Datasets:
vgainullin
/
xciting_data

Dataset card Data Studio Files
xet
 Community
1
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int64
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1
DISCUSSION
1
18–20
[ "B18 B19 B20", "B16", "B17" ]
17,426,135
NA|pmid-12971721|pmid-14517543|pmid-11700282|pmid-12787766|pmid-12067651|pmid-11865056|pmid-12700350
Insulators are a class of DNA sequences that restrain regulatory interactions within eukaryotic genomes (18–20).
[ "18–20", "16", "17" ]
112
100
1
false
Insulators are a class of DNA sequences that restrain regulatory interactions within eukaryotic genomes.
[ "18–20" ]
Insulators are a class of DNA sequences that restrain regulatory interactions within eukaryotic genomes.
true
true
true
true
true
17
1
DISCUSSION
1
18–20
[ "B18 B19 B20", "B16", "B17" ]
17,426,135
NA|pmid-12971721|pmid-14517543|pmid-11700282|pmid-12787766|pmid-12067651|pmid-11865056|pmid-12700350
In the p2L line, we have shown that the insulator identified within the Idefix retrotransposon acts as an enhancer blocker on the eye enhancer of the ZAM retrotransposon ((16) and this study).
[ "18–20", "16", "17" ]
192
101
0
false
In the p2L line, we have shown that the insulator identified within the Idefix retrotransposon acts as an enhancer blocker on the eye enhancer of the ZAM retrotransposon and this study).
[ "(16" ]
In the p2L line, we have shown that the insulator identified within the Idefix retrotransposon acts as an enhancer blocker on the eye enhancer of the ZAM retrotransposon and this study).
true
true
true
true
true
17
1
DISCUSSION
1
18–20
[ "B18 B19 B20", "B16", "B17" ]
17,426,135
NA|pmid-12971721|pmid-14517543|pmid-11700282|pmid-12787766|pmid-12067651|pmid-11865056|pmid-12700350
However, a single copy of the insulator is not sufficient to completely block ZAM enhancer activity.
[ "18–20", "16", "17" ]
100
102
0
false
However, a single copy of the insulator is not sufficient to completely block ZAM enhancer activity.
[]
However, a single copy of the insulator is not sufficient to completely block ZAM enhancer activity.
true
true
true
true
true
17
1
DISCUSSION
1
18–20
[ "B18 B19 B20", "B16", "B17" ]
17,426,135
NA|pmid-12971721|pmid-14517543|pmid-11700282|pmid-12787766|pmid-12067651|pmid-11865056|pmid-12700350
Two copies of the Idefix insulator, on the other hand, inserted between the enhancer and the transcription start site of the target gene, can more efficiently block the enhancer.
[ "18–20", "16", "17" ]
178
103
0
false
Two copies of the Idefix insulator, on the other hand, inserted between the enhancer and the transcription start site of the target gene, can more efficiently block the enhancer.
[]
Two copies of the Idefix insulator, on the other hand, inserted between the enhancer and the transcription start site of the target gene, can more efficiently block the enhancer.
true
true
true
true
true
17
1
DISCUSSION
1
18–20
[ "B18 B19 B20", "B16", "B17" ]
17,426,135
NA|pmid-12971721|pmid-14517543|pmid-11700282|pmid-12787766|pmid-12067651|pmid-11865056|pmid-12700350
Several previously described insulators have also been shown to have greater enhancer-blocking ability when present in several copies.
[ "18–20", "16", "17" ]
134
104
0
false
Several previously described insulators have also been shown to have greater enhancer-blocking ability when present in several copies.
[]
Several previously described insulators have also been shown to have greater enhancer-blocking ability when present in several copies.
true
true
true
true
true
17
1
DISCUSSION
1
17
[ "B18 B19 B20", "B16", "B17" ]
17,426,135
NA|pmid-12971721|pmid-14517543|pmid-11700282|pmid-12787766|pmid-12067651|pmid-11865056|pmid-12700350
For example, enhancer-blocking activity is increased when two copies of the extensively described D. melanogaster insulators, scs and scs′, are associated (17).
[ "18–20", "16", "17" ]
160
105
1
false
For example, enhancer-blocking activity is increased when two copies of the extensively described D. melanogaster insulators, scs and scs′, are associated.
[ "17" ]
For example, enhancer-blocking activity is increased when two copies of the extensively described D. melanogaster insulators, scs and scs′, are associated.
true
true
true
true
true
17
1
DISCUSSION
1
18–20
[ "B18 B19 B20", "B16", "B17" ]
17,426,135
NA|pmid-12971721|pmid-14517543|pmid-11700282|pmid-12787766|pmid-12067651|pmid-11865056|pmid-12700350
This flexibility might help modulate the function of Idefix insulators within the genome.
[ "18–20", "16", "17" ]
89
106
0
false
This flexibility might help modulate the function of Idefix insulators within the genome.
[]
This flexibility might help modulate the function of Idefix insulators within the genome.
true
true
true
true
true
17
1
DISCUSSION
1
18–20
[ "B18 B19 B20", "B16", "B17" ]
17,426,135
NA|pmid-12971721|pmid-14517543|pmid-11700282|pmid-12787766|pmid-12067651|pmid-11865056|pmid-12700350
We have further demonstrated that the function of the Idefix insulator not only depends on its copy number, but also that it is enhancer specific.
[ "18–20", "16", "17" ]
146
107
0
false
We have further demonstrated that the function of the Idefix insulator not only depends on its copy number, but also that it is enhancer specific.
[]
We have further demonstrated that the function of the Idefix insulator not only depends on its copy number, but also that it is enhancer specific.
true
true
true
true
true
17
1
DISCUSSION
1
18–20
[ "B18 B19 B20", "B16", "B17" ]
17,426,135
NA|pmid-12971721|pmid-14517543|pmid-11700282|pmid-12787766|pmid-12067651|pmid-11865056|pmid-12700350
For instance, while it is able to block the ZAM enhancer, it can block neither white gene enhancers, even though they are active in the same eye tissue as ZAM, nor ftz gene enhancers, which are specific to embryonic tissues (unpublished data).
[ "18–20", "16", "17" ]
243
108
0
false
For instance, while it is able to block the ZAM enhancer, it can block neither white gene enhancers, even though they are active in the same eye tissue as ZAM, nor ftz gene enhancers, which are specific to embryonic tissues (unpublished data).
[]
For instance, while it is able to block the ZAM enhancer, it can block neither white gene enhancers, even though they are active in the same eye tissue as ZAM, nor ftz gene enhancers, which are specific to embryonic tissues (unpublished data).
true
true
true
true
true
17
1
DISCUSSION
1
18–20
[ "B18 B19 B20", "B16", "B17" ]
17,426,135
NA|pmid-12971721|pmid-14517543|pmid-11700282|pmid-12787766|pmid-12067651|pmid-11865056|pmid-12700350
These results indicate that the function of the Idefix insulator also depends on specific enhancer characteristics.
[ "18–20", "16", "17" ]
115
109
0
false
These results indicate that the function of the Idefix insulator also depends on specific enhancer characteristics.
[]
These results indicate that the function of the Idefix insulator also depends on specific enhancer characteristics.
true
true
true
true
true
17
2
DISCUSSION
1
21
[ "B21", "B12", "B22" ]
17,426,135
pmid-1848159|pmid-1569958|pmid-14996934|pmid-11106742|pmid-12925706
Our results also indicate that the Idefix insulator is active within the whole space of the nucleus and does not localize to any particular nuclear regions.
[ "21", "12", "22" ]
156
110
0
false
Our results also indicate that the Idefix insulator is active within the whole space of the nucleus and does not localize to any particular nuclear regions.
[]
Our results also indicate that the Idefix insulator is active within the whole space of the nucleus and does not localize to any particular nuclear regions.
true
true
true
true
true
18
2
DISCUSSION
1
21
[ "B21", "B12", "B22" ]
17,426,135
pmid-1848159|pmid-1569958|pmid-14996934|pmid-11106742|pmid-12925706
Similar results have recently been reported concerning the enhancer-blocker activity of the gypsy insulator, which is also functional from the nuclear periphery to the nuclear interior (21).
[ "21", "12", "22" ]
190
111
1
false
Similar results have recently been reported concerning the enhancer-blocker activity of the gypsy insulator, which is also functional from the nuclear periphery to the nuclear interior.
