Middendorf TR , Aldrich RW .

EY01543 NEI NIH HHS , NS23294 NINDS NIH HHS

	Figure 1. Effect of UV light on currents through RET channels activated by saturating and low concentrations of ligand. (A and B) Current in response to 0 to +50 mV potential steps in the presence of: (A) saturating (1 mM) cGMP, and (B) 2 μM cGMP. Cyclic GMP-dependent current amplitudes before UV and after cumulative doses of 4.91 and 9.82 × 109 photons · μm−2 were: for 1 mM cGMP: 2,110 ± 4, 980 ± 5, and 297 ± 9 pA; and for 2 μM cGMP: 7 ± 2, 22 ± 3, and 40 ± 4 pA. Note the difference in vertical scales for traces in A and B, which are from the same patch. (C) Effect of UV light on RET channel cGMP dose–response relation. The cGMP-activated current (I) divided by the maximal current in 1 mM cGMP before irradiation (Imax)is plotted as a function of cyclic GMP concentration on double logarithmic coordinates. Relations were measured before UV exposure (•), and after cumulative doses of 4.91 × 109 photons · μm−2 (□), and 9.82 × 109 photons · μm−2 (▵). The continuous curves show fits to the results using the Hill equation ( of the text). The Hill coefficient, h, and the apparent affinity, K1/2, were: before UV exposure, h = 1.85 and K1/2 = 70.2 μM; after 4.91 × 109 photons · μm−2, h = 0.97 and K1/2 = 125 μM; after 9.82 × 109 photons · μm−2, h = 0.53 and K1/2 = 149 μM. Results from same patch as in A and B. The patch was irradiated with 280 nm UV in the absence of cGMP. The light intensity at the patch was 1.96 × 108 photons · μm−2 · s−1.
	Figure 2. Effect of UV light on currents through rat olfactory CNG (OLF) channels activated by saturating and low concentrations of ligand. (A and B) Currents in response to potential steps from 0 to +50 mV in the presence of (A) saturating (1 mM) cGMP, and (B) 0.2 μM cGMP. Cyclic GMP–dependent current amplitudes before UV and after cumulative doses of 4.91 × 109 and 1.96 × 1010 photons · μm−2 were: for 1 mM cGMP: 5,187 ± 12, 4,899 ± 9, and 2,210 ± 5 pA; and for 0.2 μM cGMP: 36.8 ± 3.3, 46.0 ± 4.0, and 80 ± 7 pA. Note the difference in vertical scales for traces in A and B, which are from the same patch. (C) Effect of UV light on OLF channel cGMP dose–response relation. The cGMP-activated current before UV exposure (•), and after cumulative doses of 4.91 × 109 (□) and 1.96 × 1010 (▵) photons · μm−2, divided by the maximal current in 1 mM cGMP before irradiation, are plotted as a function of cGMP concentration on double logarithmic coordinates. The continuous curves show fits to the results using the Hill equation (). The Hill coefficient, h, and the half-saturating cGMP concentration, K1/2, were: before UV exposure, h = 1.90 and K1/2 = 2.81 μM; after 4.91 × 109 photons · μm−2, h = 1.44 and K1/2 = 4.87 μM; and after 96 × 1010 photons · μm−2, h = 0.72 and K1/2 = 18.7 μM. Results are from same patch as in A and B. The patch was irradiated with 280 nm UV in the absence of cGMP.
	Figure 3. UV effect on OLF channels activated by different, initially saturating cGMP concentrations. (A) UV dose–response relations for OLF channels activated by 10 μM cGMP (open symbols, five experiments), 100 μM cGMP (gray symbols, two experiments), and 1,000 μM cGMP (black symbols, seven experiments). D1/2, the UV dose that reduced the current amplitude to one half its initial value, was estimated for each experiment by fitting the UV dose–response relation with the all-or-none model (). The points from each experiment were then shifted along the abscissa so that the D1/2 value of the shifted results was equal to the average D1/2 value of the unshifted results for all experiments at the same cGMP concentration. Different symbols represent separate experiments. Continuous curves are fits to the pooled results for each concentration using . Patches were irradiated with 280 nm UV in the absence of cGMP. (B) Half-maximal UV dose in photons × 108 · μm−2, (squares), and slope factor (circles) from the fits in A, plotted as a function of cGMP concentration. The UV parameters are listed in Table .
