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McLaughlin Research Institute, Great Falls, MT 59405, USA
Correspondence
Rajeev Kumar
kumar{at}po.mri.montana.edu
George A. Carlson
gac{at}po.mri.montana.edu
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ABSTRACT |
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Supplementary figures are available with the online version of this paper.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). Prion replication involves conversion of benign cellular isoforms, designated PrPC, into disease-specific isoforms, designated PrPSc. The cellular site for prion replication is not well defined; in vitro and in vivo studies suggest that it takes place at the plasma membrane, where the initial interaction between endogenous glycosylphosphatidylinositol (GPI)-anchored PrPC and exogenous PrPSc occurs, and in endosomal compartments (Campana et al., 2005; Harris, 1999). Substantial evidence suggests that PrPSc generation takes place in cholesterol-rich, detergent insoluble membrane domains that are identified by various names, including caveolae-like domains (CLD), detergent resistant membranes and lipid rafts (Caughey & Raymond, 1991; Kaneko et al., 1997; Sarnataro et al., 2004; Vey et al., 1996). Cholesterol is required for PrPC cell-surface expression and stability (Caughey & Raymond, 1991; Gilch et al., 2006; Kaneko et al., 1997; Sarnataro et al., 2004) and pharmacological treatments that lower cellular cholesterol reduce PrPSc generation and prolong prion incubation time (Bate et al., 2004; Gilch et al., 2006; Marella et al., 2002; Taraboulos et al., 1995).
Genes involved in cholesterol metabolism and transport are consistently found among differentially expressed genes (DEGs) in prion-infected mice and cell lines. Among them is Abca1, whose mRNA levels were increased by 2–3 fold in the brains of prion-infected C57Bl/6J and FVB/NCr mice (Riemer et al., 2004; Xiang et al., 2004, 2007). We have recently extended these observations and found that increased Abca1 expression is detectable in the whole brain, beginning at approximately two thirds of the incubation period, before the onset of clinical signs, in multiple prion strain–mouse strain combinations (D. Hwang and others, unpublished results). This lack of mouse strain or prion strain specificity suggests that the increased expression of ABCA1 is a common feature of prion disease. However, as is the case for many DEGs, the significance of Abca1 mRNA elevation in prion disease is not clear.
ABCA1 is a membrane-associated protein that belongs to the ATP-binding cassette protein superfamily of multicellular organisms and is localized in membranous cellular compartments including the plasma membrane, the Golgi stack and endosomes. In the brain, ABCA1 is expressed in neurons, astrocytes and glial cells (Fukumoto et al., 2002; Koldamova et al., 2003). ABCA1 is involved in the transport of intracellular cholesterol and caveolae from the trans-Golgi to the plasma membrane and Abca1 mutations cause Tangier disease (Lawn et al., 1999; Orso et al., 2000). The potential importance of cholesterol in prion disease has been established by the inhibitory effect of pharmacological depletion of cellular cholesterol (Bate et al., 2004; Gilch et al., 2006; Marella et al., 2002; Taraboulos et al., 1995). The involvement of cholesterol in prion disease and the role of ABCA1 in cholesterol transport provided the impetus to examine interactions among ABCA1, PrP and PrPSc formation.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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), anti-ABCA1 and β-actin from Novus Biologicals, and anti-caveolin-1 from Sigma. FVB Tg(MoPrP-A)B4053 mice overexpressing mouse PrP-A (Carlson et al., 1994), FVB.129-Prnptm1Zrch null mice (Bueler et al., 1992) and FVB/NCr mice were maintained in the Animal Resource Center at the McLaughlin Research Institute. All protocols were reviewed and approved by the Institutional Animal Care and Use Committee.
Scrapie inoculation and brain harvest.
