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Interleukin-10 inhibits osteoclastogenesis by reducing NFATc1 expression and preventing its translocation to the nucleus
Kathryn E Evans1 &
Simon W Fox1
IL-10 has a potent inhibitory effect on osteoclastogenesis. In vitro and in vivo studies confirm the importance of this cytokine in bone metabolism, for instance IL-10-deficient mice develop the hallmarks of osteoporosis. Although it is known that IL-10 directly inhibits osteoclastogenesis at an early stage, preventing differentiation of osteoclast progenitors to preosteoclasts, the precise mechanism of its action is not yet clear. Several major pathways regulate osteoclastogenesis, with key signalling genes such as p38, TRAF6, NF-κB and NFATc1 well established as playing vital roles. We have looked at gene expression in eleven of these genes using real-time quantitative PCR on RNA extracted from RANKL-treated RAW264.7 monocytes.
There was no downregulation by IL-10 of DAP12, FcγRIIB, c-jun, RANK, TRAF6, p38, NF-κB, Gab2, Pim-1, or c-Fos at the mRNA level. However, we found that IL-10 significantly reduces RANKL-induced NFATc1 expression. NFATc1 is transcribed from two alternative promoters in Mus musculus and, interestingly, only the variant transcribed from promoter P1 and beginning with exon 1 was downregulated by IL-10 (isoform 1). In addition, immunofluorescence studies showed that IL-10 reduces NFATc1 levels in RANKL-treated precursors and suppresses nuclear translocation. The inhibitory effect of IL-10 on tartrate-resistant acid phosphatase-positive cell number and NFATc1 mRNA expression was reversed by the protein kinase C agonist phorbol myristate acetate, providing evidence that interleukin-10 disrupts NFATc1 activity through its effect on Ca2+ mobilisation.
IL-10 acts directly on mononuclear precursors to inhibit NFATc1 expression and nuclear translocation, and we provide evidence that the mechanism may involve disruption of Ca2+ mobilisation. We detected downregulation only of the NFATc1 isoform 1 transcribed from promoter P1. This is the first report indicating that one of the ways in which IL-10 directly inhibits osteoclastogenesis is by suppressing NFATc1 activity.
Osteoclasts are terminally differentiated TRAP-positive cells derived from monocyte-macrophage lineage precursors and are responsible for bone resorption. The process of osteoclast formation includes the proliferation and the differentiation of osteoclast progenitors into mononuclear preosteoclasts and the fusion of preosteoclasts into multinucleated osteoclasts. Excessive osteoclast activity plays a role in the development of several debilitating disorders such as osteoporosis, rheumatoid arthritis, and osteolytic metastases, and so it is vital that osteoclast development and function is properly regulated.
Some of the signalling pathways that contribute to osteoclast differentiation have started to emerge. Signalling by RANKL, an osteoblast-expressed member of the tumour necrosis factor superfamily, is essential for terminal differentiation of monocytes into osteoclasts. Resorptive stimuli initiate osteoclast formation by promoting the expression of osteoblastic RANKL, which binds to its receptor RANK. Binding of RANKL to RANK recruits several signalling intermediates including NF-κB, which is redistributed to the nucleus by TRAF family intermediates [1], and NFATc1, which induce the transcription of genes involved in osteoclast differentiation. NFATc1 is critical to osteoclast formation [2, 3].
Negative regulators of RANKL signalling exist, including osteoprotegerin, a soluble decoy receptor for RANKL, and IFN-β, a negative regulator of transcription factor c-Fos expression [4]. Several cytokines, including IFN-γ, IL-4, and another tumour necrosis factor family member, TRAIL, interfere with the ability of RANKL to induce osteoclast differentiation. There is rapid degradation of TRAF6 abolishing signalling in the case of IFN-γ [5]. In the case of IL-4, signal transducer and activator of transcription 6 appears to be a key upstream regulatory molecule [6–9]. In the case of TRAIL, the mechanism is related to inhibition of the p38/MAPK pathway via reduced p38/MAPK phosphorylation [10].
IL-10 is a potent anti-inflammatory cytokine that suppresses both immunoproliferative and inflammatory responses. It is produced primarily from T cells and activated macrophages and acts on the macrophage lineage. Animal studies implicate IL-10 in the development and progression of arthritis [11–14] and chronic colitis [15, 16]. IL-10 has a critical role in the in vivo regulation of pro-inflammatory cytokine levels [13, 14, 17]. It functions in a negative feedback loop, in which it suppresses the release of inflammatory cytokines and dampens the acute inflammatory response.
IL-10 also has potent inhibitory effects on osteoclastogenesis [18], but the molecular basis of its action is poorly understood. IL-10 inhibits the early stages of osteoclastogenesis, preventing differentiation of osteoclast progenitors to preosteoclasts. It has been shown to mediate this action through both direct and indirect actions. IL-10 indirectly inhibits bone resorption by upregulating osteoprotegerin expression while downregulating expression of RANKL and macrophage colony stimulating factor [19]. IL-10 also directly inhibits osteoclast formation [20]. It was found that the inhibitory effect of IL-10 on osteoclast formation is mediated through a direct action on osteoclast precursors [20, 21]. Furthermore, enhanced osteoclastogenesis has been observed in cultures of bone marrow macrophages deficient in IL-10 production [22]. However, the molecular mechanism mediating this direct effect is unknown.
IL-10-deficient mice are now available and results from these mice confirm the importance of this cytokine in bone metabolism. They have been shown to develop the hallmarks of osteoporosis, namely, reduced bone mass, increased mechanical fragility, and suppressed bone formation [23]. IL-10 is an important endogenous suppressor of infection-stimulated bone resorption in vivo, and it appears that the anti-osteoclastic mechanisms induced by IL-10 on bone are more effective than those mediated by IL-4 [24]. IL-10-deficient mice exhibit significantly higher levels of periodontal alveolar bone loss than a matched control group [25]. This increased alveolar bone loss appears to be a late onset condition, and analysis of serum levels of type I collagen C-telopeptide suggests that lack of IL-10 may have a direct effect on bone homeostasis [26]. Clinical studies back up the theoretical importance of this work: an IL-10 promoter gene polymorphism has been found that is associated with reduced bone mineral density and predisposes women to osteoporosis at the lumbar spine [27].
In this paper we set out to learn more about how interleukin-10 directly inhibits the process of osteoclastogenesis by looking at its effects on selected gene expression in RAW264.7, a murine monocytic cell line.
IL-10 suppresses osteoclast formation
Three groups of RAW264.7 cells were set up – an untreated control group, a group treated with RANKL, and a final group treated with RANKL plus IL-10. As shown previously, after five days numerous mono and multinuclear TRAP-positive cells were seen in the RANKL-treated cultures. The percentage of TRAP-stained cells in each group was determined by light microscopy and it was found that IL-10 significantly inhibits osteoclast formation but does not abolish it completely (Figure 1). These results indicate that IL-10 acts directly on monocytes to inhibit osteoclast differentiation.
Osteoclast formation is suppressed by IL-10. RAW264.7 cells were incubated with RANKL or RANKL plus IL-10 for 5 days. All cytokine concentrations were 50 ng/ml. Cells were fixed and stained for TRAP and the number of TRAP-positive mono and multinuclear osteoclasts quantified. Results are expressed as the mean ± SEM for each group from three separate experiments. IL-10 significantly suppressed osteoclast formation. * p < 0.05 versus control, ** p < 0.05 versus RANKL-treated group.
NFATc1 is downregulated by IL-10
RANKL was found to induce the expression of NFATc1 mRNA approximately 8-fold, and this was significantly suppressed by co-incubation with IL-10 (Figure 2). This is in keeping with the direct action of IL-10 on osteoclast formation. NFATc1 expression was not however completely abolished. Isoforms of NFATc1 are known to exist in both humans [28] and mice [29]. These isoforms are transcribed from two separate promoters, which can be arbitrarily designated P1 and P2. Transcripts beginning from P1 start with exon 1 (isoform 1) and are longer than those beginning from P2 and starting with exon 2 (isoform 2). It is possible to design primers to differentiate between these variants and we did this. We found that RAW264.7 cells express both NFATc1 isoforms (isoform 1: 7.5 × 103 copies, isoform 2: 3.4 × 102 copies) and RANKL induced a significant 14.5-fold increase in isoform 1 expression, which IL-10 suppressed (Figure 2B). In contrast RANKL and IL-10 had little effect on the expression of isoform 2 (Figure 2C). Therefore, it appears that IL-10 may suppress osteoclastogenesis by blunting expression of NFATc1 isoform 1 rather than isoform 2. Because NFATc1 is central to osteoclast formation, any change in its expression would be expected to have a major effect on downstream gene expression.
NFATc1 expression is suppressed by IL-10. RAW264.7 cells were incubated with cytokines (RANKL 50 ng/ml and IL-10 50 ng/ml) for 2 days and total RNA extracted. NFATc1 expression was assessed using quantitative PCR using specific primers recognising both isoforms (A) isoform 1 (B) or isoform 2 (C). Results are expressed as the mean ± SEM for each group from three separate experiments normalised for β-actin. * p < 0.05 versus control, ** p < 0.05 versus RANKL-treated group.
Expression of other osteoclast signalling genes is unaffected
None of the other osteoclast signalling genes tested – RANK, TRAF6, p38, NF-κB, c-Fos, c-jun, FcγRIIB, DAP12, Gab2, and Pim1 – were upregulated as strongly as NFATc1 by RANKL, and none of them were downregulated by IL-10 (data not shown). The key signalling factors known to trigger NFATc1 expression are TRAF6 and c-Fos [2], and so the lack of response of these genes in our experiments suggests that the effect of IL-10 on monocytes is not mediated through these pathways, in which case it must be mediated through an alternative mechanism.
IL-10 alters cellular localisation of NFATc1
NFATc1 is the most strongly induced transcription factor gene following RANKL stimulation [2, 3]. RANKL also evokes Ca2+ oscillations that lead to calcineurin-mediated activation of NFATc1. In resting T cells NFATc1 is restricted to the cytoplasm. Following T-cell activation, a sustained increase in intracellular calcium activates the phosphatase calcineurin. The activated calcineurin dephosphorylates NFATc1 and leads to increased nuclear accumulation. Therefore it was of interest to determine the cellular location of NFATc1 in the RANKL- and IL-10-treated monocytes. In keeping with our qPCR results, RANKL-treated cells showed intense cytoplasmic staining and nuclear accumulation was also noted (Figure 3). Similarly, again in keeping with our qPCR results, IL-10 reduced the intensity of cytoplasmic staining and little nuclear accumulation was observed in these cultures. This correlates with NFATc1 being highly active in the RANKL-treated cells and less active in the presence of IL-10.
IL-10 reduces NFATc1 immunostaining intensity and nuclear translocation. NFATc1 staining was noted in the cytoplasm and nuclei of RANKL treated RAW264.7 cells (B and C), whereas only weak cytoplasmic staining was observed in RANKL + IL-10 treated cells (D.) No staining was noted in control cultures (A). Photographs taken at a magnification of × 400 A, B, D and ×1000 C.
IL-10 may disrupt NFATc1 activity through its effect on Ca2+ mobilisation
PKC plays a critical role in T cell receptor-induced NFAT activation [30]. Deficiency of PKC primarily abrogates NFAT transactivation. This NFAT defect appears to be secondary to reduced inositol 1,4,5-triphosphate generation and intracellular Ca2+ mobilisation. Since we had not found any effect of IL-10 on TRAF6 or c-Fos, we wanted to see if we could find any evidence that IL-10 is acting through its effects on Ca2+ mobilisation, and this was done using the PKC agonist PMA. Cells were treated with RANKL, RANKL plus IL-10, and RANKL plus IL-10 plus PMA, and viewed under the microscope. The suppressive effect of IL-10 was abolished by PMA treatment, as determined by extent of TRAP staining (Figure 4). Quantitative PCR results were in agreement, with PMA reversing the inhibitory effect of IL-10 on NFATc1 expression (Table 1).
Table 1 Effect of PMA on IL-10 induced suppression of NFATc1
PMA inhibits the suppressive effect of IL-10 on osteoclast formation. RAW264.7 cells were incubated with RANKL, IL-10 or PMA for 3 days. Cultures were washed to remove PMA and then incubated for a further two days with RANKL or RANKL + IL-10. Cells were fixed and stained for TRAP and the number of TRAP-positive mono and multinuclear osteoclasts quantified. IL-10 suppressed the number of TRAP positive cells and this was prevented by PMA. Results are expressed as the mean ± SEM for each group from three separate experiments n = 9. * p < 0.05 versus all other groups.
IL-10 is an anti-inflammatory cytokine that suppresses both immunoproliferative and inflammatory responses. It is produced primarily from T cells and activated macrophages. Animal studies implicate IL-10 in the development and progression of arthritis and chronic colitis. IL-10 has a critical role in the in vivo regulation of pro-inflammatory cytokine levels. It functions in a negative feedback loop, in which it suppresses the release of inflammatory cytokines and dampens the acute inflammatory response. Clinical studies and IL-10-deficient mice back up the theoretical importance of this work, as discussed in the introduction. IL-10 has been known for some time to have a potent inhibitory effect on osteoclastogenesis [18]. It prevents differentiation of osteoclast progenitors to preosteoclasts, however its mechanism of action is still unclear.
