* Department of Food Science and Human Nutrition,
Department of Microbiology and Molecular Genetics, and
Institute of Environmental Toxicology, Michigan State University, East Lansing, Michigan 48824
Received January 19, 2003; accepted April 16, 2003
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ABSTRACT |
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Key Words: lipopolysaccharide; immunotoxicology; apoptosis; deoxynivalenol; vomitoxin; trichothecene; mycotoxin; thymus; Peyers patch; bone marrow; IL-1ß; corticosterone.
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INTRODUCTION |
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Deoxynivalenol (DON or vomitoxin), a trichothecene mycotoxin produced by Fusarium graminearum, commonly contaminates human and animal dietary staples such as wheat, corn, and barley (Rotter et al., 1996). Since DON is recalcitrant to milling and processing, it can sometimes be present at p.p.m. levels in grain-based food products consumed by humans. Numerous human toxicoses related to trichothecenes including DON have been reported in China, India, Japan, and Korea (JECFA, 2001
). Gastroenteritis outbreaks in China that reportedly occurred during a recent 30-year period (19601991) have been associated with the consumption of moldy grain. Samples from some of these outbreaks contained as much as 54 mg/kg DON and lower levels of other tricothecenes such as nivalenol and T-2 toxin (Li et al., 1999
). Interestingly, differences in DON occurrence between high and low risk esophageal cancer regions in China suggest that exposure may be etiologically related to disease (Hsia et al., 1988
; Luo et al., 1990
; Meky et al., 2003
).
Hallmarks of experimental and accidental exposure to high doses of trichothecenes include rapid diminution of lymphoid tissue and lymphopenia that precede death via circulatory shock-like syndrome (Bondy and Pestka, 2000). DON induces gene expression of a number of cytokines including TNF-
, IL-6 and IL-1ß in experimental mice (Zhou et al., 1997
, 1998
). Trichothecene immunotoxicity is synergistically enhanced by low dose LPS exposure in mice, where pronounced thymic and splenic lymphocyte depletion are characteristically observed (Tai and Pestka, 1988
; Taylor et al., 1991
). Coexposure to subtoxic doses of LPS and DON markedly induces apoptotic cell death in lymphoid tissues that include the thymus, Peyers patches, bone marrow, and spleen of mouse (Islam et al., 2002
, 2003
; Zhou et al., 1999
, 2000
). LPS and DON interact to elevate and prolong corticosterone levels, which is critical for apoptosis induction, as evidenced by the ameliorating effects of the glucocorticoid receptor antagonist, RU 486 (Islam et al., 2002
). LPS also potentiates induction of proinflammatory cytokines and cyclooxygenase-2 (COX-2) by DON, which might contribute to corticosterone upregulation and subsequent apoptosis in mice (Islam et al., 2002
; Zhou et al., 1999
). However, TNF-
or IL-6 deficiencies in mice do not attenuate the interactive effects of LPS and DON on corticosterone production or apoptosis (Islam et al., 2002
, 2003
). Similar studies with pharmacologic inhibitors of COX-2 indicate that this enzyme is not critical in LPS plus DON-induced corticosterone production and lymphoid apoptosis.
