CAWS administration increases the expression of interferon γ and complement factors that lead to severe vasculitis in DBA/2 mice
- Noriko Nagi-Miura†1,
- Daisuke Okuzaki†2, 3,
- Kosuke Torigata2,
- Minami A Sakurai2,
- Akihiko Ito4,
- Naohito Ohno1Email author and
- Hiroshi Nojima2, 3Email author
© Nagi-Miura et al.; licensee BioMed Central Ltd. 2013
Received: 21 June 2013
Accepted: 10 September 2013
Published: 24 September 2013
Candida albicans water-soluble fraction (CAWS), a mannoprotein-β-glucan complex obtained from the culture supernatant of C. albicans NBRC1385, causes CAWS-mediated vasculitis (CAWS-vasculitis) in B6 and DBA/2 mice with mild and lethal symptoms, respectively. Why CAWS is lethal only in DBA/2 mice remains unknown.
We performed DNA microarray analyses using mRNA obtained from peripheral blood mononuclear cells (PBMCs) of B6 and DBA/2 mice and compared their respective transcriptomes. We found that the mRNA levels of interferon-γ (Ifng) and several genes that regulate the complement system, such as C3, C4, Cfb, Cfh, and Fcna, were increased dramatically only in DBA/2 mice at 4 and 8 weeks after CAWS administration. The dramatic increase was confirmed by quantitative real-time polymerase chain reactions (qRT-PCR). Moreover, mRNA levels of immune-related genes, such as Irf1, Irf7, Irf9, Cebpb, Ccl4, Itgam, Icam1, and IL-12rb1, whose expression levels are known to be increased by Ifng, were also increased, but only in DBA/2 mice. By contrast, the mRNA level of Dectin-2, the critical receptor for the α-mannans of CAWS, was increased slightly and similarly in both B6 and DBA/2 mice after CAWS administration.
Taken together, our results suggest that CAWS administration induces Dectin-2 mediated CAWS-vasculitis in both B6 and DBA/2 mice and the expression of Ifng, but only in DBA/2 mice, which led to increased expression of C3, C4, Cfb, Cfh, and Fcna and an associated increase in lethality in these mice. This model may contribute to our understanding of the pathogenesis of severe human vasculitis.
KeywordsCAWS DNA microarray DBA/2 Kawasaki disease Complement factors Ifng
Vasculitis is characterized by the localized infiltration of inflammatory cells into the intravascular wall and its surroundings, and is accompanied by denaturation and necrosis, leading to potentially life-threatening conditions. The Candida albicans water-soluble fraction (CAWS), a mannoprotein-β-glucan complex obtained from the culture supernatant of C. albicans NBRC1385, exhibits vasculitis-inducing activity in mice (CAWS-vasculitis), which acts as a trigger for the induction of vasculitis in the coronary artery[2–4]. Indeed, CAWS has strong induction potency for murine vasculitis and induces lethal toxicity in certain mouse strains[5, 6]. Unlike polypeptides derived from Candida albicans, however, CAWS does not display superantigen-like activities because the part of the CAWS complex that elicits physiological activity is the polysaccharide chain. Dectin-2, a C-type lectin expressed by dendritic cells (DCs) and macrophages, functions as the critical DC receptor for α-mannans of CAWS and plays a pivotal role in host defense against C. albicans by inducing Th17 cell differentiation. A subtype of CAWS with a higher ratio of β-mannosyl linkages, named CAWS727, failed to cause severe vasculitis in DBA/2 mice but inhibited the inflammatory response via a competitive association with α-mannan specific lectins, including dectin-2: this result indirectly demonstrated dectin-2 involvenment in the development CAWS mediated vasculitis. Intraperitoneal injection of CAWS induced coronary arteritis in both C57BL/B6 (B6 hereafter) and DBA/2 mice[10, 11]. However, only DBA/2 mice exhibited severe necrotizing coronary arteritis and aortitis leading to nearly 100% mortality within weeks from stenosis in the left ventricular outflow tract and severe inflammatory changes of the aortic valve with fibrinoid necrosis. Although Dectin-2 may be essential for CAWS-vasculitis in both B6 and DBA/2 mice, it remains elusive as to why CAWS-vasculitis is fatal to DBA/2 mice, but not to B6 mice.
