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First published online 5 January 2006
doi: 10.1242/dev.02229
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Institut für Genetik, Universität Mainz, 55099 Mainz, Saarstraße 21, Germany.
* Author for correspondence (e-mail: jurban{at}uni-mainz.de)
Accepted 29 November 2005
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Drosophila, Temporal specification, Neuroblast, Seven-up, Prospero, Hunchback
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Harris, 1997;
Ohnuma et al., 1999).
Similarily, the neural stem cells of the mammalian cortex always generate the
cells of the different cortical layers in the same sequence
(Desai and McConnell, 2000;
Frantz and McConnell, 1996;
McConnell, 1992;
McConnell and Kaznowski,
1991). In both examples, the combination of extrinsic and
intrinsic factors is needed for the correct development of the stem cells
along the time axis. However, the mechanisms that lead to the temporal
specification of cell fates are still largely unknown.
Recently, the embryonic neuroblasts (NBs) of Drosophila have been
established as a model system to tackle this issue
(Brody and Odenwald, 2000;
Isshiki et al., 2001;
Kambadur et al., 1998;
Novotny et al., 2002). These
NBs are multipotent precursor cells that divide in a stem cell mode generating
a chain of ganglion mother cells (GMCs). These GMCs subsequently perform one
additional division to produce two postmitotic cells, which can be neuronal or
glial in nature. Each NB in the developing ventral nerve cord (VNC) can be
identified individually (Broadus et al.,
1995), and produces a specific and reproducible set of progeny,
always in the same temporal sequence
(Bossing et al., 1996;
Schmidt et al., 1997;
Schmid et al., 1999). In
Drosophila, this change of temporal identity of NBs is thought to
occur cell autonomously, and is linked to the sequential expression of the
transcription factors Hunchback (Hb), Krüppel (Kr), Pdm1/Pdm2, Castor
(Cas) and Grainyhead (Grh) (Brody and
Odenwald, 2000; Isshiki et
al., 2001; Kambadur et al.,
1998; Novotny et al.,
2002). The genes encoding these transcription factors are
consecutively expressed in a given NB in certain time windows. At the end of
each time window, the expression is switched off in the NB but stays on in the
GMC and its progeny. For two of these factors, Hb and Kr, it has been shown
that they are indeed necessary and sufficient to specify the fate of the early
born cells in certain NB lineages (Isshiki
et al., 2001; Novotny et al.,
2002). Moreover, hb has been shown to be able to keep
certain NBs in a multipotent state, which becomes restricted after hb
expression has vanished from the cell
(Pearson and Doe, 2003). Thus,
the temporal specification of NB progeny, as well as the developmental
competence of the NB, depends strongly on the correct timing of the on and off
switch of the temporal specification genes within the NB. Recently it has been
shown that svp (seven-up) is required to switch off
hb at the proper time (Kanai et
al., 2005). Unlike for the other temporal specification genes,
this off switch is dependent on the process of mitotic cell division
(Isshiki et al., 2001;
Großkortenhaus et al.,
2005).
In this work, we concentrate on two questions: how is the timing of svp activity regulated and why is hb switched off only in the NB and not in the GMC after mitotic division? Our results show that the maintenance of hb expression in the GMC is dependent on the asymmetrically distributed cell-fate determinant Prospero (Pros). This transcription factor antagonises svp activity in the GMC, thereby inhibiting the downregulation of hb in this cell. Additionally, we provide evidence that the svp mRNA is not translated efficiently before mitosis; this probably leads to the observed link of svp activity to mitosis. Finally, we show that the lineage-specific timing of svp expression is independent of the number of NB divisions.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). To
misexpress svpI, we combined a second and third chromosomal insertion
of UAS-svpI (a gift of M. Hoch), crossed this line to
en-GAL4 (Bloomington Stock Center) and let the embryos develop at
29°C (for scoring the NB7-1 lineage). To misexpress pros, we
crossed UAS-pros (H. Vässin, Columbus, OH) to en-GAL4
at 29°C for scoring the NB7-3 lineage.
Generation of the anti-Hb antibody
For protein expression, BL21 bacteria were transformed with the expression
plasmid pAR-6His (Kosman et al.,
1998). Protein purification was carried out by the use of Ni-NTA
spin columns (Qiagen) under denaturing conditions, as described in the manual.
After purification, the protein was dialysed with phosphate buffered saline
(PBS, pH 7.4). Guinea pigs were immunised with purified protein (BioGenes,
Berlin), and the obtained serum tested in embryos for specific Hb staining and
then used preabsorbed without further purification.
