1Medical Pharmacology and Physiology, College of Medicine, University of Missouri-Columbia; 2Department of Cell Biology and Histology, University of Nijmegen, Nijmegen, The Netherlands; 3Department of Biomedical Sciences, College of Veterinary Medicine; and 4Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
Submitted 23 November 2004 ; accepted in final form 13 January 2005
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ABSTRACT |
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AMP deaminase; tetanic contraction; muscle relaxation; calcium handling; cross-bridge cycling
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When the rate of ATP hydrolysis is out of balance with the rate of ATP synthesis, the need to limit the accumulation of ADP and Pi is the greatest. The reaction catalyzed by CK via the transfer of a phosphate from phosphocreatine (PCr) to ADP, serves as an ATP buffer, thereby maintaining ATP content utilizing ADP. Furthermore, the reaction catalyzed by AK functions to minimize ADP accumulation through the transfer of a phosphate from one ADP to another ADP forming ATP and AMP. In addition, the capacity of AK to limit ADP accumulation is magnified by the coupled reaction catalyzed by AMP deaminase (AMPD). The AMP formed by AK is rapidly deaminated to inosine 5'-monophosphate (IMP) by AMPD. This keeps the AK catalyzed reaction proceeding in the direction limiting ADP accumulation. The tight coupling of AK and AMPD is evident by the exceptional accumulation of IMP that can occur in fast twitch muscle [3.5 µmol/g wet wt (40)], which is orders of magnitude greater than the estimated free AMP accumulation (12)
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The contractile ATPase and the sarco(endo)plasmic reticulum calcium ATPase (SERCA) account for the vast majority (95%) of the energetic cost of a muscle contraction (46, 47). The cost of maintaining a low cytosolic calcium concentration by SERCA, pumping calcium back in to the sarcoplasmic reticulum (SR) after a contraction, is
30% of the total cost of contraction. In addition, the cost to maintain the large calcium gradient between the cytosol and the SR (a ratio
10,000:1) is near the limit of how much
GATP is available (21). Therefore, ADP accumulation and the coordinate reduction in the
GATP, could lead to compromised SERCA function and prolonged elevation in cytosolic calcium. Consistent with this idea, a study by Dawson et al. (9) revealed a close relationship between small reductions in the free energy of ATP hydrolysis, and slowed relaxation in frog skeletal muscle (implying a prolonged calcium transient that led to delayed relaxation kinetics). Therefore, minimizing ADP accumulation likely preserves normal contraction kinetics.
The appropriate management of intracellular calcium in muscle cells is critical for contraction and relaxation. The rate calcium returns to resting concentrations after muscle activation influences the rate of relaxation. This has been demonstrated using models of altered expression of the calcium-binding protein parvalbumin (7, 48, 50). Whereas overexpression enhances the calcium-buffering capacity, it also results in faster relaxation kinetics (7). Conversely, the opposite pattern was observed in fast-twitch muscle from parvalbumin-deficient mice (48, 50). These results imply that the rate of calcium dissociation from troponin C has an impact on muscle relaxation. Furthermore, Luo et al. (34) demonstrated that as the affinity of troponin C for calcium is either increased or decreased, a corresponding increase or decrease in the time for relaxation is observed. Therefore, altering the rate with which calcium leaves troponin C can have an impact on muscle relaxation. Thus if ADP accumulation slows the rate that cytosolic calcium returns to the SR, calcium should remain longer on troponin C and the rate of relaxation should be slowed.
An inordinate accumulation of ADP may also impact myosin cross-bridge dynamics. Tension generated by muscle is ultimately a function of the balance between the cyclical attachment and detachment of actin and myosin. The steps leading to myosin detachment from actin involve the dissociation of ADP and subsequent binding of ATP to the nucleotide-binding site on myosin (see Ref. 17 for a review). The rate of ADP dissociation from myosin limits the rate of cross-bridge cycling at the fastest cross-bridge cycling rates, and therefore inhibits the unloaded shortening velocity (8, 51, 59). Furthermore, elevated concentrations of ADP compete with ATP for the nucleotide-binding site, thereby slowing the overall cycling rate because more cross-bridges populate an ADP-myosin-actin force-generating state. Chase and Kushmerick (5) examined whether the ADP accumulation, at values estimated from intact muscle, impacted contractile parameters, such as the unloaded shortening velocity and tension development, and found that the effect was minimal. Therefore, an ADP-dependent slowed cross-bridge cycling rate is not apparent in intact muscle because ADP accumulation is limited.