We have studied the expression of eleven osteoclast signalling genes and have found that one of the ways in which IL-10 directly inhibits osteoclastogenesis is by disrupting NFATc1 mRNA expression and nuclear translocation. NFATc1 is crucial for osteoclastogenesis, and so its downregulation may be expected to have major downstream effects. We also provide evidence that this disruption to NFATc1 may be mediated through the effect of IL-10 on Ca2+ mobilisation. In addition, it was found that only NFATc1 isoform 1 transcribed from promoter P1 was downregulated by IL-10.
Osteoclast formation was not abolished in the presence of IL-10 and similarly NFATc1 levels did not revert to basal level in the IL-10 treated cells. Several pathways contribute to induction of NFATc1 levels and it may well be the case that IL-10 does not inhibit all of them. The initial expression of NFATc1 is dependent on both the TRAF6 and c-Fos pathways, which are unaffected by IL-10. RANKL stimulation also results in the induction of Ca2+ oscillations which activate NFATc1 via a calcineurin-dependent mechanism, targeting it to the nucleus [2]. For the generation of osteoclasts it has been demonstrated that the high NFATc1 levels generated by autoregulation are necessary for cell lineage commitment [reviewed in [31]]. Therefore the reduction in levels, rather than complete abrogation, brought about by IL-10 will be sufficient to cause the potent inhibition of osteoclastogenesis shown in these studies.
There are two variants of NFATc1 in Mus musculus but only one of these, isoform1, was downregulated by IL-10. It is not known why the shorter isoform 2 is not similarly modified by IL-10. This may in part be related to the relative inability of RANKL to induce the expression of isoform 2 in RAW cells, or it could be that the conformation of the DNA is such that IL-10-induced transcription factors only have access to the P1 promoter. Linked in with this, it is likely that the finding that NFATc1 expression was not completely abolished is due to a combination of residual expression from the P1 promoter and the inability of IL-10 induced factors to suppress basal expression from the P2 promoter. Alternatively, it could also be that IL-10 acts only on a subset of the various pathways that contribute to NFATc1 upregulation.
The activity of NFATc1 is not only dependent on its level of expression, but also its location within the cell. It is active only when in the nucleus, as would be expected of a transcription factor. This nuclear transport relies upon active calcineurin which triggers dephosphorylation of NFATc1. Therefore we used antibodies to establish the intracellular distribution of NFATc1. The fact that very little staining, and in particular nuclear staining, was observed in the IL-10 sample strengthens our evidence that the inhibitory effect of IL-10 on osteoclastogenesis can be explained at least in part by its effect on NFATc1 expression and activity.
PKC plays a critical role in T cell receptor-induced NFAT activation [30]. Deficiency of PKC primarily abrogates NFAT transactivation. This NFAT transactivation defect appears to be secondary to reduced inositol 1,4,5-triphosphate generation and intracellular Ca2+ mobilisation. Therefore, we set out to test whether IL-10 is disrupting NFATc1 activity through its effect on Ca2+ mobilisation. We found that PMA inhibits the suppressive effect of IL-10 on osteoclast formation, as determined by TRAP staining and NFATc1 expression. PMA is an activator of PKC, and so if PMA is overcoming the suppressive effects of IL-10, knowing how PMA acts it would appear that IL-10 is disrupting NFATc1 activity through its effect on Ca2+ mobilisation. Therefore the effect of IL-10 could involve PKC as PMA reverses the suppressive action of IL-10.
The mechanism by which IL-10 interferes with osteoclast formation appears to be different from that used by other inhibitors, namely IFN-γ, IL-4, and TRAIL. IL-4 also downregulates NFATc1 but it acts through suppression of c-Fos [32], we did not find any evidence for c-Fos being downregulated although it remains possible that it could be inactivated by other means. IFN-γ causes rapid degradation of TRAF6 protein; we found no difference in TRAF6 mRNA levels but did not look at protein levels. Likewise, TRAIL interferes with the p38 pathway and there was no downregulation of p38 mRNA in IL-10 treated cultures.
It is valuable to pinpoint the effect of IL-10 on osteoclast signalling pathways since evidence is accumulating, particularly from studies of IL-10-deficient mice, to illustrate the importance of this cytokine in bone homeostasis. We have demonstrated that one of the ways by which IL-10 directly inhibits osteoclast formation is to suppress NFATc1 expression and activation. In vivo, IL-10 may be expected to have an even more pronounced effect due to its indirect action of suppressing RANKL expression [19] which would further reduce NFATc1 activation through TRAF6. This is the first report indicating that one of the ways in which IL-10 inhibits osteoclastogenesis is by suppressing NFATc1 activity.
IL-10 acts directly on mononuclear precursors to inhibit NFATc1 expression and nuclear translocation, and we provide evidence that the mechanism may involve disruption of Ca2+ mobilisation. We detected downregulation only of the NFATc1 isoform transcribed from promoter P1 and beginning with exon 1. This is the first report indicating that one of the ways in which IL-10 directly inhibits osteoclastogenesis is by suppressing NFATc1 activity.
Cell culture and cytokines
RAW264.7 cells were maintained in Dulbecco's modified Eagle's medium with 10% heat-inactivated fetal calf serum. They were transferred to a 24-well plate for cytokine addition and plated at a concentration of 105 cells per well. Cultures were fed every 2–3 days. TRAP staining (see below) was used to determine the extent of osteoclast formation. Cytokines were obtained from Insight Biotechnology (Wembley, UK). RANKL was added to cells to give a final concentration of 50 ng/ml, IL-10 was added to give a final concentration of 50–100 ng/ml.
TRAP cytochemistry
Osteoclast formation was evaluated by quantification of TRAP-positive cell number using a modification of the method of Burstone [33]. After incubation, coverslips were washed in phosphate-buffered saline, fixed in 10% formalin for 10 min, and stained for acid phosphatase in the presence of 0.05 M sodium tartrate (Sigma). The substrate used was naphthol AS-BI phosphate (Sigma). The number of TRAP-positive mono and multi nuclear cells was counted using an eyepiece graticule at a magnification of ×100.
Selection of genes for study
NFATc1, c-jun [34], RANK [35], TRAF6 [36], p38, NF-κB, and c-Fos [37] are well known to play an important role in osteoclastogenesis. It has recently been shown that signals other than those transmitted by RANKL and M-CSF are required for osteoclastogenesis, and DAP12 [38] and FcγRIIB [39] are key molecules in this respect. Gab2 is a novel downstream effector of RANKL signalling [40]. Pim-1 was chosen because it interacts directly with human NFATc1 [41], and it was thought that it may play a role in the mouse signalling pathway.
Extraction of RNA and quantitative RT-PCR
RNA was extracted using a Qiagen kit from control, RANKL treated, and RANKL plus IL-10 treated cells that had been incubated for 48 hours. The RNA was reverse transcribed using a Sigma kit. Primers were designed using Primer3 and their sequences are given below. Real-time PCR was conducted with a Techne Quantica machine and Quansoft software using the DNA-binding dye SYBR Green (Sigma) for the detection of PCR products. For the generation of standard curves, the corresponding cDNA was cloned into pGEM-T Easy (Promega). The concentration of DNA plasmid stock was determined by the OD at 260 nm and agarose gel electrophoresis. Copy number for each plasmid was calculated on these measurements. The linear range of the assay was determined by the amplification of log serial dilutions of plasmids from 500 to 5 × 106. The progress of the PCR amplification was monitored by real-time fluorescence emitted from SYBR Green during the extension time. The cycles were 95°C for 15 min, followed by 35 cycles of 95°C for 20 s, 58°C for 20 s, and 72°C for 20 s. At the end of each PCR run, a melt curve analysis was performed to show the absence of non-specific bands. For each sample, mRNA levels were expressed as relative copy number normalised against β-actin mRNA. This was achieved by constructing a standard curve for each PCR run from serial dilutions of purified plasmid DNA with specified amplicon. The mRNA copy number was calculated for each sample from the standard curves by the instrument's software. Samples were analysed in triplicate. For each sample copy number relative to 106 β-actin copies in the same sample was calculated.
Primers used for PCR were as follows: NFATc1 sense, 5'-CCGTTGCTTCCAGAAAATAACA-3'; NFATc1 antisense, 5'-TGTGGGATGTGAACTCGGAA-3'; NFATc1 P1 isoform sense, 5'-GCCAAGTACCAGCTTTCCAG-3'; NFATc1 P1 isoform antisense, 5'-AGGGTCGAGGTGACACTAGG-3'; NFATc1 P2 isoform sense, 5'-TTCGATTTCCTCTTCGAGTTC-3'; NFATc1 P2 isoform antisense, 5'-TGATTGGCTGAAGGAACAGC-3'; β-actin sense, 5'-GTCATCACTATTGGCAACGAG-3'; β-actin antisense, 5'-CCTGTCAGCAATGCCTGGTACAT-3', which yield products of 152, 185, 165, and 197 bp, respectively.
Cells were grown on 2 mm glass coverslips in 6 well plates for 48 hours with or without RANKL or RANKL plus IL-10. The coverslips were then removed, washed in PBS, fixed in 4% paraformaldehyde/phosphate-buffered saline pH 7.2 for 15 minutes, washed in 70% alcohol and then air dried. The cellular distribution of NFATc1 was assessed as follows. Cells were rehydrated through graded alcohols, permeablised with 0.1% Triton X-100, incubated with 1% goat serum for 30 minutes to block non-specific binding and then incubated with a specific mouse NFATc1 monoclonal (Santa Cruz Biotechnology, Heidelberg, Germany) diluted 1:50 in 1% goat serum for 1 hour. The cells were washed in PBS, incubated for 2 hours with a biotinylated goat anti-mouse secondary (Vector Labs, Burlingame, USA), washed in PBS and then incubated for 2 hours with fluorescein conjugated streptavidin (Vector Labs, Burlingame, USA) Immunofluorescence was then visualised using a Leica HC microscope. Photographs were taken with a JVC TK C13603 digital camera linked to image pro plus software at a magnification of ×400 or ×1000.
Differences between groups were assessed using Fisher's analysis of variance (StatView version 5.01, Abacus Concepts, Berkley, CA). A difference of p < 0.05 was considered significant.
Bioinformatics analysis
Information, including sequence data, on the genes discussed in this paper was obtained via the NCBI website [42].
M-CSF:
macrophage colony stimulating factor
NFAT:
PKC:
protein kinase C
PMA:
phorbol myristate acetate
receptor activator of NF-κB
RANKL:
receptor activator of NF-κB ligand
tumour necrosis factor
TRAF:
TNF receptor associated factor
TNF-related apoptosis-inducing ligand
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Kamel Mohamed SG, Sugiyama E, Shinoda K, Hounoki H, Taki H, Maruyama M, Miyahara T, Kobayashi M: Interleukin-4 inhibits RANKL-induced expression of NFATc1 and c-Fos: a possible mechanism for downregulation of osteoclastogenesis. Biochem Biophys Res Commun. 2005, 329: 839-845. 10.1016/j.bbrc.2005.02.049.
Burstone MS: Histochemical demonstration of acid phosphatases with naphthol AS-phosphate. J Natl Cancer Inst. 1958, 21: 523-539.
Ikeda F, Nishimura R, Matsubara T, Tanaka S, Inoue J-i, Reddy SV, Hata K, Yamashita K, Hiraga T, Watanabe T, Kukita T, Yoshioka K, Rao A, Yoneda T: Critical roles of c-Jun signalling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest. 2004, 114: 475-484. 10.1172/JCI200419657.
Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Yano K, Morinaga T, Higashio K: RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun. 1998, 253: 395-400. 10.1006/bbrc.1998.9788.
Kobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S, Inoue J: Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J. 2001, 20: 1271-1280. 10.1093/emboj/20.6.1271.
Grigoriadis AE, Wang ZQ, Cecchini MG, Hofstetter W, Felix R, Fleisch HA, Wagner EF: c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodelling. Science. 1994, 266: 443-448. 10.1126/science.7939685.
Paloneva J, Mandelin J, Kiialainen A, Bohling T, Prudlo J, Hakola P, Haltia M, Konttinen YT, Peltonen L: DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. J Exp Med. 2003, 198: 669-675. 10.1084/jem.20030027.
Mocsai A, Humphrey MB, Van Ziffle JA, Hu Y, Burghardt A, Spusta SC, Majumdar S, Lanier LL, Lowell CA, Nakamura MC: The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc Natl Acad Sci USA. 2004, 101: 6158-6163. 10.1073/pnas.0401602101.
Wada T, Nakashima T, Oliveira-dos-Santos AJ, Gasser J, Hara H, Schett G, Penninger JM: The molecular scaffold Gab2 is a crucial component of RANK signalling and osteoclastogenesis. Nat Med. 2005, 11: 394-399. 10.1038/nm1203.
Rainio E-M, Sandholm J, Koskinen PJ: Transcriptional activity of NFATc1 is enhanced by the Pim-1 kinase. J Immunol. 2002, 168: 1524-1527.
NCBI. [http://www.ncbi.nlm.nih.gov]
This work was supported by the Wellcome Trust.
Ecotoxicology and Stress Biology Research Group, School of Biological Science, University of Plymouth, UK
Kathryn E Evans
& Simon W Fox
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Correspondence to Kathryn E Evans.
KE participated in the selection of genes for study, carried out the molecular genetic work, and drafted the manuscript. SF conceived of and directed the study, carried out the TRAP cytochemistry and immunofluorescence work, and helped to draft the manuscript. Both authors read and approved the final manuscript.
Evans, K.E., Fox, S.W. Interleukin-10 inhibits osteoclastogenesis by reducing NFATc1 expression and preventing its translocation to the nucleus. BMC Cell Biol 8, 4 (2007) doi:10.1186/1471-2121-8-4
Osteoclast Formation
Alveolar Bone Loss
Osteoclast Progenitor
Trap Staining
Inhibit Osteoclast Formation