The complement system, comprised of more than 30 serum and cellular proteins, plays a major role in innate immune defenses against infectious agents. Complement activation appears to be involved in the pathogenesis of systemic autoimmune diseases. The alternative pathway involving C3 convertase (C3bBb), a potent enzymatic protein complex capable of rapidly converting C3 into powerful effector fragments (C3a and C3b), amplifies the initial response, inducing a variety of effector functions. In acute coronary syndrome (an inflammatory disease), the complement cascade is activated and the C3 and C4 concentration ratio (C3/C4 ratio) in serum is a readily available marker of recurrent cardiovascular events. Complement activation produces the complement C5 (C5), a precursor to the effector molecules, C5a and C5b; C5a acts as a trigger for the cellular immune response and C5b acts as an initiator of the formation of the membrane attack complex. C5a mediates inflammatory responses through the C5a receptor 1 (C5aR); however, C5a also exerts an anti-inflammatory effect, putatively through its second receptor, the C5a-like receptor 2 (C5L2), which may act either as a decoy receptor or by forming the C5aR/C5L2/β-arrestin complex, depending on the cell type, species and disease context. Notably, DBA/2 mice are defective in C5, though it remains unknown how this C5 deficiency may contribute to the fatal effect of CAWS.
Ifng, the only member of the type II class of interferons, is a soluble homodimer with potent proinflammatory properties that plays critical roles in innate and adaptive immunity against viral and intracellular bacterial infections. Ifng-induced inflammation is involved in aging and aging-associated medical and psychiatric disorders. Notably, Ifng level was increased in splenocyte culture supernatants following stimulation with lipopolysaccharide, by a Gram-negative bacterial cell wall component or with CAWS[10, 22]. Thus, it appears that complement factors and Ifng are somehow involved in CAWS-vasculitis; however, no direct data to confirm this have been reported.
In the present study, we report the results of DNA microarray analysis of mRNAs from PBMCs comparing differences in gene expression patterns in B6 and DBA/2 mice. We found that mRNA levels of Ifng and complement factors such as C3, C4, Cfb, Cfh, and Fcna were conspicuously augmented only in DBA/2 mice at 4 and 8 weeks after CAWS administration. Moreover, mRNA levels of immune-related genes, such as Irf1, Irf7, Irf9, Cebpb, Ccl4, Itgam, Icam1, and IL-12rb1, whose expression levels are known to be augmented by Ifng, were also increased only in DBA/2 mice. Based on these results, we propose a molecular model to explain how CAWS treatment induces fatal vasculitis in DBA/2 mice.
Induction of arteritis by injection of CAWS into DBA/2 mice
CAWS enhanced expression of complement system genes only in DBA/2 mice
To identify genes whose expression levels were up- or downregulated in the PBMCs of DBA/2 mice, but not in B6 mice, following CAWS treatment, we examined the transcriptome profiles of mRNA prepared from DBA/2 and B6 PBMCs at 2 w, 4 w, 8 w, or 9 w following CAWS administration using Agilent’s Whole Mouse Genome Microarray (G4122F). When the relative intensities of the signals at 2 w, 4 w, 8 w, or 9 w were compared with those at 0 w following CAWS administration, the genome-wide expression profiles were found to be distinct between these two mouse strains (Additional file1: Figure S2A). Heat map representation of the signal intensities revealed that a number of genes were dramatically up- or downregulated in DBA/2 mice compared to B6 mice (Additional file1: Figure S2B).
To determine whether changes in the expression levels of these genes is physiologically significant, a scatter plot was used to analyze the distribution of the expression levels of many genes at a glance. Indeed, C3, C4, Cfb, Cfh, Fcna, and Cr2 showed expression levels high enough to conduct physiologically significant comparison (>10 raw signal intensity) in DBA/2 mice at 2 w or 4 w following CAWS administration (Figure 2B). By contrast, complement genes that showed very low expression levels compared to above described activated complement genes in both B6 and DBA/2 mice were not deemed significant (Figure 2B). C3ar1 mRNA levels were low at 2 w or 4 w and its expression level was enhanced only at 9 w following CAWS administration. Thus, we conclude that the enhanced mRNA levels of C3, C4, Cfb, Cfh, and Fcna observed after CAWS administration in DBA/2 mice are significant.