[ "21" ]
Similar results have recently been reported concerning the enhancer-blocker activity of the gypsy insulator, which is also functional from the nuclear periphery to the nuclear interior.
true
true
true
true
true
18
2
DISCUSSION
1
21
[ "B21", "B12", "B22" ]
17,426,135
pmid-1848159|pmid-1569958|pmid-14996934|pmid-11106742|pmid-12925706
Anchorage to certain specific nuclear structures has been suggested as a mechanism for the insulation effect of some insulators (12,22).
[ "21", "12", "22" ]
136
112
0
false
Anchorage to certain specific nuclear structures has been suggested as a mechanism for the insulation effect of some insulators.
[ "12,22" ]
Anchorage to certain specific nuclear structures has been suggested as a mechanism for the insulation effect of some insulators.
true
true
true
true
true
18
3
DISCUSSION
0
null
null
17,426,135
pmid-15815711|pmid-11161205|pmid-11161206|pmid-16227580|pmid-11106742
Although two Idefix insulators are more effective than one, we further demonstrated that this function can be lost if each LTR, which carries the insulator function, is associated with a second fragment of Idefix.
null
213
113
0
false
null
null
Although two Idefix insulators are more effective than one, we further demonstrated that this function can be lost if each LTR, which carries the insulator function, is associated with a second fragment of Idefix.
true
true
true
true
true
19
3
DISCUSSION
0
null
null
17,426,135
pmid-15815711|pmid-11161205|pmid-11161206|pmid-16227580|pmid-11106742
Indeed, when two Idefix LTRs are both flanked by the Idefix 5′ UTR, their enhancer-blocking activity disappears and the downstream mini-white gene is highly expressed.
null
167
114
0
false
null
null
Indeed, when two Idefix LTRs are both flanked by the Idefix 5′ UTR, their enhancer-blocking activity disappears and the downstream mini-white gene is highly expressed.
true
true
true
true
true
19
3
DISCUSSION
0
null
null
17,426,135
pmid-15815711|pmid-11161205|pmid-11161206|pmid-16227580|pmid-11106742
This loss of function is restricted to the specific combination of two pairs of [LTR–5′UTR].
null
92
115
0
false
null
null
This loss of function is restricted to the specific combination of two pairs of [LTR–5′UTR].
true
true
true
true
true
19
3
DISCUSSION
0
null
null
17,426,135
pmid-15815711|pmid-11161205|pmid-11161206|pmid-16227580|pmid-11106742
The combinations of one insulator with two 5′ UTRs, or two insulators with one 5′UTR, had no effect on enhancer-blocker activity.
null
129
116
0
false
null
null
The combinations of one insulator with two 5′ UTRs, or two insulators with one 5′UTR, had no effect on enhancer-blocker activity.
true
true
true
true
true
19
3
DISCUSSION
0
null
null
17,426,135
pmid-15815711|pmid-11161205|pmid-11161206|pmid-16227580|pmid-11106742
When the two pairs of [LTR–5′UTR] were present, they abolished the enhancer-blocker function, regardless of their respective orientations.
null
138
117
0
false
null
null
When the two pairs of [LTR–5′UTR] were present, they abolished the enhancer-blocker function, regardless of their respective orientations.
true
true
true
true
true
19
3
DISCUSSION
0
null
null
17,426,135
pmid-15815711|pmid-11161205|pmid-11161206|pmid-16227580|pmid-11106742
Further, we found that this loss of function is due to specific properties of the 5′ UTR sequence, because its replacement by another segment of Idefix, namely a fragment of the gag gene, had no effect on enhancer-blocker function.
null
231
118
0
false
null
null
Further, we found that this loss of function is due to specific properties of the 5′ UTR sequence, because its replacement by another segment of Idefix, namely a fragment of the gag gene, had no effect on enhancer-blocker function.
true
true
true
true
true
19
4
DISCUSSION
0
null
null
17,426,135
pmid-7637789|pmid-8557045|pmid-11106742
In a complementary analysis, we have found that p2[LU]-tagged loci are perinuclear regardless of whether the transgenes are transcriptionally active or inactive.
null
161
119
0
false
null
null
In a complementary analysis, we have found that p2[LU]-tagged loci are perinuclear regardless of whether the transgenes are transcriptionally active or inactive.
true
true
true
true
true
20
4
DISCUSSION
0
null
null
17,426,135
pmid-7637789|pmid-8557045|pmid-11106742
Indeed, loci tagged with the p2[LU] transgenes assumed similar distributions along the radius when scored in two types of cells: (i) eye disc cells, in which the mini-white gene is known to be activated by the ZAM enhancer (Figure 4); and (ii) cells from the peripodial membrane enveloping the eye disc, where the white gene is not activated by ZAM (Supplementary Data, Figure 1).
null
380
120
0
false
null
null
Indeed, loci tagged with the p2[LU] transgenes assumed similar distributions along the radius when scored in two types of cells: (i) eye disc cells, in which the mini-white gene is known to be activated by the ZAM enhancer (Figure 4); and (ii) cells from the peripodial membrane enveloping the eye disc, where the white gene is not activated by ZAM (Supplementary Data, Figure 1).
true
true
true
true
true
20
4
DISCUSSION
0
null
null
17,426,135
pmid-7637789|pmid-8557045|pmid-11106742
A clear displacement of the foci towards the nuclear periphery was observed in both cases, indicating that the expression of transgenes does not dictate their perinuclear position.
null
180
121
0
false
null
null
A clear displacement of the foci towards the nuclear periphery was observed in both cases, indicating that the expression of transgenes does not dictate their perinuclear position.
true
true
true
true
true
20
4
DISCUSSION
0
null
null
17,426,135
pmid-7637789|pmid-8557045|pmid-11106742
Thus, the altered localisation of the loci is not linked to transcriptional activation.
null
87
122
0
false
null
null
Thus, the altered localisation of the loci is not linked to transcriptional activation.
true
true
true
true
true
20
5
DISCUSSION
1
12
[ "B12", "B23 B24 B25", "B21" ]
17,426,135
pmid-10331252|pmid-11865056|pmid-10331252|pmid-11106742|pmid-9286681|pmid-12629048|pmid-12062099|pmid-14996934
The fact that two Idefix LTRs are necessary for bypassing enhancer-blocking activity when they are associated with two 5′ UTRs, together with the fact that a single insulator cannot bypass the activity even if fused to two 5′ UTRs, suggests that the interaction between two Idefix insulator motifs is an absolute requirement for the bypass.
[ "12", "23–25", "21" ]
340
123
0
false
The fact that two Idefix LTRs are necessary for bypassing enhancer-blocking activity when they are associated with two 5′ UTRs, together with the fact that a single insulator cannot bypass the activity even if fused to two 5′ UTRs, suggests that the interaction between two Idefix insulator motifs is an absolute requirement for the bypass.
[]
The fact that two Idefix LTRs are necessary for bypassing enhancer-blocking activity when they are associated with two 5′ UTRs, together with the fact that a single insulator cannot bypass the activity even if fused to two 5′ UTRs, suggests that the interaction between two Idefix insulator motifs is an absolute requirement for the bypass.
true
true
true
true
true
21
5
DISCUSSION
1
12
[ "B12", "B23 B24 B25", "B21" ]
17,426,135
pmid-10331252|pmid-11865056|pmid-10331252|pmid-11106742|pmid-9286681|pmid-12629048|pmid-12062099|pmid-14996934
This kind of pairing suggests that loops are created that could organize chromatin within the nucleus, as has been described for other insulators (12,23–25).
[ "12", "23–25", "21" ]
157
124
0
false
This kind of pairing suggests that loops are created that could organize chromatin within the nucleus, as has been described for other insulators.
[ "12,23–25" ]
This kind of pairing suggests that loops are created that could organize chromatin within the nucleus, as has been described for other insulators.
true
true
true
true
true
21
5
DISCUSSION
1
12
[ "B12", "B23 B24 B25", "B21" ]
17,426,135
pmid-10331252|pmid-11865056|pmid-10331252|pmid-11106742|pmid-9286681|pmid-12629048|pmid-12062099|pmid-14996934
However, this result also indicates that the pairing of two Idefix insulator copies is not sufficient to explain the loss of enhancer-blocking activity.