There is no funding for Shanahoe road repairs, councillors heard at the recent Borris in Ossory electoral area meeting.
Councillor Marty Phelan asked at the meeting that the road be repaired between Shanahoe Church and Killaney.
He said that it was a busy area and told the other councillors present at the meeting that the road floods there often and needed to be fixed soon.


text:
A bronzfarkú pávafácán (Polyplectron chalcurum) a madarak osztályának tyúkalakúak (Galliformes)  rendjébe és a fácánfélék (Phasianidae)  családjába tartozó faj.

Rendszerbesorolás
Korábban a Chalcurus nembe sorolták, Chalcurus chalcurum néven.

Előfordulása
Indonéziához tartozó Szumátra szigetén  honos. A természetes élőhelye hegyi és síkvidéki erdők.

Alfajai
Polyplectron chalcurum chalcurum (Lesson, 1831) - Szumátra déli részén honos
Polyplectron chalcurum scutulatum Chasen, 1941 - Szumátra északi részén él

Megjelenése
Eléggé elkülönül megjelenése alapján a Polyplectron nem többi fajától. Valószínűleg ez a legprimitívebb faj mind közül. A többi faj széles és kerek végű, fényvisszaverő pávaszemekkel díszített farkával ellentétben a bronzfarkú pávafácán hímjének farka hosszú, hegyes és egyszerű bronzbarna. Testhossza 56 centiméter.

Szaporodása
Fészekalja 2 tojásból áll, melyen 22 napig kotlik.

Források

Gbwf.org

További információk
Képek az interneten a fajról
Videó a fajról

Polyplectron
Madárfajok
Indonézia endemikus madarai

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2kg Loumet Rope Ball 4 out of 5 based on 24 ratings.
One of the ethnic minorities in ChinaMiaoThe hairstyle is characterized by a huge attachment which knitted rope hair, hair which inherited the.
and the weight isThe average is 2 kg as well. In anci.
All of these choices are correct. Forces always act in pairs. Forces act on each object. The ground reacts with as much force as was used to get the ball to its starting height. The ball experiences a.
He was nearly run out off the first ball. He picked off two runs off the fourth. And blocked out the next two. Fifteen were required off the final over. And Dhoni asked for a change of bat. "A 2kg bat.


text:
Home » crime » Unknown Gunmen: Enugu Govt denies designating anybody as SSA to Gov on Security, donates 2 new Hilux vans to 82 Div Army Command
Unknown Gunmen: Enugu Govt denies designating anybody as SSA to Gov on Security, donates 2 new Hilux vans to 82 Div Army Command
The Enugu State Government has distanced itself from a news report purporting that one Tochukwu Okeke is a Senior Special Assistant (SSA) to the Governor on Security, stating that the state government has not designated any person, whosoever, as either Special Adviser, Senior Special Assistant or Special Assistant to the Governor on Security.
In a it's statement signed by the Commissioner for Information, Nnanyelugo Chidi Aroh, the Government said it is very concerned about the rising security challenges faced by the country and appreciates the untiring efforts of the various security agencies in tackling acts of criminality.
The Government affirmed that "the state government will continue to support the various security agencies in this arduous task of restoring security and protecting the lives and property of the people of Enugu State within the ambit of the extant laws".
It encouraged the people of Enugu State to continue to support the various security agencies in the state in different ways, "including the provision of useful information on the activities of criminal elements, as the state government will handsomely reward any person who provides useful information on the activities of these criminal elements terrorizing our society and interfering with the much-treasured peace in Enugu State".
It read in parts:
Eha Amufu Killings: Enugu Govt swings to action, deploys more security, releases medical support, funds for victims
ENUGU STATE: Nkerefi community stage protests over imposition of taxes and levies at Eke Market
"The attention of the Enugu State Government has been drawn to the trending news story on social media, regarding one Tochukwu Okeke purported to be a Senior Special Assistant to the Governor on security for the avoidance of doubt, we wish to state categorically that the state government has not designated any person, whosoever, as either Special Adviser, Senior Special Assistant or Special Assistant to the Governor on security.
"The good people of Enugu State are encouraged to continue to support the various Security Agencies in the State, including the provision of useful information on the activities of criminal elements, as the State Government will handsomely reward any person who provides useful information on the activities of these criminal elements terrorizing our society and interfering with the much-treasured peace in Enugu State".
Meanwhile, the state government has donated two additional brand new Toyota Hilux patrol vehicles to the 82 Division of the Nigeria Army, Enugu, to further aid its security operations in the state.
Presenting the vehicles to the Garrison Commander, 82 Division, Nigerian Army, Brigadier General Christopher A. Ataki, Gov. Ugwuanyi represented by the Secretary to the State Government, Prof. Simon Uchenna Ortuanya, disclosed that the gesture was in keeping with the present administration's cardinal objective of sustaining the peace and security in Enugu State.
It would be recalled that Gov. Ugwuanyi's administration had on different occasions in the past donated security vehicles to the Nigerian Army, including 100 units of Innoson Vehicle Manufacturing (IVM) Patrol Vans equipped with communication gadgets procured and distributed proportionally to all the security agencies in the state to aid their operations.
Receiving the vehicles at the Government House, Enugu, on Tuesday, Brig. Gen. Ataki said that "today is a special day not only for the Nigerian Army but for the people of Enugu State".
READ ALSO: Ugwuanyi empowers Udi/Ezeagu youths, women at UEPA ward executives inauguration
The Garrison Commander therefore expressed gratitude to Gov. Ugwuanyi for the gesture, assuring the governor and the people of Enugu State that "we will continue to do our best to ensure that the peace we are enjoying in Enugu and indeed across the South East is sustained".
Also in his speech, Prof. Ortuanya applauded Gov. Ugwuanyi for his steadfastness and sustained efforts in ensuring peace and providing security for the people of the state.
"It is in recognition of the above and in pursuit of his administration's cardinal objective of sustaining the peace and security in Enugu State that His Excellency (Gov. Ugwuanyi) has approved the procurement of these two brand new Toyota Hilux vehicles for the Nigerian Army to the help the Army in providing security in the state.
"We are happy to say that Enugu State has been rated as one of the most peaceful and secure states in Nigeria. Today, we want to use this opportunity to thank His Excellency, the Governor of Enugu State, for this milestone achievement", he added.
Tags: Enugu State GovernmentTochukwu Okeke alias Owo
Troops Nab Governor's Aide as a Mastermind Behind 'Unknown Gun Men" in South-East
2023: Ohanaeze, Arewa, other groups drum support for Ohuabunwa as Nigeria's next president