The alternative complement pathway is activated in DBA/2 mice following CAWS administration
CAWS induced upregulated expression of interferon-related genes only in DBA/2 mice
In the pathway identified as the “Role of Prk in interferon induction and antiviral response”, mRNA levels of eukaryotic translation factor 2 alpha kinase 4 (Eif2aka) and Irf1 were enhanced (Figure 5B). Eif2aka is a heterotrimeric GTPase that controls the selection of correct start codons on mRNA, and thus regulates translation initiation by facilitating the preferential translation of selected transcripts in response to cellular stresses, in this case CAWS administration. Our results suggest that DBA/2 mice are more sensitive to this type of stress than B6 mice.
In the “acute phase response signaling” pathway (Figure 5C), three genes other than C3 and Cfb were upregulated; CCAAT/enhancer-binding protein beta (Cebpb or C/EBPβ), IL-5, and lipopolysaccharide-binding protein (Lbp). Cebpb, a member of the C/EBP family of basic region-leucine zipper (bZIP) proteins, is largely expressed in macrophages and is important for the antibacterial activity of macrophages through binding to the regulatory regions of several acute phase and cytokine genes. Enhanced expression of Cebpb following CAWS administration suggests that downstream target genes of Cebpb, including IL-4 (see below), may be widely activated. IL-5 exerts pleiotropic effects on various target cells, including B cells, eosinophils, and basophils, and overexpression of IL-5 in vivo significantly increases the number of eosinophils and B cells. Lbp is involved in the acute phase immunologic response to Gram-negative bacterial infections through binding to bacterial lipopolysaccharide (LPS), thereby eliciting immune responses by presenting the LPS to the cell surface pattern recognition receptors CD14 and Tlr4. In this case, CAWS, rather than LPS, may have been recognized as an infectant.
In the “acute phase myeloid leukemia signaling” pathway (Figure 5D), two genes were upregulated: spleen focus-forming virus proviral integration 1 (Sfpi1 or PU.1) and colony stimulating factor 1 receptor (Csf1r). Sfpi1 is a transcription factor that plays a key role in hematopoietic cell fate decisions through mutual negative regulation that occurs between Sfpi1and GATA-1, a zinc finger transcription factor that is the central mediator of erythroid gene expression. Csf1r is a single pass type I membrane protein that acts as a receptor tyrosine kinase for a cytokine called colony stimulating factor 1, which is a primary growth factor and monocyte/macrophage chemokine that regulates survival, proliferation and differentiation of macrophages and other mononuclear phagocytic lineage cells. Enhanced expression of Csfr1 suggests the activation of macrophages following CAWS administration.
A scatter plot of Irf1, Irf9, C3, Cebpb, Csf1r, Trf, Ifng, Eif2aka, and Cfb expression showed expression levels high enough to conduct physiologically significant comparisons (>10 raw signal intensity) in DBA/2 mice at 2 w or 4 w following CAWS administration (Figure 2B), suggesting that their enhanced mRNA levels indicated by the heatmap (Figure 5E) are significant. By contrast, mRNA levels of Lbp and Sfpi1 may be too low for comparison between B6 and DBA/2 mice to be significantly different.
Transcription factor genes showing upregulated expression only in DBA/2 mouse
Zinc finger protein 384 (Zfp384), also called Nmp4 (nuclear matrix protein 4), is a nucleo-cytoplasmic shuttling transcription factor that regulates the expression of collagen and matrix metalloproteinases and represses bone formation induced by parathyroid hormone. Ankyrin repeat and SOCS box-containing protein 2 (Asb2) interacts with mixed lineage leukemia (MLL) protein, a key epigenetic regulator of normal hematopoietic development, and overexpression of Asb2 degrades MLL to reduce its transactivation activity. Zinc finger protein 3612 (Zfp3612), a member of the tristetraprolin family of tandem CCCH finger proteins that bind to AU-rich elements in the 3’-untranslated region of mRNAs, is a critical modulator of definitive hematopoiesis. Zinc finger protein 819 (Zfp819), a member of the C2H2-zinc finger (C2H2-Znf) family of proteins, appears to function as a transcriptional and cell cycle/apoptosis regulator and play a role in the establishment and maintenance of pluripotency. Although these proteins play roles in several important cellular events such as hematopoiesis, these functions do not appear to be relevant to the pathogenesis of CAWS-induced vasculitis.