Three-week-old FVB/NCr mice were anaesthetized with isoflurane and inoculated intracerebrally with 20 µl of a 1 : 10 dilution of brain homogenate in phosphate buffered saline from either clinically ill Rocky Mountain Laboratory scrapie-inoculated mice (RML) or from normal mice (clean) and observed for clinical signs as previously described (Carlson et al., 1994). Brains were harvested from euthanized mice and snap frozen at –80 °C for storage. For some experiments, brains were dissected into fore- and hindbrain. Forebrain consisted of olfactory bulb, cortex, hippocampus, thalamus and hypothalamus, and hindbrain consisted of cerebellum, medulla, pons and the majority of the midbrain.
Western blot analysis.
Brain lysates were prepared in ice-cold lysis buffer (10 mM Tris/HCl pH 7.5, 150 mM NaCl, 0.5 % Triton X-100, 0.5 % Na-deoxycholate) by repeatedly passing through successively smaller gauge needles. Lysates were cleared by centrifugation at 4400 g for 5 min at 4 °C and were stored at –80 °C with or without complete protease inhibitor (Roche). N2a or ScN2a cells were washed three times with chilled PBS (calcium- and magnesium-free) and lysed in chilled lysis buffer and prepared as described above. Total protein content was determined using the detergent-compatible BCA protein assay (Pierce) with BSA as a standard. For PrPSc detection, 40 µg protein lysate was digested with proteinase K (PK) at 1 : 50 (w/w) for 30 min at 37 °C. Digestion was stopped using Pefabloc (Roche) at a final concentration of 1 mM. All samples were boiled with sample buffer at 100 °C for 10 min, except samples designated for ABCA1 detection. ABCA1-specific samples were incubated with sample buffer at room temperature for 30 min. Unless otherwise noted, samples containing 40 µg protein were run on 12 % SDS-PAGE Tris/Glycine gels (Invitrogen). Proteins were transferred onto nitrocellulose membranes (1 h, 25 V) that were then blocked in 5 % milk in TBST (10 mM Tris/HCl, pH 7.8, 150 mM NaCl, 0.05 % Tween-20) for 1 h at room temperature. Blots were incubated overnight at 4 °C with primary antibodies (1 µg anti-PrP ml–1; 1 : 1000 anti-ABCA1; 1 : 1000 anti-cav-1) followed by incubation with corresponding secondary antibodies conjugated with horseradish peroxidase (HRPO) for 1 h at room temperature. Protein bands were developed with SuperSignal West Pico chemiluminescence substrate (Pierce) for 5 min, and exposed to CL-XPosure film (Pierce). Band intensities were quantified using Quantity One software using a VersaDoc Imaging System 3000 (Bio-Rad). To control for loading differences, immunoblots were stripped in stripping buffer (50 mM Tris/HCl, pH 6.8, 2 % SDS and 100 mM β-mercaptoethanol) for 30 min at 50 °C followed by washing with TBST and reblocking. Blots were then probed with anti-β-actin antibody (1 : 2000) and HRPO-conjugated secondary antibody, prior to development. The different sample preparation methods for PrPC and ABCA1 detection necessitated their detection on separate filters; therefore PrPC and ABCA1 signals were normalized to β-actin on the corresponding filter. PK digestion precluded β-actin detection on PrPSc filters.
RT-PCR.
Total RNAs were isolated using an RNeasy mini kit (Qiagen) and equal amounts of RNA were reverse-transcribed into cDNA using SuperScript III first-strand synthesis system for RT-PCR (Invitrogen) and an oligo-dT primer. The cDNAs were used for gene-specific PCR-mediated amplification. For specific PCR amplification of Prnp cDNA the primers were 5'-AAAAAGCGGCCAAAGCCTGG-3' and 5'-CTTGTTCCACTGATTAT-3', which yield a 229 bp product. The Gpdh primers were 5'-ATGGGTGTGAACCACGAGAA-3' and 5'-AGGCATGGACTGTGGTCAT-3' and yield a 144 bp product. The Abca1 primers, which yield a 82 bp product, were 5'-CATTAAGGACATGCACAAGGTCC-3' and 5'-AGGATTTTCTGGTGGACAATGAAA-3'. For Prnp and Gpdh, PCR was performed for 40 cycles of 95 °C for 30 s, 52 °C for 15 s and 72 °C for 45 s. For Abca1, the annealing temperature was 54 °C. The amplified products were analysed by agarose gel electrophoresis.