	Figure 4. Energy additive model for channel current reduction by UV light. (A) Schematic showing the effect of modifying UV target residues on the standard free energy difference between open and closed channel states. The symbols Ok and Ck represent open and closed states of fully liganded channels with k modified target residues. ΔG 0(k) is the standard free energy difference between Ok and Ck, and ΔΔG 0(k) is the change in this free energy difference caused by modifying k targets. Since ΔΔG 0(k) is assumed to vary in linear proportion to k, the thermodynamic parameters are related as ΔG 0(k) = ΔG 0(0) + k · ΔΔG 0(1). (B–D) UV dose–response relations calculated using energy additive model. Smooth curves were calculated using for the following ΔG 0(0) values (RT units): −1.5 (dotted line), −3.0 (solid line), −4.6 (short-dashed line), −7.8 (medium-dashed line), and −9.9 (long-dashed line). These values correspond to the standard free energy differences for various channel/ligand combinations tested (Table ). ΔΔG 0(1) values were (RT units): (B) +40, (C) +4, and (D) +0.2. The top and bottom set of curves in each panel were calculated for the minimum (1) and maximum (10) possible number of tryptophan target residues per subunit.
	Figure 5. UV effects on currents through different CNG channels. (A) UV dose–response relations for RET and OLF channels activated by saturating (1 mM) cGMP. Fraction of current remaining is plotted as a function of the logarithm of the photon dose. Collected results from 10 experiments on RET channels (open symbols) and 7 experiments on OLF channels (solid symbols). Different symbols indicate separate experiments. (B) Same as in A, except results for each type of channel were shifted along the abscissa as in Fig. 3 A. Continuous curves are fits to the pooled results using of the text. D1/2 values and slope factors obtained from the fits are given in Table . Patches were irradiated with 280 nm UV in the absence of cGMP.
	Figure 7. UV effects on currents through CNG channels activated by different cyclic nucleotide ligands. (A) UV dose–response relations for RET channels activated by cAMP and cGMP. Results are from two patches. For both experiments, the patch current in saturating cAMP and in saturating cGMP solutions was measured after each UV exposure. Closed symbols are for cAMP, open symbols are for cGMP. Ligand concentrations were, for patch 1 (circles): cAMP, 3 mM, and cGMP, 1 mM; for patch 2 (squares): cAMP, 10 mM, and cGMP, 1 mM. Continuous curves show fits to the combined results for cAMP or cGMP using . The D1/2 and slope factors from the fits are given in Table . Pre-UV current amplitudes were: for patch 1, IcAMP = 1,603 pA and IcGMP = 1,926 pA; for patch 2, IcAMP = 3,311 pA and IcGMP = 4,251 pA. Bath solutions for all experiments in A contained 10 μM Ni2+ (see text). (B) UV dose–response relations for OLF channels activated by saturating (2 mM) cAMP or saturating (1 mM) cGMP. Results are from two patches. For each patch, currents were recorded before UV and after each UV dose in both cGMP and cAMP. Other experimental conditions were as in A, except Ni2+ was omitted from the bath solutions. Smooth curves are fits as in A. D1/2 and slope factors from the fits are given in Table . Pre-UV current amplitudes were: for patch 1 (circles), IcAMP = 4,652 pA and IcGMP = 4,742 pA; for patch 2 (squares), IcAMP = 359 pA and IcGMP = 365 pA. Patches in A and B were irradiated with 280 nm UV in the absence of cyclic nucleotides.