Scatter plot analysis indicated that mRNA levels of Irf1, Cebpb, Stat1, Nurp1, Irf7, and Brd8 were high enough to conduct physiologically significant comparison between B6 and DBA/2 mice according to their heatmaps (Figure 6B) at both 2 w and 4 w following CAWS administration (Figure 6C), suggesting that their superficially augmented expression is physiologically significant. By contrast, mRNA levels of Asb2, Zfp819, Zfp384, Zfp37, Zfp3612, and Tbx20 were too low to conclude that heatmap comparison of these genes between B6 and DBA/2 mice is physiologically significant.
Finally, CAWS administration resulted in a slight, but comparable increase in Dectin-2 mRNA levels in both B6 and DBA/2 mice (Additional file1: Figure S7A). Moreover, scatter plot analysis indicated that the mRNA levels of Dectin-2 mRNA were lower than those of Dectin-1, a similar C-type lectin molecule (Additional file1: Figure S7B).
In the present study, we used DNA microarray analysis to identify genes whose mRNA levels in PBMCs were upregulated in DBA/2 mice (with lethal vasculitis) but not in B6 mice (with non-lethal vasculitis) at 2 w, 4 w, 8 w, and 9 w following CAWS administration (Figure 1). We found that the mRNA levels of C3, C4, Cfb, and Cfh (Figure 2), which regulate the alternative pathway of the complement system (Figure 3), are conspicuously increased in DBA/2 mice at 4 w, 8 w, and 9 w following CAWS administration, whereas B6 mice showed decreased mRNA levels of these proteins, and this notable difference was confirmed by qRT-PCR (Figure 4). We also observed that mRNA levels of Ifng and interferon-related genes were augmented in the PBMCs of DBA/2 mice compared with those of B6 mice (Figure 4F and Figure 5A). Ifng expression is induced upon infection by pathogens such as viruses, bacteria, or parasites, suggesting that some components of CAWS, possibly the polysaccharide chains of α and β mannoproteins in the cell wall extract, are recognized as pathogens after injection.
Ifng enhanced C3 mRNA and protein expression levels in a human astroglioma cell line. Ifng increased steady state mRNA levels of both C3 and C4 in three different human cell types (Hep G2, U937, and primary fibroblasts). Ifng stimulation also increased C3 and C4 protein synthesis. Moreover, Ifng induced biosynthesis of complement components C2, C4, and Cfh at the transcriptional level in human proximal tubular epithelial cells. In mice, Cfb mRNA expression was synergistically upregulated in murine macrophages, and Ifng directly stimulated transcription or stabilized complement C3 and C4 mRNAs. Transgenic mice over-expressing Ifng in the brain exhibited neuroinflammation induced by upregulation of the early components of the complement cascade, including C3 and C4a. Thus, increased C3 and C4 mRNA expression following CAWS administration appears to be due to increased Ifng expression, which may occur due to recognition of CAWS as a pathogen.
Interferon regulatory factors, including Irf1 (Figure 5F, Figure 6C), Irf7 (Figure 6C), and Irf9 (Figure 5F), are Ifng-induced genes encoding transcription regulators that induce the expression of other immune-related genes, including genes that mediate the antiviral activity of Ifng and play pivotal roles in the regulation of cellular responses, such as inflammation in host defense. Indeed, Ifng enhanced the expression of Itgam, Icam1, and IL-12rb1. In particular, Irf1, which regulates the expression of Ifn-induced genes and type I interferon, is an early signal that promotes inflammation; Irf1-deficient mice are protected from autoimmune brain inflammation through regulation of Th2-type cytokines. Moreover, expression levels of Irf1 were significantly higher in the synovium of joints with rheumatoid arthritis than in that of those with osteoarthritis. Irf1 gene activation by reactive oxygen species is an early signal that promotes inflammation after ischemic renal injury. Notably, Ifng increases the expression of Irf9 protein in human PBMCs, and Cebpb (Figure 6F), which plays a fundamental role in regulating activated macrophage functions, is necessary for Ifng-induced upregulation of Irf9 mRNA in cultured mouse bone marrow-derived macrophages. Cebpb is also involved in expression of Ccl4 mRNA (Figure 6F) induced by Ifng and lipopolysaccharide.
