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,1
* Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka, Japan;
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA; and
The Third Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Japan
2Correspondence: Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1–8 Yamadaoka, Suita, Osaka 565-0871, Japan, E-mail: kwada{at}dent.osaka-u.ac-jp; or C.N.S., Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, 20 Shattuck St., Thorn 724, Boston, MA 02115, USA. E-mail: cnserhan{at}zeus.bwh.harvard.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: inflammatory mediators • neural inflammation • BLT receptor • ALX receptors • neuron
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2
3
4)
. Leukotriene B4 (LTB4) serves as a signal causing initiation of an acute inflammatory response, while lipoxin A4 (LXA4) dampens and promotes resolution (5)
. Aspirin also triggers the biosynthesis of an endogenous epimer of LXA4, namely aspirin-triggered 15-epi-LXA4, which shares the potent anti-inflammatory actions of LXA4. These mediators can also regulate proliferation of several cell types, including epithelial, endothelial, and mesangial cells (6
7
8)
. To date, the activities of LTB4, LXA4, and aspirin-triggered 15-epi-LXA4 in neural stem cell (NSC) have not been studied and are of considerable interest.
In the central nervous system (CNS), most self-renewal is dependent on NSCs. These cells, which can be isolated from embryonic brains, are multipotent, self-renewing progenitor cells that can differentiate into neurons and glial cells (9
10
11)
. NSCs are expected to be useful in treating neurodegenerative disorders such as Parkinson’s disease, Huntington’s disease, nerve injury, stroke, and multiple sclerosis. Hence, the mechanisms and factors involved in the proliferation and differentiation of NSCs are of wide interest (12
13
14
15
16)
. Lipid mediators such as LTB4 and LXA4 can be produced in the CNS either from endogenous synthesis by microglial and astroglial cells (17)
or by surrounding cells and tissues, such as peripheral blood leukocytes recruited through the blood-brain barrier in response to CNS injury.
Here we report that LTB4 and LXA4 are potent counter-regulatory signals in NSCs regulating both proliferation and differentiation.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Preparation of neural stem cells
All mice were treated humanely according to the National Institutes of Health and AERI-BBRI Animal Care and Use Committee guidelines. All animal experiments were approved by the institutional Animal Care and Use Committee of Osaka University.
Preparation of neural stem cells was carried out as in Gritti et al. (18)
with some modifications. A pregnant BALB/c mouse was anesthetized and euthanatized on day 13 or 14 of gestation. The brain was removed from the embryo and placed in a culture medium that consisted of Dulbecco’s modified Eagle medium (DMEM)/F12 medium (Life Technologies, Inc., Grand Island, NY, USA) containing 0.6% glucose (Glc), 0.1% NaHCO3, 5 mM HEPES, 100 µg/ml bovine transferrin (Life Technologies), 25 µg/ml bovine insulin (Sigma, St. Louis, MO, USA), 10 µg/ml putrescine (Sigma), 30 nM sodium selenite (Sigma), 20 nM progesterone (Sigma), 20 ng/ml human epidermal growth factor (EGF) (PeproTech EC, Rocky Hill, NJ, USA), 20 ng/ml human FGF (PeproTech EC), 100 µg/ml penicillin, 100 U/ml streptomycin (Life Technologies). The cells were dissociated by mechanical dispersion with a flamed-narrowed Pasteur pipette. After centrifugation, cells were resuspended in culture medium and primary stem cell proliferation was observed after 7–8 days. Neurospheres were collected, gently triturated with a flamed-narrowed Pasteur pipette, and subcultured at a density < 5 x 104 cells/ml in a culture bottle (Nalge Nunc, Naperville, IL, USA). Confirmation of neural stem cells was performed by detection of nestin expression and neurosphere formation according to previous reports (12
, 14
, 18)
. Maintenance of an undifferentiated state of neural stem cells was performed in uncoated culture bottles (Nalge Nunc).
