Cerebral Cortex Advance Access originally published online on March 31, 2006
Cerebral Cortex 2007 17(3):522-530; doi:10.1093/cercor/bhj177
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A Transcriptional Enhancer That Directs Telencephalon-Specific Transgene Expression in Mouse Brain
1 Laboratory for Neurobiology of Synapse, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, 2 Department of Physiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan, 3 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Osaka 560-0082, Japan
Address correspondence to Yoshihiro Yoshihara, PhD, Laboratory for Neurobiology of Synapse, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. Email: yoshihara{at}brain.riken.go.jp.
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Abstract |
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Telencephalin (TLCN, intercellular adhesion molecule-5 [ICAM-5]) is a cell adhesion molecule belonging to the immunoglobulin superfamily, which plays important roles in dendritic morphogenesis and synaptic plasticity. The expression of TLCN is restricted to neurons in the most rostral brain segment, telencephalon. Here, we examined a transcriptional regulatory mechanism underlying the telencephalon-specific expression of TLCN. TLCN gene is located in the ICAM gene cluster containing ICAM-1, ICAM-4, and TLCN (ICAM-5) within 30 kb on the mouse chromosome 9. The nucleotide sequence of the 5'-flanking region of mouse TLCN gene is highly homologous to that of human and dog orthologs, suggesting the presence of important regulatory elements for its transcription. To determine the telencephalon-specific enhancer region, we generated several lines of transgenic mice that harbor transgenes consisting of different length of the 5'-flanking region of mouse TLCN gene (3.9, 1.5, 1.1, and 0.2 kb) fused to humanized renilla green fluorescent protein cDNA as a fluorescent reporter. Consequently, we identified a crucial region between 1.1 and 0.2 kb upstream of the transcription start site that directs the telencephalon-specific expression. This enhancer was applied to the Cre/loxP-mediated conditional expression system to generate several transgenic lines with different patterns of recombination in the telencephalon and will be further used as a powerful tool for genetic manipulation in the telencephalic neurons.
Key Words: Cre/loxP • ICAM-5 • telencephalin • telencephalon • transcription • transgenic mouse
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Introduction |
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The telencephalon is the most rostral brain segment comprising more than 80% in volume of the human brain. Regions responsible for the higher brain functions such as cognition, emotion, motivation, learning, and memory typically reside in the telencephalon that includes the cerebral neocortex, hippocampus, striatum, and amygdala. Recent advance in the gene-targeting and transgenic technology began to enable us to address the roles of individual genes in such functions in the telencephalic regions. However, many genes are generally expressed not only in the telencephalon but also in the nontelencephalic regions, including the midbrain, brain stem, spinal cord, and even in the peripheral organs that are important to maintain animals' life. Thus, in many cases, the deletion of genes in the whole body results in embryonic or neonatal lethality. Even if the targeted animals can survive into adulthood when the higher brain functions can be assayed, it is difficult to determine whether the observed phenotypes are due to the abnormality in either the telencephalic or nontelencephalic regions. Therefore, it is necessary to delete the genes of interest selectively in the telencephalon without affecting the development and functions of other brain segments.
Telencephalin (TLCN, intercellular adhesion molecule-5 [ICAM-5]) is a cell adhesion molecule belonging to the ICAM subgroup of the immunoglobulin (Ig) superfamily (Yoshihara and Mori 1994
; Yoshihara and others 1994), which is specifically expressed in neurons within the telencephalon from early postnatal period to adulthood (Mori and others 1987; Oka and others 1990). In the telencephalic neurons, TLCN protein is selectively targeted to dendrites but not to axons (Murakami and others 1991; Benson and others 1998; Mitsui and others 2005). TLCN interacts with plural types of molecules, such as lymphocyte function–associated antigen-1 (CD11a/CD18, 
Lß2 integrin) (Mizuno and others 1997; Tian and others 1997), presenilin-1 (Annaert and others 2001; Esselens and others 2004), and TLCN itself (Tian, Nyman, and others 2000), and plays distinct roles in various cell–cell interaction events such as dendritic morphogenesis during development (Matsuno and others 2006), synaptic plasticity in mature brains (Sakurai and others 1998; Nakamura and others 2001), and neuron–microglia or neuron–lymphocyte interactions in pathological conditions (Rieckmann and others 1998; Mizuno and others 1999; Guo and others 2000; Tian, Kilgannon, and others 2000; Lindsberg and others 2002; Hasegawa and others 2004).