Immunohistochemistry
Overnight egg collections at 25°C or 29°C were stained and
dissected, as previously described (Nose
et al., 1992; Patel,
1994). The following primary antibodies were used: rabbit
anti-Hunchback (1:500, J. Reinitz), guinea pig anti-Hunchback (1:1000), mouse
anti-Eagle (1:10, M. Freeman and C. Q. Doe, Eugene, OR), rabbit anti-Eagle
(1:500) (Dittrich et al.,
1997), mouse anti-Svp (Kanai
et al., 2005) (signal amplification with TSA-Kit, Perkin Elmer),
rat anti-Zfh-2 (1:200, M. Lundell, San Antonio, USA), rabbit anti-ß-Gal
(1:1000, Cappel), rabbit anti-Repo (1:500)
(Halter et al., 1995), rabbit
anti-Eve (1:5000, M. Frasch, New York, USA), mouse anti-Eve (1:2,
Developmental Studies Hybridoma Bank). The following secondary antibodies were
used: anti-rabbit-FITC, anti-guinea pig Cy3, anti-mouse Cy5, anti-rat Cy3
(1:250, all obtained from Dianova). Flat preparations of embryos were mounted
in Vectashield mounting medium (Vector Laboratories). Embryos were analysed
with a confocal laser scanning microscope (Leica TCS SP2). Scanning images
were processed with Adobe Photoshop. All images show projections of multiple
focal planes. Original scans will be provided upon request. In all images
anterior is upwards.
In situ hybridisation
Fixed embryos were incubated for 10 minutes in 0.1% sodium borohydride in
PBT to reduce autofluorescence. Whole-mount RNA in situ hybridisation was
carried out as described previously (Jiang
et al., 1991) using digoxigenin-(Dig) or FITC-labelled RNA probes
made from hb (Margolis et al.,
1995) and svp1
(Mlodzik et al., 1990) cDNA.
Probes were detected using anti-Dig-POD or anti-FITC-POD, depending on the
labelling (1:1000, Roche), and the signal was amplified using the TSA
amplification kit with Tyramide-Cy5 or Tyramide-Cy3 (Perkin Elmer). Additional
antibody staining was performed after the final amplification step.
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), and that it is switched off by the activity of Svp, a
member of the orphan receptor family of zinc finger transcription factors
(Kanai et al., 2005). However,
svp mRNA expression has already started before the NB divides, after
which hb expression is terminated. As a result both progeny, the NB
and the GMC, inherit svp mRNA and produce Svp protein, although the
GMC continues to express hb
(Kanai et al., 2005). This
suggests that one or more GMC-specific factors are able to suppress the
Svp-mediated repression of hb within the GMC. Good candidates for
such factors are the asymmetrically segregating cell-fate determinants Numb
and Prospero (Pros). Both of these proteins form a basal crescent within the
NB prior to division, and both are inherited only by the newly formed GMC
(Hirata et al., 1995;
Knoblich et al., 1995;
Spana and Doe, 1995).
Therefore, we analysed the hb expression in loss-of-function alleles
of these genes. Although we did not find an obvious difference in the number
of Hb-positive (Hb+) cells in the absence of Numb function (data
not shown), there was a strong reduction in the number of these cells in
pros mutant embryos (compare Fig.
1A and 1B).
pros codes for a homeodomain transcription factor that enters the
nucleus of the GMC after mitosis, subsequently regulating GMC-specific gene
expression (Chu-Lagraff et al.,
1991; Doe et al.,
1991; Spana and Doe,
1995; Vässin et al., 1991). To confirm that the observed
reduction of Hb+ cells is indeed due to a lack of hb
maintenance within the GMCs and their progeny, we compared the timing of
hb expression within different lineages between wild type and the
pros loss-of-function alleles prosC7 and
pros17. We analysed the lineages of the thoracic NB2-4T
and NB6-4T, as well as the abdominal NB7-3. As in wild type, NB7-3 in both
pros alleles is initially Hb+ and generates a
Hb+ GMC (GMCa) after its first division (compare
Fig. 2A and 2G). At early stage
12, the NB is Hb-negative (Hb-) and generates a second GMC (GMCb)
that is Hb- too. At this stage, GMCa maintains hb
expression in wild type, whereas this is reduced or already undetectable in
pros mutants (compare Fig. 2B and
2H). In stage 14 pros mutant embryos, 100% of the NB7-3
derived cell clusters (n=110) do not show any Hb+ cells,
whereas there are two cells in wild type, the EW1 and GW neurons (compare
Fig. 2C and 2I). To rule out
that the lack of Hb+ cells in NB7-3 is due to a loss of these cells
by programmed cell death, we recombined prosC7 with the
deficiency H99 to prevent apoptosis
(White et al., 1994). Again,
only Hb- progeny of NB7-3 were found in later stages
(Fig. 2O, n=70),
confirming that the phenotype is indeed due to lack of hb
maintenance. Consistent with its role as a repressor of hb, we see
the opposite phenotype in svp mutants: here the NB stays
Hb+ after its first division and produces at least one additional
Hb+ GMC before becoming Hb-
(Fig. 2D-F).