Cell culture of NSCs and compound treatments
NSCs formed neurospheres in uncoated culture bottles, representing a state of undifferentiation (12
, 14
, 15
, 18)
; when cultured on poly-L-ornithine/laminin-coated plates (Biocoat, Becton Dickinson, Bedford, MA, USA), NSCs adhered to the plates, proliferated, extended their neurites, and differentiated into neurons. Exposure to LTB4 agonist, antagonists, synthetase inhibitors, or vehicle (ethanol) was started when NSCs were scattered onto ornithine/laminin-coated plates. Three days after exposure, morphological changes and the rate of cell growth were investigated.
Evaluation of cell growth
After NSCs were treated with compounds or vehicle for 3 days, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) solution (Sigma-Aldrich, Tokyo, Japan) was added to the culture medium and cells were incubated for 4 h (13
, 14)
. SDS (20%) was then added, the cells were left at room temperature for 5 h, and absorbance at a wavelength of 595 nm was measured. Cell growth rates were measured by MTT assay and expressed as a percentage compared with the vehicle control. Neuroblastoma-like cell lines, such as NB1 (human neuroblastoma), NB2a (mouse neuroblastoma), and C1300N18 (mouse neuroblastoma), were also used to evaluate cell growth in comparison to the NSCs.
Chromatin staining for detection of apoptosis
NSCs treated with LTB4 receptor antagonist or LT synthetase inhibitors were cultured on poly-L-ornithine/laminin-coated Lab-Tek II Chamber Slides for 24 h. The cells were fixed with 4% paraformaldehyde in PBS for 10 min and chromatin staining was performed with Hoechst 33342 (Sigma-Aldrich, Tokyo, Japan) to determine nuclear condensation, a morphological change associated with apoptosis, using a fluorescence microscope (IX 70, Olympus, Tokyo, Japan).
RT-polymerase chain reaction (RT-PCR)
Amplification was carried out with HotStartTaq DNA polymerase (Qiagen, Valencia, CA, USA) by using specific primers; 5'-ACCAAACCCCTGGAGAGAGT-3' and 5'-GAAGATCACCACCGTCAGGT-3', which amplify the 650 bp product for 5-LO; and 5'-GATCTGCGCTCCGAACTATC-3' and 5'-GACTCAGGAATGGTGGAGGA-3', which amplify 546 bp product for BLT1; and 5'-CTCATCTGAGCCTGGAGACC-3' and 5'-TGCCCCATTACTTTCAGCTT-3', which amplify 475 bp product for BLT2; and 5'-GATGCTAGAGGGGATGTGCAC-3' and 5'-TCTTCAGGAAGTGAAGCC-3', which amplify 529 bp product for ALX1; and 5'-TGCTGTCAAGATCAACAGAAG-3' and 5'-TGCAGGAGGTGAAGTAGAAC-3', which amplify 361 bp product for ALX2; and 5'-AGACGTGGGATCACTTTTGG-3' and 5'-ACGTCGTAATTGGGCTTGAC-3', which amplify 460 bp product for LTA4H; and 5'-GACCACAGTCCATGCCATCACT-3' and 5'-TCCACCACCCTGTTGCTGTAG-3', which amplify 430 bp product for GAPDH. For FLAP, nested polymerase chain reaction (PCR) was carried out using 1st set of primers (5'-ACAAGGTGGAGCATGAAAGC-3' and 5'-ATCGTCGTGCTTACCGTTCT-3') and 2nd set of primers (5'-ATGAAAGCAAGGCGCATAAT-3' and 5'-CGCTTCCGAAGAAGAAGATG-3').
Western blot analysis
NSCs were exposed to LTB4 (24 h, 37°C). The cells were collected and homogenized in lysis buffer (20 mM Tris-HCl, 150 mM NaCl, 4 mM EGTA, 1% Triton X-100) containing a cocktail of protease inhibitors (Sigma-Aldrich, Tokyo, Japan). Cell extracts, prepared by centrifugation at 16,000 g, were resolved by sodium dodecyl sulfate-PAGE (SDS-PAGE) and Western blot analysis was performed. Western blots were probed with anti-EGF receptor, anti-cyclin E, antip27, anticaspase-8, and anti-cleaved caspase-3 polyclonal antibody (pAb) at 4°C, overnight and treated with a horseradish peroxidase-conjugated secondary Ab for 1 h; detection was achieved using an enhanced chemiluminescence-plus kit (Amersham, London, UK).