RNA interference (RNAi).
All duplex siRNAs were synthesized by Dharmacon. Control siRNA was directed against a luciferase gene. N2a and ScN2a cells were transfected using Lipofectamine 2000 (Invitrogen) with a non-specific siRNA (sense sequence 5'-UAAGGCUAUGAAGAGAUACUU-3', antisense sequence 5'-GUAUCUCUUCAUAGCCUUAUU-3'), or Abca1 siRNA probes targeting different positions of Abca1 (NM_013454
[GenBank]
) mRNA. Abca1 siRNA probes, with sense sequence followed by antisense sequence, are: ABCA1 #1, 5'-GAAGAAAUAUUCCUCAAAGUU-3' and 5'-CUUUGAGGAAUAUUUCUUCUU-3'; ABCA1 #2, 5'-CCAAAUGGCUCUGUGUAUAUU-3' and 5'-UAUACACAGAGCCAUUUGGUU-3'; ABCA1 #3, 5'-GGAGAGAACUAAUAAGAUCUU-3' and 5'-GAUCUUAUUAGUUCUCUCCUU-3'; and ABCA1 #4, 5'-GGAGAGAAGCUUUCAAUGAUU-3' and 5'-UCAUUGAAAGCUUCUCUCCUU-3'. Cells were lysed 72 h after transfection for Western blot analysis with anti-ABCA1, anti-caveolin-1 and anti-PrP antibodies.
Immunocytochemistry and microscopy.
Neuroblastoma cells were transfected with GFP–ABCA1 (Fitzgerald et al., 2001) or GFP (Clontech) constructs using Lipofectamine 2000 (Invitrogen) and 48 h after transfection, cells were seeded to glass coverslips for 24 h. The coverslips were washed with PBS and fixed in 4 % paraformaldehyde (PFA)-PBS for 30 min. Cross-linking was terminated by 0.1 M glycine-PBS treatment for 30 min. Cells were washed with PBS and non-specific binding sites were blocked by incubating with 5 % BSA and 5 % normal goat serum in PBS for 1 h. After blocking, the cells were washed with PBS and incubated with primary antibody (5 µg anti-PrP ml–1) in 1 % BSA and 1 % normal goat serum in PBS overnight at 4 °C. Following overnight incubation, cells were incubated with diluted (1 : 1000) nuclear DNA stain (DAPI) (Molecular Probes-Invitrogen) for 2 min and washed twice with PBS for 10 min. Cells were incubated with fluorophore-conjugated secondary antibody (rhodamine-labelled goat anti-human Ig; Pierce) for 2 h. Cells were washed three times with PBS and coverslips were mounted with anti-fade mounting medium (Molecular Probes-Invitrogen). All incubations and solutions were at 4 °C. Fluorescence microscopy was performed using a Nikon TE2000 photomicroscope and fluorescence intensity was quantified using MetaMorph software (Molecular Devices). Comparison of the PrP fluorescence intensity in GFP–ABCA1- and GFP-transfected cells was based on the result that the intensity distribution of the signal in non-transfected cells (GFP negative) in the two samples was identical.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Koldamova et al., 2003). Both bands were included in our quantification and levels normalized to β-actin staining on the same blot. ABCA1 levels were approximately twofold higher (P
0.05) in the brains of clinically ill mice infected with the RML mouse-adapted scrapie prion strain than in age-matched mice given normal brain homogenate (Fig. 1a and c). Similar results were obtained in cell culture. Since each pair of cell cultures was analysed on a separate blot, β-actin-normalized intensity level of ABCA1 in infected ScN2a cells was assigned a value of 100 and the normalized ABCA1 in N2a cells expressed as a percentage. ABCA1 protein levels were approximately twofold higher (P0.05) in three independent cultures of persistently scrapie-infected N2a cells (ScN2a) than in three cultures of uninfected N2a cells (Fig. 1b and d).