The low but similar expression levels of Dectin-2 (Additional file1: Figure S7) in B6 and DBA/2 mice suggest that Dectin-2 plays similar roles in CAWS-vasculitis in these two mice. The lethality of CAWS-vasculitis in DBA/2 mice, but not in B6 mice, may be due to the increased expression and activity of components in the Ifng-complement axis. Dectin-1, a β-glucan specific receptor, may not be involved in CAWS-vasculitis, because CAWS is a mannoprotein and lacks the dectin-1 ligand, beta-1,3-glucan, which results in no signal being transmitted via the dectin-1 route. A recent report suggests that the mannan-Dectin-2/FceRIc pathway promotes phosphorylation of a protein called linker for activation of B cells (Lab), which induces natural killer and T cell-mediated Ifng production following C. albicans infection.
It was recently shown that CAWS-treated DBA/2 mice developed left ventricular dilution and dysfunction with macroscopic cardiomegaly and concentric left ventricular hypertrophy. We propose here that this chronic mortality of CAWS-treated DBA/2 mice is due to abnormal activation of the complement system induced by Ifng upregulation. This proposal is supported by recent reports showing that C5a elicits anti-inflammatory action through C5L2, and that inflammation in DBA/2 mice deficient in C5 cannot be inhibited following CAWS treatnment[17, 20]. The proposal is also supported by the observation that inflammation cannot be inhibited in a mutant mouse deficient in C5 expression with acute pancreatitis and associated lung injury. CAWS also induced vasculitis in other mouse strains, such as C3H/HeN, C3H/HeJ (TLR4 mutation), DBA/1, A/J, CBA/N, C57Bl, AKR, and BALB/c mice. It would be interesting to test whether the Ifng-complement axis is also activated following CAWS administration in these mouse models in the future.
We and others have reported that complement activation is involved in the pathogenesis of systemic autoimmune diseases[14, 54–56]. In active anti-neutrophil cytoplasmic antibody-associated vasculitis with renal lesions, significantly higher levels of plasma C3a, C5a, soluble C5b-9, and Bb, a component of the alternative complement pathway, was observed during active development of the disease. Ficolin-1 mRNA level showed a four-fold increase in the PBMCs of TA patients, and that ficolin-1 protein expression was observed in the inflamed regions of surgical aorta specimens, in particular in CD68-positive cells (macrophages or dendritic cells), which are involved in the induction of inflammation. Ficolin-1 mRNA level was also higher in PBMCs isolated from microscopic polyangiitis (MPA) patients than in PBMCs isolated from healthy volunteers. Moreover, increased expression of ficolin-1 protein was also detected by immunostaining in renal specimens taken from MPA patients, and many of the ficolin-1 positive cells coincided with CD68-positive cells in the glomeruli of MPA patients. These results suggest that enhanced expression of ficolin-1 in monocytes and macrophages is also involved in the pathogenesis of human vasculitis.
Our results suggest that CAWS administration induces non-lethal CAWS-vasculitis in both B6 and DBA/2 mice via a Dectin-2 pathway, but induces enhanced expression of Ifng only in DBA/2 mice, which leads to augmented expression of C3, C4, Cfb, Cfh, and Fcna, thereby causing lethal inflammation of the arteries and severe vasculitis. Thus, the Ifng-complement axis may play an important role in the pathogenesis of lethal CAWS-vasculitis, and suggest that this axis may also be important in the pathogenesis of human vasculitis.
Mouse and fungi
Male B6 and DBA/2 mice were obtained from Japan SLC and Charles River Japan. Mice (5–14 weeks of age) were raised in a specific pathogen-free environment. All animal experiments were performed at the Tokyo University of Pharmacy and Life Sciences (TUPLS), and the experimental protocol was approved by the Committee of Laboratory Animal Experiments of TUPLS. Fungi (C. albicans strain NBRC1385) was acquired from the National Institute of Technology and Evaluation Biological Resource Center, stored on Sabouraud agar medium (Difco) at 25°C, and subcultured once every 3 months.
Preparation of CAWS
CAWS was prepared from C. albicans strain NBRC1385 by conventional methods. Culture was performed in 5 liters of C-limiting medium for 2 days at a rotation speed of 400 rpm while pumping in air at 5 L/min and 27°C. After culturing, an equal volume of ethanol was added, and after allowing it to stand undisturbed overnight, the precipitate was recovered. This fraction was dissolved in 250 ml of distilled water, ethanol was added, and the solubilized fraction was again allowed to stand undisturbed overnight. The precipitate was recovered and dried with acetone to obtain CAWS.