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;
Freeman and Doe, 2001;
Isshiki et al., 2001;
Ragone et al., 2001). Again,
the glial precursor and its progeny normally maintain hb expression,
whereas it is switched off in the parental NB
(Fig. 3A). As is expected in
pros mutants, the hb expression in the glial cells is not
maintained (compare Fig. 3A and
3E), whereas there is a considerable delay in switching off
hb in svp mutants (compare
Fig. 3A and 3C). This lack of
svp function leads to one additional Hb+ glial cell in 56%
of the hemineuromeres (n=34; compare
Fig. 3G and 3H). Concomitantly,
we observed a reduction of the number of NB6-4T-derived neurons in almost all
hemineuromeres in svp mutants (compare
Fig. 3B and 3D).
Because NB7-3 and NB6-4T terminate hb expression after their first
division, we next asked whether pros is also necessary for
hb maintenance in NBs that produce two Hb+ GMCs. NB7-1
generates such a lineage and it has already been shown that it also produces
additional Hb+ progeny in svp mutant embryos
(Kanai et al., 2005).
Unfortunately we could not analyse this lineage in pros mutants
because the expression of even skipped (eve), which is
needed as a marker for the detection of the first NB7-1 progeny, is itself
pros dependent (Doe et al.,
1991; McDonald et al.,
2003). Therefore, we analysed NB2-4T, which we also found to be a
neuroblast generating two Hb+ GMCs leading to four Hb+
neurons (Fig. 4A-C). In this
lineage too, hb expression stays switched on longer in
svp-mutant embryos, and as a result there are about five to eight
Hb+ cells in 86% of the analysed thoracic hemineuromeres
(n=35; Fig. 4D-F). In
pros mutants, the hb expression within the NB2-4T lineage
seems initially to be normal (Fig.
4G,H), but at stage 14, in about 53%, there are only two
Hb+ neurons detectable (n=40;
Fig. 4I). Thus, in all lineages
analysed Pros seems to counteract the hb-downregulating activity of
Svp.
To test whether Pros is not only necessary but also sufficient for
hb maintenance, we made use of the GAL4/UAS-system to express
pros ectopically within the NBs
(Brand and Perrimon, 1993). We
used engrailed-GAL4 (en-GAL4) to drive pros
expression within NB7-3 and its progeny. Ectopic Pros caused a precocious stop
in cell divisions within this lineage in all hemineuromeres analysed. This was
expected, as Pros has been shown to activate dacapo, which
subsequently inhibits further mitotic divisions (Li and Vässin, 2000;
Liu et al., 2002).
Nevertheless, in some hemineuromeres we could identify three NB7-3-derived
cells. In most of these cases, all three cells were Hb+
(Fig. 2N). This shows that Pros
activity is indeed sufficient for maintaining hb expression, because
one of these cells must be the NB that has divided at least once.
Prospero antagonises Seven up activity
The opposite phenotypes of svp and pros mutants suggest
that hb maintenance in the GMC is due to Pros activity, which
inhibits the repressive function of svp. If this is the case, a
concomitant loss of Pros and Svp function should show a svp-like
phenotype. To test this, we generated a svpe22,
prosC7 double mutant and stained the embryonic CNS for
hb expression. We indeed found generally more Hb+ cells,
which is similar to the phenotype in svp single mutant embryos
(compare Fig. 1C and D). This
was also confirmed on the lineage level: in the NB7-3 derived cluster of stage
14 svp-mutant embryos, there were three or four Hb+ cells
in 75% of the hemineuromeres (n=103). This is similar to the double
mutants, which showed this in 67% of the hemineuromeres (n=91;
Fig. 2L), thus supporting our
hypothesis that Pros antagonises Svp activity in the GMC. But on which level
does this occur? One possibility is that svp transcription, which is
initiated before mitosis, is suppressed by Pros in the GMC after division.