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). We then tested the possibility that elevation of ABCA1 in prion-infected mice was a local effect of accumulation of PrPSc. PrPSc does not accumulate uniformly throughout the brain and varies depending on the particular prion strain and host. We exploited the regional differences in PrPSc distribution in mice infected with RML scrapie prions to assess the effect of PrPSc concentration on ABCA1 levels. In these mice, more PrPSc is found in the hippocampus, thalamus and cerebral cortex than in hindbrain structures such as the brain stem and cerebellum. Significantly more (approx. eightfold, P0.01) PK-resistant PrPSc is found in the forebrain than in the hindbrain of clinically ill mice (Fig. 2b and c). In contrast, levels of ABCA1, which were approximately twofold higher in prion-infected mice than in uninfected mice, were similar in the forebrain and hindbrain (Fig. 2b and c). Mice inoculated with normal brain homogenate also had similar ABCA1 levels in the forebrain and hindbrain (Fig. 2b and c). The twofold increase in forebrain and hindbrain was consistent with the increase in ABCA1 seen in whole-brain homogenates from infected mice (Fig. 1a and c
). These results suggest that the increase in ABCA1 levels is not a direct response to PrPSc accumulation. The independence of ABCA1 levels and regional PrPC or PrPSc concentrations suggests that the elevation of ABCA1 in prion-infected cells or mice is a consequence of infection, not PrPSc deposition. Although direct involvement of ABCA1 in conversion seems unlikely, the consequences of alteration of ABCA1 concentration were explored.
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). Consistent with previous observations in N2a and 293 cells (Fitzgerald et al., 2001; Fukumoto et al., 2002), GFP–ABCA1 decorated perinuclear compartments and cytoplasmic vesicular structures, while GFP-transfected control cells showed a uniform distribution of fluorescence throughout the cytosol (Fig. 3a, b and e). Quantification of PrP-specific fluorescence intensity in GFP-expressing cells showed significantly (P<0.0001, Student's t-test) higher levels of PrP in GFP–ABCA1-expressing cells than in cells transfected with GFP alone or in non-transfected cells (Fig. 3c and d). The PrP intensity distribution of cells transfected with GFP alone was not different from that of non-transfected cells in populations containing either GFP–ABCA1-expressing cells or GFP-expressing cells. PrPC and GFP–ABCA1 did not co-localize (Fig. 3e).
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). The Prnp gene lacks consensus CRE sites and PrP mRNA levels are not increased by cAMP analogue treatment (Cabral et al., 2002). cAMP analogues have often been used to induce ABCA1 expression for studying its role in cholesterol transport (Lawn et al., 1999; Le Goff et al., 2006) and are used here to induce endogenous ABCA1 expression and study its impact on the concentration of PrPC or PrPSc. Treatment of N2a cells with the cAMP analogue 8-Br-cAMP at 1 or 2 mM for 24 h caused a dose-dependent increase of both ABCA1 and PrP in N2a cells (Fig. 4a and b). Densitometric analysis of Western blots, one of which is shown in Fig. 4(a), with the β-actin-normalized PrPC and ABCA1 levels in untreated cultures produced a positive correlation (r2=0.674, P=0.022) between the levels of ABCA1 and PrPC in response to 8-Br-cAMP (Fig. 4b). A Western blot from a second experiment is shown in Supplementary Fig. S1 (available with the online version of this paper).