The IL-1 family comprises two agonists (IL-1 and IL-1ß), an endogenous receptor antagonist (IL-1ra), two membrane-bound receptors (IL-1R1 and IL-1R2), and an accessory protein (IL-1RAcP) (Parker et al., 2000
). IL-1R1 is the functional form and interacts with IL-1RAcP to initiate signal transduction; IL-1R2 does not signal and acts as a decoy receptor for free IL-1. Both IL-1
and IL-1ß are released as a consequence of cell injury (Hogquist et al., 1991
). All necrotic forms of injury result in release and processing of IL-1
, whereas IL-1ß is released only in the unprocessed pro form. When the cell injury leads to apoptosis, both IL-1
and IL-1ß are efficiently processed and released. IL-1ß is a pro-inflammatory cytokine, which is induced in vivo by LPS (Laye et al., 2000
; Suzuki et al., 2002
). IL-1ß mRNA is synergistically increased in LPS plus DON-treated mice (Zhou et al., 1999
). IL-1ß is a principal pro-inflammatory cytokine that is critical for innate immunity (Suzuki et al., 2002
), modulates immune and inflammatory responses (Hogquist et al., 1991
), and is an important factor in inducing apoptosis in vivo in nonlymphoid tissues (Holmin and Mathiesen, 2000
; Nesic et al., 2001
; Ruckert et al. 2000
; Srivastava et al., 2002
; Suzuki et al., 2001
). IL-1ß has a capacity to induce cortiocsterone in two ways. First, the cyotokine can enter into the central nervous system and stimulate the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the release of adrenocorticotropic hormone (ACTH) and corticosterone (Parsadaniantz et al., 2000
). Second, IL-1ß can trigger adrenal gland production of corticosterone, either directly via IL-1R1 (Mazzocchi et al., 1998
; Nagano et al., 2000
) or indirectly with the local release of catecholamines (Gwosdow et al., 1995
). These latter two pathways may function independently of corticotropin releasing hormone (Sapolsky et al., 1987
) or ACTH (Parsadaniantz et al., 2000
) and thus be independent of the HPA axis.
IL-1ßs capacity to induce corticosterone might enable it to mediate leukocytotoxicity upon coexposure to subtoxic doses of LPS and trichothecenes. The purpose of this study was to test the hypothesis that IL-1ß plays a critical role in inducing corticosterone and subsequent leukocyte apoptosis in mice exposed to LPS and DON. Specifically, we compared plasma corticosterone concentrations and apoptosis in lymphoid organs and plasma corticosterone of (1) IL-1 receptor 1-deficient and wild-type (WT) mice and (2) mice preinjected with IL-1 receptor antagonist or a vehicle control. The results showed that IL-1ß was required for LPS plus DON-induced plasma corticosterone elevation and leukocyte apoptosis, and that these effects were likely to be evoked in an ACTH-independent fashion.
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MATERIALS AND METHODS |
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Mice.
Male B6C3F1 (C57B1/JHC3H/ HeJ) mice (7 weeks) were obtained from Charles River (Portage, MI). Mice were housed three per cage in a pathogen-free environment under a 12 h light/dark cycle, and provided standard rodent chow and water ad libitum. All animal handling was conducted in accordance with recommendations established by the National Institutes of Health. Experiments were designed to minimize the number of animals required to adequately test the proposed hypothesis, and were approved by the Michigan State University Laboratory Animal Research Committee.
For IL-1 receptor 1 (IL-1R1) knockout studies, B6.129S7-IL1r1tm1Imx and its donor strain, C57BL/6J (7 wk), were obtained from Jackson Laboratory (Bar Harbor, ME). B6.129S7-IL1r1tm1Imx mice are homozygous for targeted disruption of the IL-1R1 and fail to respond to IL-1 (Glaccum et al., 1997).
Experimental design.
LPS was dissolved in tissue culture-grade, endotoxin-free water (Sigma), aliquoted, and stored at -80°C. DON was also dissolved in tissue culture grade, endotoxin-free water and stored at 4°C. LPS (0.1 mg/kg, bw) was injected ip (100 µl/mouse). DON (12.5 mg/kg, bw) was gavaged po (100 µl/mouse) right after ip injection of LPS. The dose of LPS and DON were chosen based on dose response studies to induce thymic apoptosis (Islam et al., 2002, 2003
). Four to five mice per group were used for the individual experiments. Food and water were withdrawn from cages 1 h before toxin administration. In a typical experiment, mice were treated with vehicle (VH, ip) plus VH (po) [VH], LPS (ip) plus VH (po) [LPS], VH (ip) plus DON (po) [DON], LPS (ip) plus DON (po) [LPS plus DON].
For IL-1ß mRNA and protein determination, blood was collected from retroorbital plexus of metaflurane-anesthetized mice. Mice were immediately euthanized by cervical dislocation and spleens removed for RNA isolation.