[ "12", "23–25", "21" ]
152
125
0
false
However, this result also indicates that the pairing of two Idefix insulator copies is not sufficient to explain the loss of enhancer-blocking activity.
[]
However, this result also indicates that the pairing of two Idefix insulator copies is not sufficient to explain the loss of enhancer-blocking activity.
true
true
true
true
true
21
5
DISCUSSION
1
12
[ "B12", "B23 B24 B25", "B21" ]
17,426,135
pmid-10331252|pmid-11865056|pmid-10331252|pmid-11106742|pmid-9286681|pmid-12629048|pmid-12062099|pmid-14996934
Indeed, when these two copies were fused without the 5′ UTR sequences, they conserved their enhancer-blocker activity.
[ "12", "23–25", "21" ]
118
126
0
false
Indeed, when these two copies were fused without the 5′ UTR sequences, they conserved their enhancer-blocker activity.
[]
Indeed, when these two copies were fused without the 5′ UTR sequences, they conserved their enhancer-blocker activity.
true
true
true
true
true
21
5
DISCUSSION
1
12
[ "B12", "B23 B24 B25", "B21" ]
17,426,135
pmid-10331252|pmid-11865056|pmid-10331252|pmid-11106742|pmid-9286681|pmid-12629048|pmid-12062099|pmid-14996934
Therefore, we postulate that the loss of enhancer-blocking activity cannot be achieved simply via higher-order ‘looped’ domains generated by specific interactions between insulators.
[ "12", "23–25", "21" ]
182
127
0
false
Therefore, we postulate that the loss of enhancer-blocking activity cannot be achieved simply via higher-order ‘looped’ domains generated by specific interactions between insulators.
[]
Therefore, we postulate that the loss of enhancer-blocking activity cannot be achieved simply via higher-order ‘looped’ domains generated by specific interactions between insulators.
true
true
true
true
true
21
5
DISCUSSION
1
21
[ "B12", "B23 B24 B25", "B21" ]
17,426,135
pmid-10331252|pmid-11865056|pmid-10331252|pmid-11106742|pmid-9286681|pmid-12629048|pmid-12062099|pmid-14996934
Consistent with this, sequences other than the Su(Hw) insulator have been suggested to be responsible for the localization of gypsy retrotransposons at the nuclear periphery (21).
[ "12", "23–25", "21" ]
179
128
1
false
Consistent with this, sequences other than the Su(Hw) insulator have been suggested to be responsible for the localization of gypsy retrotransposons at the nuclear periphery.
[ "21" ]
Consistent with this, sequences other than the Su(Hw) insulator have been suggested to be responsible for the localization of gypsy retrotransposons at the nuclear periphery.
true
true
true
true
true
21
5
DISCUSSION
1
12
[ "B12", "B23 B24 B25", "B21" ]
17,426,135
pmid-10331252|pmid-11865056|pmid-10331252|pmid-11106742|pmid-9286681|pmid-12629048|pmid-12062099|pmid-14996934
Rather, the combination of two separable phenomena, such as the formation of loops and specific positioning within the nucleus (established, e.g.
[ "12", "23–25", "21" ]
145
129
0
false
Rather, the combination of two separable phenomena, such as the formation of loops and specific positioning within the nucleus (established, e.g.
[]
Rather, the combination of two separable phenomena, such as the formation of loops and specific positioning within the nucleus (established, e.g.
true
true
true
true
true
21
5
DISCUSSION
1
12
[ "B12", "B23 B24 B25", "B21" ]
17,426,135
pmid-10331252|pmid-11865056|pmid-10331252|pmid-11106742|pmid-9286681|pmid-12629048|pmid-12062099|pmid-14996934
by the two 5′ UTRs), would be required to bypass enhancer-blocker activity.
[ "12", "23–25", "21" ]
75
130
0
false
by the two 5′ UTRs), would be required to bypass enhancer-blocker activity.
[]
by the two 5′ UTRs), would be required to bypass enhancer-blocker activity.
false
true
true
true
false
21
6
DISCUSSION
1
26
[ "B26" ]
17,426,135
pmid-3002631
Interestingly, when the 5′ UTR sequence was analysed in silico, we identified a sequence that shares characteristics with sequences described in the literature as matrix attachment regions or MARs (MAR-Wiz software: www.futursoft.org) (Supplementary Data, Figure 2A).
[ "26" ]
267
131
0
false
Interestingly, when the 5′ UTR sequence was analysed in silico, we identified a sequence that shares characteristics with sequences described in the literature as matrix attachment regions or MARs (MAR-Wiz software: www.futursoft.org) (Supplementary Data, Figure 2A).
[]
Interestingly, when the 5′ UTR sequence was analysed in silico, we identified a sequence that shares characteristics with sequences described in the literature as matrix attachment regions or MARs (MAR-Wiz software: www.futursoft.org).
true
true
true
true
true
22
6
DISCUSSION
1
26
[ "B26" ]
17,426,135
pmid-3002631
This predicted MAR in the 5′ UTR was also detected through in vitro binding assays with high-salt-extracted nuclei, as described (26) (Supplementary Data, Figure 2B).
[ "26" ]
166
132
1
false
This predicted MAR in the 5′ UTR was also detected through in vitro binding assays with high-salt-extracted nuclei, as described (Supplementary Data, Figure 2B).
[ "26" ]
This predicted MAR in the 5′ UTR was also detected through in vitro binding assays with high-salt-extracted nuclei, as described.
true
true
true
true
true
22
7
DISCUSSION
0
null
null
17,426,135
null
Based on our present data, it is still uncertain whether this putative MAR domain in the 5′ UTR of Idefix is responsible for the loss of insulator activity in the Idefix LTR.
null
174
133
0
false
null
null
Based on our present data, it is still uncertain whether this putative MAR domain in the 5′ UTR of Idefix is responsible for the loss of insulator activity in the Idefix LTR.
true
true
true
true
true
23
7
DISCUSSION
0
null
null
17,426,135
null
However, it is interesting to note that gag fragments replacing the 5′ UTR fragments in the p2[LG] transgenes did not abolish the enhancer-blocker property of the Idefix LTRs, and that they do not display any MAR domains (see Supplementary Data, Figure 2B).
null
257
134
0
false
null
null
However, it is interesting to note that gag fragments replacing the 5′ UTR fragments in the p2[LG] transgenes did not abolish the enhancer-blocker property of the Idefix LTRs, and that they do not display any MAR domains (see Supplementary Data, Figure 2B).
true
true
true
true
true
23
8
DISCUSSION
1
27–29
[ "B27 B28 B29" ]
17,426,135
pmid-10580007|pmid-2840282|pmid-1495984
Might DNA sequences that are defined as MARs, because they precipitate in high salt solutions in vitro, have specific properties that allow them to interfere with insulator function?
[ "27–29" ]
182
135
0
false
Might DNA sequences that are defined as MARs, because they precipitate in high salt solutions in vitro, have specific properties that allow them to interfere with insulator function?
[]
Might DNA sequences that are defined as MARs, because they precipitate in high salt solutions in vitro, have specific properties that allow them to interfere with insulator function?
true
true
true
true
true
24
8
DISCUSSION
1
27–29
[ "B27 B28 B29" ]
17,426,135
pmid-10580007|pmid-2840282|pmid-1495984
Investigating such potential genomic effects is all the more important because the data in the literature on the biological significance of the matrix and its associated DNA sequences are far from clear, and because various reports have attributed different and apparently opposite functions to MARs (27–29).
[ "27–29" ]
308
136
1
false
Investigating such potential genomic effects is all the more important because the data in the literature on the biological significance of the matrix and its associated DNA sequences are far from clear, and because various reports have attributed different and apparently opposite functions to MARs.
[ "27–29" ]
Investigating such potential genomic effects is all the more important because the data in the literature on the biological significance of the matrix and its associated DNA sequences are far from clear, and because various reports have attributed different and apparently opposite functions to MARs.
true
true
true
true
true
24
9
DISCUSSION
1
15
[ "B15", "B15", "B16" ]
17,426,135
pmid-10331252|pmid-10331252|pmid-11865056
Whatever the functional modules involved, our present data helps us understand the phenotype of flies from the RevIV line which was identified in our laboratory some years ago (15).
[ "15", "15", "16" ]
181
137
1
false
Whatever the functional modules involved, our present data helps us understand the phenotype of flies from the RevIV line which was identified in our laboratory some years ago.