Alternatively, Pros could suppress the activity of the Svp protein. To
distinguish between these two possibilities, we analysed the dynamics of
svp mRNA expression in the NB7-3 lineage in wild-type and
pros mutant embryos. In both genotypes, svp expression in
the NB starts before its first division
(Fig. 5A,E) and svp
mRNA is still present in the NB after mitosis
(Fig. 5B,C,F). However, when we
examined svp mRNA expression in GMCa before the NB divides again, we
found a difference between the wild-type and pros mutant embryos. In
wild type, 70% of these GMCs (n=26) were negative for svp
mRNA (Fig. 5B). In contrast to
that, all GMCs examined in pros mutants expressed svp mRNA,
although on a lower level than the NBs did (n=16;
Fig. 5F). After the birth of
GMCb, there is detectable svp mRNA in only eight out of 21 cases in
GMCa in wild type, whereas in pros mutants 13 out of 20 are still
positive for this transcript (Fig.
5D,G). This suggests that Pros might participate in the
GMC-specific transcriptional downregulation of svp. However,
overexpression of pros could not eliminate svp expression
within the NBs (data not shown).
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svp activity but not transcription is mitosis dependent
It has been shown that hb downregulation in the NB is mitosis
dependent, because Hb is maintained in string (stg) mutant
NBs, where mitosis is blocked at the G2/M transition
(Isshiki et al., 2001;
Großkortenhaus et al.,
2005). However, in NB7-3, svp mRNA begins to be expressed
prior to the division that leads to hb downregulation
(Kanai et al., 2005) (this
work). This timing of svp expression seems to be a general feature,
as we also see this in other lineages. NB6-4T, which generates only one
hb-positive progeny, switches on svp expression before its
first division (Fig.
6A,A'), whereas NB2-4T and NB7-1, which both generate two
Hb+ GMCs, start svp expression before the Hb+
GMCb is born (Fig.
6B,B',F,F'). This suggests that either there is no
svp mRNA expression in stg mutant NBs, or that the
svp-mediated hb-repressing activity is
post-transcriptionally upregulated after division.
To distinguish between these two possibilities, we analysed svp mRNA expression in stg mutant embryos in Eg-positive NBs at different developmental time points. We found a normal onset of svp expression within NB2-4T and NB7-3 (Fig. 6C,C'), showing that lack of hb-downregulation in stg mutants in these NBs is not due to a lack of svp transcription. To test whether the regulation could be on the level of protein translation, we analysed stg mutant embryos for the presence of Svp protein in the NBs. Indeed, we found only a low or undetectable amount of this protein in these cells up to early stage 12, suggesting that the translation of the svp mRNA is very low (Fig. 6D,D'). The reason for this might be the unusual localisation of the svp mRNA: when comparing the distribution of hb and svp mRNAs, we realised that almost all of the visible svp mRNA is localised in the nucleus, whereas the hb mRNA is enriched in the cytoplasm (compare Fig. 7C' and 7C''). This nuclear localisation of the svp mRNA is also evident in the in situ hybridisation for svp mRNA combined with the antibody staining for Hb protein in stg mutant embryos (Fig. 7A-A''). We assume that this localisation might prevent efficient translation of the Svp protein, which takes place in the cytoplasm. However, some of the svp mRNA molecules seem to escape from the nucleus, as we could detect a low level of Svp protein in NBs from around stage 12 onwards (Fig. 6D,D', Fig. 7B-B''). This seems to lead to a reduction of hb expression because the amount of hb mRNA and protein in the svp-expressing NBs is lower than in the other cells (Fig. 7).
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DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) (this
work). Why then does svp downregulate hb only within the NB
and not in the GMC? Our results show that this is due to the activity of Pros,
a homeodomain transcription factor that is asymmetrically distributed only to
the GMC (Hirata et al., 1995;
Knoblich et al., 1995;
Li et al., 1997;
Spana and Doe, 1995). Earlier
work by other groups has suggested that Pros is involved in the regulation of
GMC-specific gene activity (Doe et al.,
1991; Vässin et al., 1991; Li and Vässin, 2000) In
principle this is also true for the function of pros in the context
of hb regulation, because it inhibits the NB-specific
svp-mediated downregulation of hb. How is this antagonistic
activity of Svp and Pros achieved at the molecular level? On the one hand, our
data suggest that Pros downregulates svp transcription, because the
svp mRNA in the first GMC of NB7-3 was present longer in
pros mutants than in wild type. On the other hand, it seems likely
that Pros also inhibits Svp activity, because the Hb+ GMC often
possesses Svp protein even after the parental NB is Hb-. An
attractive model for this would be that Pros neutralises Svp repressor
function by binding to the same regulatory region of hb. In fact, we
found an evolutionarily conserved enrichment of putative Svp-binding sites in
the vicinity of a potential Pros-binding site
(Cook et al., 2003;
Hassan et al., 1997;
Zelhof et al., 1995), within a
regulatory region that is necessary for neural hb regulation (J.
