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Nociceptive sensitization is a common feature in chronic pain, but its basic cellular mechanisms are only partially understood. The present study used the Drosophila melanogaster model system and a candidate gene approach to identify novel components required for modulation of an injury-induced nociceptive sensitization pathway presumably downstream of Hedgehog. This study demonstrates that RNAi silencing of a member of the Bone Morphogenetic Protein (BMP) signaling pathway, Decapentaplegic (Dpp), specifically in the Class IV multidendritic nociceptive neuron, significantly attenuated ultraviolet injury-induced sensitization. Furthermore, overexpression of Dpp in Class IV neurons was sufficient to induce thermal hypersensitivity in the absence of injury. The requirement of various BMP receptors and members of the SMAD signal transduction pathway in nociceptive sensitization was also demonstrated. The effects of BMP signaling were shown to be largely specific to the sensitization pathway and not associated with changes in nociception in the absence of injury or with changes in dendritic morphology. Thus, the results demonstrate that Dpp and its pathway play a crucial and novel role in nociceptive sensitization. Because the BMP family is so strongly conserved between vertebrates and invertebrates, it seems likely that the components analyzed in this study represent potential therapeutic targets for the treatment of chronic pain in humans.
SIGNIFICANCE STATEMENT This report provides a genetic analysis of primary nociceptive neuron mechanisms that promote sensitization in response to injury. Drosophila melanogaster larvae whose primary nociceptive neurons were reduced in levels of specific components of the BMP signaling pathway, were injured and then tested for nocifensive responses to a normally subnoxious stimulus. Results suggest that nociceptive neurons use the BMP2/4 ligand, along with identified receptors and intracellular transducers to transition to a sensitized state. These findings are consistent with the observation that BMP receptor hyperactivation correlates with bone abnormalities and pain sensitization in fibrodysplasia ossificans progressiva (Kitterman et al., 2012). Because nociceptive sensitization is associated with chronic pain, these findings indicate that human BMP pathway components may represent targets for novel pain-relieving drugs.
Chronic pain, perpetuated by the neuroplastic process of nociceptive sensitization, affects millions of people worldwide (Gaskin and Richard, 2012). Sensitization in response to tissue damage can produce a reduction in nociceptive thresholds that in some cases can outlast the initial injury. A more detailed knowledge of the pathways that lead to nociceptive neuron sensitization may allow for the identification of novel targets for the treatment of chronic pain. It has been estimated that 75% of known human disease genes have relatives in the Drosophila genome (Reiter et al., 2001), allowing the genetically tractable fly to serve as a relevant model for human ailments, including neurological disorders (Pandey and Nichols, 2011; Wangler et al., 2015).
Previous studies have used ultraviolet (UV)-induced tissue damage to sensitize nociceptive neurons in Drosophila larvae. A defined dose of UV irradiation was delivered to anesthetized animals; and 24 h later, wild-type animals demonstrated an increase in sensitivity to a light touch with a thermal probe at a normally subthreshold temperature, referred to as thermal allodynia (Babcock et al., 2009). Using this model, three pathways have been identified: TNF-α (Babcock et al., 2009; Jo et al., 2017), Hedgehog (Hh) (Babcock et al., 2011), and tachykinin (TK) (Im et al., 2015), which are required for communication among the injured epidermis, the underlying nociceptive neurons, and the CNS to bring about the observed thermal allodynia. The Drosophila Bone Morphogenetic Protein (BMP) Decapentaplegic (Dpp) lies downstream of Hh, yet its involvement in the sensitization of nociceptive neurons remains unknown.