	Figure 6. Effects of divalent nickel ions on the UV dose–response relation and the ligand dose–response relations of RET channels. (A) UV dose–response relations for channels activated by 1 mM cGMP in the presence (closed symbols, 3 experiments) or absence (open symbols, 10 experiments) of 10 μM cytoplasmic Ni2+. Different symbols indicate separate experiments. Results were shifted along the abscissa as in Fig. 3 A. Continuous curves are fits to the combined results for cGMP or cGMP + Ni2+ using . D1/2 values and slope factors from the fits are given in Table . Channels were irradiated with 280 nm UV in the absence of cGMP. Since the washout of Ni2+ was extremely slow, it was present during irradiation when used. (B) Ligand dose–response relations of RET channels activated by cGMP (circles) and cAMP (squares) in the absence (open symbols) and presence (closed symbols) of 10 μM cytoplasmic Ni2+. Patch current is plotted as a function of ligand concentration on double logarithmic coordinates. Continuous curves are fits to the results using the Hill equation (). The Hill coefficients (h), half-saturating ligand concentrations (K1/2) and maximal currents [I max(0)] obtained from the fits were: for cGMP + Ni2+: h = 2.01, K1/2 = 4.10 μM, and Imax = 1,902 pA; for cGMP, h = 2.01, K1/2 = 69.9 μM, and Imax = 2,050 pA; for cAMP + Ni2+, h = 1.58, K1/2 = 398 μM, and Imax = 1,656 pA; for cAMP, h = 1.38, K1/2 = 1,595 μM, and Imax = 27 pA. Results in B were recorded for one of the patches in A before irradiation, and agree with published results (Gordon and Zagotta 1995a).
	Figure 8. Evidence for differential effects of UV light on RET and OLF channels. (A) UV dose–response relations for RET channels activated by: saturating (1 mM) cGMP (○, results from Fig. 5); 1 mM cGMP + 10 μM Ni2+ (▵, results from Fig. 6 A); and saturating (3 or 10 mM) cAMP + 10 μM Ni2+ (▴, results from Fig. 7 A). (B) UV dose–response relations for OLF channels activated by: saturating (1 mM) cGMP (□, results from Fig. 5); and saturating (2 mM) cAMP (▪, results from Fig. 7 B). The smooth curves in A and B are fits to the combined results for each channel/ligand combination using of the text. The D1/2 values and the slope factors obtained from the fits are listed in Table . The dashed curve is a reproduction of the fit in A to the results for RET channels activated by saturating cGMP+ Ni2+ (▵). (C) D1/2 values (in photons × 108 · μm−2) obtained from the fits to the UV dose–response relations in A and B, plotted as a function of the initial free energy difference between open and closed channel states, ΔG 0(0) (see Table ). (D) Slope factors obtained from the fits in A and B, plotted as a function of ΔG 0(0). Symbols in C and D correspond to the same channel/ligand pairs in A and B.
	Figure 9. Modeling of UV effect on CNG channel currents. (A and B) UV dose–response relations for: (A) RET and (B) OLF channels. Results are the same as in Fig. 8A and Fig. B. Relations were fit using the energy additive model () for all possible values of n, the number of UV target residues per channel subunit. The continuous curves show fits for n = 2; excellent fits (not shown) were also obtained for 3 ≤ n ≤ 10. The free energy cost of target modification, ΔΔG 0(1), was allowed to vary for the different channel/ligand pairs. The photochemical quantum yield, φ, was constrained to be the same for RET and OLF channels for all conditions studied. ΔG 0(0) values used in the fits are given in Table . (C) Free energy cost for target modification in CNG channels. ΔΔG 0(1) values obtained from the fits in A and B are plotted as a function of n. The solid lines connect the points. The average values of ΔΔG 0(1) for 2 ≤ n ≤ 10 (RT units) were: for RET/cGMP (○), 6.19 ± 0.03; for OLF/cGMP (□), 3.41 ± 0.11; for RET/cAMP (▴), 3.07 ± 0.04; and for OLF/cAMP (▪), 1.72 ± 0.05. (D) Quantum yield for target modification in CNG channels. Quantum yields (♦), obtained from the fits in A and B are plotted as a function of n. The smooth curve is a fit to the results using the relation φ = B/n, with the constant B = 0.02.
	Figure 12. UV effects on currents through CNG channel pore tryptophan mutants activated by different ligands. (A and B) UV dose–response relations for OLF/W332Y (A) and OLF/W332H (B) mutant channels activated by saturating cAMP (1 mM, solid symbols) or saturating cGMP (1 mM, open symbols). Collected results from three experiments in cAMP and eight experiments in cGMP for OLF/W332Y channels, and three experiments in cAMP and five experiments in cGMP for OLF/W332H channels. Different symbols represent separate experiments. Results from separate experiments on each channel/ligand pair were combined as described in Fig. 3 A. Continuous curves are fits to the combined results for each channel activated by cGMP or cAMP using . D1/2 values and slope factors from the fits are given in Table . Channels were irradiated with 280 nm UV in the absence of ligand.