[ "15" ]
Whatever the functional modules involved, our present data helps us understand the phenotype of flies from the RevIV line which was identified in our laboratory some years ago.
true
true
true
true
true
25
9
DISCUSSION
1
15
[ "B15", "B15", "B16" ]
17,426,135
pmid-10331252|pmid-10331252|pmid-11865056
As mentioned above, RevIV contains an allele of the white gene that has two adjacent copies of Idefix inserted between a ZAM element and the endogenous white gene promoter.
[ "15", "15", "16" ]
172
138
0
false
As mentioned above, RevIV contains an allele of the white gene that has two adjacent copies of Idefix inserted between a ZAM element and the endogenous white gene promoter.
[]
As mentioned above, RevIV contains an allele of the white gene that has two adjacent copies of Idefix inserted between a ZAM element and the endogenous white gene promoter.
true
true
true
true
true
25
9
DISCUSSION
1
15
[ "B15", "B15", "B16" ]
17,426,135
pmid-10331252|pmid-10331252|pmid-11865056
It is derived from the de novo insertion of Idefix at the white locus in a line called RevII, which already had an Idefix element inserted between ZAM and the white gene (15).
[ "15", "15", "16" ]
175
139
1
false
It is derived from the de novo insertion of Idefix at the white locus in a line called RevII, which already had an Idefix element inserted between ZAM and the white gene.
[ "15" ]
It is derived from the de novo insertion of Idefix at the white locus in a line called RevII, which already had an Idefix element inserted between ZAM and the white gene.
true
true
true
true
true
25
9
DISCUSSION
1
16
[ "B15", "B15", "B16" ]
17,426,135
pmid-10331252|pmid-10331252|pmid-11865056
The two Idefix copies abolish the action of the single Idefix element, producing flies with a brick-red instead of an orange eye colour phenotype (16).
[ "15", "15", "16" ]
151
140
1
false
The two Idefix copies abolish the action of the single Idefix element, producing flies with a brick-red instead of an orange eye colour phenotype.
[ "16" ]
The two Idefix copies abolish the action of the single Idefix element, producing flies with a brick-red instead of an orange eye colour phenotype.
true
true
true
true
true
25
9
DISCUSSION
1
15
[ "B15", "B15", "B16" ]
17,426,135
pmid-10331252|pmid-10331252|pmid-11865056
These flies containing an endogenous mutation involving successive Idefix insertions are consistent with our present results.
[ "15", "15", "16" ]
125
141
0
false
These flies containing an endogenous mutation involving successive Idefix insertions are consistent with our present results.
[]
These flies containing an endogenous mutation involving successive Idefix insertions are consistent with our present results.
true
true
true
true
true
25
9
DISCUSSION
1
15
[ "B15", "B15", "B16" ]
17,426,135
pmid-10331252|pmid-10331252|pmid-11865056
The opposite effects of one versus two copies of the full-length Idefix retrotransposon may be accounted for by the fact that two [LTR–UTR] fragments are present in the white allele of RevIV, whereas only one [LTR–UTR] fragment is present in the white allele of RevII.
[ "15", "15", "16" ]
268
142
0
false
The opposite effects of one versus two copies of the full-length Idefix retrotransposon may be accounted for by the fact that two [LTR–UTR] fragments are present in the white allele of RevIV, whereas only one [LTR–UTR] fragment is present in the white allele of RevII.
[]
The opposite effects of one versus two copies of the full-length Idefix retrotransposon may be accounted for by the fact that two [LTR–UTR] fragments are present in the white allele of RevIV, whereas only one [LTR–UTR] fragment is present in the white allele of RevII.
true
true
true
true
true
25
10
DISCUSSION
0
null
null
17,426,135
null
We have shown here that the length of the sequence separating the two [LU] pairs is not critical for bypassing the enhancer-blocking activity, since we observed an equivalent loss of activity whether the two [LU] pairs were separated by 150 bp or by 4 kb.
null
255
143
0
false
null
null
We have shown here that the length of the sequence separating the two [LU] pairs is not critical for bypassing the enhancer-blocking activity, since we observed an equivalent loss of activity whether the two [LU] pairs were separated by 150 bp or by 4 kb.
true
true
true
true
true
26
10
DISCUSSION
0
null
null
17,426,135
null
Although longer genomic fragments remain to be tested, our data are consistent with a model in which two independent pairs of [LTR-5′UTR] sequences can interact over long distances to enable the insulator bypass, regardless of their respective genomic locations.
null
262
144
0
false
null
null
Although longer genomic fragments remain to be tested, our data are consistent with a model in which two independent pairs of [LTR-5′UTR] sequences can interact over long distances to enable the insulator bypass, regardless of their respective genomic locations.
true
true
true
true
true
26
11
DISCUSSION
1
24
[ "B24", "B30", "B31", "B32", "B33", "B34", "B35" ]
17,426,135
pmid-12629048|pmid-15931207|pmid-16418531|pmid-10545463|pmid-14522946|pmid-9165128|pmid-15831473
Consistent with the idea of long-range interactions, some studies have shown that scs and scs’ are in close proximity in Drosophila nuclei (24).
[ "24", "30", "31", "32", "33", "34", "35" ]
144
145
1
false
Consistent with the idea of long-range interactions, some studies have shown that scs and scs’ are in close proximity in Drosophila nuclei.
[ "24" ]
Consistent with the idea of long-range interactions, some studies have shown that scs and scs’ are in close proximity in Drosophila nuclei.
true
true
true
true
true
27
11
DISCUSSION
1
24
[ "B24", "B30", "B31", "B32", "B33", "B34", "B35" ]
17,426,135
pmid-12629048|pmid-15931207|pmid-16418531|pmid-10545463|pmid-14522946|pmid-9165128|pmid-15831473
Furthermore, recent studies have provided examples of eukaryotic genes that are located on separate chromosomes but that associate physically in the nucleus via interactions that may have a function in coordinating gene expression (30,31).
[ "24", "30", "31", "32", "33", "34", "35" ]
239
146
0
false
Furthermore, recent studies have provided examples of eukaryotic genes that are located on separate chromosomes but that associate physically in the nucleus via interactions that may have a function in coordinating gene expression.
[ "30,31" ]
Furthermore, recent studies have provided examples of eukaryotic genes that are located on separate chromosomes but that associate physically in the nucleus via interactions that may have a function in coordinating gene expression.
true
true
true
true
true
27
11
DISCUSSION
1
24
[ "B24", "B30", "B31", "B32", "B33", "B34", "B35" ]
17,426,135
pmid-12629048|pmid-15931207|pmid-16418531|pmid-10545463|pmid-14522946|pmid-9165128|pmid-15831473
Such examples of long-range interactions in D. melanogaster have involved elements of the Bithorax complex (32,33).
[ "24", "30", "31", "32", "33", "34", "35" ]
115
147
0
false
Such examples of long-range interactions in D. melanogaster have involved elements of the Bithorax complex.
[ "32,33" ]
Such examples of long-range interactions in D. melanogaster have involved elements of the Bithorax complex.
true
true
true
true
true
27
11
DISCUSSION
1
24
[ "B24", "B30", "B31", "B32", "B33", "B34", "B35" ]
17,426,135
pmid-12629048|pmid-15931207|pmid-16418531|pmid-10545463|pmid-14522946|pmid-9165128|pmid-15831473
Interestingly, the regulatory elements required for these latter examples of long-distance communication contain both an insulator and a Polycomb-response element (34,35).
[ "24", "30", "31", "32", "33", "34", "35" ]
171
148
0
false
Interestingly, the regulatory elements required for these latter examples of long-distance communication contain both an insulator and a Polycomb-response element.
[ "34,35" ]
Interestingly, the regulatory elements required for these latter examples of long-distance communication contain both an insulator and a Polycomb-response element.
true
true
true
true
true
27
11
DISCUSSION
1
24
[ "B24", "B30", "B31", "B32", "B33", "B34", "B35" ]
17,426,135
pmid-12629048|pmid-15931207|pmid-16418531|pmid-10545463|pmid-14522946|pmid-9165128|pmid-15831473
In our model, since two LTRs plus two UTRs are necessary to convert an enhancer-blocker function into an insulator bypass, it can be hypothesized that the two insulators act as an essential module that drives the interaction between the distant sites, with the two 5′ UTRs being involved in the positioning within the nucleus.