Dpp, a fly ortholog of mammalian BMP2 (Ozkaynak et al., 1990) and BMP4 (Jones et al., 1991), is a member of the TGF-β superfamily of signaling proteins (Padgett et al., 1993) and, as depicted in Figure 1, binds to receptors (Massagué and Like, 1985) in the serine/threonine kinase family (Lin et al., 1992). Dpp's primary receptor Punt (Put) (Letsou et al., 1995), orthologous to Type II TGF-β receptors, activates Thick Veins (Tkv) (Ruberte et al., 1995) and Saxophone (Sax) (Xie et al., 1994; Nellen et al., 1994), both orthologous to Type I TGF-β receptors. In turn, the Type I receptors modify the intracellular transducer Mothers Against Decapentaplegic (Mad) (Sekelsky et al., 1995) by phosphorylation and subsequent translocation to the nucleus (Newfeld et al., 1997) as a complex with Medea (Med) (Wisotzkey et al., 1998). Mad and Med are members of the SMAD group named after the small Caenorhabditis elegans SMA mutant (Brenner, 1974) and Drosophila melanogaster Mad. As examples of the strong conservation between mammalian and Drosophila BMP components, prior studies have shown that Dpp can induce endochondral bone formation in mice (Sampath et al., 1993), and human BMP4 DNA sequences inserted into the fly genome rescue Dpp-deficient larvae to normal development (Padgett et al., 1993).
In the Drosophila larva, four classes of primary afferent neurons, referred to as dendritic arborization neurons, innervate the body wall. Classification is based on increasing levels of dendritic arborization (Grueber et al., 2012). Class IV dendritic arborization neurons, referred to as nociceptive neurons in this report, have the most elaborate epidermal arbors of naked dendrites and respond to noxious mechanical and thermal (heat) stimulation (Tracey et al., 2003). These neurons express nocisensitive ion channels, such as Painless, a Transient Receptor Potential (TRP) channel orthologous to mammalian TRPA1 (Tracey et al., 2003); Pickpocket (Ppk), a degenerin-like mechanosensory channel (Adams et al., 1998); the Drosophila dTRPA1, sensitive to electrophiles (Kang et al., 2012) and heat (Neely et al., 2011); and the mechanosensor Piezo (Kim et al., 2012).
In this study, cell-specific RNAi suppression of BMP pathway components in nociceptive neurons was used to demonstrate that BMP signaling via a canonical pathway is required for UV-injury induced allodynia. Because of the high degree of functional conservation between mammalian and Drosophila BMP components, components of the human BMP pathway may represent new leads with potential therapeutic value.
Materials and Methods
Fly stocks and genetics.
Flies were maintained in 6 oz stock bottles on sucrose-cornmeal-yeast medium at a temperature of 25°C with a humidity of 50%–60%. Stock bottles were kept in Percival Scientific Incubators with a 12 h light/12 h dark cycle. The arbitrary dawn time for the incubators was set to 9:00 A.M. The GAL4/UAS system was used to drive expression of UAS-inverted repeat (IR) RNAi transgenes targeting specific genes of interest. The driver in all experiments was Ppk1.9-Gal4, which expresses GAL4 specifically in the Class IV multidendritic nociceptive neurons (Ainsley et al., 2003). The Ppk1.9-Gal4 line used also contained a Ppk-GFP element, allowing direct visualization of morphology of these neurons (generous gift from Daniel Cox). All other flies were obtained from the Bloomington Drosophila Stock Center (BDSC; Bloomington, Indiana). The transgenic UAS-RNAi lines used, featuring IR construction for RNAi suppression, were as follows: DppIR (BDSC #35214, 25782), PutIR (BDSC #35195, 27514), TkvIR (BDSC #35166, 35653), SaxIR (BDSC #55865, 36131), MadIR (BDSC #35648, 43183), and MedIR (BDSC #31928, 43961). Additionally, a UAS-Dpp line (BDSC #1486) (Ward and Berg, 2005) was used to overexpress Dpp. Animals were included without regard to sex.
UV injury.
A method of UV induced allodynia was applied (Babcock et al., 2009). Third instar larvae were collected 4 d after egg laying, rinsed, and anesthetized with diethyl ether. Anesthetized larvae were gently adhered dorsal side up to double-sided tape on a microscope slide and were subjected to 12–15 mJ/cm2 of UV light delivered in ∼2–5 s in a Spectronics Spectrolinker XL-1000 ultraviolet crosslinker. The larvae were then placed in a small vial containing ∼1 ml of sucrose-cornmeal-yeast media and allowed to recover for 24 h before assays were performed.
Thermal nociception assay.