To gain insights into the telencephalon-specific expression of TLCN, we here investigated mouse TLCN gene locus in the ICAM gene cluster on chromosome 9. By using transgenic mouse system, we determined the transcriptional enhancer of TLCN within the 1.1-kb 5'-flanking region, which directs restricted expression of reporter genes in the telencephalic neurons. Thus, the telencephalon-specific and postnatal period–specific induction of transgene expression by this enhancer provides an ideal tool for manipulation of genes involved in the higher brain functions.
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Materials and Methods |
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Plasmid Construction
Humanized renilla green fluorescent protein (hrGFP) cDNA was excised from pIRES-hrGFP-1a (Stratagene, La Jolla, CA) and inserted into an EcoRI site of pBstN vector (containing human ß-globin gene intron and Simian virus 40 (SV40) polyadenylation signal) to construct pBstN-GFP. The 3.9-kb 5'-flanking region of mouse TLCN gene was excised with EcoRV and HindIII from pBluescript-mTLCN genomic DNA (Sugino and others 1997) and inserted into a BamHI site of pBstN-GFP to construct pTLCN3.9-GFP. TLCN3.9-GFP, TLCN1.5-GFP, TLCN1.1-GFP, and TLCN0.2-GFP transgenes with different lengths of the TLCN promoter/enhancer region were excised from pTLCN3.9-GFP plasmid by digestion with XbaI/AscI, KpnI, XhoI, and NheI/KpnI, respectively. To construct pTLCN3.9-Cre, the same procedure was used as described above, except that cDNA encoding Cre recombinase fused to a nuclear-localizing signal was used instead of hrGFP cDNA. TLCN3.9-Cre transgene was excised from the plasmid by digestion with XbaI/AscI.
Animals
Generation of transgenic mice was performed as described previously (Kobayashi and others 1994). Briefly, gel-purified transgenes were microinjected into the pronucleus of fertilized eggs that were obtained from crossing (C57BL/6J x DBA/2J) F1 mice. The manipulated eggs were cultured to 2-cell stage and transferred into oviducts of pseudopregnant foster females (ICR strain). CAG-CAT-Z transgenic mice were kindly provided by Dr J. Miyazaki (Araki and others 1995). Integration of the transgenes was screened by polymerase chain reaction of tail DNA. All animal experiments were approved by the Animal Care and Use Committee of RIKEN and conformed to National Institutes of Health guidelines.
Antibody Production
Anti-hrGFP peptide antibody was produced by immunizing rabbits with the C-terminal 15-amino acid peptide of hrGFP (LTSLGKPLGSLHEWV) conjugated to keyhole limpet hemocyanin. Anti-TLCN polyclonal antibody was produced by immunizing guinea pigs with recombinant TLCN/Fc protein that consists of the whole extracellular region of mouse TLCN fused to human IgG1 Fc region.
Western Blot Analysis
Various tissue samples collected from individual transgenic mouse lines were homogenized in 10 mM Tris–HCl (pH 7.5) containing protease inhibitors (complete protease inhibitor cocktail, Roche Diagnostics, Indianapolis, IN), dissolved in Laemmli buffer, run on sodium dodecyl sulfate–polyacrylamide gel (20 µg protein per lane), and transferred onto polyvinylidene difluoride membranes. The membranes were blocked with 10 mM Tris–HCl (pH 7.4) containing 150 mM NaCl, 0.02% Tween-20, and 5% skim milk and then incubated with anti-hrGFP antibody (rabbit, 1:10 000). Horseradish peroxidase–conjugated anti-rabbit IgG (goat, 1:10 000, Jackson ImmunoResearch, West Grove, PA) was used as a secondary antibody. Immunoreactive protein bands were detected with ECL Plus western blotting detection system (GE Health care Bio-Sciences, Piscataway, NJ), and images were captured with luminescence image analyzer (LAS-1000 mini, Fujifilm, Tokyo, Japan).