Total RNA of leukocytes from whole blood of B6 and DBA/2 mice was stabilized by RNAlater™ (Ambion) and then isolated using LeukoLOCK™, a total RNA Isolation System (Ambion, Austin, TX, USA), according to the manufacturer’s instructions. The integrity of the total RNAs used for the microarray analysis was confirmed using the RNA 6000 Nano LabChip Kit (p/n 5067–1511) on the Agilent 2100 Bioanalyzer (G2938C; Agilent Technologies Inc., Palo Alto, CA), and only samples with an RNA integrity number (RIN) above 8.8 were used for gene expression profiling.
DNA microarray analysis
Microarray analyses were performed as single-color hybridizations. Total RNAs obtained from mouse PBMCs were independently reverse- transcribed using oligo-dT primers containing the T7 RNA polymerase promoter sequence to generate cDNAs and MMLV-RTase. These were then subjected to in vitro transcription using T7 RNA polymerase to label the cRNAs with Cy3-CTP (Amersham Pharmacia Biotech, Piscataway, NJ) using a Fluorescent Linear Amplification Kit (Agilent Technologies). Purified Cy3-labeled cRNAs (825 ng) from individual B6 or DBA/2 mice were then hybridized on the microarrays. Washing, scanning, and gene analysis with Agilent’s Whole Mouse Genome Microarray (4×44K; G4122F), on which 31,226 known genes were spotted, were conducted according to the manufacturer’s protocol (Agilent Technologies). Agilent Feature Extraction software (v. 9.5.1) was used to assess spot quality and extract feature intensity statistics. The Subio Platform and Subio Basic Plug-in (v1.11; Subio Inc., Aichi, Japan) were then used to calculate the between-sample fold change. When a large number of genes were automatically classified by the software into a signaling pathway heatmap, only the genes whose mRNA levels were distinct between B6 and DBA/2 mice following CAWS treatment were selected. The details of the microarray data have been deposited in the Gene Expression Omnibus (GEO; http://informahealthcare.com/doi/abs/10.3109/08923973.2013.830124) database (accession number GSE44803).
Mouse tissues were fixed in 4% paraformaldehyde immediately after removal, then embedded in paraffin and cut into sections (4 μm thick). Sections were stained with H&E according to standard procedures.
Expression profiling using quantitative reverse transcription-polymerase chain reaction (qPCR)
Assay-on-Demand TaqMan probes with relevant primers were used for qPCR analysis using the ABI PRISM 7900 according to the manufacturer’s instructions (PE Applied Biosystems, Foster City, CA). Total RNA (500 ng) obtained using the PAXgene Blood RNA Kit was reverse-transcribed with the High Capacity cDNA Archive Kit (ABI). PCR consisted of an initial denaturation (95°C, 10 min) followed by 40 cycles of denaturation (95°C, 15 sec) and annealing/extension (60°C, 1 min). A standard curve was generated from the amplification data for each primer using a dilution series of PBMC RNA as the template. Fold change values were normalized to GAPDH expression levels using the standard curve method according to the manufacturer’s protocol.
All experiments in which mice were used were performed with the approval of the ethics committee of Tokyo University of Pharmacy and Life Sciences.
Ankyrin repeat and SOCS box-containing
Candida albicans water-soluble fraction
CCAAT/enhancer-binding protein beta
Component 3a receptor 1
Component 5a receptor 1
Complement factor b
Complement factor h
Complement factor i
Double-stranded RNA binding domain
Eukaryotic translation initiation factor 2-alpha kinase 2
Hematoxylin and eosin
Interferon regulatory factor-1
Linker of activated T cells
Protein activator of the interferon-induced protein kinase
Peripheral blood mononuclear cell
Phosphate buffered saline
Protein kinase R
Quantitative real-time polymerase chain reaction
T cell-replacing factor
We are indebted to Dr. Hodaka Fujii for insightful advice throughout this work. We thank Dr. Claudia Gaspar of Bioedit Ltd. for critically reading this manuscript. We also thank Ms. Maki Fukuda and Ms. Chiharu Nakashima for technical assistance with the microarray experiments. This work was supported in part by grants-in-aid for Scientific Research S (No. 15101006), Scientific Research B (No. 20370081) and Exploratory Research (No. 21651085) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (http://www.mext.go.jp/english/) to HN. This study was also supported in part by grants from the Health Science Foundation and Ministry of Health, Labour and Welfare of Japan to HN and NO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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