[ "24", "30", "31", "32", "33", "34", "35" ]
326
149
0
false
In our model, since two LTRs plus two UTRs are necessary to convert an enhancer-blocker function into an insulator bypass, it can be hypothesized that the two insulators act as an essential module that drives the interaction between the distant sites, with the two 5′ UTRs being involved in the positioning within the nucleus.
[]
In our model, since two LTRs plus two UTRs are necessary to convert an enhancer-blocker function into an insulator bypass, it can be hypothesized that the two insulators act as an essential module that drives the interaction between the distant sites, with the two 5′ UTRs being involved in the positioning within the nucleus.
true
true
true
true
true
27
12
DISCUSSION
0
null
null
17,426,135
null
One major issue raised by this study is why the subnuclear localization established by the 5′ UTR might allow the reactivation of target genes by the enhancer.
null
159
150
0
false
null
null
One major issue raised by this study is why the subnuclear localization established by the 5′ UTR might allow the reactivation of target genes by the enhancer.
true
true
true
true
true
28
12
DISCUSSION
0
null
null
17,426,135
null
Tethering genes to the nuclear pore complex may be one way in which gene activity could be restored.
null
100
151
0
false
null
null
Tethering genes to the nuclear pore complex may be one way in which gene activity could be restored.
true
true
true
true
true
28
12
DISCUSSION
0
null
null
17,426,135
null
Could the 5′ UTR help tether chromatin sites to the nuclear pores?
null
66
152
0
false
null
null
Could the 5′ UTR help tether chromatin sites to the nuclear pores?
true
true
true
true
true
28
12
DISCUSSION
0
null
null
17,426,135
null
Alternatively, could it modify chromatin accessibility or promote RNA export?
null
77
153
0
false
null
null
Alternatively, could it modify chromatin accessibility or promote RNA export?
true
true
true
true
true
28
12
DISCUSSION
0
null
null
17,426,135
null
These are the questions that are currently under investigation.
null
63
154
0
false
null
null
These are the questions that are currently under investigation.
true
true
true
true
true
28
0
INTRODUCTION
1
1
[ "b1" ]
17,182,632
pmid-11931781
Synthetic oligonucleotides and their analogs are commonly used as research reagents to modulate gene expression in cell culture and in animal models.
[ "1" ]
149
155
0
false
Synthetic oligonucleotides and their analogs are commonly used as research reagents to modulate gene expression in cell culture and in animal models.
[]
Synthetic oligonucleotides and their analogs are commonly used as research reagents to modulate gene expression in cell culture and in animal models.
true
true
true
true
true
29
0
INTRODUCTION
1
1
[ "b1" ]
17,182,632
pmid-11931781
The most broadly utilized mechanism by which oligonucleotides are exploited for modulation of gene expression is through binding of the antisense oligonucleotide (ASO) to a specific mRNA or pre-mRNA by Watson–Crick base pairing.
[ "1" ]
228
156
0
false
The most broadly utilized mechanism by which oligonucleotides are exploited for modulation of gene expression is through binding of the antisense oligonucleotide (ASO) to a specific mRNA or pre-mRNA by Watson–Crick base pairing.
[]
The most broadly utilized mechanism by which oligonucleotides are exploited for modulation of gene expression is through binding of the antisense oligonucleotide (ASO) to a specific mRNA or pre-mRNA by Watson–Crick base pairing.
true
true
true
true
true
29
0
INTRODUCTION
1
1
[ "b1" ]
17,182,632
pmid-11931781
Upon binding, the oligonucleotide can modulate RNA processing, inhibit translation or promote degradation.
[ "1" ]
106
157
0
false
Upon binding, the oligonucleotide can modulate RNA processing, inhibit translation or promote degradation.
[]
Upon binding, the oligonucleotide can modulate RNA processing, inhibit translation or promote degradation.
true
true
true
true
true
29
0
INTRODUCTION
1
1
[ "b1" ]
17,182,632
pmid-11931781
Mechanisms of degradation include recruitment of RNase H, which cleaves the RNA strand of a DNA:RNA duplexes, and activation of the RNA interference (RNAi) pathway utilizing short RNA duplexes (siRNA) or hairpins (shRNA).
[ "1" ]
221
158
0
false
Mechanisms of degradation include recruitment of RNase H, which cleaves the RNA strand of a DNA:RNA duplexes, and activation of the RNA interference (RNAi) pathway utilizing short RNA duplexes (siRNA) or hairpins (shRNA).
[]
Mechanisms of degradation include recruitment of RNase H, which cleaves the RNA strand of a DNA:RNA duplexes, and activation of the RNA interference (RNAi) pathway utilizing short RNA duplexes (siRNA) or hairpins (shRNA).
true
true
true
true
true
29
0
INTRODUCTION
1
1
[ "b1" ]
17,182,632
pmid-11931781
In addition to the use of oligonucleotides as research reagents there is increasing interest in exploiting oligonucleotides as therapeutic agents.
[ "1" ]
146
159
0
false
In addition to the use of oligonucleotides as research reagents there is increasing interest in exploiting oligonucleotides as therapeutic agents.
[]
In addition to the use of oligonucleotides as research reagents there is increasing interest in exploiting oligonucleotides as therapeutic agents.
true
true
true
true
true
29
0
INTRODUCTION
1
1
[ "b1" ]
17,182,632
pmid-11931781
Currently there is one approved antisense product (Vitravene, fomivirsen) (1) and >30 products in active development.
[ "1" ]
117
160
1
false
Currently there is one approved antisense product (Vitravene, fomivirsen) and >30 products in active development.
[ "1" ]
Currently there is one approved antisense product (Vitravene, fomivirsen) and >30 products in active development.
true
true
true
true
true
29
1
INTRODUCTION
1
2
[ "b2", "b3", "b4", "b4", "b3" ]
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
The first generation of ASO therapeutics were 2′-DNA oligomers uniformly modified with the phosphorothioate (PS) backbone substitution and work predominantly through an RNase H-dependent mechanism.
[ "2", "3", "4", "4", "3" ]
197
161
0
false
The first generation of ASO therapeutics were 2′-DNA oligomers uniformly modified with the phosphorothioate (PS) backbone substitution and work predominantly through an RNase H-dependent mechanism.
[]
The first generation of ASO therapeutics were 2′-DNA oligomers uniformly modified with the phosphorothioate (PS) backbone substitution and work predominantly through an RNase H-dependent mechanism.
true
true
true
true
true
30
1
INTRODUCTION
1
2
[ "b2", "b3", "b4", "b4", "b3" ]
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
The substitution of sulfur for oxygen in the phosphate ester confers several properties onto ASOs which are crucial for their use as systemic drugs (2).
[ "2", "3", "4", "4", "3" ]
152
162
1
false
The substitution of sulfur for oxygen in the phosphate ester confers several properties onto ASOs which are crucial for their use as systemic drugs.
[ "2" ]
The substitution of sulfur for oxygen in the phosphate ester confers several properties onto ASOs which are crucial for their use as systemic drugs.
true
true
true
true
true
30
1
INTRODUCTION
1
3
[ "b2", "b3", "b4", "b4", "b3" ]
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
Foremost, the PS linkage greatly increases stability to nucleolytic degradation (3), such that they possess sufficient stability in plasma, tissues and cells to avoid metabolism prior to reaching the target RNA after systemic administration to an animal.
[ "2", "3", "4", "4", "3" ]
254
163
1
false
Foremost, the PS linkage greatly increases stability to nucleolytic degradation, such that they possess sufficient stability in plasma, tissues and cells to avoid metabolism prior to reaching the target RNA after systemic administration to an animal.
[ "3" ]
Foremost, the PS linkage greatly increases stability to nucleolytic degradation, such that they possess sufficient stability in plasma, tissues and cells to avoid metabolism prior to reaching the target RNA after systemic administration to an animal.
true
true
true
true
true
30
1
INTRODUCTION
1
4
[ "b2", "b3", "b4", "b4", "b3" ]
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
Additionally, the PS modification confers a substantial pharmacokinetic benefit by increasing the binding to plasma proteins, which prevents rapid renal excretion (4).
[ "2", "3", "4", "4", "3" ]
167
164
1
false
Additionally, the PS modification confers a substantial pharmacokinetic benefit by increasing the binding to plasma proteins, which prevents rapid renal excretion.