	Figure 10. UV sensitivity and gating properties of CNG channels lacking a conserved pore tryptophan residue. (A and B) UV dose–response relations in saturating (1 mM) cGMP for OLF channels (open symbols, A and B, seven experiments), OLF/W332Y mutant channels (solid symbols, A, eight experiments), and OLF/W332H mutant channels (solid symbols, B, five experiments). Results from experiments on each type of channel were shifted along the abscissa as in Fig. 3 A. Different symbols represent separate experiments. Continuous curves are fits to the pooled results for each construct using . D1/2 values and slope factors from the fits are given in Table . Patches were irradiated with 280 nm UV in the absence of cGMP. (C) Cyclic GMP dose–response relations for OLF channels (open symbols, six experiments) and OLF/W332Y mutant channels (solid symbols, six experiments) before irradiation. The cGMP-activated current, I, divided by the maximal current in 1 mM cGMP, Imax, is plotted as a function of cGMP concentration on double logarithmic axes. Results from each experiment were shifted along the abscissa so that the half-saturating ligand concentration, K1/2, was equal to the average value of K1/2 for all experiments on the same channel. Different symbols represent separate experiments. Continuous curves are fits to the pooled results for each type of channel using the Hill equation (). The fitting parameters were: for OLF channels, h = 2.35 and K1/2 = 2.47 μM; for OLF/W332Y channels, h = 2.17 and K1/2 = 17.7 μM. (D) Relative efficacies of cAMP and cGMP for activating wild-type OLF, OLF/W332Y mutant, and OLF/W332H mutant channels. Ordinate is the ratio of the current amplitude in saturating cAMP (>3 mM) to that in saturating cGMP (1 mM). The current ratios, (mean ± SEM) and the number of experiments (in parentheses) were: for OLF, 1.01 ± 0.02 (4); for OLF/W332Y, 0.30 ± 0.05 (8); and for OLF/W332H, 0.45 ± 0.11 (5).
	Figure 11. Wavelength dependence of the UV effect on mutant CNG channels lacking a conserved pore tryptophan residue. (A and B) UV dose–response relations in saturating (1 mM) cGMP for (A) OLF/W332Y and (B) OLF/W332H mutant channels irradiated with 280 nm UV (solid symbols) or 300 nm UV (open symbols). Collected results from eight experiments at 280 nm and three experiments at 300 nm for OLF/W332Y, and five experiments at 280 nm and three experiments at 300 nm for OLF/W332H. Results were shifted along the abscissa as in Fig. 3 A. Different symbols represent separate experiments. Continuous curves are fits to the pooled results using . D1/2 values and slope factors from the fits are given in Table . Patches were irradiated in the absence of cGMP. (C) Wavelength dependence of photon absorption by tryptophan and tyrosine compared with wavelength dependence of CNG channel UV sensitivity. The left-hand ordinate, S280/S300, is the ratio of the channels' UV sensitivities at 280 and 300 nm (defined as the reciprocals of the corresponding D1/2 values). The UV sensitivity ratios were 15.9 ± 6.3 (mean ± SEM) for OLF/W332Y channels and 11.9 ± 4.5 for OLF/W332H channels. The UV sensitivity ratio of 17.1 ± 2.0 for wild-type RET channels (Middendorf et al. 2000) is shown also for comparison. The right-hand ordinate, A280/A300, is the ratio of the photon absorption probabilities in aqueous solution at 280 and 300 nm. The absorption probability ratios were 15.7 for tryptophan and 111 for tyrosine, and were computed from their absorption spectra using of Middendorf et al. 2000.
	Figure 13. Energy additive model for increase in channel open probability by UV light. (A) Schematic showing effect of modifying (−) targets (see text) on the standard free energy difference between the channels' open and closed states. Symbols are equivalent to those in Fig. 4. (B–D) UV dose–response relations calculated using energy additive model. Smooth curves were calculated using for the following ΔG 0(0) values (RT units): +7.0 (solid line), +5.7 (long-dashed line),+5.0 (medium-dashed line), and +3.9 (short-dashed line). ΔΔG 0(1) values (RT units) were: (B) −40; (C) −1; and (D) −0.1. The top and bottom set of curves in each panel were calculated for 1 and 10 (−) target residues per channel subunit, respectively.
