell killing. As expected, in converse experiments, it was found that silencing of Eiger had no influence upon Wengen-induced cell killing. Together, these results support a ligand/receptor relationship for Eiger and Wengen (Kauppila, 2003).
Since the JNK phosophatase Puckered is an effective suppressor of Eiger-dependent phenotypes in the animal (Igaki, 2002), the effects of forced puckered expression were examined in cultured cells. This phosphatase clearly protected against cell killing via the Eiger/Wengen axis. In these assays, Puckered had pronounced suppressive effects upon killing by Wengen and the short isoform of Eiger and significant -- but less potent effects -- against the long Eiger isoform. These effects were specific for Eiger/Wengen signaling since, in parallel assays, it was found that puckered had no effect upon levels of cell killing elicited by grim or rpr (Kauppila, 2003).
Each of the two recently published studies on Eiger found only a single isoform, each of which differ by five amino-acid residues (Igaki, 2002; Moreno, 2002). This report has clarified that both isoforms are authentic and expressed at the mRNA level. However, so far no differential expression of these two isoforms during embryogenesis or following genotoxic stress has been discovered. In addition, using the assays undertaken, no overt difference was found in killing activity conferred by the two isoforms. However, the above results are not surprising since the difference between the two isoforms of Eiger is located outside the TNF homology domain, which is usually the main determinant of receptor binding (Kauppila, 2003).
Unlike mammalian TNF family receptors, only a single cysteine-rich domain is present in Wengen. It is conceivable that multiple copies of cysteine-rich domains contribute to increase in affinity and/or specificity of receptor-ligand interaction. Consistent with the above hypothesis, no significant physical interactions were found between soluble Eiger and Wengen (Kauppila, 2003).
The in vivo roles of Eiger and its receptor during development await further characterization but the expression patterns, particularly for the ligand Eiger, raise intriguing possibilities. Eiger is highly localized to a narrow stripe along the dorsal surface of pregastrulating embryos at a time coincident with specification of ventral cell fates via the Toll/Dorsal pathway. Few precedents exist for this unusual transcript distribution. One such precedent, zen, is localized to the dorsal surface as a consequence of repression by dorsal proteins and, in a recent genome-wide analysis, the Eiger locus was also identified as dorsal target. Together with the fact that Eiger can be cleaved to form a soluble ligand, these observations raise the possibility that Eiger may function during early embryonic patterning along the dorsal ventral axis and/or in the specification of dorsal structures such as the amnioserosa. In subsequent embryonic stages, Eiger and Wengen are expressed in nonoverlapping but neighboring tissues. For example, in germ-band-extended embryos, Wengen is expressed in mesodermal tissues, while Eiger is expressed in the adjacent neurogenic ectoderm. Hence, it is possible that TNF-like signaling occurs among these tissues as they develop in the embryo (Kauppila, 2003).
Both Eiger and Wengen triggered cell death which could be blocked by Puckered, an inhibitor of the Drosophila JNK pathway. These results confirm earlier reports from Igaki (2002) and Moreno 2002) who also demonstrated a requirement for JNK signaling. Interestingly, a mammalian TNFR family member has been described that also lacks a death domain, TAJ, that similarly activates the JNK pathway and promotes cell death (Eby, 2000). Thus, it seems plausible that Wengen and TAJ could share evolutionarily conserved mechanisms to trigger cell death. However, unlike TAJ, Eiger- and Wengen-induced cell death was partially blocked by caspase inhibitors. Further characterization of Eiger/Wengen-induced cell death may shed light on this novel evolutionary conserved pathway of apoptosis and open up new therapeutic opportunities for the treatment of cancer (Kauppila, 2003).
Heightened nociceptive (pain) sensitivity is an adaptive response to tissue damage and serves to protect the site of injury. Multiple mediators of nociceptive sensitization have been identified in vertebrates, but the complexity of the vertebrate nervous system and tissue-repair responses has hindered identification of the precise roles of these factors. This study established a new model of nociceptive sensitization in Drosophila larvae, in which UV-induced tissue damage alters an aversive withdrawal behavior. UV-treated larvae develop both thermal hyperalgesia, manifested as an exaggerated response to noxious thermal stimuli, and thermal allodynia, a responsiveness to subthreshold thermal stimuli that are not normally perceived as noxious. Allodynia is dependent upon a tumor necrosis factor (TNF) homolog, Eiger, released from apoptotic epidermal cells, and the TNF receptor, Wengen, expressed on nociceptive sensory neurons. These results demonstrate that cytokine-mediated nociceptive sensitization is conserved across animal phyla and set the stage for a sophisticated genetic dissection of the cellular and molecular alterations responsible for development of nociceptive sensitization in sensory neurons (Babcock, 2009).