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, ScN2a cultures were treated with 0.25, 0.5, 1 or 2 mM 8-Br-cAMP and levels of PK-resistant PrPSc and ABCA1 were determined by immunoblotting; the additional two experiments are shown in Supplementary Fig. S2 (available with the online version of this paper). Since ABCA1 has been reported to have a function in the transport of caveolae (Orso et al., 2000), we also monitored the levels of caveolin-1 (CAV1) in some experiments; no effect of 8-Br-cAMP treatment on CAV1 levels was found. The 8-Br-cAMP-induced elevation of ABCA1 and PrPSc concentrations were highly correlated (r2=0.8277, P<0.001) as shown in Fig. 4(d). The increase of PrPSc in ScN2a cells (Fig. 4c and d) likely reflects the ABCA1-induced increase in PrPC concentration (Fig. 4a and b). Prnp mRNA levels in N2a and ScN2a appeared to be unchanged by 8Br-cAMP treatment, while there was a clear increase in ABCA1 mRNA levels detectable by RT-PCR (Fig. 4e and f). This is consistent with the previous observations made in PC-12 and C6 cells and with the presence of a CRE sequence in Abca1 but its absence in Prnp. Although the effects of many other cAMP-inducible genes, such as solute carrier family 15 member 3 (Slc15a3), which is also increased in prion disease, on PrPC concentration cannot be ruled out, our results are consistent with an effect of ABCA1 as shown in Fig. 3 where transient overexpression of an ABCA1–GFP construct increased PrPC. Although there is a highly significant correlation of ABCA1 and PrP, this is only a correlation and, on its own, is only consistent with an effect of ABCA1 and does not demonstrate a direct link.
Knockdown of Abca1 expression reduces PrPC levels and production of PrPSc
RNAi-mediated knockdown of ABCA1 expression was used to further assess the effects of ABCA1 concentration on PrP levels. In two independent experiments, four RNAi probes targeting different regions of the ABCA1 mRNA and a pool of the four Abca1-specific probes were used to reduce expression of Abca1 in N2a and ScN2a cells, a non-specific RNAi was used as control. Western blots for N2a and ScN2a cells are shown in Fig. 5(a and c), and in Supplementary Figs S3 and S4 (available with the online version of this paper). Among the RNAi probes siRNA #2 and #3 were the most effective in reducing ABCA1 levels. Due to the variability in PrPSc among ScN2a cultures, four additional ScN2a cultures were treated with non-specific RNAi or ABCA1 #3; Western blots from these cultures are shown in Supplementary Fig. S5. The RNAi probes had no effect on CAV1 levels. The four siRNA probes individually and pooled varied in their efficiency in reducing ABCA1 protein levels in N2a and ScN2a cells, which allowed us to assess the concentration-dependent correlation between target (ABCA1) and effector (PrP) gene products (Fig. 5b and d). Intensity of immunostaining, normalized to β-actin, of control cultures in each experiment was assigned a value of 100. As shown in Fig. 5(b and d), the degree of PrPC and PrPSc reduction corresponded to the efficiency of Abca1 knockdown, and ABCA1 and PrPC or PrPSc concentrations were directly correlated (PrPC, r2=0.5184, P=0.0032; PrPSc, r2=0.4781, P<0.0005). These results demonstrate that PrPC concentrations in the cell are affected by and proportional to ABCA1 levels, and that reduction of ABCA1 inhibits PrPSc production.
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DISCUSSION |
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; Xiang et al., 2004, 2007) (D. Hwang and others, unpublished results). To mention only a few examples, the sterol-O-acyltransferase 1 gene (Soat1) that encodes acyl-coenzyme A : cholesterol acyltransferase (ACAT) is overexpressed in prion-infected mice. Expression of the apolipoprotein genes Apod and Apoe also increases in parallel with Abca1 during the course of infection. LDL receptor mRNA is reduced in scrapie-infected mouse brain (Riemer et al., 2004). The mechanism by which prion infection alters cholesterol homeostasis is not known, but may be related to alterations in recycling of PrP, synaptic membrane degeneration or to cellular stress responses.