Histochemistry
Double- or triple-fluorescence immunohistochemistry of brain sections was carried out as described previously (Mitsui and others 2005). The following primary antibodies were used: anti-hrGFP (rabbit, 1:1000), anti-TLCN/Fc (guinea pig, 1:1000–3000), anti-T-box gene 21 (Tbx21) (guinea pig, 1:10000) (Yoshihara and others 2005), anti-Aristaless-related homeobox gene (Arx) (rabbit, 1:1000) (Kitamura and others 2002), and anti-calbindin (rabbit, 1:1000, Chemicon, Temecula, CA). Secondary antibodies labeled with Cy3, Cy5, or Alexa488 were purchased from Jackson ImmunoResearch and Molecular Probes (Eugene, OR). Fluorescent images were obtained with a fluorescent microscope (Axioplan, Carl Zeiss, Oberkochen, Germany) equipped with a charge-coupled device (CCD) camera and an image analysis system (DP-70, Olympus, Tokyo, Japan) or a confocal laser scanning microscope (Fluoview FV1000, Olympus).
For mapping Cre protein expression in TLCN3.9-Cre transgenic mice, anti-Cre recombinase (mouse, 1:1000, Chemicon) and horseradish peroxidase–conjugated anti-mouse IgG (donkey, 1:300, Jackson ImmunoResearch) were used as primary and secondary antibodies, respectively. Signals were developed with diaminobenzidine as a substrate, and specimens were observed with a light microscope (AX-80, Olympus) equipped with a CCD camera and an image analysis system (DP-50, Olympus).
LacZ staining of brain sections from the crosses between TLCN3.9-Cre and CAG-CAT-Z transgenic mice was performed with X-gal as a substrate as described previously (Sassa and others 2004). Specimens were observed with a stereomicroscope (MZFLIII, Leica Microsystems, Wetzlar, Germany) equipped with a CCD camera and an image analysis system (DP-70, Olympus).
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Conservation of 5'-Flanking Sequences between Mouse and Human TLCN Genes
The 4 ICAM genes (ICAM-1, ICAM-3, ICAM-4, and TLCN [ICAM-5]) are densely packed in a small region on the human chromosome 19 and mouse chromosome 9 (Fig. 1A,B) (Sugino and others 1997; Kilgannon and others 1998). Because the expression profiles of ICAM members are markedly distinct (ICAM-1 in leukocytes and inflammatory sites, ICAM-3 in leukocytes, ICAM-2 in erythrocytes, and TLCN in telencephalic neurons) (Gahmberg 1997; Hayflick and others 1998), there must exist tightly regulated mechanisms for the transcription of individual genes. We first compared nucleotide sequences between the mouse and human ICAM clusters encompassing ICAM-1, ICAM-4, and TLCN. The highest homology, other than the exons of individual genes, was detected in the 1.6-kb intervening sequence located downstream of ICAM-4 and upstream of TLCN genes (Fig. 1C), implicating the presence of crucial cis-regulatory elements in this region for TLCN expression.
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Telencephalon-Specific Transcriptional Enhancer Upstream of Mouse TLCN Gene
To identify the telencephalon-specific transcriptional enhancer, we constructed 4 transgenes that carry different lengths of 5'-flanking sequence of mouse TLCN gene (3.9, 1.5, 1.1, and 0.2 kb) fused to a fluorescent reporter hrGFP cDNA (Fig. 1D). Several lines and founders of transgenic mice were generated for each construct and analyzed for GFP expression in the brain.
With the longest construct containing 3.9-kb 5'-flanking region of TLCN gene (TLCN3.9-GFP), GFP was expressed strongly in the telencephalon for 2 lines and 1 founder, although there are some variations in the expression patterns possibly due to the positional effects from chromosomal integration sites of the transgene. Whole-mount dorsal, ventral, and lateral views of the adult brain from a representative line (TLCN3.9-GFP #3) showed an intense GFP fluorescence exclusively in the telencephalon but not in other brain segments (Fig. 2A–C,G).
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Next, we analyzed 3 shorter fragments (1.5, 1.1, and 0.2 kb) of the 5'-flanking region of TLCN gene. The telencephalon-specific expression of GFP was observed in transgenic mice that harbor 1.5 and 1.1 kb of the 5'-flanking sequence (Fig. 2D,E,G), with a pattern similar to the longest one (3.9 kb, Fig. 2A–C). However, the shortest fragment with 0.2-kb promoter region failed to induce the telencephalon-specific GFP expression (Fig. 2F,G). These results indicate that a crucial element for the telencephalon-specific expression resides within –1.1 and –0.2 kb from the transcription start site of mouse TLCN gene.