For corticosterone and ACTH studies, mice were maintained under conditions of reduced noise and disturbance during the experiment period. Experiments were terminated and blood collected the same time of day to prevent diurnal and nocturnal variations of serum corticosterone levels. Trunk blood was obtained in EDTA-treated tubes from Beckton Dickinson Vacutainer Systems (Franklin Lakes, NJ) following decapitation within 1 min after touching the cage to minimize handling-induced increases in corticosterone levels. Plasma was collected and stored at -80°C until needed.
For apoptosis measurements, mice were euthanized by cervical dislocation under metaflurane anesthesia. Thymus, Peyers patches, and femurs (for bone marrow cells) were immediately removed for subsequent apoptosis measurements by agarose gel electrophoresis and flow cytometry.
Plasma IL-1ß quantitation.
IL-1ß ELISA was performed with DuoSet mouse IL-1ß from R & D Systems with Immulon IV Removawell microtiter strips (Dynatech Lab, Chantilly, VA) according to the manufacturers procedure. IL-1ß concentrations were determined from a standard curve using Softmax software (Molecular Devices, Menlo Park, CA).
Splenic IL-1ß mRNA quantitation.
Total RNA was extracted from spleen with an RNAqueous kit from Ambion Inc. (Woodward Street, TX) according to the manufacturers instructions. IL-1ß mRNA concentrations were quantified using a Quantikine mRNA colorimetric ELISA kit (R&D Systems) in conjunction with Softmax data analysis.
Cell preparation.
Upon removal, thymus and Peyers patches were immediately submerged into ice-cold Dulbeccos phosphate buffered saline (Sigma). Single cell suspensions were prepared according to a previously described method (Islam et al., 1998). Briefly, cells were released from thymus and Peyers patches by gently pressing tissue through 100 mesh screen (Collector Tissue Sieve, Bellco Glass Inc., Vineland, NJ) with a glass pestle. Bone marrow cells collected from femur were treated with erythrocyte lysing buffer (144 mM ammonium chloride and 17 mM Tris, pH 7.2) for 5 min at room temperature to remove erythrocytes and then washed twice with PBS. The cell suspension was passed through a 41-mm nylon sieve (Spectrum Laboratories, Inc., Laguna Hills, CA) and cell number was determined using Coulter Particle Counter (Coulter Co., Miami, FL).
DNA fragmentation analysis.
DNA from thymus was extracted as described by Sellins and Cohen (1987). In brief, cells (1 x 107) in PBS were centrifuged for 5 min (500 x g) at 4°C, and the pellet was suspended in 0.1 ml hypotonic lysing buffer (10 mM Tris, pH 7.4, 10 mM EDTA, pH 8.0, 0.5% [v/v] Triton X-100). Cells were incubated for 10 min at 4°C. The resultant lysate was centrifuged for 30 min (13,000 x g) at 4°C. Supernatant containing fragmented DNA was digested for 1 h at 37°C with 0.4 mg/ml of RNase A (Boehringer Mannheim, Indianapolis, IN) and then incubated an additional h at the same temperature with 0.4 mg/ml of proteinase K (Boehringer Mannheim, Indianapolis, IN). DNA was precipitated in 50% (v/v) isopropanol in 0.5 M NaCl at -20°C overnight. The precipitate was centrifuged at 13,000 x g for 30 min at 4°C. The resultant pellet was air dried and resuspended in 10 mM Tris (pH 7.4), 1 mM EDTA (pH 8.0). An aliquot equivalent to 2 x 106 cells was electrophoresed at 70 V for 2 h in 2% (w/v) agarose gel in 90 mM Tris-borate buffer containing 2 mM EDTA (pH 8.0). After electrophoresis, the gel was stained with ethidium bromide (0.5 µg/ml), and the nucleic acids were visualized with a UV transilluminator. A 100-bp DNA ladder (GIBCO-BRL, Rockville, MD) was used for molecular sizing.
Quantitation of apoptosis by flow cytometry.
