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char = .;code = 46
result sql = Cooperative interaction of arginine-19 and the N-terminal signaling domain in the affinity and potency of parathyroid hormone.
Cooperative interaction of arginine-19 and the N-terminal signaling domain in the affinity and potency of parathyroid hormone.
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char = k;code = 107
char = i;code = 105
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char = m;code = 109
char = o;code = 111
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = N;code = 78
char = -;code = 45
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = u;code = 117
char = s;code = 115
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char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = f;code = 102
char = i;code = 105
char = r;code = 114
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = i;code = 105
char = d;code = 100
char = u;code = 117
char = e;code = 101
char = ;code = 32
char = 1;code = 49
char = 9;code = 57
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = j;code = 106
char = u;code = 117
char = x;code = 120
char = t;code = 116
char = a;code = 97
char = m;code = 109
char = e;code = 101
char = m;code = 109
char = b;code = 98
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = r;code = 114
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = P;code = 80
char = T;code = 84
char = H;code = 72
char = 1;code = 49
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = p;code = 112
char = a;code = 97
char = c;code = 99
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = P;code = 80
char = G;code = 71
char = 5;code = 53
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = o;code = 111
char = g;code = 103
char = u;code = 117
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = s;code = 115
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = P;code = 80
char = T;code = 84
char = H;code = 72
char = (;code = 40
char = 1;code = 49
char = -;code = 45
char = 3;code = 51
char = 4;code = 52
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = i;code = 105
char = d;code = 100
char = u;code = 117
char = e;code = 101
char = ;code = 32
char = 1;code = 49
char = 0;code = 48
char = -;code = 45
char = 1;code = 49
char = 4;code = 52
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = g;code = 103
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = P;code = 80
char = T;code = 84
char = H;code = 72
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = v;code = 118
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = j;code = 106
char = u;code = 117
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = m;code = 109
char = p;code = 112
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = k;code = 107
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = f;code = 102
char = u;code = 117
char = n;code = 110
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = o;code = 111
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = b;code = 98
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = f;code = 102
char = u;code = 117
char = r;code = 114
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = u;code = 117
char = c;code = 99
char = t;code = 116
char = u;code = 117
char = r;code = 114
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = e;code = 101
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = g;code = 103
char = l;code = 108
char = y;code = 121
char = c;code = 99
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char = n;code = 110
char = e;code = 101
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = k;code = 107
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = i;code = 105
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = P;code = 80
char = T;code = 84
char = H;code = 72
char = 1;code = 49
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = c;code = 99
char = i;code = 105
char = r;code = 114
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = r;code = 114
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char = d;code = 100
char = i;code = 105
char = c;code = 99
char = h;code = 104
char = r;code = 114
char = o;code = 111
char = i;code = 105
char = s;code = 115
char = m;code = 109
char = ,;code = 44
char = ;code = 32
char = (;code = 40
char = 1;code = 49
char = );code = 41
char = H;code = 72
char = ;code = 32
char = N;code = 78
char = M;code = 77
char = R;code = 82
char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = t;code = 116
char = e;code = 101
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char = s;code = 115
char = i;code = 105
char = v;code = 118
char = e;code = 101
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char = l;code = 108
char = i;code = 105
char = g;code = 103
char = a;code = 97
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char = d;code = 100
char = /;code = 47
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = e;code = 101
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = d;code = 100
char = y;code = 121
char = n;code = 110
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = s;code = 115
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = m;code = 109
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = u;code = 117
char = c;code = 99
char = t;code = 116
char = u;code = 117
char = r;code = 114
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = t;code = 116
char = a;code = 97
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = e;code = 101
char = a;code = 97
char = r;code = 114
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = l;code = 108
char = l;code = 108
char = u;code = 117
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = h;code = 104
char = e;code = 101
char = l;code = 108
char = i;code = 105
char = x;code = 120
char = -;code = 45
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = i;code = 105
char = l;code = 108
char = i;code = 105
char = z;code = 122
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = A;code = 65
char = r;code = 114
char = g;code = 103
char = (;code = 40
char = 1;code = 49
char = 9;code = 57
char = );code = 41
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = b;code = 98
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = t;code = 116
char = u;code = 117
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = p;code = 112
char = a;code = 97
char = g;code = 103