The distribution of transgene expression was examined by western blot analysis with anti-GFP antibody on various tissue samples prepared from 5 transgenic mouse lines (Fig. 2H). In the transgenic lines that showed GFP fluorescence in the telencephalon (TLCN3.9-GFP #2, #3; TLCN1.5-GFP #1; TLCN1.1-GFP #3), a strongly GFP-immunoreactive band was observed predominantly in the brain but not at all in the spinal cord, demonstrating the telencephalon-specific transgene expression in the nervous system. No immunoreactive protein band was detected in all tissues of TLCN0.2-GFP #5. Faint signals were present in a few peripheral tissues of 2 lines (spleen and testis in TLCN3.9-GFP #3 and lung in TLCN3.9-GFP #2).
GFP Expression in Subpopulations of Telencepahlic Neurons
A comparison of expression was made between a transgene reporter GFP (Fig. 3A) and endogenous TLCN protein (Fig. 3B) by double immunofluorescence labeling of a parasagittal brain section from the representative transgenic line with the highest expression of GFP, TLCN3.9-GFP #3, which showed a similar pattern of GFP expression to the shorter construct, TLCN1.1-GFP #3. The overall patterns of expression of GFP and TLCN were similar, although there appeared differences in a merged image (Fig. 3C). This is partly because the 2 proteins are localized to different subcellular compartments in neurons: GFP is a soluble molecule diffused in the cytoplasm of axons, dendrites, and cell bodies, whereas TLCN is a membrane protein specifically sorted into dendrites (Murakami and others 1991; Benson and others 1998; Mitsui and others 2005).
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A careful observation of brain sections revealed that the GFP expression was restricted to subpopulations of neurons in individual telencephalic regions such as the cerebral neocortex, olfactory bulb, hippocampus, striatum, amygdala, and olfactory cortical areas. In the cerebral neocortex, GFP was expressed in a layer-specific manner with the strong fluorescence in the layer II/III and VI pyramidal neurons (Fig. 3D–F). In the olfactory bulb, GFP fluorescence was detected in Arx-positive granule cells but not in Tbx21-positive mitral cells (Fig. 3G–J) (Yoshihara and others 2005
). These expression patterns in the cerebral neocortex and olfactory bulb are consistent with that of endogenous TLCN (Mori and others 1987; Imamura and others 1990; Murakami and others 1991). In the hippocampus, GFP was expressed strongly in calbindin-positive granule cells of the dentate gyrus and weakly in pyramidal cells of the CA1 area (Fig. 3K,M,N), although the endogenous TLCN was distributed evenly in all types of the hippocampal projection neurons (Fig. 3L,N). This may be because the 3.9-kb 5'-flanking region of TLCN gene is not sufficient to induce completely faithful expression of transgene to the endogenous TLCN in the hippocampus. GFP fluorescence in the substantia nigra of the midbrain was of telencephalon origin, derived from axonal terminals projecting from the striatum (Fig. 3A,C). These results suggest that 3.9-kb 5'-flanking region of mouse TLCN gene is capable of inducing the telencephalon-specific transgene expression, similar to the expression pattern of endogenous TLCN. Ontogenic Analysis of the Telencephalon-Specific Enhancer Activity
The telencephalon-specific enhancer activity was examined at several developmental stages in the TLCN3.9-GFP #3 transgenic mice. At postnatal day 1 (P1), a weak GFP expression was detected by anti-hrGFP immunohistochemistry in the olfactory bulb granule cells, piriform cortex, and hippocampus, concomitant with the first appearance of endogenous TLCN in these regions (Fig. 4A–D). At P7, GFP expression was increased and observed in the cerebral neocortex, striatum, and amygdala, as well as in the brain regions mentioned above (Fig. 4E–H). At P14, the pattern of transgene expression was almost similar to that of adult brain (Fig. 4I–L). Thus, the ontogenic expression of the telencephalon-specific enhancer activity parallels that of the endogenous TLCN.