[ "4" ]
Additionally, the PS modification confers a substantial pharmacokinetic benefit by increasing the binding to plasma proteins, which prevents rapid renal excretion.
true
true
true
true
true
30
1
INTRODUCTION
1
4
[ "b2", "b3", "b4", "b4", "b3" ]
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
While greatly increasing the stability of ASOs, PS modified drugs are still subject to metabolism, and have tissue half-lives of 1–3 days (4), which is sub-optimal for a parenterally administered drug.
[ "2", "3", "4", "4", "3" ]
201
165
1
false
While greatly increasing the stability of ASOs, PS modified drugs are still subject to metabolism, and have tissue half-lives of 1–3 days, which is sub-optimal for a parenterally administered drug.
[ "4" ]
While greatly increasing the stability of ASOs, PS modified drugs are still subject to metabolism, and have tissue half-lives of 1–3 days, which is sub-optimal for a parenterally administered drug.
true
true
true
true
true
30
1
INTRODUCTION
1
3
[ "b2", "b3", "b4", "b4", "b3" ]
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
Furthermore, the PS modification reduces affinity for the target RNA (the ultimate biological receptor for ASO drugs) (3), which adversely effects potency.
[ "2", "3", "4", "4", "3" ]
155
166
1
false
Furthermore, the PS modification reduces affinity for the target RNA (the ultimate biological receptor for ASO drugs), which adversely effects potency.
[ "3" ]
Furthermore, the PS modification reduces affinity for the target RNA (the ultimate biological receptor for ASO drugs), which adversely effects potency.
true
true
true
true
true
30
2
INTRODUCTION
1
5
[ "b5", "b6" ]
17,182,632
pmid-15205459|pmid-8390996
In order to improve upon the first generation ASO drugs, many different modifications to the core nucleoside monomer unit of the ASO have been evaluated for their effects on affinity for complementary RNA, nuclease resistance and ASO potency.
[ "5", "6" ]
242
167
0
false
In order to improve upon the first generation ASO drugs, many different modifications to the core nucleoside monomer unit of the ASO have been evaluated for their effects on affinity for complementary RNA, nuclease resistance and ASO potency.
[]
In order to improve upon the first generation ASO drugs, many different modifications to the core nucleoside monomer unit of the ASO have been evaluated for their effects on affinity for complementary RNA, nuclease resistance and ASO potency.
true
true
true
true
true
31
2
INTRODUCTION
1
5
[ "b5", "b6" ]
17,182,632
pmid-15205459|pmid-8390996
Most of the modifications which enhance affinity and nuclease resistance, in particular the 2′-substituted nucleosides, also limit the ability of the ASO to support RNase H-mediated cleavage of the targeted RNA (5).
[ "5", "6" ]
215
168
1
false
Most of the modifications which enhance affinity and nuclease resistance, in particular the 2′-substituted nucleosides, also limit the ability of the ASO to support RNase H-mediated cleavage of the targeted RNA.
[ "5" ]
Most of the modifications which enhance affinity and nuclease resistance, in particular the 2′-substituted nucleosides, also limit the ability of the ASO to support RNase H-mediated cleavage of the targeted RNA.
true
true
true
true
true
31
2
INTRODUCTION
1
5
[ "b5", "b6" ]
17,182,632
pmid-15205459|pmid-8390996
Efforts to optimize the design of ASOs to retain the beneficial properties of 2′-modifications, yet maintain RNase H activity have led to the development of chimeric oligonucleotide designs which employ higher affinity 2′-substituted nucleosides combined with DNA regions which support RNase H activity.
[ "5", "6" ]
303
169
0
false
Efforts to optimize the design of ASOs to retain the beneficial properties of 2′-modifications, yet maintain RNase H activity have led to the development of chimeric oligonucleotide designs which employ higher affinity 2′-substituted nucleosides combined with DNA regions which support RNase H activity.
[]
Efforts to optimize the design of ASOs to retain the beneficial properties of 2′-modifications, yet maintain RNase H activity have led to the development of chimeric oligonucleotide designs which employ higher affinity 2′-substituted nucleosides combined with DNA regions which support RNase H activity.
true
true
true
true
true
31
2
INTRODUCTION
1
6
[ "b5", "b6" ]
17,182,632
pmid-15205459|pmid-8390996
There are several designs for such chimeric oligonucleotides with ‘gapmer’ designs being most common in which a central DNA region of 7–14 nt is flanked on the 5′ and 3′ ends by 2–6 2′-modifications (Figure 1a) (6).
[ "5", "6" ]
215
170
1
false
There are several designs for such chimeric oligonucleotides with ‘gapmer’ designs being most common in which a central DNA region of 7–14 nt is flanked on the 5′ and 3′ ends by 2–6 2′-modifications (Figure 1a).
[ "6" ]
There are several designs for such chimeric oligonucleotides with ‘gapmer’ designs being most common in which a central DNA region of 7–14 nt is flanked on the 5′ and 3′ ends by 2–6 2′-modifications (Figure 1a).
true
true
true
true
true
31
3
INTRODUCTION
0
null
null
17,182,632
pmid-14963330|pmid-12667443|pmid-10749144
(a) Gap design of current generation of ASO therapeutics having 2′-modified ‘wings’ at the 3′ and 5′ ends flanking a central 2′-deoxy gap region.
null
145
171
0
false
null
null
(a) Gap design of current generation of ASO therapeutics having 2′-modified ‘wings’ at the 3′ and 5′ ends flanking a central 2′-deoxy gap region.
false
false
true
true
false
32
3
INTRODUCTION
0
null
null
17,182,632
pmid-14963330|pmid-12667443|pmid-10749144
(b) Structures of MOE and LNA nucleosides.
null
42
172
0
false
null
null
(b) Structures of MOE and LNA nucleosides.
false
false
true
true
false
32
4
INTRODUCTION
1
7
[ "b7", "b8", "b9", "b10", "b11", "b13", "b14", "b15", "b15", "b19", "b20", "b20", "b22" ]
17,182,632
NA|pmid-10360355|pmid-9880552|NA|pmid-11181921|pmid-14570775|pmid-10932156|pmid-11160622|pmid-11160622|pmid-15716585|pmid-17030687|pmid-17030687|pmid-12438559|pmid-15625915|pmid-10360355
The most advanced second generation antisense designs are 2′-O-methoxyethylribose (7) (MOE) gapmer oligonucleotides (Figure 1).
[ "7", "8", "9", "10", "11", "13", "14", "15", "15", "19", "20", "20", "22" ]
127
173
1
false
The most advanced second generation antisense designs are 2′-O-methoxyethylribose (MOE) gapmer oligonucleotides (Figure 1).
[ "7" ]
The most advanced second generation antisense designs are 2′-O-methoxyethylribose (MOE) gapmer oligonucleotides (Figure 1).
true
true
true
true
true
33
4
INTRODUCTION
1
8
[ "b7", "b8", "b9", "b10", "b11", "b13", "b14", "b15", "b15", "b19", "b20", "b20", "b22" ]
17,182,632
NA|pmid-10360355|pmid-9880552|NA|pmid-11181921|pmid-14570775|pmid-10932156|pmid-11160622|pmid-11160622|pmid-15716585|pmid-17030687|pmid-17030687|pmid-12438559|pmid-15625915|pmid-10360355
MOE modified ASOs show increased affinity toward a complementary RNA, and are highly resistant toward degradation by nucleases (8).
[ "7", "8", "9", "10", "11", "13", "14", "15", "15", "19", "20", "20", "22" ]
131
174
1
false
MOE modified ASOs show increased affinity toward a complementary RNA, and are highly resistant toward degradation by nucleases.
[ "8" ]
MOE modified ASOs show increased affinity toward a complementary RNA, and are highly resistant toward degradation by nucleases.
true
true
true
true
true
33
4
INTRODUCTION
1
7
[ "b7", "b8", "b9", "b10", "b11", "b13", "b14", "b15", "b15", "b19", "b20", "b20", "b22" ]
17,182,632
NA|pmid-10360355|pmid-9880552|NA|pmid-11181921|pmid-14570775|pmid-10932156|pmid-11160622|pmid-11160622|pmid-15716585|pmid-17030687|pmid-17030687|pmid-12438559|pmid-15625915|pmid-10360355
These improvements result in a substantial (>20-fold) increase in oligonucleotide potency in cell culture, relative to first generation ASOs (9,10).