To test nociceptive behavior, the larvae were assayed with a thermal probe (Pro-Dev Engineering) 24 h after UV exposure. The probe tip was gently applied to the dorsal side of the larvae and held on abdominal segments 2–4 for a maximum of 20 s. To test for allodynia, the larvae were subjected to 41°C, the highest temperature that did not elicit a behavioral response in our hands (Fig. 2). The larval response consisted of a nocifensive 360° lateral rolling that larvae only exhibit in response to a noxious stimulus (Tracey et al., 2003). The latency for response was recorded and categorized as follows: fast was 0–6 s (indicated by black regions on graphs), slow was 6–20 s (gray), and no response if the 20 s cutoff was reached (white). To assay normal nociceptive function (see Fig. 10), larvae were tested at 45°C, and the time to respond was recorded and presented as average response latency. The probe operator was blinded to the UV treatment and genotype, and all groups contained a sample size of at least 90 animals.
Quantification of dendritic morphology.
Class IV multidendritic neurons were analyzed for total dendritic length and number of dendritic branches (Iyer et al., 2013). Third instar larvae were anesthetized with CO2 and placed on a microscope slide with a halocarbon-ether mixture (2:1). Larvae were imaged with a Leica SP5 confocal laser microscope using a 20× objective. ddaC neurons, the most dorsal pair of Class IV nociceptive neurons (Grueber et al., 2012), were imaged from abdominal segments 4–6, and z stacks were taken with a 0.76 μm step size to capture the whole dendritic field. Images were taken with a resolution of 1024 × 1024. Images were skeletonized and analyzed for parameters of dendritic length and dendritic branching in the open source image-processing package Fiji (https://imagej.net/Fiji).
Immunohistochemistry conditions and imaging.
Third instar larvae bearing Ppk-GFP to specifically visualize the nociceptive neurons were filleted longitudinally by incision along the ventral midline without anesthesia, and all tissues internal to the muscular body wall were removed. The body wall was pinned flat on a silicone (Sylgard) surface, fixed 20 min in fresh 4% PFA in PBS, washed in PBS 0.1% Triton X-100 (PBS-T), and blocked overnight at 4°C with 5% normal goat serum in PBS-T. The intensity of BMP receptor and transducer immunoreactivity were compared in control and UAS-RNAi-expressing animals. Primary antibodies to Put (Abcam 14680, 1:100) were incubated 1 h at room temperature, then overnight at 4°C washed in PBS-T and visualized with fluorescently conjugated secondary antibodies (AlexaFluor-568, Abcam) at 1:500, incubated for 2 h at room temperature followed by washing with PBS-T. Suitable antibodies to Med, Sax, and Tkv were not available. The Mad antibody was raised against mammalian p-Smad1/5/8 (generous gift from Volkhard Lindner, Maine Medical Center Research Institute) and used at 1:500. Animals were analyzed 0, 2, 4, 8, 16, and 24 h after UV injury. For each BMP component, eight larvae were analyzed. The ddaC nociceptive neurons in abdominal segments 4–6 were identified by eGFP fluorescence and studied for a total of 10–12 cells per component, and analyzed by confocal microscopy. Images were collected using a Leica SP5 Scanning Confocal Microscope using a 40× oil objective. All images were resolved at 1024 × 1024, and a Z stack was collected to ensure that the entire cell was analyzed. The Z stacks were collapsed into maximum projections, and the relative intensity of staining was analyzed using Fiji (https://imagej.net/Fiji). For immunohistochemistry results, mean integrated density was measured as the product of the area of the region of interest and the mean gray value in the desired channel. All images were obtained with the same exposure and camera conditions to compare integrated densities.
Visualization of BMP receptor expression by GFP tagging.
Because suitable antibodies to Sax and Tkv were not available, a GFP tagging approach was used (Venken et al., 2011). MiMIC lines were produced by the Gene Disruption Project, in which a GFP coding sequence was inserted intronically such that target genes produce the cognate protein translationally fused to GFP, thus making the protein directly visible via GFP fluorescence. Two MiMIC lines were selected, MI05726 and MI08515, corresponding to Sax and Tkv, respectively. Before use in imaging, the normal function of the GFP-modified genes was confirmed by determining their ability to complement deficient alleles (sax5 and tkv4). GFP/deficient flies developed successfully in both cases.