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = N;code = 78
char = -;code = 45
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = f;code = 102
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
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char = 1;code = 49
char = 9;code = 57
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = l;code = 108
char = y;code = 121
char = c;code = 99
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = k;code = 107
char = e;code = 101
char = r;code = 114
char = .;code = 46
char = ;code = 32
char = O;code = 79
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = s;code = 115
char = e;code = 101
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char = s;code = 115
char = t;code = 116
char = u;code = 117
char = d;code = 100
char = i;code = 105
char = e;code = 101
char = s;code = 115
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char = s;code = 115
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char = g;code = 103
char = g;code = 103
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
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char = a;code = 97
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char = a;code = 97
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char = p;code = 112
char = h;code = 104
char = a;code = 97
char = -;code = 45
char = h;code = 104
char = e;code = 101
char = l;code = 108
char = i;code = 105
char = x;code = 120
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = f;code = 102
char = e;code = 101
char = r;code = 114
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = i;code = 105
char = d;code = 100
char = u;code = 117
char = e;code = 101
char = ;code = 32
char = 1;code = 49
char = 5;code = 53
char = -;code = 45
char = 2;code = 50
char = 0;code = 48
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = g;code = 103
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = P;code = 80
char = T;code = 84
char = H;code = 72
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = i;code = 105
char = d;code = 100
char = u;code = 117
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = 1;code = 49
char = 0;code = 48
char = -;code = 45
char = 1;code = 49
char = 4;code = 52
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = q;code = 113
char = u;code = 117
char = i;code = 105
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = f;code = 102
char = u;code = 117
char = l;code = 108
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = c;code = 99
char = y;code = 121
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = h;code = 104
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
result sql = Residue 19 of parathyroid hormone (PTH) plays a unique role in the interaction process with the PTH1 receptor. A Glu(19) --> Arg(19) substitution, based on the Arg(19) of the PTH-related protein (PTHrP), increases the binding affinity when incorporated into the N-terminus of PTH [i.e., PTH(1-20)] and has no effect when introduced into the C-terminus of PTH [i.e., PTH(15-31)]. To explore Arg(19) and the midregion (residues 10-15), we designed the novel PTH scaffold peptide, PG5, which has the PTH(1-9) domain linked to the PTH(15-31) segment via a pentaglycine spacer. Substitution of Glu(19) with Arg(19) in PG5 resulted in a 9-fold increase in binding affinity. Additionally, the substitution enhanced stimulated cAMP formation in cells expressing PTH1-delNt, a PTH1 receptor construct lacking most of the N-terminus, confirming that residue 19 is interacting with the juxtamembrane portion of PTH1. The binding and signaling capacities of the PG5 analogues were diminished relative to those of PTH(1-34), indicating that the residue 10-14 region of PTH provides more than just a simple linker function. To probe this further, the structural consequences of the glycine linker and its interaction with PTH1 were examined by circular dichroism, (1)H NMR, and extensive ligand/receptor molecular dynamics simulations. The structural data clearly illustrate the helix-stabilizing effect of Arg(19) substitution propagating N-terminally from position 19 to the pentaglycine linker. Overall, these studies suggest that an alpha-helix is the preferred conformation for the residue 15-20 region of PTH and that residues 10-14 are also required for full affinity and potency of the hormone.

Publication: Biochemistry 2004 Mar 30 ;43(12)::3459-70.
Publication Date: 2004 Mar 30
Study Author(s): Tsomaia, Natia;Shimizu, Masaru;Shimizu, Naoto;Gardella, Thomas J;Mierke, Dale F;
Institution: Department of Molecular Pharmacology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA.
Shortcut link to this study:
Residue 19 of parathyroid hormone (PTH) plays a unique role in the interaction process with the PTH1 receptor. A Glu(19) --> Arg(19) substitution, based on the Arg(19) of the PTH-related protein (PTHrP), increases the binding affinity when incorporated into the N-terminus of PTH [i.e., PTH(1-20)] and has no effect when introduced into the C-terminus of PTH [i.e., PTH(15-31)]. To explore Arg(19) and the midregion (residues 10-15), we designed the novel PTH scaffold peptide, PG5, which has the PTH(1-9) domain linked to the PTH(15-31) segment via a pentaglycine spacer. Substitution of Glu(19) with Arg(19) in PG5 resulted in a 9-fold increase in binding affinity. Additionally, the substitution enhanced stimulated cAMP formation in cells expressing PTH1-delNt, a PTH1 receptor construct lacking most of the N-terminus, confirming that residue 19 is interacting with the juxtamembrane portion of PTH1. The binding and signaling capacities of the PG5 analogues were diminished relative to those of PTH(1-34), indicating that the residue 10-14 region of PTH provides more than just a simple linker function. To probe this further, the structural consequences of the glycine linker and its interaction with PTH1 were examined by circular dichroism, (1)H NMR, and extensive ligand/receptor molecular dynamics simulations. The structural data clearly illustrate the helix-stabilizing effect of Arg(19) substitution propagating N-terminally from position 19 to the pentaglycine linker. Overall, these studies suggest that an alpha-helix is the preferred conformation for the residue 15-20 region of PTH and that residues 10-14 are also required for full affinity and potency of the hormone.
PMID: 15035617

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