	Figure 14. Opposite effects of UV light on currents through RET channels activated by saturating concentrations of cAMP and cGMP. (A) UV effect on current amplitude for RET channels activated by saturating (20 mM) cAMP. Current amplitudes were 17.2, 30.5, and 49.3 pA after cumulative UV doses of 0, 3.75 × 109 and 1.13 × 1010 photons · μm−2 at 280 nm. (B) UV effect on current amplitude for RET channels activated by saturating (1 mM) cGMP. Current amplitudes were 4,150, 2,660, and 883 pA after the same UV doses as in A. Note difference in vertical scales for traces in A and B, which are from the same patch. (C) UV dose–response relation for channels activated by saturating cAMP. Patch current in 20 mM cAMP (•) is plotted as a function of UV dose on a semilogarithmic scale. Solid lines connect the experimental points. (D) UV dose–response relation for channels activated by saturating cGMP. Patch current in 1 mM cGMP (○) for results in B is plotted as a function of UV dose on a semilogarithmic scale. Continuous curve is a fit to the results using with D1/2 = 3.75 × 109 photons · μm−2 and n* = 1.6. Results from C (•) are shown on the same scale for comparison. Note the difference in vertical scales for C and D.
	Figure 15. Differential effect of UV light on spontaneous and cGMP-activated currents. (A and B) UV dose dependence of currents through wild-type OLF channels in the absence of cGMP (A) and in the presence of saturating (1 mM) cGMP (B). Current amplitudes before UV exposure and after a UV dose of 9.49 × 109 photons · μm−2 were 12.3 and 353 pA in the absence of cGMP, and 16.2 and 11.2 nA in 1 mM cGMP. Spontaneous currents were taken as the difference between the currents in standard NaCl control solutions lacking cGMP with and without 10 mM MgCl2. Note the difference in vertical scales for traces in A and B, which are from the same patch. Channels were irradiated with 280 nm UV in the absence of ligand. (C) UV dose–response relation for spontaneous OLF channel currents. Collected results from five patches showing spontaneous current as a function of UV dose on a semilogarithmic scale. To facilitate comparison between different patches, the spontaneous current for each patch, Isp, was normalized by the maximal current in 1 mM cGMP for the same patch before UV, Imax. The continuous curve is a fit to the results using the modified all-or-none model () with n* = 1.29 and M = 67. (D) Block by Mg2+ of cGMP-activated currents and UV-induced spontaneous currents. The fraction of unblocked current is plotted as a function of added MgCl2 for currents through OLF channels activated by 1 mM cGMP before UV exposure (□) and spontaneous currents through OLF channels after exposure to 9.49 × 109 photons · μm−2 at 280 nm (▪). Results are from different patches. Smooth curves show fits to the results using . The inhibition constants were 350 ± 43 μM for channels activated by 1 mM cGMP (dotted line), and 201 ± 23 μM for channels activated spontaneously after UV (solid line).
	Figure 16. Analysis of UV effects on CNG channels using the expanded energy additive model. (A–D) UV dose–response relations for: (A) RET channels activated by saturating (1 mM) cGMP in the presence (▵) and absence (○) of 10 μM cytoplasmic Ni2+. (B) RET channels activated by saturating cAMP (1 mM) in the presence of 10 μM cytoplasmic Ni2+ (▴) and saturating (20 mM) cAMP in the absence of Ni2+ (•). (C) OLF channels activated by saturating (1 mM) cAMP (▪) and saturating (1 mM) cGMP (□). (D) OLF channels with no ligand present (⋄). The smooth curves show simultaneous fits to the results in A–D using the expanded energy additive model (). The fitted curves were calculated assuming three (+) targets and two (−) targets per channel subunit; however, the results were fit equally well for other target numbers. ΔG 0(0) values used in the fits are listed in Table . The quantum yield for each type of target was constrained to be the same for all channel/ligand combinations, and the values obtained from the fits were φ+ = 0.006 and φ− = 0.02. The free energy costs for modifying the (+) and (−) targets were allowed to vary for the different channel/ligand combinations. The values of ΔΔG 0(1+) and ΔΔG 0(1−) obtained from the fits were (RT units): for RET/cGMP, +8 and −0.95; for RET/cAMP, +7 and −0.95; for OLF/cGMP, +4.8 and −0.7; for OLF/cAMP, +3 and −0.7; and for OLF/no ligand, 0 and −0.7.