Although the cause for increased Abca1 expression in prion disease has not been determined, it is unlikely to be a direct effect of increased levels of extracellular PrPSc, since the levels of ABCA1 were reduced to the same extent in regions of the brain that differ in the amount of PrPSc that has accumulated. In the case of FVB/NCr mice infected with RML scrapie prions shown in Fig. 2(b and c), much less PK-resistant PrPSc is found in hindbrain structures than in more anterior regions, while ABCA1 in forebrain and hindbrain showed similar increases. Other combinations of prion strains, mouse strains or species show entirely different patterns of PrPSc deposition (DeArmond & Ironside, 1999; Kuczius & Groschup, 1999). There is no evidence for direct interactions among PrP isoforms and ABCA1; we noted no effect of PrPC concentrations on ABCA1 levels (Fig. 2a) and GFP–ABCA1 and PrP did not colocalize (Fig. 3e). It is likely that ABCA1 is not directly involved in prion replication, but increases as a secondary consequence of prion infection.
Although Abca1 is only one of several genes involved in cholesterol homeostasis that is differentially expressed in prion-infected mice, altering its concentration is sufficient to modulate levels of PrP in cultured cells. Our studies did not address the mechanism by which ABCA1 affects PrPC and PrPSc in cultured cells. ABCA1 is a multifunctional protein and, in addition to its role in cholesterol transport, has reported functions in apoptosis, lipoprotein metabolism and flipping of the bilipid membrane. As noted above, we did not observe colocalization of PrPC with GFP–ABCA1, which was expected since ABCA1 is not found in CLD whereas PrPC is (Mendez et al., 2001; Vey et al., 1996), so a direct effect of ABCA1 on PrP seems unlikely. CAV1 is expressed in N2a and ScN2a cells, but its levels do no change in proportion to changes in ABCA1 concentration (Fig. 4c and Supplementary Figs S2 and S5). Therefore, it seems unlikely that the role of ABCA1 on PrP concentration is mediated by an effect on CAV1 or caveolae. Given the well-documented effects of changes in cholesterol levels on PrPSc formation and prion incubation time in culture, an effect of ABCA1 on cholesterol is an attractive possibility. Reduction of membrane cholesterol, either by inhibition of its biosynthesis with lovastatin or squalestatin or by removal from the membrane with filipin, dramatically reduces production of PrPSc in cultured cells (Bate et al., 2004; Gilch et al., 2006; Marella et al., 2002; Taraboulos et al., 1995). Simvastatin treatment also prolonged prion incubation time in mice (Mok et al., 2006). Although ABCA1 transports cholesterol to lipoprotein acceptors, increased expression of ABCA1 can also cause a general increase in membrane cholesterol. Once cholesterol is in the membrane, it is distributed non-uniformly by lateral diffusion and condensation into cholesterol-rich CLD, which do not provide cholesterol for efflux to apolipoproteins (Mendez et al., 2001). Under this scenario, our demonstration that increased ABCA1 enhances PrPSc formation might be explained by an increased supply of PrPC due to more or larger CLD that serve as sites for the GPI-anchored protein. Since Prnp gene expression was not affected by changes in ABCA1 levels, increased membrane cholesterol and CLD may enhance cell surface localization and stability of PrPC. Additional work is needed to determine the mechanism by which changes in ABCA1 concentration affect levels of PrP.
The effects of ABCA1 on prion incubation time in mice are unknown at present. Preliminary results from analysis of a newly identified Abca1 mutant mouse with low serum cholesterol levels indicate reduced concentrations of PrPC in brain (unpublished results), which is consistent with the in vitro results presented here. PrP transgenic and Prnp gene ablated mice were used to demonstrate that prion incubation time is proportional to the concentration of PrPC and even a modest change in PrPC levels can substantially alter the rate of PrPSc formation and disease progression (Bueler et al., 1994; Carlson et al., 1994; Prusiner et al., 1990). Our studies in N2a and ScN2a cells lead us to hypothesize that reduced ABCA1 concentration in mice may lead to longer incubation times. Whether the elevation of ABCA1 in prion-infected mice has any consequences on prion replication will require additional studies.
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ACKNOWLEDGEMENTS |
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Received 7 August 2007;
accepted 9 February 2008.
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