Statistical analysis.
To estimate the predicted probability of reacting for the different treatment groups in sensitization experiments, the response variable (reaction time) was collapsed into a binary variable and a generalized linear mixed model (with a logistic link function) was fit to the data for each pathway component using the lme4 package (version 1.1.7) (Bates et al., 2014) in R 3.1.3 (R Core Team, 2015) where larvae batch was modeled as a random effect (mixed logistic regression [MLR] analysis). To estimate the 99% CIs for the various contrasts found in Table 1, a parametric bootstrap (10,000 iterations) was performed using the corresponding models fit to the data. To test whether the differences between the postinjury reaction probabilities were significant, bootstrap CIs were constructed (at the α = 0.05, 0.01, and 0.001 levels) and inverted to test the significance of various comparisons at the corresponding α level. In graphs depicting results of allodynia experiments, whiskers indicate SEM of at least three groups of larvae. For normal nociceptive behavior and morphometry, a Welch's t test was performed. Immunoreactivity was compared using a one-way ANOVA with Tukey–Kramer Multiple Comparisons Test.
To optimally assay the nociceptive behavior of Drosophila larvae, a thermal dose–response study was performed on a standard control genotype (w1118). Beginning at 39°C, the temperature of the thermal probe was increased in 1°C increments; and at each temperature, 90 larvae were assayed for behavioral response. The response latency of each larva to its particular test temperature was recorded. From 39°C to 41°C, most larvae did not respond. However, beginning at 42°C, there was a steady increase in responsiveness with temperature, continuing to 50°C (Fig. 2). Because no animals responded at 41°C and a statistically significant number responded at 42°C (MLR), 41°C was selected as the maximum innocuous temperature at which to test for allodynia in this study.
To test for the development of thermal allodynia following injury, control flies (w1118) were divided into two groups: a UV-irradiated group and a non–UV-irradiated group. In the non–UV-irradiated group, very few animals responded to 41°C stimulation, whereas a significantly greater number of animals responded at this temperature after exposure to UV irradiation (p < 0.001, MLR; Fig. 3A). The possibility that UV irradiation affects the dendritic architecture of nociceptive neurons was examined in animals bearing a Ppk-GFP transgene that causes expression of GFP specifically in these cells. Nociceptive neurons dendritic branching and length (Fig. 3B) were measured after either UV treatment (right bars) or mock treatment (left bars). Neurons were analyzed at 24 h after injury, the time of peak development of allodynia (Babcock et al., 2009). No statistically significant differences were observed between treatment groups (MLR).
Using IR transgenics to trigger RNAi-mediated knockdown of Dpp expression in the nociceptive neurons, we observed that suppressing the availability of the Dpp reduced the development of thermal allodynia. Compared with controls, the DppIR animals demonstrated a strong attenuation of allodynia (p < 0.001, MLR; Fig. 4A). It was previously observed that overexpression of TNF-α by the epidermal cells can induce allodynia via paracrine signaling in the absence of injury (Babcock et al., 2009) as well as induce autocrine activation of Hh signaling (Babcock et al., 2011) and TK signaling (Im et al., 2015). In a similar experiment, UAS-Dpp was used to drive overexpression of Dpp in the nociceptive neurons to determine whether increased Dpp availability was sufficient to induce thermal allodynia without prior injury via UV irradiation (p < 0.001, MLR; Fig. 4B). Uninjured larvae with elevated Dpp expression showed significantly higher sensitivity to the 41°C probe, compared with control animals (p < 0.001, MLR; Fig. 4B).