The rate of cross-bridge detachment is ultimately what causes tension to fall after a contraction. ADP has been shown to slow the rate of cross-bridge detachment after fully activated isometric contractions in skeletal (23, 30, 55) and cardiac (52) muscle fibers. This is thought to be the same reason that unloaded shortening velocity is slowed: more cross-bridges populate the strong bound ADP state longer with higher ADP concentrations. Thus, the consequences of ADP accumulation include impaired calcium uptake by the SR, and a slowed myosin cross-bridge detachment rate, both of which are factors involved in relaxation.
The purpose of this study was to examine the functional consequences of ADP accumulation on muscle in situ. To achieve this we have examined the metabolic and functional profile of AK-deficient (/) muscle in vivo at high-energy demands. We hypothesized that AK deficiency would result in ADP accumulation when energy demands were highest, and this would lead to the functional consequence of slowed relaxation consistent with impaired calcium uptake, and/or slowed cross-bridge kinetics. Our results demonstrate that in intact muscle, ADP can transiently increase to concentrations well in excess of 1 mM in AK/ muscle. This degree of ADP accumulation did not modify the ability to develop force but did coincide with a substantial slowing of relaxation kinetics. These results illustrate the importance of AK and AMPD in minimizing inordinate ADP accumulation and identify the consequences of ADP accumulation on muscle function.
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METHODS |
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Animal care. AK1/ transgenic mice and wild-type (WT) control mice were described in detail previously (25). Animals were kept in a temperature-controlled environment (22°C) with a 12:12-h light:dark cycle, and fed standard rodent chow ad libitum. The Animal Care and Use Committee at the University of Missouri-Columbia approved the animal use and care protocols.
Muscle phenotype. To evaluate relevant phenotypic adaptations between AK1/, we performed histochemical analysis of myofibrillar ATPase and capillarity of the gastrocnemius-plantaris-soleus (GPS) muscle complex in both AK1/ and WT muscle. For histochemical analysis, cross-sections were taken from the middle of the GPS muscle group. To determine qualitative differences in ATPase activity in the muscle groups, cross sections were stained for ATPase activity after acid preincubation (pH 4.6) according to the method described by Guth and Samaha (20). Three degrees of ATPase were apparent and the qualitative distribution of fiber types was evaluated for the soleus, plantaris, and the lateral and medial gastrocnemius muscles. Capillaries were visualized by alkaline phosphate stain as done previously (63, 64), which rendered the fiber yellow with the capillary appearing dark. Capillarity was expressed as capillary contacts per fiber. In addition, we examined two sections of the gastrocnemius muscle for citrate synthase activity, using the method described previously (53), as an index of mitochondrial content. Recent work (25, 26) has identified an increased abundance of intermyofibrillar mitochondrial content in AK1/ gastrocnemius muscle compared with WT, as measured by electron microscopy. We sought to verify this observation in the superficial gastrocnemius (13 ± 1% of GPS mass, n = 12), which has relatively low oxidative capacity, and the remaining lateral gastrocnemius muscle (26 ± 2% of GPS mass, n = 12), a mixed oxidative capacity muscle (3).
Isometric contractions.
Sixty isometric tetanic contractions (each 100 ms long) of the GPS muscle complex were elicited from an in situ muscle preparation via electrical stimulation (3- to 5-V stimulation, 0.05-ms square wave, at a frequency of 150 Hz with the use of a Grass S48 stimulator) of the sciatic nerve at contraction frequencies of 30, 60, 90, and 120 tetanic contractions/min. The in situ muscle preparation was similar to that used previously in the rat (38, 40). Mice were anesthetized with 70 mg/kg ip pentobarbital sodium injection. The hamstrings were cut away from the GPS and the femur was secured on the medial and lateral sides of the knee with two 16-gauge pins to prevent movement. The foot was also secured by clamping it to the platform to eliminate movement of the lower leg. The sciatic nerve was exposed, tied off, and cut to facilitate direct stimulation. The experiments were performed in a heated chamber with a temperature probe placed next to the GPS muscle complex to ensure a consistent temperature of 37°C. The GPS complex was isolated by securing the Achilles tendon to a Cambridge force transducer lever arm (model 305B, Aurora Scientific) with a shortened lever arm to permit a calibrated range of tension of 0700 g. Supplemental oxygen (100%) was supplied across the nose of the animal throughout the procedure.