Margolis, PhD thesis, University of California at San Diego, 1992). We are
currently testing whether these sequences are indeed functional in the
proposed context.
|
|
;
Großkortenhaus et al.,
2005) (this work), the repressing activity of svp must
somehow depend on mitosis. This regulation cannot be at the level of the
transcriptional activation of svp because its mRNA is already present
before the NBs enter the decisive M-phase. Moreover, in stg mutant
embryos, where the G2/M transition is blocked, we find co-expression of
svp mRNA and Hb for several hours, although at later stages the
average amount of Hb molecules seems to be generally lower than in cells
without svp expression. At the protein level the situation is
somewhat different: in wild-type embryos we do hardly see any Svp protein
before the NB divides, suggesting that the svp mRNA cannot be
efficiently translated before mitosis occurred. This might be due to a low
translation rate, because in stg mutants we found only a slowly
increasing Svp protein level in the NBs despite a permanently strong
svp mRNA expression. One reason for this might be the nuclear
localisation of the svp mRNA, which we found in NBs of stg
mutant embryos as well as in wild type. This localisation might be able to
largely prevent svp mRNA from becoming translated before the cell
divides. Clearly, further work is needed to test this interesting
hypothesis.
|
)
provided evidence that U2 is specified by a reduction of hb activity
within the NB or GMC. Thus, it is possible that a low level of Svp protein
present in the NB before the second GMC is born might be responsible for this.
Indeed, when svp is expressed in NB7-1 prematurely before the birth
of the first GMC, there is no U1 neuron and the chain of U neurons often
starts with only one Hb+ neuron, which has a U2 identity
(Kanai et al., 2005) (U.M. and
J.U., unpublished). According to our hypothesis, this would be due to a
reduced Hb activity caused by the premature svp expression. Likewise,
in the absence of svp function the NB first produces many additional
Hb+ U1 neurons before it eventually generates the other U neurons
starting with U2 (Kanai et al.,
2005) (U.M. and J.U., unpublished). In this case, hb
expression level might initially remain high resulting in the production of
several U1 neurons before it drops down leading to the specification of a U2
neuron.
The lineage-specific timing of svp expression is cell cycle independent
It has been shown that the lineage-specific timing of the switching on of
svp expression defines the end of the Hb+ time window, and
thereby the number of the progeny generated during this phase
(Kanai et al., 2005) (U.M. and
J.U., unpublished). How is this timing regulated? In one group of NBs, the
expression of svp already starts before its first division (e.g.
NB7-3 and NB6-4T). This could be directly dependent on the activity of
proneural genes. Indeed, the early expression of svp within the
developing Malphigian tubules has been shown to be regulated by these genes
(Sudarsan et al., 2002). In
this context, it is interesting to note that, in Drosophila, svp
expression in certain NB lineages has already begun in their proneural
clusters within the neuroectoderm (Broadus
and Doe, 1995). A second group of NBs show svp
upregulation after the generation of their first GMCs (e.g. NB2-4T and NB7-1),
suggesting that the mitotic division is the trigger for this event. To our
surprise, this is not the case: in stg mutant embryos, NB7-1
upregulates svp at the same time as in wild type, although no
division has occurred. The same was found for NB2-4T. Thus, lineage-specific
timing of svp expression is independent of the number of cell
divisions. However, currently we cannot rule out that earlier stages of the
cell cycle, like the S-Phase, could be the trigger instead. Interestingly, the
sequential transitions of the temporal specification genes acting after
hb expression have recently been shown to occur independently of the
cell cycle (Großkortenhaus et al.,
2005). According to our results, this might be also true for the
timing of svp expression.
Conclusion
To our knowledge, the regulatory interactions between hb, svp and
pros are the first example where mitosis-dependent gene activity acts
together with an asymmetric cell fate determinant to regulate differential
gene expression in space and time (Fig.
8). We currently do not know whether such a regulation also exists
in other organisms. Interestingly, Svp shows a high homology with COUP-TF
orphan receptors from vertebrates, which are also necessary for CNS
development (Pereira et al.,
2000). Prox1, the vertebrate homologue of Pros is not
asymmetrically distributed during division but is expressed and needed during
neurogenesis (Tomarev et al.,
1998; Yamamoto et al.,
2001). During retinal development, Prox1 is involved in the
specification of the fate of the early born horizontal neurons
(Dyer et al., 2003). Future
investigations will show whether during vertebrate CNS development these
homologous factors play a role comparable to Svp and Pros in
Drosophila.
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ACKNOWLEDGMENTS |
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