Several membrane receptors have been implicated in transducing Dpp signals. These are Put (Letsou et al., 1995), Tkv (Ruberte et al., 1995), and Sax (Nellen et al., 1994; Xie et al., 1994). The various receptors for Dpp can be detected via immunohistochemistry and protein tagging in the nociceptive neurons (Figs. 5; 6). The expression of these Dpp receptors was suppressed to test for their requirement in nociceptive neurons for the formation of allodynia following UV irradiation. Significant reduction (Fig. 5D,E) in the level of Put expression was confirmed by immunocytochemistry. Expression of Sax and Tkv in the somata and dendrites of nociceptive neurons and other cells was observed using a GFP tagging approach (Fig. 6). Very faint Sax expression, but not Tkv expression, was observed in axon terminals (data not shown). Injury did not alter the expression pattern of either Tkv or Sax (data not shown). Larvae in which each receptor, Put (Fig. 7A), Sax (Fig. 7B), or Tkv (Fig. 7C), was individually suppressed showed strong attenuation in the formation of allodynia (p < 0.001, MLR). Similar reductions in sensitization were observed in animals in which Dpp, Put, Tkv, and Sax were individually suppressed using RNAi lines independent from and nonoverlapping with those shown above, indicating that the effects observed are not due to off-target suppression (data not shown).
To test for the requirement of canonical SMAD signaling downstream of these receptors (see Fig. 1), the expression of Mad in nociceptive neurons was suppressed through Ppk1.9-Gal4-mediated expression of a UAS-RNAi transgene targeting Mad, MadIR. Larvae with suppressed Mad demonstrated significantly less injury-induced sensitization compared with relevant controls (p < 0.001, MLR; Fig. 8A). When the co-SMAD Med was suppressed, the larvae again demonstrated significantly less injury-induced sensitization (p < 0.001, MLR; Fig. 8B) compared with the no UAS control group (Ppk1.9-Gal4>y1v1). Mad activation by the Type I BMP receptors Tkv and Sax following UV injury was quantified by immunohistochemistry using an antibody specific to the phosphorylated form of Mad (anti-pSmad1/5/8) at various times after UV damage. Eight hours after injury, predominantly nuclear basal phospho-Mad (p-Mad) immunoreactivity was increased by 125.53% (p < 0.001, Tukey–Kramer Multiple Comparisons Test) and returned to normal levels by 24 h (Fig. 9).
To confirm that larvae in which BMP components were suppressed maintained their ability to respond to noxious stimulation, nociceptive responses of uninjured animals to a suprathreshold temperature (45°C) were examined. The behavioral response latencies to this noxious thermal stimulus for all of the knockdown groups were not significantly different from both control groups (Fig. 10; Welch's t test).
The suppression of Dpp or the BMP receptors Tkv and Sax in nociceptive neurons did not result in any changes in dendritic length or in total dendritic branches. Suppression of Put, Mad, or Med resulted in small increases in dendritic branching (Put, p < 0.007; Mad, p < 0.022; and Med, p < 0.04, Welch's t test), but no significant changes to dendritic length were observed (Fig. 11). Larvae overexpressing Dpp in the nociceptive neurons showed a statistically significant reduction in length (p < 0.04, Welch's t test) and dendritic branching (p < 0.025, Welch's t test).
This study demonstrates a requirement for the BMP signaling pathway, particularly the components immediately downstream of Dpp (see Fig. 1), for the formation of thermal allodynia in Drosophila larvae in response to UV-induced tissue injury. BMPs are known to play important roles in developmental contexts, including Drosophila imaginal discs (Affolter and Basler, 2007) and bone formation in vertebrates (Wisotzkey et al., 1998). These roles include control of cell proliferation and specification of cell fate. The BMP pathway has been implicated in neural and synaptic development in vertebrates and invertebrates (Guha et al., 2004; James et al., 2014). BMP functions are well conserved across species, and particularly strong orthology exists between mammalian BMP 2/4 and invertebrate Dpp (Padgett et al., 1993; Sampath et al., 1993). This report describes a novel role for BMP signaling in nociceptive sensitization.
In previous studies performed in Drosophila and other animals, the Dpp signaling pathway has been well elucidated (Liu and Niswander, 2005; Affolter and Basler, 2007). Exogenous Dpp has been shown to specify cell fates, for example, in the developing wing, by binding its Type II receptor Put. Put then activates either of two Type I receptors, Tkv (ortholog of mammalian ALK3/6) or Sax (ortholog of mammalian ALK1/2). In many mammalian contexts, BMPs act as morphogens that trigger the specification of bone (Urist, 1965). With regard to roles in sensory processes, BMPs (Ai et al., 1999) and another member of the TGF-β superfamily, activin (Xu et al., 2007), are known to increase expression of calcitonin gene-related peptide in sensory neurons. TGF-β is known to regulate opioid transmitter synthesis (Kamphuis et al., 1997), and mice deficient in a TGF-β signaling inhibitor, BAMBI, are hyposensitive to noxious stimuli (Tramullas et al., 2010).