The cytokine TNF-α and its receptors have been implicated in both cell death and nociceptive sensitization in mammals. Indeed, exposure to UV light causes human keratinocytes to synthesize and release TNF. The Drosophila genome contains one clear homolog of the TNF ligand and TNF receptor, and this study examined whether these genes are responsible for alterations in nociceptive sensitivity. Larvae with null mutations in eiger, the gene encoding the TNF-α homolog, were exposed to UV radiation and, 24 hr later, were stimulated with the highest normally subthreshold temperature, 38°C, and their withdrawal responses were recorded. It was found that larvae transheterozygous for independent eiger null alleles showed a complete absence of thermal allodynia. Larval epidermal-specific expression of a UAS-eigerIR transgene also led to a complete absence of thermal allodynia, suggesting that the epidermis is the source of the TNF that mediates sensitization. Expression of UAS-eigerIR in sensory neurons via the ppk1.9-Gal4 driver did not affect development of allodynia, indicating that Eiger derived from sensory neurons does not contribute to sensitization (Babcock, 2009).
One possibility suggested by the epidermal requirement for Eiger in nociceptive sensitization is that the primary function of Eiger released from UV-treated epidermal cells is to initiate apoptosis, which then leads to production of factors that mediate the development of allodynia. Three lines of evidence argue against this model. (1) Blocking TNF signaling through epidermal expression of an RNAi transgene targeting the Drosophila TNF receptor, Wengen, does not block allodynia. This RNAi transgene has potent on-target effects: it efficiently blocks Eiger-induced cell death in the developing Drosophila eye disc. (2) Larvae transheterozygous for eiger null mutations have a normal epidermal apoptosis response to UV irradiation. (3) To test whether Eiger directly targets nociceptive sensory neurons after UV-induced tissue damage, expression of Wengen was knocked down by using a nociceptive sensory-neuron-specific Gal4 driver (ppk1.9-Gal4). Larvae expressing UAS-wengenIR in the class IV sensory neurons recently shown to be sufficient for nociception displayed normal nociceptive responses but failed to develop thermal allodynia after UV treatment, suggesting that Eiger does not act through the production of signaling intermediates such as prostaglandins or other cytokines. Importantly, neither eiger null mutants nor any combination of Gal4 and UAS transgenes affected developmental progression through the larval stages to pupariation (Babcock, 2009).
Finally, tests were performed to see whether ectopic expression of Eiger is sufficient to induce allodynia even in the absence of UV irradiation. Pan-epidermal overexpression of Eiger is lethal, suggesting either that the ligand is sequestered from its receptor in the untreated epidermis or that it is produced and/or released locally in response to irradiation. It was found, however, that viable larvae could be obtained by ectopically expressing Eiger from nociceptive sensory neurons via ppk1.9-Gal4. In these experiments, only larvae carrying both the Gal4 insert and the Eiger overexpression transgene developed allodynia even in the absence of UV irradiation. Taken together, these results indicate that a conserved cytokine and cytokine receptor module directly mediates a subset of nociceptive sensitization responses in Drosophila larvae (Babcock, 2009).