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Application of the Telencephalon-Specific Enhancer to Cre/loxP System
The Cre/loxP system is a powerful tool for conditional activation or inactivation of genes of interest. We generated 5 lines of transgenic mice that express Cre recombinase under the control of the telencephalon-specific enhancer (3.9 kb) of TLCN and crossed them with CAG-CAT-Z transgenic mice in which LacZ reporter is expressed under the strong and ubiquitous CAG promoter upon Cre-induced recombination (Araki and others 1995). Different patterns of LacZ expression in the telencephalon were observed among transgenic lines (Fig. 5). In TLCN3.9-Cre line A, Cre was expressed in a small population of neurons in the superficial layer of cerebral neocortex and piriform cortex (Fig. 5A-1–A-4). In line B, Cre-mediated recombination was observed in the cerebral neocortex with a gradient along the anteroposterior axis (Fig. 5B-1–B-4). In line C, Cre expression was detected in the anterior olfactory nucleus, striatum, amygdala, and dentate gyrus in addition to the cerebral neocortex (Fig. 5C-1–C-4). In line D, various telencephalic neurons were positive for Cre expression except for the olfactory bulb, olfactory tubercle, and striatum (Fig. 5D-1–D-4). In line E, Cre-mediated recombination occurred throughout the brain (Fig. 5E-1–E-4). Detailed patterns of Cre protein expression were investigated in the 4 TLCN3.9-Cre transgenic lines A–D by anti-Cre immunohistochemistry and summarized in Table 1.
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Curiously, the ectopic expression of LacZ was observed in cells of the medulla oblongata and choroid plexus in the fourth ventricle consistently in all the transgenic lines (Fig. 5A-1,B-1,C-1,D-1,E-1), although Cre protein was not expressed in this region of the adult brain (Table 1). Because TLCN is not expressed in the medulla at any developmental stages from embryonic day (E10) to adult (data not shown) and we have not encountered such ectopic expression with other transgenes (hrGFP, CD8, CD8/TLCN) driven by the same promoter/enhancer elements (Fig. 3A; Mitsui and others 2005
), it is likely that the nucleotide sequence in Cre cDNA may have affected the transcriptional regulatory activity of TLCN promoter/enhancer to induce the ectopic expression of Cre transgene itself in the medulla transiently at a certain developmental stage. |
Discussion |
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TLCN is a cell adhesion molecule that plays multiple roles in various cell–cell interaction events in neural development and functions, such as dendritic morphogenesis (Matsuno and others 2006
), neural plasticity (Sakurai and others 1998; Nakamura and others 2001), and neuron–immune cell interactions (Rieckmann and others 1998; Mizuno and others 1999; Guo and others 2000; Tian, Kilgannon, and others 2000; Lindsberg and others 2002; Hasegawa and others 2004). In particular, we have recently shown that TLCN slows spine maturation by the formation of dendritic filopodia and the maintenance of immature synapses and may function as "a softener of synapse" that endows plastic and flexible properties to dendritic protrusions of the telencephalic neurons (Matsuno and others 2006). The telencephalon-specific expression of TLCN would be important for its proper functioning in these processes.
A mechanism for the tight transcriptional regulation of TLCN gene should be required for its telencephalon-specific expression. Several transcription factors that are mainly expressed in the forebrain, such as brain factor-1 (BF-1) (Tao and Lai 1992), empty spiracle homeobox gene-1 (Emx-1), Emx-2 (Simeone and others 1992), distal-less homeobox gene-1 (Dlx-1), Dlx-2 (Bulfone and others 1993), T-box brain gene-1 (Tbr-1), and Tbr-2 (Bulfone and others 1995, 1999), have been reported. Among them, a winged helix transcription factor, BF-1, exhibits the telencephalon-specific expression that is apparently in accord with that of TLCN. However, the expression of BF-1 starts at a very early stage of embryonic development (E11 in mouse), reaches maximal level at E17, and decreases postnatally (Tao and Lai 1992). In contrast, the expression of TLCN is hardly detectable in embryonic brain, dramatically increases after birth, and remains high in adulthood (Mori and others 1987; Yoshihara and others 1994). Thus, little overlap for the 2 molecules is observed from a developmental point of view, suggesting that BF-1 is not involved in the transcriptional regulation of TLCN.