Metabolic analysis. Muscle sections of the gastrocnemius muscle mentioned above were quick frozen within 35 s using aluminum tongs cooled in liquid nitrogen. In addition, the remainder of the GPS was taken for analysis of total muscle water weight. Metabolites relevant to high-energy phosphate metabolism (ATP, ADP, AMP, IMP, PCr, Cr, and lactate) were measured from the mixed lateral gastrocnemius muscle section mentioned above at three time points during the stimulation of the GPS corresponding to 20, 40, and 60 contractions. After the contracted muscle was frozen, corresponding muscle sections were taken from the resting contralateral leg. Muscle samples were stored at 80°C until use.
Metabolite analysis were made possible by homogenizing muscle in cold 3.5% perchloric acid, followed by centrifugation to remove protein and neutralization with tri-n-octylamine and 1,1,2-trichlorotrifluoroethane (6). Adenine nucleotides (ATP, ADP, and AMP) and IMP were quantified by reverse-phase HPLC, as described previously (56). PCr and creatine (Cr) concentrations were quantified by ion exchange HPLC (62). Metabolites are expressed as micromoles per gram wet weight and corrected to a constant total water content of 76%. Lactate content was determined by measuring NADH fluorescence using the lactate dehydrogenase reaction. The net accumulation of ADP during contractions was calculated by taking the difference of the contracted muscle measure from the resting average.
To assess the energy state of WT and AK1/ muscles, the GATP was calculated both from resting gastrocnemius, and from contracting muscles with the
G°
of 32 kJ/mol (42). The free ADP was estimated either from the known stoichiometry with the CK reaction (57), or in contracting muscle the difference in total ADP from rested ADP was used. The concentration of Pi was estimated in resting muscle based on previously reported values in mouse skeletal muscle (29) and in contracting muscle, Pi was estimated by the addition of the resting content to the decline in PCr, which has been found to mirror the accumulation of Pi (41). An additional correction for the loss of PCr (increase in Pi) that occurs with muscle freezing was also used to calculate both free ADP at rest and Pi accumulation during contractions (1).
Contractile function.
GPS function was analyzed with the use of Chart software (ADInstruments), which captured data at 1,000 Hz for isometric contractions. Before the beginning of each experiment, 68 tetanic contractions were elicited to stretch the muscle to a length that yielded maximal force. Specific force was calculated from an estimated GPS mass determined from the ratio of GPS to whole quadriceps (0.72 ± 0.02; n = 14) determined in preliminary work. The peak force of each contraction was evaluated as well as the peak rate of force development. The peak rate of force development was normalized to the tension developed for each given contraction. This was necessary because the fall in the rate of force development parallels the fall in tension that occurs with fatigue (see Ref. 15 for review). Relaxation from tetanic contraction occurs in at least two different phases, an initial phase characteristic of uniform isometric sarcomeres, followed by an exponential fall in force characteristic of nonuniform sarcomeres (see Ref. 16 for review). Thus we measured an early relaxation time (time for force to fall 5% of force at the end of stimulation) and a late relaxation time (time for force to fall from 50 to 25% of force at the end of stimulation) to have an index of relaxation during both of these phases. The exponential portion of the relaxation data was fit best by a single exponential function with the use of SigmaPlot version 7.101. Calculations were made on all contractions with the aid of a script created to process the text output from the Chart software.
Unloaded shortening velocity.