Previous studies have shown that upon cutaneous tissue injury by UV exposure and subsequent TNFα signaling by the apoptotic epidermal cells (Babcock et al., 2009), Hh is released from nociceptive neurons in response to TK signaling from the CNS (Im et al., 2015). Hh activation of its receptor Patched, located on nociceptive neurons, produces allodynia (Babcock et al., 2011). The observation that allodynia requires Dpp is consistent with previous data demonstrating Hh upregulation of Dpp expression in developmental contexts (Hooper and Scott, 2005). This study establishes that Dpp is necessary for injury-induced sensitization of nociceptive neurons. Furthermore, experimental overexpression of Dpp in nociceptive neurons produces allodynia in the absence of injury, supporting the conclusion that Dpp is sufficient for the formation of allodynia. Last, knockdown of Dpp does not alter normal nociceptive function, indicating that Dpp signaling is specific for nociceptive neuron sensitization.
The requirement of BMP components (see Fig. 1) in nociceptive neurons to produce sensitization was investigated by suppressing their expression in these neurons using Ppk1.9-Gal4 to drive expression of gene-specific IR RNAi constructs, which trigger the destruction of the matching endogenous mRNA, specifically in the nociceptive neurons. Results indicate that Dpp, its Type II primary receptor Put, and the Type I receptors Tkv and Sax are all necessary in the nociceptive neuron for the formation of allodynia. This suggests, but does not confirm, the possibility that the Dpp nociceptive sensitization pathway involves an autocrine signaling strategy. Because suppression of either Dpp or its receptors specifically in the nociceptive neurons produces a blockade of injury-induced thermal allodynia, it may be that Dpp is produced in the nociceptive neuron following epithelial tissue damage, then is released and interacts with that same nociceptive neuron's Dpp receptors. BMPs are known to signal through autocrine mechanisms at the neuromuscular junction (James et al., 2014), but a role for autocrine BMP signaling in sensory neurons has not been previously reported.
The effects of BMP signaling on nociception are specific to nociceptive neuron sensitization, as supported by the finding that manipulation of receptor expression via RNAi did not alter behavioral responses to noxious thermal stimulation. To demonstrate that the results of manipulating BMP signaling are specific to the sensitization pathway and not a general loss of nociceptive functioning in these neurons, uninjured RNAi-suppressed larvae were tested at the normally noxious 45°C (Babcock et al., 2009, 2011). No changes to normal nociception were observed.
The necessity of both Type I receptors, Sax and Tkv, for the formation of allodynia suggests that Dpp binds as a dimer, as has been demonstrated in prior studies of TGF-β members (Daopin et al., 1992), to trigger the allodynia-producing pathway in this cell. Both Type I receptors are independently necessary; thus, both must be activated to produce allodynia. Perhaps this mechanism of sensitization suggests a reason why congenital Type I BMP receptor ALK2 hyperactivation in human patients suffering from fibrodysplasia ossificans progressiva increases the incidence of neuropathic pain and allodynia (Kitterman et al., 2012).
The Type I BMP receptors are known to activate the canonical SMAD signaling protein Mad (Raftery et al., 1995) through phosphorylation to form p-Mad (see Fig. 1). Then p-Mad forms a complex with the co-SMAD Med, homolog of human SMAD4 (Wisotzkey et al., 1998), which translocates to the nucleus to regulate gene expression. Upon suppression of Mad and Med, the formation of allodynia was significantly attenuated, demonstrating that the canonical pathway is required for the manifestation of allodynia. Furthermore, immunolocalization of p-Mad, following UV-induced tissue damage, revealed that nuclear p-Mad levels were nominally elevated by 4 h after injury, reached a statistically significant peak 8 h after injury, and returned to baseline at 24 h following injury. This time course is consistent with the onset of hypersensitivity (Babcock et al., 2009).