Gene chip analysis
NSCs were exposed to vehicle or LTB4 (100 nM) for 12 h, then cells were collected. Total RNA was prepared from vehicle or LTB4-treated group, respectively. Amino-allyl amplified RNA was then prepared from total RNA using an Amino-allyl MessageAmp aRNA kit (Ambion, Inc., Austin, TX, USA). Amino-allyl amplified RNAs from vehicle or the LTB4-treated group was labeled by Cy3 or Cy5 using FluoroLink Cy3 or Cy5 mono-functional Dye 5-Packs (Amersham Bioscience, London, UK), then applied to mouse gene chip system (Sigma Genosis Japan, Sapporo, Japan). Expression of genes was detected by the fluorescent intensity of Cy3 and Cy5. After normalization, alteration of the major up-regulated or down-regulated genes on NSCs treated with LTB4 was expressed as fold increase in comparison with those treated with vehicle.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A, vehicle). NSCs exposed to LTB4 for 3 days stimulated cell growth rate from 3 nM to 100 nM (Fig. 1A, B
). The stimulation of cell growth by LTB4 showed a bell-shaped curve, since a weak inhibition of cell growth was conversely observed at a concentration of LTB4 > 1 µM (Fig. 1B
). This biphasic response in cell growth was not observed when NSCs were treated with other LTs such as peptidoleukotrienes LTC4 and LTD4 (at 3 nM to 10 µM, n=3–5; not shown).
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We also investigated LTB4 and cell growth with several neuroblastoma cell lines. The stimulation of cell growth by LTB4 was not observed in neuroblastoma-like cell lines, including NB1, NB2a, and C1300N18 (data not shown). Together, these results suggest that the action of LTB4 on cell growth is specific for NSC, supporting a function role for LTB4 in NSCs but not in neuroblastomas cell lines.
The expression level of LTB4 receptor type 1 (BLT1) in NSCs was much higher than in neuroblastoma-like cell lines (Fig. 2
A). The high levels of BLT1 protein in NSCs were decreased in differentiated neurons. This was confirmed by RT-PCR and immunohistochemistry. BLT1 receptor mRNA expression was observed in undifferentiated NSCs, and its expression gradually decreased in neurons differentiated for 2–3 days. LTB4 receptor type 2 (BLT2) mRNA was not detected in this system (Fig. 2C
). Furthermore, high-level expression of BLT1 protein was observed in the area of the future lateral ventricle in mouse brain at embryo day 15, in contrast to that in mouse brain at postnatal day 1 (Fig. 2B
). These results indicate that high-level expression of BLT1 protein may be important for immature NSCs but not for differentiated neurons. Also, staining of BLT1 and nestin (a marker of immature NSCs) was closely related in the area of the future lateral ventricle in embryonic brain (data not shown), the main area of NSC localization in embryos (9
, 12
, 18)
. This finding further emphasized the potential importance of LTB4 receptors in proliferation of immature NSCs in embryos.