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SET-listed developer Major Development Plc (MJD) plans to launch 10 new projects worth a combined 15 billion baht in the second half, aiming to have 10 billion baht in presales by the end of the year.
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1. This study examines the nature of the Islamic State in Iraq and Greater Syria (ISIS), an Islamic Salafist-jihadi terrorist organization founded a decade ago as a branch of Al-Qaeda in Iraq. It established itself during the fighting against the United States in the Sunni regions of western Iraq and spread to eastern and northern Syria during the Syrian civil war. In the summer of 2014 ISIS scored dramatic achievements, among them the occupation of Mosul, Iraq's second largest city, and the declaration of the "Islamic Caliphate," headed by a charismatic Iraqi terrorist operative nicknamed Abu Bakr al-Baghdadi.
3. ISIS began as a branch of Al-Qaeda, founded in Iraq in 2004 after the American invasion and headed by Ayman al-Zawahiri. It filled the security and governmental void created by the disintegration of the Iraqi army and Saddam Hussein's regime, accompanied by the increasing alienation of the Sunni Muslims from the central, Shi'ite-affiliated governmentin Baghdad sponsored by the United States. The branch of Al-Qaeda gradually established itself in Iraq during the fighting against the United States and its allies, adopted the name the Islamic State in Iraq (ISI), and became a central force among the anti-American insurgents.
4. Towards the end of the American presence in Iraq the ISI was weakened (as were other insurgents), the result of America's military successes combined with its wise policy of fostering the Sunni tribes in western Iraq (ISIS' principal domain). However, the Americans did not continue the policy, and later policies carried out by Shi'ite Adnan al-Maliki and the American withdrawal from Iraq all contributed to strengthening the ISI. That gave it a convenient starting point for its operations when the Americans eventually withdrew from Iraq.
5. The civil war that broke out in March 2011 made Syria fertile ground for the spread of the ISI to Syria. In January 2012 the Al-Nusra Front ("support front") was founded as the Syrian branch of the ISI. However, the two disagreed early on and the Al-Nusra Front split off from the Islamic State in Iraq, which then changed its name to the Islamic State in Iraq and Greater Syria (ISIS). Al-Qaeda, under the leadership of Ayman al-Zawahiri, announced its support for the Al-Nusra Front and its dissociation from the ISI. After the split ISIS gained military successes, leading it to declare the Islamic State (or the "Caliphate State"), while the rival Al-Nusra Front has weakened.
6. ISIS is an Islamic Salafist-jihadi organization. Salafism is an extremist Sunni political-religious movement within Islam that seeks to restore the golden era of the dawn of Islam(the time of the prophet Muhammad and the early Caliphs who followed him). That is to be done, according to Salafist jihadist ideology, by jihad (a holy war) against both internal and external enemies. Jihad, according to Salafist jihadism, is the personal duty of every Muslim. Al-Qaeda and the global jihad organizations (of which ISIS is one) sprang from Salafist jihadism.
7. According to the ISIS concept, Islam's golden era will be restored through the establishment of a supranational Islamic Caliphate modeled after the regimes of the first Caliphs after the death of Muhammad. It will be ruled by Islamic religious law (the sharia), according to its most extreme interpretation. The Caliphate will arise on the ruins of the nation states established in the Middle East after the First World War. Some of them, including Syria and Iraq, where ISIS operates, are in the process of disintegrating in the wake of the upheaval in the Middle East, creating favorable conditions for the vision of an Islamic Caliphate.
8. The territory of the Caliphate State, whose establishment was declared by Abu Bakr al-Baghdadi, lies in eastern Syria and western Iraq. ISIS seeks to expand the Caliphate throughout Syria and Iraq and finally take control of them. After that, the states belonging to "greater Syria" will be annexed, that is, Jordan, Lebanon, Israel and the Palestinian Authority, and after them other countries in the Middle East and beyond. According to the ISIS vision as it appears on its maps, the future Islamic Caliphate will include vast stretches of North Africa, Asia and the Caucasus, and parts of Europe that were once under Muslim rule, such as Spain and the Balkans.
3) Areas of control: Today ISIS controls an estimated third of the territory of Iraq and between a quarter and a third of Syria, from the outskirts of Baghdad to the outskirts of Aleppo. The vast area, according to various estimates, is home to between five and six million people. Several important cities are in the ISIS-controlled region, among them Mosul (the second largest city in Iraq), Fallujah(symbol of the struggle against the United States) and Al-Raqqah (the ISIS "capital city" in northern Syria). It is noteworthy that a relatively small number of ISIS operatives control a broad swath of territory, which is one of ISIS' weak points. To overcome it, ISIS relies on local supporters and allies, and is making an effort to enlist operatives from Syria, Iraq and abroad.
4) Establishment of alternative administration networks: In the areas under its control ISIS instituted alternative administrations to replace those of Syria and Iraq which collapsed. They include educational, judicial, policing and law enforcement networks. ISIS uses them to provide vital services and at the same time to enforce its Salafist-jihadi ideology on the local population. To that end it uses brutal measures against its opponents and the minorities living under its control(including mass executions). Nevertheless, so far the local populations seem to have come to terms with ISIS control and sometimes even support it. They do so especially in view of its ability to provide basic services, restore daily life to the status quo ante, and fill the administrative void that was created.
5) High financial capabilities: In Syria and Iraq ISIS took control of the state infrastructure, including most of the oil fields in eastern Syria and several oil fields in Iraq. The export of petroleum products is the main source of ISIS' income and its profits are estimated at several million dollars a day. However, profits fell in the wake of the aerial attacks carried out by the United States and its allies on its oil infrastructure. Other sources of ISIS income are various types of criminal activity(extortion, collecting ransom for abductees, trading in antiquities), collectingdonations and imposing local taxes. Thus it is an exceptional example of a terrorist organization which managed to acquire semi-national financial capabilities to fund its military infrastructure and allow it to establish an alternative governmental system.
1) Dramatic success (June – August 2014): ISIS captured the oil city of Mosul from the Iraqi army. The Iraqi army, in whose establishment and training the United States invested enormous resources for years, collapsed and fled. An ISIS force also captured the Mosul Dam with its hydroelectric plant (north of the city on the Tigris), driving out the Kurdish Peshmerga force defending it. (An ISIS force also tried to capture the Haditha Dam on the Euphrates, the second largest dam in the country, but was met with resistance from the Iraqi army stationed there.) ISIS also took control of the city of Tikrit, Saddam Hussein's birthplace and a former stronghold of the Iraqi Ba'ath party.
2) Containment and halt (second half of August – September 2014): During the second half of August and September 2014 (when the United States began its pinpointed aerial attacks) ISIS' advance was halted. The Kurdish Peshmerga forces, the Iraqi army and the Shi'ite militias retook the Mosul Dam. The Iraqi army drove ISIS forces from the large Haditha Dam and the oil city of Baiji (an important logistic passage besieged by ISIS). ISIS enemies saved the lives of minority groups considered "infidels" by ISIS and targeted for harassment, attack and slaughter: Yazidi refugees were rescued from Mt. Sinjar (in northern Iraq) and the siege of the predominantly Shi'ite-Turkmen town ofAmerli (south of Kirkuk) was lifted.
3) Establishment of control over the Al-Anbar province, possibly a step in a campaign against Baghdad (end of September – mid-November 2014): ISIS forces cleared pockets of resistance in the Al-Anbar province (Iraq's largest Sunni district) and advanced towards the capital city of Baghdad. At the same time, ISIS carried out a series of suicide bombing attacks in Baghdad, mainly in Shi'ite neighborhoods. The news agencies reported ISIS forces located several dozen miles from the city and fighting in the city of Abu Ghraib, west of Baghdad. However, the Iraqi army, the Shi'ite militias and the Kurdish forces had several military achievements, the most prominent of which was relieving the siege of Baiji.
12. So far ISIS has not yet taken full control of the Sunni Al-Anbar province. In ITIC assessment, in the future ISIS is planning to take over Baghdad, but apparently the campaign will be far more difficult than the easy conquest of Mosul, because its operatives are liable to encounter fierce resistance from the Shi'ite militias and the Iraqi army, which will have Iranian support and aerial cover from the American-led coalition. It is also likely that ISIS' rivals will cooperate against it. In can be expected that ISIS will attempt to overcome resistance by besieging Baghdad and disrupting life in the city (by firing rockets and mortar shells, and detonating IEDs and car bombs). During October and to mid-November 2014 hundreds of civilians were killed in Baghdad, most of them Shi'ite, in suicide bombings and car bomb attacks, for at least some of which ISIS was responsible.
13. While launching military campaigns, ISIS has firmly established its grip on extensive areas of eastern and northern Syria. It has expelled its rivals and enemies (among them other rebel organizations, the Al-Nusra Front and the Syrian army), and attempted to gain control of new key areas (as of this writing the campaign for the Kurdish region of Qobanê near the Turkish border has not yet ended). It established its control over Al-Raqqah, turning it into its "capital city" in Syria, and solidified its control over the local population. Its accomplishments are funded by the enormous sums of money pouring in from its control of the country's infrastructure, especially the sale of petroleum products from the fields in eastern Syria (although its profits have decreased since the Americans and their allies began aerial attacks).
1) Iraq: ISIS conquests in the summer of 2014 accelerated the disintegration of Iraq into religious and ethnic components. It can be said that Iraq no longer functions as a nation state. Three quasi-entities arose: a Sunni district controlled by ISIS in western and northern Iraq; an autonomous Kurdish region in the north and a Shi'ite region in the center and south affiliated with the Shi'ite regime in Baghdad. The borders between them are blurred and unstable, and ISIS, which is gaining strength,can be expected to continue its efforts to enlarge the areas under its control at the expense of the other entities, which are currently on the defensive.