Morphometric analysis was performed to determine whether the induction of allodynia following UV-mediated tissue damage was accompanied by changes to the dendritic architecture of the nociceptive neurons. No significant morphological differences between the neurons of UV-irradiated larvae and those of unirradiated controls were found, indicating that the observed hypersensitivity following UV damage is a result of intrinsic mechanisms of sensitivity, rather than changes in dendritic morphology. This also suggests that the morphological changes observed in some RNAi manipulations may be the result of a developmental effect of BMP perturbation.
In some experimental groups, there were some differences in dendritic morphology that may indicate a separate role for BMP signaling in these peripheral tissues (Fig. 11). First, Put knockdown resulted in a significant increase in the amount of dendritic branching. The direction of this effect is opposite from what might be expected given the observed failure of UV injury to produce allodynia in this manipulated animal. Similarly, when Dpp was upregulated in the nociceptive neurons, a decrease in both dendritic branching and overall dendritic length of these nociceptive neurons was observed. The direction of these effects is also in opposition to the formation of injury-independent allodynia. These inconsistencies between the results of a genetic manipulation on dendritic morphology and allodynia suggest that some factor other than the degree of dendritic arborization connects BMP signaling to the development of allodynia. The literature describing the role of BMP signaling in plasticity of the neuromuscular junction (James and Broihier, 2011; James et al., 2014) suggests that the effect of BMP signaling on injury-induced allodynia could be to produce changes in synaptic strength at the central terminals of the nociceptive neurons in the ventral nerve cord, where connections are made with the first-order interneurons of the central nociceptive circuitry (Ohyama et al., 2015).
It has been reported that BMP released from epithelial tissues acts to control the degree of sensory neuron innervation through density of terminal fields and total number of neurons in the DRGs of mice (Guha et al., 2004). Inhibition of dendritic growth by epithelially derived Dpp could explain why the RNAi manipulations of BMP receptor Put resulted in an increase in total dendritic branching. This model is consistent with our observation that, in animals with Dpp suppressed in nociceptive neurons, normal dendritic morphology was observed. In this case, Dpp knockdown in the nociceptive neurons would not be expected to have any effect on the pool of Dpp that might be released from the epithelial cells; however, the nociceptive neurons of such animals still have intact receptor machinery to perceive and transduce the epithelial-derived Dpp signal, thus resulting in normal dendritic architecture. On the other hand, upregulating Dpp in the nociceptive neuron would lead to an increase in Dpp signaling around that neuron and would increase the inhibitory signal, cuing a decrease in dendritic growth, as observed.
In conclusion, this report demonstrates that Dpp expression in the nociceptive neuron is both necessary and sufficient for the production of thermal allodynia. Dpp signals to the primary Type II receptor Put, in turn activating Type I receptors Tkv and Sax, which then activate the canonical signaling pathway by phosphorylating Mad to ultimately produce allodynia (Fig. 1). Suppression of these components has no observed effect on the normal nociceptive functioning of these cells and only minor effects on their dendritic morphology. Because of the high degree of conservation of the BMP system between vertebrates and invertebrates, the pharmacological manipulation of BMP pathways might offer an effective avenue for the treatment of chronic pain in humans.
This work was supported by National Institutes of Health/National Institute of General Medical Sciences Award 1P20GM103643–01A1 to Ian Meng, National Institutes of Health/National Institute of Neurological Disorders and Stroke Award 1R15NS095195–01 to G.K.G., Peter Caradonna, and the University of New England Microscope Core Facility supported by National Science Foundation 0116398 and 1125672. Stocks obtained from the Bloomington Drosophila Stock Center (National Institutes of Health P40OD018537) were used in this study. We thank Daniel Cox for assistance with morphometric approaches and for fly lines; Ian Meng for critical comments on the manuscript; Volkhard Lindner for the p-mad antibody; and Rema Weston, Michael Esty, and Cody Barba for technical support.
The authors declare no competing financial interests.