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The 5-lipoxygenase, 5-lipoxygenase-activating protein (FLAP), and LTA4 hydrolase (LTA4H) are involved in the formation of leukotrienes and lipoxins (1
, 4)
; since 5-lipoxygenase, FLAP, and LTA4H were abundantly expressed in NSCs (Fig. 2C
), we examined 5-lipoxygenase inhibitors (parthenoide, AA-861, and nordihydroguaiaretic acid) on NSC proliferation. The three 5-lipoxygenase inhibitors each blocked cell growth of NSCs in a concentration-dependent manner (Fig. 1C
). Indeed, LTB4 was present in the NSC culture media (7.22±3.54 ng LTB4/106 cells), which was completely blocked by 5-lipoxygenase inhibitors (LTB4 was not detected with 10 µM of parthenoride and AA-861, 1.47±0.92 ng LTB4/106 cells by 1 µM of nordihydroguaiaretic acid), suggesting that NSCs endogenously generate as well as release LTB4. To confirm the role of this LTB4 receptor-mediated pathway on NSC proliferation, we investigated the effect of the specific BLT1 antagonists, ONO-4057 and U-75302, on NSC growth. The two LTB4 receptor antagonists inhibited cell growth in a concentration-dependent manner (Fig. 1D
), indicating that the stimulation of cell growth by LTB4 is mediated by BLT1. We also used LB-405, a partial LTB4 receptor agonist, to investigate the exogenous and stable LTB4 mimetics on NSC growth. LB-405 stimulated cell growth at concentrations of 100 nM to 1 µM; at >3 µM, cell death was observed (Fig. 3
A, B). Together, these results indicate that activation of the LTB4 receptor-mediated pathway induces cell growth but that excessive and permanent activation can also cause cell death.
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We next investigated whether the decrease in NSC growth in the presence of 5-lipoxygenase inhibitors or LTB4 receptor antagonist was due to apoptosis. Nuclear condensation, a morphological change associated with apoptosis, was assessed by staining with Hoechst 33342. Treatment of NSCs with 5-lipoxygenase inhibitors or BLT1 antagonist caused nuclear condensation (Fig. 3C
). These results indicate that LTB4 signaling may protect NSCs from the induction of apoptosis and promote their cellular proliferation and expansion.
The LXA4 pathway signal acts as a "stop" signal in inflammatory responses and can oppose the actions of LTB4 (4
, 5
, 19
, 20)
. We therefore investigated LXA4, its aspirin-triggered epimer 15-epi-LXA4, and its stable analog, 15-epi-16-(parafluorophenoxy)-LXA4 methyl ester (ATLa), in proliferation of NSCs. These compounds inhibited cell growth of NSCs in a concentration-dependent manner (Fig. 1E
). To date, in mice two separate LXA4 receptors of G-protein coupling type (mALX1/Fpr-rs1 and mALX2/Fpr-rs2) were identified (20
, 21)
. Mouse ALX2/Fpr-rs2 mRNA was expressed in both undifferentiated NSCs and differentiated neurons, whereas ALX1/Frp-rs1 mRNA was not found in this system (Fig. 2C
). Mouse ALX1/Fpr-rs1 is the first described mouse LXA4 receptor (Kd=1.5 nM) highly expressed in leukocytes and spleen (20)
. Later, a second LXA4 receptor mALX2/Fpr-rs2, which shared 83% sequence identity with mALX, was identified from a macrophage that functionally responds to LXA4 as a ligand in recombinant systems (21)
. These results demonstrate for the first time the possible physiological role of this second LXA4 receptor mALX2 in controlling regenerative response of NSCs in the CNS.
To investigate the potential mechanisms of LTB4 and LXA4 on proliferation of NSCs, we performed a gene chip analysis to identify the molecules regulated by LTB4. Several molecules involved in cell cycle and growth, such as the EGF receptor cyclin E, were up-regulated, and caspase 8 was down-regulated in NSCs exposed to LTB4 (Supplemental Fig. 1). To confirm this finding, we performed Western blot analysis. NSC protein levels of EGF receptor and cyclin E were up-regulated in a concentration-dependent manner with LTB4 and were down-regulated with LXA4 (Fig. 4
). In contrast, caspase-8 was down-regulated by LTB4 but not by LXA4. The decrease in caspase-8 protein by LTB4 was accompanied by a decrease in caspase-3 cleavage, a marker of caspase-3 activation. Conversely, LXA4 caused an increase in caspase-8 protein levels and activation of caspase-3. Caspase-8 is known as a critical mediator for Fas-TNF-mediated apoptosis (22)
. These results indicate that LTB4- LXA4 signaling may regulate the Fas-TNF-mediated apoptosis pathway by controlling the levels of caspase-8.