2) Syria: In Syria as well ISIS' increase in strength contributed to deepening the country's de facto division. ISIS secured its control over the northern and eastern parts of the country and weakened its various rivals (the Syrian regime, the Al-Nusra Front and the other rebel organizations). However, ISIS has not been able to break the Syrian regime's hold on Damascus and other core areas in the north and west, or of the rebel organizations on the southern part of the country (including most of the area of the Golan Heights along the border with Israel). The strengthening of ISIS and the American-led campaign against it increased the existing complexity of the Syrian civil war and made the situation more volatile, making it more difficult to resolve the Syrian crisis in the foreseeable future.
3) The establishment of the global jihad in the Middle East: ISIS' successes in Syria and Iraq turned them into a new focus for the global jihad, inheriting the place of Afghanistan and Pakistan. As opposed to the era of Osama bin Laden, today there are two principal hostile, rival jihadi organizations: one, ISIS, affiliated with the global jihad but at odds with the Al-Qaeda leadership of Ayman al-Zawahiri; and the other,the Al-Nusra Front, a branch of Al-Qaeda in Syria. Between the two are global jihad networks within the Middle East and beyond. Some of the jihadi networks in the Middle East, mainly the Egyptian-based Ansar Bayt al-Maqdis, have already taken a stand and sworn allegiance to ISIS, which is gaining power against the Al-Qaeda leadership. In addition, in the future ISIS' potential for subversion and terrorism is liable to destabilize countries in the Middle East and to export jihadi terrorism to Israel and the West.
4) Regional Middle East significance: The foothold gained by ISIS and the global jihad in Syria and Iraq reflects and may aggravate the regional upheaval in the Middle East: the flashpoints include the tensions, schisms and hostility among the various ethnic, religious and tribal groups, especially between the Sunnis and Shi'ites; the political weakness of the nation states created and forced upon the region by the French and British after the First World War; the loss by the key states in the Middle East of their ability to govern; and the establishment of alternative ideologies and governance in the places where nation states collapsed. The establishment of the Salafist-jihadi organizations in Syria and Iraq are manifestations of the power of radical Islamic ideology to attract followers and present itself as a magical solution for the ongoing distress and basic ills that have plagued the nation states since their inception.
15. Thus additional instability and volatility were injected into the already unstable situation in the Middle East by the establishment of ISIS and the global jihad organizations' power base in Syria and Iraq. They are liable not only to accelerate the disintegration of Syria and Iraq but to filter into the entire region. In the foreseeable future ISIS can be expected to continue its military occupation of Syria and Iraq, establish its control and oppose the campaign the United States is waging against it. However, in the long run, as it establishes itself more firmly in Syria and Iraq, its influence may gradually spread to other Arab states; its growing cooperation with the Ansar Bayt al-Maqdis is proof thereof. Veterans of the fighting in Syria who return to their countries of origin in the Middle East are liable to become "carriers" of terrorism and subversion, whether at ISIS instigation or on their own initiative, thereby contributing to political instability in their own countries (as has already happened in Darnah in eastern Libya, taken over by a jihadi network which expressed its support for ISIS).
16. ISIS' dramatic successes in the summer of 2014 were a strong blow to American foreign policy in Iraq. America's objective was to establish a democratic Iraqi regime that would fight terrorism and provide the country with a stable administration. That proved to be completely unrealistic. The Iraqi army, in whose establishment the United States invested enormous resources, was exposed as weak, as was the Shi'ite-affiliated central regime in Baghdad supported by America. Moreover, the Americans regarded the rapid establishment of ISIS and the Al-Nusra Front in Syria and Iraq as threatening the stability of Middle Eastern countries (among them Jordan, Egypt, Saudi Arabia, Lebanon and the Gulf States). In addition, there was a significant rise in the number of foreign fighters who fought in the ranks of ISIS and other jihadi organizations in Syria and Iraq and who might endanger the security of America and other Western countries when they returned to their countries of origin.
18. The United States altered its policy from underestimating ISIS to demonizing it and representing it as a significant regional and international threat. The change in concept required an American response, which was given in two stages: the first (June – August 2014) consisted of "pinpointed" responses intended to support the local forces in Iraq in halting the momentum of ISIS attacks. The pinpointed responses mostly involved sporadic aerial attacks, the dispatch of a small number of advisors and providing besieged minorities with humanitarian aid. However, it quickly became clear that pinpointed responses were ineffective and did not provide a satisfactory answer to the challenges to American interests posed by the successes of ISIS.
19. For that reason, the second stage was formulated as a comprehensive strategy for a campaign against ISIS, as noted in a speech given by President Obama on September 10, 2014. The objective of the new strategy was to "degrade and ultimately destroy" ISIS in the following ways: massive aerial bombings in Syria and Iraq; reinforcing the local forces in Syria and Iraq (the Iraqi army, the Kurdish forces, the so-called moderate rebel organizations in Syria); damaging the sources of ISIS' power (especially its financial resources);improving the United States' and the international community's deterrent capabilities against the foreign fighters and deepening international collaboration against them. President Obama and spokesmen for the American administration repeatedly stressed thatthe new strategy did not include sending a significant ground force to fight in Syria or Iraq, the so-called "boots on the ground."
20. To implement the strategy, in a relatively short period of time the United States established an international coalition of Western and Arab countries. The Western allies (most importantly France and Britain) participated in the aerial attacks on Iraq while some of the Arab states (Saudi Arabia, the UAE, Jordan and Bahrain) joined the aerial attacks on Syria. By the end of October 2014 the United States and its allies had carried out 632 aerial attacks against ISIS' military and economic infrastructure in Syria and Iraq (286 in Syria and 346 in Iraq). The attacks have continued into November.
24. As to ISIS' responses to the American campaign, ISIS has publicly beheaded five abductees, three American and two British. On September 21, 2014, ISIS called on its supporters around the globe to use a variety of methods to kill civilians in the United States and its allied countries. It is possible that a number of terrorist attacks, including the vehicular and shooting attacks in Canada, the planned beheading of Australians and attacks in other countries were the first responses to the call.
1) The Golan Heights and the Sinai Peninsula might be turned into active terrorist fronts: As of today, the Golan Heights are controlled by rebel organizations, the most prominent of which is the Al-Nusra Front, Al-Qaeda's branch in Syria. While ISIS does not currently have a significant presence there, the dynamics can easily changethe Golan Heights from a relatively quiet area into an active terrorist front where the Al-Nusra Front may be dominant. In the Sinai Peninsula ISIS-affiliated Ansar Bayt al-Maqdis (which has become the Sinai province of the Islamic State) is expected to launch terrorist attacks against Israel, although its strategic priority is its campaign against the Egypt regime.
4) Cooperation between the United States-led coalition and Iran: Despite Iran's basic hostility towards the United States, and despite Iran's subversion of American interests in the Middle East, it might collaborate with the United States against ISIS and global jihad in Syria and Iraq, the common enemy. Such collaboration might occur at Israel's expense and harm its vital interests (for example, Iran's concessions on the nuclear issue). In addition, collaborating against ISIS might increase Iranian influence in Syria and Iraq, and might also strengthen Hezbollah's status in Lebanon, possibly strengthening the Iranian-led radical camp in the Middle East.
27. ISIS (sometimes ISIL) is an acronym for The Islamic State in Iraq and Greater Syria. Once the Caliphate was declared ISIS began calling itself the "Islamic State (IS)" or the "Caliphate State." However, this study refers to the organization as ISIS, the term usually used by the international community, the Arab and Western media, and even by "Islamic State" supporters.
3) The need to integrate information from various disciplines and fields: ISIScannot be analyzed and examined only as a terrorist organization operating within a local national framework. A study of ISIS necessitates integrating various fields of knowledge, among them the history of Islam (including the Sunni-Shi'ite schism); the Salafist-jihadi movement from which ISIS sprang; the changes in Al-Qaeda and the global jihad; the developments in the civil wars in Syria and Iraq and the various aspects of the Middle Eastern upheaval. In preparing the study the ITIC used the existing literature and studies, and received support from experts in the various fields.
4) Problematic sources of information: In preparing the study we used primary sources from ISIS and other jihadi organizations. ISIS frequently posts information on the Internet about itself and its activities, but it is self-glorifying propaganda meant to sully the reputations of its rivals, threaten its enemies and deflect accusations. There is also a vast amount of information posted by ISIS' many rivals, which tend to defame the organization and sometimes manipulate the extent of its potential threat. In preparing this study we used investigative reports from correspondents (some of them Western) who had been allowed into areas under ISIS control. However the information to which they were exposed was sometimes directed and supervised by ISIS and intended to serve its political and propaganda objectives. Because of the awareness of the problem and because of the lack of trustworthy sources of information, all sources were treated carefully and critically.