Apoptosis in thymus, Peyers patches and bone marrow was quantified by flow cytometric cell cycle analysis (Pestka et al., 1994). Thymus, Peyers patch, and bone marrow cells (2 x 106), prepared as described above, were resuspended in 0.2 ml PBS. Following addition of 0.2 ml heat-inactivated fetal bovine serum, cells were immediately fixed by dropwise addition of 1.2 ml ice-cold 70% (v/v) ethanol with gentle mixing, and then held at 4°C overnight. Cells were washed and incubated in 1 ml propidium iodide (PI) DNA staining reagent (PBS containing 50 µg/ml PI, 50 µg/ml RNase A, 0.1 mM EDTA disodium, and 0.1% [v/v] Triton X-100) on ice until analysis. Cell cycle distribution for single cells was measured with a Becton Dickinson FACS Vantage (San Jose, CA). Data from 10,000 cells were collected in list mode. The 488 line of an argon laser was used to excite PI, and fluorescence was detected at 615645 nm. The cell cycle of individual cells was done using doublet discrimination gating to eliminate doublet and cell aggregate based on DNA fluorescence. The gate was drawn to include hypofluorescent cells. Cells in the DNA histogram with hypofluorescent DNA were designated apoptotic. All other cells distributed themselves in a normal cell cycle profile.
Plasma corticosterone and ACTH quantitation.
Plasma corticosterone and ACTH were quantified using commercial rat Corticosterone-3H and human ACTH-125I radioimmunoassay kits, respectively (ICN Biomedicals, Inc., Costa Mesa, CA) according to the manufacturers protocols. Corticosterone radioactivity was measured with a liquid scintillation system (Beckman Coulter, Inc., Fullerton, CA). ACTH radioactivity was measured in a precipitate with a gamma counter (Beckman Instrument, Inc., Irvine, CA)
Statistics.
Data were analyzed using Sigma Stat for Windows (Jandel Scientific, San Rafael, CA). For comparisons of two groups of data, Students t test was performed. For comparisons of multiple groups of data, a Kruskal-Wallis one-way ANOVA on ranks was performed. Data sets showing significant differences were further analyzed for synergy. Values from vehicle treated mice were randomly subtracted from LPS, DON, or LPS plus DON groups. Then LPS and DON replicates were randomly combined to calculate an expected mean additive response with variance. This calculated value was compared to actual cotreated samples using Mann-Whitney Rank Sum test. Data sets were considered significantly different when p < 0.05. The significant changes were reproducible in all the repeat experiments.
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RESULTS |
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IL-1R1 Deficiency Impairs LPS Plus DON-Induced Plasma Corticosterone Response
Previously we have shown that LPS plus DON treatment significantly induces plasma corticosterone in mice for up to 12 h and that corticosterone was required for synergistic induction of leukocyte apoptosis (Islam et al., 2002, 2003
). Therefore, induction of plasma corticosterone was compared in LPS plus DON-treated WT and IL-1R1 knockout mice at 12 h (Fig. 2
). The corticosterone concentrations in IL-1R1 knockout mice were significantly lower than WT mice (115 versus 297 ng/ml, respectively). Corticosterone levels in VH-treated WT and IL-1R1 knockout mice were minimal (3641 ng/ml). These results suggest that IL-1R1 mediated, in part, the marked upregulation of plasma corticosterone by LPS and DON coexposure.
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IL-1ra Blocks LPS Plus DON-Induced Leukocyte Apoptosis
Based on the prior experiment, two 100 µg/mouse doses of IL-1ra were given at 3 h intervals in an effort to inhibit LPS plus DON-induced leukocyte apoptosis. Flow cytometry analysis revealed that the percent apoptotic cells in LPS plus DON-treated mice to be 4.2 % in thymus, 6.4% in Peyers patches, and 1.9% in bone marrow at 12 h (Fig. 6). Consistent with the IL-1R1 knockout mice, apoptosis in the IL-1ratreated mice was also inhibited by 55, 38, and 58% in thymus, Peyers patches, and bone marrow, respectively.