[ "7", "8", "9", "10", "11", "13", "14", "15", "15", "19", "20", "20", "22" ]
148
175
0
false
These improvements result in a substantial increase in oligonucleotide potency in cell culture, relative to first generation ASOs.
[ ">20-fold", "9,10" ]
These improvements result in a substantial increase in oligonucleotide potency in cell culture, relative to first generation ASOs.
true
true
true
true
true
33
4
INTRODUCTION
1
7
[ "b7", "b8", "b9", "b10", "b11", "b13", "b14", "b15", "b15", "b19", "b20", "b20", "b22" ]
17,182,632
NA|pmid-10360355|pmid-9880552|NA|pmid-11181921|pmid-14570775|pmid-10932156|pmid-11160622|pmid-11160622|pmid-15716585|pmid-17030687|pmid-17030687|pmid-12438559|pmid-15625915|pmid-10360355
In animals, MOE ASOs have been shown to possess both excellent pharmacokinetic properties (11–13) and robust pharmacological activity (14,15).
[ "7", "8", "9", "10", "11", "13", "14", "15", "15", "19", "20", "20", "22" ]
142
176
0
false
In animals, MOE ASOs have been shown to possess both excellent pharmacokinetic properties and robust pharmacological activity.
[ "11–13", "14,15" ]
In animals, MOE ASOs have been shown to possess both excellent pharmacokinetic properties and robust pharmacological activity.
true
true
true
true
true
33
4
INTRODUCTION
1
7
[ "b7", "b8", "b9", "b10", "b11", "b13", "b14", "b15", "b15", "b19", "b20", "b20", "b22" ]
17,182,632
NA|pmid-10360355|pmid-9880552|NA|pmid-11181921|pmid-14570775|pmid-10932156|pmid-11160622|pmid-11160622|pmid-15716585|pmid-17030687|pmid-17030687|pmid-12438559|pmid-15625915|pmid-10360355
Furthermore, the selective inhibition of gene expression with MOE ASOs elicits positive pharmacological activity in several animal models of human disease when given systemically with clinically relevant routes and schedules of administration (15–19).
[ "7", "8", "9", "10", "11", "13", "14", "15", "15", "19", "20", "20", "22" ]
251
177
0
false
Furthermore, the selective inhibition of gene expression with MOE ASOs elicits positive pharmacological activity in several animal models of human disease when given systemically with clinically relevant routes and schedules of administration.
[ "15–19" ]
Furthermore, the selective inhibition of gene expression with MOE ASOs elicits positive pharmacological activity in several animal models of human disease when given systemically with clinically relevant routes and schedules of administration.
true
true
true
true
true
33
4
INTRODUCTION
1
7
[ "b7", "b8", "b9", "b10", "b11", "b13", "b14", "b15", "b15", "b19", "b20", "b20", "b22" ]
17,182,632
NA|pmid-10360355|pmid-9880552|NA|pmid-11181921|pmid-14570775|pmid-10932156|pmid-11160622|pmid-11160622|pmid-15716585|pmid-17030687|pmid-17030687|pmid-12438559|pmid-15625915|pmid-10360355
These beneficial properties have translated to human therapeutics.
[ "7", "8", "9", "10", "11", "13", "14", "15", "15", "19", "20", "20", "22" ]
66
178
0
false
These beneficial properties have translated to human therapeutics.
[]
These beneficial properties have translated to human therapeutics.
true
true
true
true
true
33
4
INTRODUCTION
1
7
[ "b7", "b8", "b9", "b10", "b11", "b13", "b14", "b15", "b15", "b19", "b20", "b20", "b22" ]
17,182,632
NA|pmid-10360355|pmid-9880552|NA|pmid-11181921|pmid-14570775|pmid-10932156|pmid-11160622|pmid-11160622|pmid-15716585|pmid-17030687|pmid-17030687|pmid-12438559|pmid-15625915|pmid-10360355
For example, a MOE ASO targeting ApoB has shown a dose-dependent reduction of target protein concurrent with lowering of LDL cholesterol.
[ "7", "8", "9", "10", "11", "13", "14", "15", "15", "19", "20", "20", "22" ]
137
179
0
false
For example, a MOE ASO targeting ApoB has shown a dose-dependent reduction of target protein concurrent with lowering of LDL cholesterol.
[]
For example, a MOE ASO targeting ApoB has shown a dose-dependent reduction of target protein concurrent with lowering of LDL cholesterol.
true
true
true
true
true
33
4
INTRODUCTION
1
20
[ "b7", "b8", "b9", "b10", "b11", "b13", "b14", "b15", "b15", "b19", "b20", "b20", "b22" ]
17,182,632
NA|pmid-10360355|pmid-9880552|NA|pmid-11181921|pmid-14570775|pmid-10932156|pmid-11160622|pmid-11160622|pmid-15716585|pmid-17030687|pmid-17030687|pmid-12438559|pmid-15625915|pmid-10360355
Doses as low as 100 mg per week produced statistically significant reductions in ApoB protein, and a dose of 200 mg per week reduced serum ApoB protein by 50% (20).
[ "7", "8", "9", "10", "11", "13", "14", "15", "15", "19", "20", "20", "22" ]
164
180
1
false
Doses as low as 100 mg per week produced statistically significant reductions in ApoB protein, and a dose of 200 mg per week reduced serum ApoB protein by 50%.
[ "20" ]
Doses as low as 100 mg per week produced statistically significant reductions in ApoB protein, and a dose of 200 mg per week reduced serum ApoB protein by 50%.
true
true
true
true
true
33
4
INTRODUCTION
1
7
[ "b7", "b8", "b9", "b10", "b11", "b13", "b14", "b15", "b15", "b19", "b20", "b20", "b22" ]
17,182,632
NA|pmid-10360355|pmid-9880552|NA|pmid-11181921|pmid-14570775|pmid-10932156|pmid-11160622|pmid-11160622|pmid-15716585|pmid-17030687|pmid-17030687|pmid-12438559|pmid-15625915|pmid-10360355
Furthermore, to date MOE ASOs have an excellent safety record in human clinical trials (20–22).
[ "7", "8", "9", "10", "11", "13", "14", "15", "15", "19", "20", "20", "22" ]
95
181
0
false
Furthermore, to date MOE ASOs have an excellent safety record in human clinical trials.
[ "20–22" ]
Furthermore, to date MOE ASOs have an excellent safety record in human clinical trials.
true
true
true
true
true
33
5
INTRODUCTION
1
23
[ "b23", "b24", "b25", "b26", "b27" ]
17,182,632
NA|NA|NA|NA|NA|pmid-16717090|pmid-11555640|pmid-11032824|pmid-8995434
The improvement in potency of MOE ASOs has, in part, been attributed to the increased affinity for target mRNA conferred by the MOE modification.
[ "23", "24", "25", "26", "27" ]
145
182
0
false
The improvement in potency of MOE ASOs has, in part, been attributed to the increased affinity for target mRNA conferred by the MOE modification.
[]
The improvement in potency of MOE ASOs has, in part, been attributed to the increased affinity for target mRNA conferred by the MOE modification.
true
true
true
true
true
34
5
INTRODUCTION
1
23
[ "b23", "b24", "b25", "b26", "b27" ]
17,182,632
NA|NA|NA|NA|NA|pmid-16717090|pmid-11555640|pmid-11032824|pmid-8995434
Although MOE provides a substantial improvement in affinity, bicyclic nucleoside modifications such as 2′,4′-methylene bridged nucleic acids (23,24) commonly called ‘locked nucleic acid’ (LNA, Figure 1b) (25,26) have been shown to provide a further increase in affinity.
[ "23", "24", "25", "26", "27" ]
270
183
0
false
Although MOE provides a substantial improvement in affinity, bicyclic nucleoside modifications such as 2′,4′-methylene bridged nucleic acids commonly called ‘locked nucleic acid’ (LNA, Figure 1b) have been shown to provide a further increase in affinity.