	Figure 17. Analysis of UV effect on ligand dose–response relation. (A–C) Schematic depiction of channel activation in: (A) Hodgkin-Huxley, (B) coupled dimer, and (C) Monod-Wyman-Changeux cyclic allosteric activation models. Each panel depicts binding of a single ligand molecule (denoted by A) to a channel gating unit (defined in text). Channel gating units may occupy a resting (T) conformation (squares), or an activated (R) conformation (circles). In the absence of ligand, the conversion between T and R conformations is described by the equilibrium constant L (=[T]/[R]). Ligand binding alters the conversion from the T to the R conformation by the factor c, where c = KR/KT is the ratio of ligand binding affinities for the R and T conformations. (D–F) Experimental and calculated ligand dose–response relations for RET channels activated by cGMP before and after UV. Results and symbols are the same as in Fig. 1 C. Smooth curves are fits of the hybrid UV-cyclic allosteric models to the relations before UV (solid line), and after cumulative UV doses of 4.91 × 109 photons · μm−2 (long-dashed line), and 9.82 × 109 photons · μm−2 (short-dashed line). The calculated curves were computed using and for the UV-HH model, with b = 4 (D), the UV-CD model with b = 2 (E), and the UV-MWC model with b = 1 (F). The channels were assumed to contain three c and two L targets per subunit (see text). The following parameter values were used: (D) KR = 1.0 × 10−6 M, L = 18.6, c = 6.7 × 10−4, φL = 0.101, φc= 0.027, ΔΔG 0(1L) = −1.19 RT, and ΔΔG 0(1c) = + 3.78 RT; (E) KR = 1.57 × 10−6 M, L = 382, c = 8.1 × 10-3, φL = 0.114, φc = 0.062, ΔΔG 0(1L) = −1.07 RT, and ΔΔG 0(1c) = +1.91 RT; and (F) KR = 1.52 × 10−6 M, L = 1.47 × 105, c = 2.4 × 10−2, φL = 0.129, φc = 0.110, ΔΔG 0(1L) = −1.03 RT, and ΔΔG 0(1c) = +1.20 RT. (G–I) Experimental and calculated ligand dose–response relations for OLF channels activated by cGMP before and after UV. Results and symbols are the same as in Fig. 2 C. Smooth curves are fits to the relations before UV (solid line), and after cumulative UV doses of 4.91 × 109 photons · μm−2 (long-dashed line), and 1.96 × 1010 photons · μm−2 (short-dashed line). The calculated curves were computed as described for D–F. Parameter values were: (G) KR = 1.91 × 10−7 M, L = 4.74, c = 2.6 × 10−6, φL = 0.028, φc = 0.010, ΔΔG 0(1L) = −0.58 RT, and ΔΔG 0(1c) = +3.98 RT; (H) KR = 3.19 × 10−7 M, L = 32, c = 8.8 × 10−4, φL = 0.045, φc = 0.014, ΔΔG 0(1L) = −0.41 RT, and ΔΔG 0(1c) = +3.88 RT; and (I) KR = 4.11 × 10−7 M, L = 1088, c = 1.5 × 10−2, φL = 0.069, φc = 0.027, ΔΔG 0(1L) = −0.36 RT, and ΔΔG 0(1c) = + 1.66 RT.
	Figure 18. Sensitivity of UV dose–response relation to changes in ΔG 0(0) that do not significantly alter channel open probability. (A) Nonlinear relation between open probability and standard free energy difference between open and closed channel states, ΔG 0. The smooth curve was computed using . For the various numbered arrows (shown in parentheses), the values of ΔG 0 (RT units) and the corresponding values of 1 − Po, were, respectively: (1) −9.9 and 5 × 10−5, (2) −20 and 2 × 10−9, (3) −35 and 6 × 10−16, (4) −50 and 2 × 10−22. (B) Simulated UV dose–response relations for channels with very different ΔG 0 that all correspond to Po values near unity. ▵ show the measured UV dose–response relation for OLF channels activated by saturating (1 mM) cGMP (Fig. 5). The bold curve (1) is the fit to these results using the parameters in Fig. 16 C. The other numbered curves were calculated using the ΔG 0 values corresponding to the equivalent numbered arrows in A, but the same UV parameters as for 1.

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