Unloaded shortening velocity of the GPS complex was examined using the slack test method described previously (13), as applied to whole muscle in situ (10). Force and lever arm position data were acquired at a frequency of 20 kHz. The lever arm position was controlled with the use of Labview software driving a PCI-MIO-16E-4 data-acquisition board (National Instruments). After a time for full development of maximal isometric force (100 ms in nonfatigued muscle and 70 ms in fatigued muscle), the lever arm was slacked by a specific distance at a rate in excess of 500 mm/s. The duration of the stimulus was always set to end 3050 ms after the initiation of the slack. Force fell from full tetanic force to 0 within 8 ms. The slack time (the time from the beginning of the slack to when force development occurred) was plotted against the distance of the slack. Unloaded shortening velocity was calculated from the slope of linear least-squares regression of 46 points (
length/time to redevelop force).
Statistical analysis. Two-way (contraction number x intensity) ANOVAs were performed within each genotype for ADP accumulation. Student's t-tests were used for all other comparisons with a Bonferroni test for multiple comparisons.
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RESULTS |
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DISCUSSION |
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ADP and relaxation rate.
The slowed relaxation kinetics coincided with the time of high ADP accumulation in AK/ muscle. Muscle relaxation is ultimately due to the detachment of myosin from actin. Increasing concentrations of ADP prolongs the rate of myosin detachment after full isometric activation (23, 30, 55). If this applies to our muscle with elevated ADP, there should be a prolonged maintenance of force after the end of stimulation, similar to the delay in early relaxation apparent in AK/ muscle (Fig. 5A). However, our findings cannot be simply attributed to altered cross-bridge cycling rate, because in intact muscle, cross-bridge detachment does not occur independent of calcium dissociation from troponin C. In fact, Luo et al. (34) demonstrated that when the affinity of troponin C for calcium is either increased or decreased, there is a corresponding increase or decrease in time for relaxation. The rate with which calcium dissociates from troponin C is a function of the rate with which the cytosolic calcium concentration declines, which occurs by pumping calcium back into the sarcoplasmic reticulum (SR). SERCA functions to sequester calcium at a high-energetic cost due to the large calcium gradient between the cytosol and the SR (a ratio near 1:10,000) (21). The energy available from ATP hydrolysis (GATP) declines with increasing concentrations of ADP and Pi (57). Dawson et al. (9) found that the decline in
GATP correlated with an increase in relaxation time in isolated frog muscle, and interpreted the slowed muscle relaxation to be due to the progressive impairment in calcium uptake. Indeed, the decline in free energy available estimated by the
GATP with an inordinate ADP accumulation in our study (Table 4) is consistent with this hypothesis and may explain the delay in relaxation that we observed at high-energy demands.
The accumulation of ADP may also affect calcium sequestration in a more direct manner, without a drop in energy state. Recent work by Macdonald and Stephenson (36) found that ADP accounted for as much as a 4.4-fold reduction in SR calcium loading ability, due in part (30%) to depressed SERCA pump rate and primarily (70%) to increased calcium leak over a concentration range of 0.01 to 1 mM. Furthermore, the ADP-dependent impairment of SR calcium uptake was observed under energetically favorable conditions (ATP and Pi were maintained and ADP was manipulated) demonstrating that ADP can inhibit SR calcium uptake independent of a large decline in GATP (36). Therefore, we would predict from our evidence of an elevated ADP, coupled with significant delay in muscle relaxation kinetics, that calcium removal from the cytosol of the AK1/ muscle is delayed. Wahr et al. (58) determined that, in frog skeletal muscle, the initial phase of relaxation (characteristic of relaxation while sarcomeres remain isometric) was more sensitive to changes in calcium than the subsequent exponential phase (characteristic of relaxation when sarcomeres are not uniform). The delay in relaxation in the AK/ muscle was first observed in the early phase after
20 contractions at the highest contraction frequency (Fig. 5A), followed by a delay in the late phase after 30 contractions (Fig. 5E). In addition, SERCA function may be impaired due to the decline in pH that occurs with fatigue (24, 35). We do not think the exaggerated relaxation seen with high ADP can be explained by a pH effect on SR function because the predicted pH, based on lactate accumulation, was similar in both groups. However, whether the exaggerated relaxation requires a high [H+], cannot be answered from our experiments. Furthermore, large differences in ADP between AK1/ and WT muscles were not always coupled to differences in relaxation rates, such as at 60 contractions at 120 tetani/min (Fig. 1B and Fig. 5, A and E), where force was substantially reduced (
56% of the force at 40 contractions was developed at 60 contractions). It is unknown whether the putative effect of high ADP requires a relatively high rate of calcium turnover (high force development). However, it seems reasonable to interpret the slowed relaxation kinetics observed in our study to be due to a transient impairment of calcium sequestration by ADP.