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DON-Induced Plasma ACTH Is Not Potentiated by LPS
IL-1ß may act indirectly via the HPA axis or directly at the adrenal cortex to stimulate the secretion of corticosterone (Parsadaniantz et al., 2000). Therefore, the capacity of LPS to potentiate DON-induced plasma ACTH was compared among mice treated with VH, LPS, DON, or LPS plus DON over a 6 h time period (Fig. 8
). At 30 min, plasma ACTH levels in VH, LPS, DON, and LPS plus DON groups were 179, 348, 838, and 589 pg/ml, respectively. Mice treated with DON alone and LPS plus DON exhibited significantly higher plasma ACTH levels than VH or LPS groups at this time point. ACTH concentration in LPS alone group was also significantly higher than the VH group. At 3 h, ACTH levels in DON group dropped to control levels, whereas the LPS group (534 pg/ml) was significantly higher than all other groups. ACTH levels in the LPS plus DON group were reduced but still was significantly higher (313 pg/ml) than VH group. At 6 h, ACTH levels in LPS alone or LPS plus DON groups were significantly higher (241280 pg/ml) than VH group. These data suggest that, although DON or LPS independently induced ACTH, the combination of the two agents did not synergistically induce this hormone; rather, they suppressed the ACTH levels to some extent. Thus, it was not possible to correlate elevated corticosterone concentrations in LPS plus DON induced mice with effects on the HPA axis.
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DISCUSSION |
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IL-1ß is not released via the classic secretory protein pathway exhibited with many other cytokines (Hogquist et al., 1991). In LPS-stimulated cells, precursor forms of IL-1ß accumulate at high levels in the cytosol, and a biologically processed active form of IL-1ß is subsequently released from the cell. This release may be due to cell death or the activation of the secretory pathway. Plasma protein data must therefore be interpreted with caution because they reflect not only total IL-1ß protein production but also secretion, metabolism, and receptor binding of this cytokine. In this study, IL-1ß mRNA was increased in the LPS plus DON group at 3 h, which was significantly greater than the mean additive responses of LPS and DON. This mRNA effect preceded similar significant increases in IL-1ß proteins observed at 3, 6, and 9 h and thus was generally consistent with release of processed IL-1ß proteins.
IL-1ß can be upregulated in response to injury, trauma, or endotoxin treatment (Jelaso et al., 1998; Zhou et al., 1998
). Ischemia reperfusion injury and spinal cord injury lead to IL-1ß-dependent apoptosis in vivo in heart and spinal cord, respectively (Nesic et al., 2001
; Suzuki et al., 2001
). Silicosis also causes IL-1ß-dependent lung inflammation and apoptosis in mice (Srivastava et al., 2002
). IL-1ß also induces apoptosis in vitro in primary ß-cells (Zaitsev et al., 2001
), glioblastoma-derived human cells (Castigli et al., 2000
), and astrocytes (Ehrlich et al., 1999
). High doses of IL-1ß induce apoptosis of hair bulb keratinocytes in vivo (Ruckert et al., 2000
). Intracerebral administration of IL-1ß induces apoptosis in intrinsic central nervous system (Holmin and Mathiesen, 2000
). Thus, there are many examples of research that relate this cytokine to apoptosis induction. Although there are few papers indicating that repeated (45 day) injections of low dose of IL-1ß causes thymic atrophy (Bumiller et al., 1999
; Morrissey et al., 1988
), there has only been a single report to date that high doses of IL-1ß induce thymic atrophy in normal mice (Okada et al., 2000
). Our results are important because they expand on this concept and, furthermore, tie in a mediating role for corticosterone.
In this study, we attempted to impair the function of IL-1ß by using IL-1R1 deficient mice as well as using the IL-1ra, in order to test the hypothesis that LPS plus DON-induced IL-1ß might contribute to lymphoid apoptosis. IL-1 receptor1 (IL-1R1)-deficient mice are unresponsive to IL-1ß (Glaccum et al., 1997). The role of IL-1 receptor antagonist (IL-1ra) appears to competitively inhibit IL-1ß binding (Arend and Gabay, 2000
). Our results revealed that the impairment of functional IL-1R1 gene or the use of IL-1ra partially inhibited LPS plus DON-induced leukocyte apoptosis, thus suggesting that IL-1ß plays a role in enhanced leukocytotoxicity in toxin cotreated mice. The observation that inhibition of LPS plus DON-induced leukocyte apoptosis in IL-1R1 deficient mice or IL-1ra-treated mice correlated with the inhibition of plasma corticosterone levels is consistent with increased glucocorticoid-driven apoptosis following LPS plus DON exposure. As found by Dunn (2000)
, plasma corticosterone in mice is induced 2 h after a single injection of recombinant mouse IL-1ß. Corticosterone production could be completely blocked here by a single injection of IL-1ra. Although corticosterone levels are elevated in LPS plus DON-treated mice for up to 12 h (Islam et al., 2002
), the half-life for IL-1ra is only 21 min (Granowitz et al., 1992
). Thus, it was not surprising to find in preliminary experiments that injection twice with IL-1ra was more effective at inhibiting LPS plus DON-induced leukocyte apoptosis than was a single injection (data not shown).