Julia loves to teach, and she is currently accepting new students! She can also help families to find an instrument to buy or rent.
Lessons are available to students of all ages from beginner to advanced.
Hour lessons are standard but shorter lessons are available to younger students at the discretion of parents and teacher. Inquire for pricing. Lesson study includes fundamentals, etudes, solo & ensemble, recital repertoire, history, theory, and reed-making.
Bassoon reeds available for purchase with advance notice. Reeds are made with the Sakakeeny-Van Hoesen (SVH) shape and can be finished for beginners or left as blanks for those who wish to finish themselves.
Julia received a Bachelor of Music and Bachelor of Neuroscience from Oberlin College & Conservatory and a Master of Music from DePaul University. Her primary teachers included George Sakakeeny, Bill Buchman, Bob Barris, and Ann Dufek. She performed with the Civic Orchestra of Chicago from 2012-2014 and played with the Northbrook Symphony from 2014-2017. Previously she performed with the Chicago Symphony Orchestra, Music of the Baroque, and Chicago Sinfonietta. Julia taught students of all ages at Lake Forest College, Interlochen Arts Camp, Oberlin Conservatory, MusiCorps, Little Marvels Early Childhood School, the Avon School of Music, and the Hyde Park Allegro Music Camp.
She is also a member of the Chicago-based woodwind quintet Second City Winds.
Julia relocated to New York City to work as a freelance musician and educator.