[ "23,24", "25,26" ]
Although MOE provides a substantial improvement in affinity, bicyclic nucleoside modifications such as 2′,4′-methylene bridged nucleic acids commonly called ‘locked nucleic acid’ (LNA, Figure 1b) have been shown to provide a further increase in affinity.
true
true
true
true
true
34
5
INTRODUCTION
1
27
[ "b23", "b24", "b25", "b26", "b27" ]
17,182,632
NA|NA|NA|NA|NA|pmid-16717090|pmid-11555640|pmid-11032824|pmid-8995434
LNA containing chimeric ASOs are just entering human clinical trials, and have recently been shown to inhibit growth in human tumor xenograft models (27).
[ "23", "24", "25", "26", "27" ]
154
184
1
false
LNA containing chimeric ASOs are just entering human clinical trials, and have recently been shown to inhibit growth in human tumor xenograft models.
[ "27" ]
LNA containing chimeric ASOs are just entering human clinical trials, and have recently been shown to inhibit growth in human tumor xenograft models.
true
true
true
true
true
34
5
INTRODUCTION
1
23
[ "b23", "b24", "b25", "b26", "b27" ]
17,182,632
NA|NA|NA|NA|NA|pmid-16717090|pmid-11555640|pmid-11032824|pmid-8995434
However, studies of the effects of LNA ASOs versus endogenous targets in liver, a tissue where antisense effects have been extensively characterized, have not been reported to date.
[ "23", "24", "25", "26", "27" ]
181
185
0
false
However, studies of the effects of LNA ASOs versus endogenous targets in liver, a tissue where antisense effects have been extensively characterized, have not been reported to date.
[]
However, studies of the effects of LNA ASOs versus endogenous targets in liver, a tissue where antisense effects have been extensively characterized, have not been reported to date.
true
true
true
true
true
34
5
INTRODUCTION
1
23
[ "b23", "b24", "b25", "b26", "b27" ]
17,182,632
NA|NA|NA|NA|NA|pmid-16717090|pmid-11555640|pmid-11032824|pmid-8995434
In order to investigate whether LNA ASOs have the potential to improve upon MOE based ASO therapeutics, we directly compared the potency and therapeutic index of several designs of MOE and LNA containing ASOs in cell culture and in rodent liver after systemic administration.
[ "23", "24", "25", "26", "27" ]
275
186
0
false
In order to investigate whether LNA ASOs have the potential to improve upon MOE based ASO therapeutics, we directly compared the potency and therapeutic index of several designs of MOE and LNA containing ASOs in cell culture and in rodent liver after systemic administration.
[]
In order to investigate whether LNA ASOs have the potential to improve upon MOE based ASO therapeutics, we directly compared the potency and therapeutic index of several designs of MOE and LNA containing ASOs in cell culture and in rodent liver after systemic administration.
true
true
true
true
true
34
5
INTRODUCTION
1
23
[ "b23", "b24", "b25", "b26", "b27" ]
17,182,632
NA|NA|NA|NA|NA|pmid-16717090|pmid-11555640|pmid-11032824|pmid-8995434
Our results indicate that although LNA modified ASOs have the potential to improve potency, they impose a significant risk of hepatotoxicity which must be considered when designing LNA containing antisense therapeutics.
[ "23", "24", "25", "26", "27" ]
219
187
0
false
Our results indicate that although LNA modified ASOs have the potential to improve potency, they impose a significant risk of hepatotoxicity which must be considered when designing LNA containing antisense therapeutics.
[]
Our results indicate that although LNA modified ASOs have the potential to improve potency, they impose a significant risk of hepatotoxicity which must be considered when designing LNA containing antisense therapeutics.
true
true
true
true
true
34
0
DISCUSSION
0
null
null
17,182,632
pmid-11931781
The main goal of our study was to determine if LNA containing ASOs would improve potency and therapeutic index relative to the current generation of MOE ASOs.
null
158
188
0
false
null
null
The main goal of our study was to determine if LNA containing ASOs would improve potency and therapeutic index relative to the current generation of MOE ASOs.
true
true
true
true
true
35
0
DISCUSSION
0
null
null
17,182,632
pmid-11931781
Our assumption entering the work was that an improvement in potency would yield an improved therapeutic index, since it has been generally believed that many of the toxicities of ASOs are due to class effects as a result of the PS backbone.
null
240
189
0
false
null
null
Our assumption entering the work was that an improvement in potency would yield an improved therapeutic index, since it has been generally believed that many of the toxicities of ASOs are due to class effects as a result of the PS backbone.
true
true
true
true
true
35
0
DISCUSSION
0
null
null
17,182,632
pmid-11931781
However, this proved not to be the case with the LNA ASOs studied.
null
66
190
0
false
null
null
However, this proved not to be the case with the LNA ASOs studied.
true
true
true
true
true
35
1
DISCUSSION
0
null
null
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
Our results clearly demonstrate the ability to improve potency with some, but not all, LNA containing ASO designs, particularly for the TRADD and PTEN targets.
null
159
191
0
false
null
null
Our results clearly demonstrate the ability to improve potency with some, but not all, LNA containing ASO designs, particularly for the TRADD and PTEN targets.
true
true
true
true
true
36
1
DISCUSSION
0
null
null
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
This improvement was occasionally fairly large, as much as 5–10-fold, and was most pronounced for LNA ASOs of length 18–20 nt which contained 2–3 LNA residues at each end.
null
171
192
0
false
null
null
This improvement was occasionally fairly large, as much as 5–10-fold, and was most pronounced for LNA ASOs of length 18–20 nt which contained 2–3 LNA residues at each end.
true
true
true
true
true
36
1
DISCUSSION
0
null
null
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
As little as 0.75–1 μmol/kg (∼5–6 mg/kg) of these ASOs given twice weekly for 3 weeks reduced target mRNA by 80%.
null
113
193
0
false
null
null
As little as 0.75–1 μmol/kg (∼5–6 mg/kg) of these ASOs given twice weekly for 3 weeks reduced target mRNA by 80%.
true
true
true
true
true
36
1
DISCUSSION
0
null
null
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
The optimal LNA ASO design in vivo appeared to be different than that observed in cell culture, where we found that two LNA nucleotides on each end of the ASO provided the largest potency increase.
null
197
194
0
false
null
null
The optimal LNA ASO design in vivo appeared to be different than that observed in cell culture, where we found that two LNA nucleotides on each end of the ASO provided the largest potency increase.
true
true
true
true
true
36
1
DISCUSSION
0
null
null
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
This is evident from a comparison of 3b and 4b, where 3b was 5-fold more potent in cell culture, but less potent in vivo.
null
121
195
0
false
null
null
This is evident from a comparison of 3b and 4b, where 3b was 5-fold more potent in cell culture, but less potent in vivo.
true
true
true
true
true
36
1
DISCUSSION
0
null
null
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
It is unlikely that the improved potency is due solely to increased affinity of the ASO for target RNA, as adding more LNA to the ASO actually decreased potency both in cell culture and in vivo (compare 2b and 3b with 1b).
null
222
196
0
false
null
null
It is unlikely that the improved potency is due solely to increased affinity of the ASO for target RNA, as adding more LNA to the ASO actually decreased potency both in cell culture and in vivo (compare 2b and 3b with 1b).
true
true
true
true
true
36
1
DISCUSSION
0
null
null
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
Because of these trends, combined with the lack of increased distribution of LNA ASOs to liver, it is likely that other factors are contributing to the increased potency of LNA modified ASOs observed in our studies.
null
215
197
0
false
null
null
Because of these trends, combined with the lack of increased distribution of LNA ASOs to liver, it is likely that other factors are contributing to the increased potency of LNA modified ASOs observed in our studies.
true
true
true
true
true
36
1
DISCUSSION
0
null
null
17,182,632
pmid-10805163|pmid-2836790|NA|NA|pmid-2836790
Additional investigations will be required to further characterize the nature of this potency improvement.
null
106
198
0
false
null
null
Additional investigations will be required to further characterize the nature of this potency improvement.
true
true
true
true
true
36
2
DISCUSSION
0
null
null
17,182,632
pmid-15205459|pmid-8390996
Unfortunately, the increased activity of LNA containing ASOs was also accompanied by the observation of severe hepatotoxicity, such that there was little or no separation between toxic doses and those that produced significant levels of mRNA reduction.
null
252
199
0
false
null
null
Unfortunately, the increased activity of LNA containing ASOs was also accompanied by the observation of severe hepatotoxicity, such that there was little or no separation between toxic doses and those that produced significant levels of mRNA reduction.
true
true
true
true
true
37