It was notable that injection of IL-1ß protein three times (500 ng/mouse, ip at 0, 2, and 4 h) caused extensive apoptosis at 12 h in thymus and Peyers patches as compared to single injections and that this correlated with the elevated plasma corticosterone concentration. This requirement for multiple injections may relate to the short half-life (3 min) reported for IL-1ß protein (Klapproth et al., 1989; Reimers et al., 1991
). It would be of interest to determine whether IL-1ß could override the ablation of LPS plus DON-induced corticosterone and apoptosis induction by IL-1ra.
Although LPS plus DON induced apoptosis in thymus, Peyers patches, and bone marrow 12 h after treatment, recombinant mouse IL-1ßinduced apoptosis was observed here in thymus and Peyers patches but not in bone marrow. This might result from the early elimination of apoptotic cells from the bone marrow by phagocytosis in the IL-1ßtreated mice. Such an effect may be inhibited by DON which has been previously shown to inhibit phagocytosis in mononuclear cells (Ayral et al., 1992; Kidd et al., 1995
). This possibility could be addressed in future studies by measuring apoptosis at an earlier time point than 12 h or by collecting bone marrow cells earlier after IL-1ß treatment and culturing cells for a short time in vitro prior to measuring apoptosis to prevent macrophage mediated removal of apoptotic cells (King et al., 2002
).
It should be noted that both IL-1 and IL-1ß fail to activate signal transduction and to induce a biological response in vitro and in vivo in mice deficient for IL-1R1 (Fantuzzi, 2001
). IL-1
has 10-fold higher binding affinity to IL-1R1 than IL-1ß (Glaccum et al., 1997
). Therefore, the involvement of IL-1
per se or together with IL-1ß in inducing leukocyte apoptosis remains to be explored.
Both hypothalamus and adrenal gland have surface receptors for IL-1ß (Nagano et al., 2000; Turrin et al., 2001
). IL-1ß also has some limited capacity to enter the brain through the blood brain barrier (Parsadaniantz et al., 2000
). Therefore, IL-1ß might stimulate both the HPA axis (Sapolsky et al., 1987
) and the adrenal gland (Gwosdow et al., 1995
; Mazzocchi et al., 1998
; Nagano et al., 2000
) to produce glucocorticoids. To assess if the HPA axis is required for LPS plus DON-induced corticosterone production, we evaluated the kinetics of plasma ACTH release but could not find a correlation with elevated corticosterone or apoptosis. Thus, the effects of LPS plus DON in the model described herein may be ACTH- and HPA-independent, whereby direct interaction of IL-1ß with the adrenal gland is a requisite for the potentiative effects. Further clarification of these findings is warranted and should focus on dose-response effects of DON and LPS as well as use of CRH- or ACTH-deficient mice.
Taken together, this study suggests that LPS potentiates DON-induced corticosterone by causing a prolonged elevation of systemic IL-1ß. Furthermore, this corticosterone elevation is likely to drive subsequent induction of leukocyte apoptosis. The finding that IL-1R1 deficiency and IL-1ra treatment did not completely abrogate LPS plus DON-induced corticosterone production or apoptosis suggests that other redundant pathways might be in operation that dont involve IL-1ß. Further investigation of the mechanisms for IL-1ß upregulation as well as possible alternate or redundant pathways is therefore warranted.
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ACKNOWLEDGMENTS |
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NOTES |
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