This study has introduce a new model of nociceptive sensitization in Drosophila larvae. In this model, UV radiation activates the apical apoptotic caspase Dronc and results in the production and/or release of Eiger from epidermal cells. Secreted or released Eiger then binds to its receptor, Wengen, on nociceptive sensory neurons underlying the epidermal sheet and lowers the threshold of the behavioral response. The complete absence of thermal allodynia upon tissue-specific knockdown of epidermal TNF (Eiger) or sensory neuron TNFR (Wengen) presented in this study suggests that TNF is a crucial mediator of this sensitization in Drosophila larvae and that its effects are direct. TNF signaling has been implicated in nociceptive sensitization in vertebrates, and there is evidence for both direct and indirect effects of this cytokine. Some studies suggest that the primary role of TNF is to mediate the production or release of secondary neuromodulatory factors (Interleukin-1β, prostaglandins) that then sensitize nearby nociceptive sensory neurons, whereas other studies have suggested that soluble TNF can directly alter the firing properties of these cells. An important experimental test of the relevance of the proposed model to vertebrate systems would probably involve assessing development of thermal allodynia in mice harboring a skin-specific knockout of TNF-alpha or a sensory-neuron-specific knockout of TNF receptors (Babcock, 2009).
Does the TNF/TNFR signaling module represent an ancestral danger-signaling system? Vertebrate TNFs have been implicated in immune responses to pathogens and toxins and in immune modulation of nervous-system function after tissue insult. TNF-family ligands have been identified in several invertebrates, including Drosophila, molluscs, and the urochordate, Ciona savignyi. In addition to their role in nociceptive sensitization described in this study, other functional data on the role of invertebrate TNFs show that Drosophila Eiger is required for combating extracellular pathogens but can also, as in vertebrates, lead to infection-induced pathologies. Thus, as in vertebrates, invertebrate TNF family ligands have both immunological and neuromodulatory functions, which may be interconnected. It is speculated that the TNF signaling system evolved as a general initiator of cell-type-specific responses to a variety of pathogens and other noxious insults. In vertebrates, TNF can act both directly on sensory neurons and indirectly by stimulating production of other nociceptive mediators, but the current data suggest that in organisms with simpler nervous and immune systems, direct effects might predominate. It will be interesting to test whether damage-induced nociceptive sensitization in urochordates (Ciona) or lower vertebrates employs a direct or indirect mode of TNF signaling and, conversely, whether damage-induced sensitization can occur in even simpler organisms, such as Cnidaria or Ctenophores, that have only a simple neural net but do possess TNF ligand and receptor homologs (Babcock, 2009).
The system established in this study provides a vehicle for the application of a new and complementary set of experimental approaches -- including the powerful toolkit of Drosophila genetics -- to the problem of nociceptive sensitization. Genetic dissection of the sensitization response described in this study should lead to identification of the specific downstream events by which sensory neuron sensitivity is altered after engagement of the TNF receptor. The robustness of the sensitization response and the clear separation of allodynia (Dronc- and TNF-dependent) and hyperalgesia (Dronc-independent) in this system suggest that there may be conserved mechanistic differences mediating the onset of these responses. Given the evolutionary conservation of genes mediating most aspects of neuronal development and function, it is expected that this system will broadly inform the understanding of both the onset and, potentially, the aberrant persistence of nociceptive sensitization in chronic pain syndromes (Babcock, 2009).
Search PubMed for articles about Drosophila Wengen
Babcock, D. T., Landry, C. and Galko, M. J. (2009). Cytokine signaling mediates UV-induced nociceptive sensitization in Drosophila larvae. Curr. Biol. 19(10): 799-806. PubMed ID: 19375319
Eby, M. T., Jasmin, A., Kumar, A., Sharma, K. and Chaudhary, P. M. (2000). TAJ, a novel member of the tumor necrosis factor receptor family, activates the c-Jun N-terminal kinase pathway and mediates caspase-independent cell death. J. Biol. Chem. 275(20): 15336-42. PubMed ID: 10809768
Igaki, T., et al. (2002). Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway. EMBO J. 21: 3009-3018. PubMed ID: 12065414
Kanda, H., Igaki, T., Kanuka, H., Yagi, T. and Miura, M. (2002). Wengen, a member of the Drosophila tumor necrosis factor receptor superfamily, is required for Eiger signaling. J. Biol. Chem. 277: 28372-28375. PubMed ID: PubMed ID; Online text
Kauppila, S., et al. (2003). Eiger and its receptor, Wengen, comprise a TNF-like system in Drosophila. Oncogene 22(31): 4860-7. PubMed ID: 12894227
Moreno, E., Yan, M. and Basler, K. (2002). Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily. Curr. Biol. 12: 1263-1268. PubMed ID: 12176339
date revised: 5 August 2021
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