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Protein levels of p27Kip1 were dramatically decreased by LTB4 and not by LXA4. p27Kip1 is a cyclin-dependent kinase (Cdk) inhibitory protein that negatively regulates cell cycle, and its phosphorylation causes degradation of p27Kip1, resulting in an increase in cell growth (23
, 24)
. Using a cell cycle-specific Ab array system, we found alterations in the phosphorylation of proteins involved in cell cycle progression within 60 min of exposure to LTB4 or BLT1 antagonist (see Supplemental Fig. 2). One of the dramatically altered proteins was p27Kip1. We confirmed that LTB4 increased phosphorylation of p27Kip1, which resulted in the degradation of p27Kip1. In contrast, BLT1 antagonist caused a decrease in phosphorylation, resulting in an increase in p27Kip1 protein level (Fig. 5
). No alterations were observed in protein levels of CREB or ERK (Supplemental Fig. 3A).
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Gene chip analysis also showed increases in the expression of mRNA coding for several ion channels, nicotinic receptors, and microtubule-associated protein 2 (MAP2). The ion channels and nicotinic receptors are required for the maturation of neurons, and MAP2 is a marker for differentiated neurons (12
, 14)
. These results indicate that LTB4 promotes differentiation of NSCs into neurons. Hence, we investigated LTB4 and BLT1 antagonist on neurite outgrowth. LTB4 caused an increase in neurite outgrowth but treatment with BLT1 antagonist did not (Fig. 6
A). The expression of MAP2, a marker of differentiated neurons, was increased by treatment with LTB4 but not by the BLT1 antagonist, ONO-4057 (Figs. 6B, C
).
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To investigate the involvement of Ca2+ on LTB4-mediated stimulation of NSC proliferation, we used the intracellular Ca2+ chelator, 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM). At high concentrations (10–30 µM), BAPTA-AM inhibited NSC proliferation (Fig. 7
A), so we used lower concentrations of BAPTA-AM (1 µM), which showed no apparent direct actions on NSC proliferation. BAPTA-AM partially, but not completely, inhibited the LTB4-mediated stimulation of NSC proliferation (Fig. 7B
). These results indicate that intracellular Ca2+ mobilization is partially involved in LTB4 stimulation of NSC proliferation.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 20)
. Here we describe for the first time the potent neuronal regulatory functions of these bioactive LOX products. Activation of the LTB4 signaling pathways in NSC by physiological levels of LTB4 promoted stem cell proliferation. Excessive activation of LTB4 signaling, with higher concentrations of LTB4 (>3 µM), resulted in inhibition of NSC growth. This biphasic action of LTB4 suggests that LTB4 signaling tightly regulates proliferation of NSCs and indicates that optimal amounts in vivo of local LTB4 might play a role in NSC survival and proliferation.
Consistent with this role of LTB4 signaling in regulating NSC proliferation, 5-lipoxygenase inhibitors and LTB4 receptor antagonist caused apoptosis of NSCs. It is of note that proliferation of human neuronal precursor cells was also blocked by 5-lipoxygenase inhibitor (25)
. These results suggest that LTB4 signaling regulates NSC growth and that programmed cell death ensues in its absence.
To investigate whether the mobilization of intracellular Ca2+ is involved in LTB4-mediated NSC proliferation, we used the intracellular Ca2+ chelator, BAPTA-AM. BAPTA-AM partially, but not completely, blocked LTB4-mediated NSC proliferation. These results indicate that mobilization of intracellular Ca2+ by LTB4 is partially involved in NSC proliferation.