Unloaded shortening velocity.
The rate of ADP dissociation from myosin limits unloaded shortening velocity, which is dependent on the rate of cross-bridge detachment (8, 17, 51, 59). We found that the decline in unloaded shortening velocity of the calf muscle group was similar with or without inordinate ADP accumulation. This suggests that the ADP accumulation in AK1/ was insufficient to meaningfully slow cross-bridge detachment, in contrast to that predicted (8, 61) or observed at lower ADP concentrations (5). Alternatively, the slowed unloaded shortening velocity that occurs with fatigue at a low pH (for review, see Ref. 15) may have obscured any ADP effect. The decline in unloaded shortening velocity that we observed with fatigue (50%) is in the range of values reported previously (10, 60, 61). Furthermore, whereas ADP accumulation of this degree has been found to depress the unloaded shortening velocity in single fiber preparations, this effect has been investigated at both lower concentrations of ATP and at much lower temperatures than are found in muscle contracting in situ (8). Interestingly, we did observe a significant slowing of the peak rate of force development, coincident with the delayed relaxation discussed above (Fig. 6). It is possible that this apparent slowing of peak rate of force development, reflects a depressed cross-bridge cycling rate, given that others have observed a high correlation between the peak rate of force development and the extrapolated measure of maximum shortening velocity (54). Thus a minor degree of delayed cross-bridge detachment due to ADP cannot be ruled out. However, it is likely that a direct effect of ADP on cross-bridge cycling is not the primary factor responsible for the decline in relaxation seen in the presence of high ADP.
ADP and isometric force production.
In isolated fiber preparations ADP has been shown to cause increased muscle tension due to more myosin cross-bridges populating a strongly bound conformation with actin (27, 33). This effect of ADP on muscle tension occurs in competition with ATP binding the myosin head that results in detachment from actin (27). Because the concentration of ATP remains manyfold higher than the concentration of ADP, even under the most demanding conditions, the effect of ADP on isometric tension has been predicted to be at most an 8% increase in tension under conditions with 1 mM ADP accumulation (27). Interestingly, we found a modest effect of improved tension maintenance within a given contraction (contraction 40, Fig. 3, E and F) in muscle with high ADP at the two most demanding contraction frequencies. This is consistent with the prediction of a relatively small effect ADP has on isometric tension (8, 27, 33). We did not, however, observe any substantial increase in the peak tension developed in muscle with high ADP throughout the contractions examined. Therefore, an inordinate accumulation of ADP does not have a large effect on whole muscle force production.
Critical assessment of our model.