Open plan spaces can have a positive impact on family life and in our Tunbridge Wells store we've noticed that more and more customers are going down this route and opening up their rooms. Therefore, in this blog we've answered some of the most popular questions we're asked.
Are floor tiles a good option for the whole space?
As floor tiles are a great practical choice to use in a kitchen, dining room and lounge they are the perfect option for an open plan area. They come in so many colours, textures and shapes that you do have the option of making a bold statement. However, we would recommend using one style throughout as mixing them up in an open plan space can look a bit mishmashed. Use tiles to tie the space together then zone each area with furniture and different decorative styles.
Aren't floor tiles quite cold?
They needn't be. As well as choosing floor tiles that have warming tones, you can really add warmth by adding underfloor heating. What was once considered to be a luxury is now becoming commonplace and is a particularly good choice for open plan spaces as it negates the need to add radiators. Ceramic and porcelain tiles are both excellent conductors of heat so they will spread it evenly throughout the room and, underfloor heating also adds a pleasant feel underfoot!
What type of tiles work best?
Large format tiles look great in an open plan space as they really emphasise the area and can make it look even larger than it actually is. As floor tiles are extremely durable and can last for many years, they are an investment. With this in mind, it's not always best to go with what's in fashion at the moment as you may not like it in a few years, so we would always recommend taking your time to choose. Travertine is always a popular choice for open plan spaces as it can fit with extremely contemporary and more traditional styling.
Are there any tiles that I shouldn't choose?
The most important thing to ensure is that your tiles are suitable for the floor. It may seem like an obvious comment, but whilst floor tiles can be used on walls, wall tiles are not suitable for use on the floor. Porcelain tiles are stronger than ceramic tiles so can be a better option, but this is something you can discuss with our team of experts. As mentioned above, large format tiles look great in open plan room, whereas smaller tiles can make the area feel a bit closed in.
All the teams in our showrooms have the expert knowledge to help you make the perfect flooring choice for your open plan space. Pop into one of the showrooms or give us a call.


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Alton Lake Sailing Association, or ALSA, is a club for catamaran and monohull sailors in the greater St. Louis area. We currently enjoy primarily recreational sailing, but there is always interest in racing as well. Alton Lake describes the pool of the Mississippi river between Alton and Grafton, where the river is much wider, with very little current compared to other parts of the river. It is a popular area for both sail and power boats. We feature mast up storage, so we can be on the water in minutes! Let us know if you would like to join us!


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We are all familiar with the modern table and how they are used, but the question is can you define a table based on the types of chairs that is uses, if it even uses chairs at all. They include the table and four chairs in most cases, though some also include other accessories to be put around the area or an umbrella.
Many of these pieces are designed to match perfectly with available outdoor dining sets, tables, chairs and other furniture, allowing you to create a complete ensemble for your patio. Getting quality patio furniture sets of Grosfillex resin.
I would love to have an outdoor fireplace, but they always worry me because of the dogs. Having blocked off the old back door we made use of the old dead space at the end of the kitchen by putting up a stud-wall which we then used for kitchen wall and base units; and the area behind the stud wall was then utilised to create a rather handy little cloakroom, with the adjoining living room.
Also, keep in mind that slender glass tables are more effective for creating the sense of space than thick wooden ones. Shop our best selection of Patio Furniture & Outdoor Seating to reflect your style and inspire your outdoor space.
If you're tired of pale walls, try kraft paper-colored brown walls for a medium-tone brown background. Whether you want to decorate an outdoor dining space, poolside bar, or patio oasis, we have the styles you're looking for at affordable prices.
Patio bar chairs save space without sacrificing comfort. If you want to add to the electrifying atmosphere that the wonderful music has managed to set rolling, then your dining furniture consisting ofdining tables and dining room chairs also has to be inviting, enticing and appealing to the senses.
If you plan to build mini houses and furniture, you will first want to know what style or type you want to build. The collections cover a wide range of dining room furniture styles, ranging from the simplicity of Shaker and early American styles to the cyma legs of the French to the ornate heavy Victorian styles of furniture.
Choosing the right dining room table goes beyond simple aesthetics. A dollhouse filled with typical everyday furniture and furnishings (miniature home) Source.
Clean your wrought iron furniture with mild soap and water. Steadily spray two separate coats of metal topcoat paint onto the entire table's surface.
If you do, wait for the paint to dry. Dine in style with our selection of elegant dining chairs.
They include the table and four chairs in most cases, though some also include other accessories to be put around the area or an umbrella. Opting for real wood rather than just laminated for the Kitchen units e.g. solid oak doors and drawers.
Getting quality patio furniture sets of Grosfillex resin. Let it dry at least the maximum recommended drying time before moving anything back onto the porch.
Having blocked off the old back door we made use of the old dead space at the end of the kitchen by putting up a stud-wall which we then used for kitchen wall and base units; and the area behind the stud wall was then utilised to create a rather handy little cloakroom, with the adjoining living room. These pieces are smaller than business furniture, more for personal use only.
Shop our best selection of Patio Furniture & Outdoor Seating to reflect your style and inspire your outdoor space. The appearance of a color will look different depending on what other colors are adjacent to it. You'll get a much better idea of how the color will look if you look at it next to your furniture, window treatments, or cabinets.
Whether you want to decorate an outdoor dining space, poolside bar, or patio oasis, we have the styles you're looking for at affordable prices. For example, choose coral and turquoise for your colors with pops of black.
If you want to add to the electrifying atmosphere that the wonderful music has managed to set rolling, then your dining furniture consisting ofdining tables and dining room chairs also has to be inviting, enticing and appealing to the senses. The wood was replaced with several metals and synthetic materials and new color schemes evolved.
The collections cover a wide range of dining room furniture styles, ranging from the simplicity of Shaker and early American styles to the cyma legs of the French to the ornate heavy Victorian styles of furniture. Gus Modern offers a collection of mid-century inspired furniture that finds its home pleasantly on display in the dining room.
A dollhouse filled with typical everyday furniture and furnishings (miniature home) Source. Though America's reproduced furniture styles were smaller in size and scale when compared to English furniture, they were better suited for the smaller rooms and lower ceilings of the typical early colonial homes.
Steadily spray two separate coats of metal topcoat paint onto the entire table's surface. At best, this is an inconvenience and you will need to chase patio chairs and the like all over the place.
Dine in style with our selection of elegant dining chairs. Barbie in her kitchen while her friend sits at the dining table waiting for a snack.
Opting for real wood rather than just laminated for the Kitchen units e.g. solid oak doors and drawers. I have never seen a table setting contest so thanks for the introduction.


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Skálmöld & Sinfóníuhljómsveit Íslands is a live album and concert video by the Icelandic heavy metal band Skálmöld and the Iceland Symphony Orchestra, released on 18 December 2013. The song material is from Skálmöld's first two albums, arranged for orchestra by Haraldur V. Sveinbjörnsson and performed during three concerts at Harpa in Reykjavík. The concerts received the Icelandic Music Award for Music Event of the Year. The album was nominated for Album of the Year – Rock and sold more than 7,000 copies.

Background and recording
The band Skálmöld formed in Reykjavík, Iceland, in 2009 and combine heavy metal music inspired by bands such as early Metallica, Iron Maiden, Anthrax and Slayer with conventions from Icelandic music and poetry traditions. The lyrics are in Icelandic and draw heavily from Norse mythology. Everybody in the band is a member of the neopagan organisation Ásatrúarfélagið.

After releasing the studio albums Baldur (2010) and Börn Loka (2012) and receiving attention for their live performances, Skálmöld were offered to collaborate with the Iceland Symphony Orchestra, which for several years had worked with bands and artists of disparate backgrounds. The composer Haraldur V. Sveinbjörnsson created orchestral arrangements of songs from Skálmöld's two albums to be performed by the band and symphony orchestra in Eldborg, the main auditorium of the concert hall Harpa in Reykjavík. The collaboration also involved the  (), the school choir of  and the choir Hymnodía. Bernharður Wilkinson was conductor. As part of the Iceland Symphony Orchestra's educational work, teenagers from primary schools in the Reykjavík region attended the final rehearsals on the morning of 28 November 2013, before three sold-out concerts were held on 28, 29 and 30 November 2013. The concerts were recorded and filmed so they could be released on CD and DVD as Skálmöld & Sinfóníuhljómsveit Íslands.

Release
The live video of the song "Hel", which features Edda Tegeder Óskarsdóttir of the band Angist as guest vocalist, was released on YouTube on 6 December 2013. The record label Sena released the CD and DVD of Skálmöld & Sinfóníuhljómsveit Íslands on 18 December 2013, two days after the initially announced date. The album was launched with an event at a record store in the Reykjavík shopping centre Kringlan where Skálmöld's members signed records.

Reception
Benedikt Bóas of Morgunblaðið praised the album, rating it five out of five, but thought the video was less impressive and rated it three and a half out of five. He had been at the live performances, which he called "some of the best concerts in Icelandic history", and described the album as "great, absolutely magnificent really" and "probably one of the best concert albums in Icelandic history". He wrote that the record company had rushed to get the release out for Christmas, which he thought shows in how the accompanying booklet has little content. He described the video as poorly edited and the camerawork as uninteresting, as it relies only on tripods and handheld cameras, with no crane shots.