We have identified a crucial region for the telencephalon-specific expression within –1.1 and –0.2 kb from the transcription start site of mouse TLCN gene. In silico database search was carried out to compare the mouse, dog, and human nucleotide sequences and to search for putative transcription factor–binding sites in this region using rVISTA program (Loots and others 2002) (Fig. 6). Several interesting transcription factor–binding sequences were observed within the telencephalon-specific enhancer region, including a neural activity-inducible transcription activator, cAMP-responsive element-binding protein (CREB) (Lonze and Ginty 2002); a winged helix transcription factor, winged-helix nude (WHN) (Nehls and others 1994); and a transcription factor, leader-binding protein 1 (LBP1), that interacts with an adapter protein of Alzheimer's ß-amyloid precursor protein Fe65 (Zambrano and others 1998; Minopoli and others 2001). However, we did not encounter any promising candidates that may be responsible for the telencephalon-specific gene expression. Although we searched for nucleotide sequences in the mouse and human genomes that show homology to the 0.9-kb telencephalon-specific enhancer region of TLCN gene by using National Center for Biotechnology Information basic local alignment search tool (BLAST) program (http://ncbi.nlm.nih.gov/blast), the analysis did not hit any candidate genes with significant homology. Deoxyribonuclease I footprinting and electrophoretic mobility shift analyses are currently ongoing in our laboratory to narrow down the telencephalon-specific cis-regulatory element and to identify a crucial transcription factor.
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0.9 kb defined in the present study. Numbers along the horizontal axis indicate the nucleotide positions from TSS of the mouse TLCN gene. The vertical axis shows the percentage of sequence conservation of mouse TLCN 5'-flanking region to the corresponding region of human and dog.In addition, there are 2 typical CpG islands in the telencephalon-specific enhancer region and in the vicinity of transcription start site of TLCN gene. The CpG islands are regions in the genome highly enriched in CpG sequences that potentially undergo DNA methylation. The DNA methylation is generally associated with the repressed chromatin state that is involved in genome imprinting, reprogramming, global gene silencing, and tissue-specific gene expression (Li 2002
). Therefore, it might be possible that the status of DNA methylation in the 5'-flanking region of TLCN gene differs between the telencephalic neurons and other types of cells, leading to the telencephalon-specific transcription of the TLCN gene.
For the forebrain-specific transgene expression, a transcriptional regulatory region of calmodulin-dependent protein kinase II (CaMKII) has been widely used (Mayford and others 1995; Tsien and others 1996; Kang and others 2001). Although the CaMKII promoter/enhancer has been proved powerful in many cases, the 8.5-kb 5'-flanking region of CaMKII gene is required for its activity. In contrast, the present study demonstrates that only the 3.9- or 1.1-kb fragment upstream of the TLCN gene is sufficient for specific and efficient expression of transgenes in the telencephalon. Because TLCN is colocalized with CaMKII in various types of neurons in the telencephalon including the hippocampal pyramidal cells (Benson and others 1998) and the ontogenic expression profiles of the two molecules are very similar (Burgin and others 1990; Yoshihara and others 1994), the 3.9- or 1.1-kb TLCN promoter/enhancer can be replaced with the CaMKII promoter/enhancer, as a more convenient genetic tool for various applications. By the use of TLCN promoter/enhancer, it will become much easier to overexpress, ectopically express, or eliminate genes of interest in the telencephalon, leading to genetic manipulation of learning, memory, emotion, and other higher brain functions (Chen and Tonegawa 1997; Mayford and Kandel 1999).
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Acknowledgments |
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We are grateful to Y. Nagaoka, M. Tanaka, and members of Brain Science Institute (BSI) Research Resource Center for generation and maintenance of transgenic mice, synthesis of peptides, and production of antibodies. We thank J. Miyazaki for providing CAG-CAT-Z mice, K. Kitamura for anti-Arx antibody, T. Sassa for advice on X-gal staining, K. Kubota for help in production of guinea pig anti-TLCN antibody, and members of the Yoshihara laboratory for helpful discussions. This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Area—Molecular Brain Science—from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and a grant from Core Research for Evolutional Science and Technology to YY. Conflict of Interest: None declared.
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