Our findings should be considered in the context of the model employed in this study; whole muscle stimulated in situ, supported by intact circulation. This model does not allow for the direct control of specific metabolites like models of isolated muscle fibers and must be understood in the context of the complex architecture and mixed fiber type inherent in the whole muscle group. For instance, while the unloaded shortening velocity value that we observed in nonfatigued muscle is comparable to that in whole rat gastrocnemius muscle in situ (10), it is probably determined by the proportion of fast fibers that make up muscle (4). We believe that it is unlikely this confounds our interpretation because the fastest fibers in our preparation should be the ones with the highest ADP accumulation, due to greater ATP turnover with a relatively low mitochondrial capacity. On the other hand, the in situ calf muscle preparation has advantages that include a more physiologically relevant experiment, which preserves the structural and enzymatic integrity to evaluate functional and metabolic changes. As with any genetic knockout model, adaptations might impact research findings. In the AK1/ mouse, an increase in intermyofibrillar mitochondrial content was reported (25, 26) in the superficial gastrocnemius muscle. Consistent with this finding, we measured a significant increase in citrate synthase activity in a small superficial section of the gastrocnemius muscle (e.g., 13%); however, we did not measure any significant differences in the mixed gastrocnemius muscle. We also observed significant enhancement in the capillarity, in this case throughout both heads of the gastrocnemius (Table 1). Therefore, under steady-state energy demands, where the ATP demand is adequately met by aerobic ATP supply, we would expect an enhanced ability for nutrient exchange. This, however, does not likely impact our findings, given the very demanding short-term conditions that we examined. Furthermore, we did not see any evidence of large differences in fiber-type distribution in the AK1/, suggesting similar ATP demands compared with WT muscle. Therefore, it is not likely that our findings are mitigated by altered fiber-type expression or arrangement, given the very similar initial contractile characteristics and unloaded shortening velocity. The only significantly different initial contractile parameter we observed was a somewhat faster (
12%) rate of relaxation in the late, or exponential phase of relaxation in AK/ muscle. In fact, faster late relaxation times were apparent throughout the contractions observed at the lowest energy demands (Fig. 5H). This small difference might be attributable to a slightly different muscle fiber alignment, or, more likely a small increase in fast twitch fibers, but within the variability of our measures. Because no other contractile parameter examined reflects such a shift in fiber type (rate of force development, early relaxation time, and unloaded shortening velocity), we conclude that the difference in relaxation times in both the late and early phases, between AK1/ and WT mice at high-energy demands, are meaningful.
Human AMPD deficiency. We believe that our results provide insight into whether functional consequences should exist due to AMPD deficiency in human muscle. While the importance of AK and AMPD in limiting ADP accumulation has been understood for many years (31, 32, 39), this study expands our understanding by illustrating what consequences ensue when this path for ADP removal is deficient. A genetic mutation in the gene encoding AMPD1 results in AMPD enzyme deficiency and has been described as "the most common muscle enzyme defect in humans" (19). AMPD enzyme deficiency is found at a frequency of roughly 2% in muscle biopsies (see Refs. 19, 43, and 44 for reviews), and has been thought to cause AMP and ADP accumulation at high-energy demands, if the deficiency were great (49). The presence of AMPD deficiency is often associated with symptoms of exertional myalgia, such as muscle cramps and stiffness, as well as exaggerated fatigue and delayed muscle relaxation (11, 49); however, deficits in muscle function are not necessarily independent of other myopathies (37). In fact, a large percentage of individuals with AMPD deficiency are asymptomatic. Indeed, Norman et al. (45) examined muscle power output using a short explosive exercise bout in healthy asymptomatic AMPD-deficient subjects and found no difference in maximum power output compared with normal subjects (45). Our results could reconcile these disparate findings. Even if AMPD deficiency caused an ADP accumulation similar to what we have observed in this study, muscle force is expected to be normal, similar to what was reported previously (45). However, ADP accumulation could delay relaxation as tended to be evident in at least one study (11) due to an expected slowed rate of calcium clearance from the cytosol. While a deficient calcium uptake can lead to contracture and muscle soreness (2), it is unlikely that this would happen with AMPD deficiency. We did not see it here with AK deficiency, where the ADP accumulation is likely far greater than any expected with AMPD deficiency alone. Any putative effects of AMPD deficiency, however, would only be expected at an extreme energy imbalance as in the study by Norman et al. (45), and not during easier submaximal exercise, where steady-state aerobic metabolism is expected to be sufficient for ADP rephosphorylation. Therefore, our results would predict that muscle performance with AMPD deficiency would be normal under most energy demands, in the absence of other myopathies.
In summary, we have shown that in the presence of high-energy demands, AK deficiency results in minimal IMP formation and inordinate ADP accumulation. ADP accumulation of 1.5 mM in intact muscle did not impair, or significantly enhance the peak tension developed or the fall in tension that occurred with fatigue. Furthermore, the clearest functional consequence of the ADP accumulation was delayed early and late relaxation kinetics, consistent with impaired calcium uptake by the SR. The results from this study directly illustrate the effectiveness of AK and AMPD in the management of ADP during high-energy demands, and demonstrate the functional tolerance to ADP accumulation in intact muscle.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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