The LXA4 signaling pathway inhibited cell growth of NSCs. Thus, it appears that LTB4-LXA4 signaling may tightly regulate the expansion and contraction of NSC mass by acting as "accelerator and brake" after pathological events in brain tissue. LTB4-LXA4 signaling-mediated alteration of cell growth was associated with changes in the protein levels of the EGF receptor, cyclin E, caspase 8, and p27Kip1. The increase in EGF receptor levels by treatment with LTB4 directly increased cell growth. The increase in cyclin E and decrease in p27Kip1 also caused an acceleration of cell cycle, resulting in the stimulation of cell growth. In contrast, treatment with LXA4 resulted in decreased protein levels of the EGF receptor and cyclin E, but slightly increased p27Kip1 levels, resulting in inhibition of cell growth. The alteration of p27Kip1 protein level is dependent on protein phosphorylation. Recently an inhibitory action of LXA4 on cell cycle progression via mediation of p27Kip1 levels was also observed in mesangial cells (26)
, suggesting a similar mechanism may be involved in NSC proliferation.
We also observed alterations in the phosphorylation of several proteins potentially involved in cell cycle and apoptosis, such as p16, p36, p73, GADD34, p21cip1, p63, NF-1, cyclin B, and CUL-1, by a cell cycle-specific Ab array system (Supplemental Fig. 2). The roles of phosphorylation of those proteins on cell cycle and apoptosis are not as clear as that of p27Kip1 phosphorylation. Additional investigations are needed to clarify the relationship between these proteins and detailed mechanisms in NSC responses. LTB4-LXA4 signaling also altered the protein level of caspase 8 but not of other caspase family members, such as caspase-2 and caspase-9 (see Supplemental Fig. 3). Caspase-8 is known as a critical mediator of Fas-TNF-mediated apoptosis. In the present experiments, activation of caspase-3 was observed to be dependent on the increase in caspase-8 protein levels. Together, these findings point to the involvement of the Fas-TNF-mediated pathway on NSC apoptosis and its regulation by LTB4 and LXA4 in NSC.
Of particular interest, LTB4 stimulated the differentiation of NSCs into neurons. This was confirmed by increased neurite outgrowth and increased expression of MAP2, as well as by increased expression of several channels and receptors, such as voltage-gated sodium channel, potassium channel, chloride channel, and nicotinic receptor. Increased levels of these molecules are required for the maturation of differentiated neurons. The present results indicate that LTB4 signals not only proliferation, but also differentiation of NSCs into neurons. In general, it is rare to observe markers of both proliferation and differentiation at the same stage in somatic cells. The mechanisms underlying stimulation of differentiation by LTB4 may differ from those required for proliferation. NSCs are considered multipotent cells that have the ability of both "self-renewal" and "differentiation." Therefore, it might be unique to the NSC system to exhibit both proliferation and differentiation phenotypes in response to LTB4.
Visible disorders were not observed for 5-lipoxygenase knockout mice during development, although various different responses against inflammation and other pathological conditions were observed with 5-lipoxygenase knockout mice compared with those of wild-type (WT) mice (27
28
29)
. These reports and our observations in the present study indicate that bioactions of 5-lipoxygenase-derived lipid mediators described in this study may be more relevant in pathophysiological conditions such as PD, Huntington’s disease, nerve injury, stroke, and multiple sclerosis than for normal CNS development and maturation.
The expression level of BLT1, but not of ALX2, was diminished in differentiated neurons compared with immature NSCs. Also, lipid mediators such as LTB4 and LXA4 can be locally produced in the CNS from either an endogenous source or local/surrounding sources such as peripheral blood leukocytes recruited locally in response to injury. A local balance between cell proliferation and cell death or survival provides the CNS with powerful self-renewing mechanisms. Hence, fine-tuning between LTB4 and LXA4 signals at both ligand and receptor levels might be useful for coordinated neurogenesis triggered as an endogenous protective mechanism of the CNS.
In summation, NSCs express both the LTB4 receptor (BLT1) and LXA4 receptor (ALX2). LTB4-LXA4 signaling regulates proliferation and differentiation on murine NSCs. These results suggest not only the involvement of LOX-derived lipid mediators in controlling regenerative response of NSCs in CNS, but also the potential therapeutic utility of these lipid mediators and their mimetics for a wide range of neuropathological disorders wherein specifically regulating neurogenesis and neuroinflammation may be beneficial.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication January 31, 2006. Accepted for publication April 25, 2006.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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