The concerts in Eldborg received the Icelandic Music Award for Music Event of the Year. Skálmöld and the Icelandic Symphony Orchestra were jointly nominated for Live Performer of the Year, but lost to Skálmöld who were also nominated on their own. Skálmöld & Sinfóníuhljómsveit Íslands was nominated for Album of the Year – Rock, losing to In the Eye of the Storm by Mono Town.

Skálmöld & Sinfóníuhljómsveit Íslands was initially released in 4,700 copies which sold out in four days. In January 2016, the album received an Icelandic platinum certificate, which meant it had sold more than 7,000 copies. Skálmöld simultaneously received gold certificates — 3,500 records sold — for the studio albums Baldur and Með vættum (2014), and celebrated this by holding concerts in Iceland in February and March 2016. Skálmöld and the Iceland Symphony Orchestra repeated their collaboration when they held four concerts in Eldborg in August 2018.

Track listing

References

2013 live albums
2013 video albums
Live video albums
Skálmöld albums


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New TV take on 'Get Shorty' is long on quality and laughs
Arts & Entertainment // TV
David Wiegand Aug. 10, 2017 Updated: Aug. 10, 2017 1:28 p.m.
New TV take on 'Get Shorty' is long on quality and...
1of3Chris O'Dowd (left), Sean Bridgers and Ray Romano star in the new Epix production of "Get Shorty."
2of3Lidia Porto is Amara, a ruthless Nevada casino owner, in "Get Shorty," a 10-episode series on Epix.Photo: Courtesy Epix
3of3Ray Romano (left), Sean Bridgers and Chris O'Dowd star in the new Epix adaptation of "Get Shorty," which is loosely based on Elmore Leonard's novel.Photo: Courtesy Epix
Before you say, "Who needs another version of 'Get Shorty'?," take a gander at the 10-episode adaptation of Elmore Leonard's sublime novel premiering on the Epix subscription channel on Sunday, Aug. 13. It's a beaut.
The credits for the Epix "Shorty" make it clear that the series is based "in part" on Leonard's novel, which is not only true, it also explains why aspects of the show won't begin to revive your memories of the 1995 film. For one thing, Chili Palmer is nowhere in sight. Instead, meet Miles Daly (Chris O'Dowd), a hitman for a ruthless, bejeweled casino owner named Amara de Escalones (Lidia Porto). Miles and his partner, Louis Darnell (Sean Bridgers) get their hands on a movie script written by a suddenly deceased screenwriter who owed a lot of money to Amara. Miles gets the idea that they could get the movie made and use it as a way of laundering money for Amara. Amara likes the scheme and wonders if they can get John Stamos for the lead. She likes John Stamos.
They take the script to Rick Moreweather (Ray Romano), a Hollywood bottom-feeder who specializes in cheap, grade Z movies.
Along the way, there are lots of inconveniences, including a rivalry between Amara's operation and a gang looking to muscle in on Amara's territory because the feds are watching her every move. Amara's box-of-rocks nephew, Yago (Goya Robles), inadvertently lets gang members into the casino counting room, and gets his face bashed in while the "bad guys" abscond with $50,000 in receipts.
Miles is also struggling in his personal life. His long-suffering wife, Katie (Lucy Walters), would like to raise their daughter, Emma (Carolyn Dodd), in a household where dad's business can never be discussed.
While creator Davey Holmes takes plot and character liberties throughout the three episodes sent to critics for review, he preserves the dark comic sensibility of Leonard's vision. The Epix series becomes a neo-Nathanael West satire of the film industry, which, of course, is as ruthless and immoral as the crime business.
The performances are sublime. O'Dowd's con-artist likability smooths over some of the overly convenient plot points in Holmes' script. Romano, Bridgers and Robles are unforgettable in their respective roles.
But for my money, Lidia Porto steals the show. Sashaying around dusty Pahrump, Nev., with a fur throw tossed over her Joan Crawford shoulders, turquoise jewelry around her neck and on most of her garishly manicured fingers, her hair teased and sprayed into a dramatic cockscomb, Amara is a woman who was victimized once in her life, but only once. Porto delivers a magnificently comic performance.
Also in the magnificently comic category is the great Alan Arkin, making a cameo as Moreweather's father. Arkin's son, Adam, is the show's co-executive producer, so he probably had his private number.
The premiere episode fires on all cylinders. While the second and third are very good, they plateau a bit. One reason for that is that Holmes wants us to care a lot about whether Miles can get his wife and daughter back. Keep trying, but we came for the buffet.
David Wiegand is an assistant managing editor and the TV critic of The San Francisco Chronicle. Follow him on Facebook. Email: dwiegand@sfchronicle.com Twitter: @WaitWhat_TV
Get Shorty: Comedy-drama, premieres 7 p.m. Sunday, Aug. 13, on Epix. Epix is a subscription channel available on some content providers, including AT&T U-Verse and Dish, and is available for subscription on several devices, including Apple TV, Roku, PlayStation 4, Amazon Fire, iPad and iPhone. Go to www.epix.tv to learn more.
David Wiegand
Follow David on:
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David Wiegand is an assistant managing editor and TV critic for the San Francisco Chronicle. A native of Rochester, N.Y., he holds a bachelor's degree in English and a master's in journalism from American University in Washington, D.C.
He joined The Chronicle in 1992 as a copy editor with the arts section and became entertainment editor in 1995 and executive features editor in 2006. He took on the job of television critic in 2010, writing regular TV reviews and columns not only for The Chronicle but for other papers in the Hearst chain.
Before The Chronicle, he was managing editor of Dole Newspapers in Somerville, Mass., and editor of the Amesbury (Mass.) News.
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Insurance costs are high. There's no getting around it. Operating a business is a hit or miss proposition anyway, and when you add the ever increasing cost of business insurance, a lot of small companies can't keep up. They are looking for relief, and some are turning to self-insurance. Following are a few tips on how to self-insure your business.
What Does It Mean to Self-Insure?
Basically it means you'll be handling any financial problems that come up by yourself, without paying premiums from an insurance company. If you decide to provide a health insurance plan for your employees, you would collect a certain amount of money from them and deposit the cash into a fund designated for that purpose. When a claim is filed, any payout would come from that fund.
The usual way a self-insurance plan works is for the employer to open a fund that will be reserved for insurance claims purposes. They will generally hire someone to manage the fund. The fund manager is paid to administer the account. They will be responsible for handling the money and making payouts when they're deemed appropriate. Because you're essentially cutting out the middle man, i.e. the insurance company, the cost of being self-insured can be minimized. This can result in saving a bit of money, which can be put back into operating the business. In order to protect the worker, most states require the employer to post a bond to cover potential problems.
When you self-insure your business, you're literally taking responsibility for the welfare of your employees. Virtually any type of business insurance can be covered by self-insuring–health, vehicles, property or workers' comp can all be self-insured. The most prevalent among businesses that self-insure is health coverage. As long as you have a designated fund, self-insuring is possible. The extent of coverage is left up to you, since you're the insurer.
There is risk involved in anything you do, including buying insurance the traditional way. No matter how well established or trustworthy an insurance company may seem, there is always the chance they won't live up to expectations. So the fact that you'll be taking a chance by self-insuring won't be anything new. One of the chief drawbacks to self-insuring is the risk of having too many claims filed within a short period of time, or one huge claim that has to be paid out, thereby draining the fund. Even if you've been extremely careful, and thoroughly researched the self-insurance process beforehand, you can't predict the future. There is always the possibility of that one enormous claim, or too many claims coming too fast.
If the worst happens and your fund is in danger of becoming depleted, there are ways of bailing yourself out. A very specialized type of insurance, called stop-loss insurance is available. A company that is self-insured knows there is a limit to how much they can pay out before the fund dries up, so they will often buy a stop-loss policy from a traditional insurance company. These policies kick in when the self-insurance fund is in danger. They work two ways.
One way is for the stop-loss policy to take over once an individual claim reaches a predetermined point. This will ensure that enough money remains in the company's insurance fund to continue to pay other claims. The stop-loss policy will continue to pay the original claim up to the limit set on the policy.
The other way a stop-loss policy works is for it to take effect if numerous claims have been filed against your self-insurance fund. When those claims reach a certain number, the stop-loss policy takes over. It remains in effect until the amount of money needed to pay those claims is reduced to a prearranged amount.
I had never heard of self-insurance, but it sounds incredibly risky. Insurance companies are in the risk business. Everything they do is carefully calculated to manage risk based on statistical probability. They adjust premiums based on variations in one's medical record, driving record, etc. They are "trained professionals". Insurance is one of those things that I would say falls into the "Don't try this at home, kids!" category.


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Rehoboth is an unincorporated community in Harris County, in the U.S. state of Georgia.

History
The community was named after Rehoboth, a place mentioned in the Hebrew Bible. A variant name was "Mobley". Rehoboth was once an incorporated municipality; its municipal charter was repealed in 1995.

References

Former municipalities in Georgia (U.S. state)
Populated places disestablished in 1995
Unincorporated communities in Harris County, Georgia


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