- Correspondence should be addressed to Dr. Geoffrey K Ganter, University of New England, 11 Hills Beach Road, Biddeford, ME 04005. gganter{at}une.edu


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Renovation assignments aren't the only causes for a 6 Yard Dumpster in Pomfret service. Functions such as significant outdoor marriage ceremonies or events compile huge amounts of garbage. Obviously it shouldn't be expected that everyone will probably walk with a dumpster to get rid of their rubbish. However, your containers tummy flatness, although in useful more so throughout the cleanup process. Items including plates, items of food, plastic tablecloths and greater objects would probably be left lying around and may show too much for a couple random average-sized rubbish bins. Aside from, those would probably already be crammed as a result of those that decided to get rid of their own objects.
Defining Height and width of Dumpster: Normally dumpster will come in five styles viz 10 cubic yard, Fifteen cubic yard, 20 cubic yard, 30 cubic yard as well as 40 cubic lawn. It is been observed which unlike 10, 20, 30, 50 cubic yard dumpster, Fifteen cubic yard dumpster are difficult to find.
Some sort of dumpster service are equipped for any kind of job, from start to finish. You will not ought to put your rubbish in luggage or storage containers. They will perform the work while you relax. They may help you get reduce all your rubbish and rubbish such as aged appliances, ovens, furniture, fridges, washing machines, hair dryers, toilets, hot tubs, cabinets, floor and such. They are able to help you get rid of the storage, shed, basement, backyard, or maybe attic. They are able to also take out broken goblet, plastics, metals, and other supplies. They will conserve time because you will not have to breakdown the items on your own or travel the trash with a dumpster.
Let me clarify you, great deal many modest industries as well as restaurants normally have trash disposal on day to day. Dumpsters waiting in entrance of entrance ways to get a choose from the city haulers structures a dirty photograph in the intellects of the consumers on their visit to the business prisms, rather you can go for renting a sizable size dumpster and have absolutely it used in the basement of your making or in a location out of your consumers view as well as dispose the garbage at intermittent intervals. Your dumpster should be used in a safe site and the entrance of the site should not chuck any challenges at the hauler while picking your dumpster.
You need to be in your own home when the organization comes by simply for acquire. If are usually absent tomorrow, you could be incurred one more week if they have another later.
You shouldn't have to have volunteers shell out extra time removing the trash or maybe bagging this when you rent the dumpster. You can allow weather decide if the 1st end of the week in the calendar month is the best time for the dumpster delivery as you can get in touch with and have the dumpster supplied the very next day inside Maryland spot. No matter what the work, it can be possible with a dumpster.
You can put your old master bedroom front door into the dumpster. It's also possible to put any old baseboards you no longer want due to breaking or if perhaps they just are certainly not the style you're looking for.
Should you and your family make a decision to jump right on the ball and get started out with setting up and losing items, as compared to you want to start using a dumpster company that will give you a overnight dumpster. You are in the climate to clean and you have taken vacation time off of work to start. You want fantastic service so you want it quick.
It can be luring to use your cellar to store just about every little cardstock or knick-knack you would imagine you'll want in the future. Consider how refreshing it could be, though, to have a nice large space clear of the muddle that can lavatory you all the way down. Bearing in mind this virtues involving simplicity, make the choice to rubbish what really is rubbish.
It's impossible that everyone in your cul-de-sac got hit on an equivalent scale. Just one household can have had their own trees attached recently, leaving behind them with much less fallen deceased wood, as opposed to another can have had a full tree uproot themselves. Encourage anyone to pitch in to your neighbors which got hit the toughest or which may not be capable to clean their own yards themselves. Pregnant women plus the elderly may well especially have got trouble, thus offer these people the neighborhood's solutions for cleaning their own yard or even carting their own debris to this dumpster. Who knows, you can find paid together with fresh cupcakes! If you are planning to perform a little major makeovers to your house, produce a new one or even carrying out any pursuit that will look at you producing a wide range of waste, some sort of dumpster is something that you desire around to allow you to move this debris to the proper dumping sites. Looking for a dumpster to rent should not be so hard because there are several firms offering the program. This however does not mean that you hurry into choosing any of them to meet your needs exactly. There are a number of products that you need to keep in mind when it comes to Dumpster accommodations.
Do you know neighborhood codes along with laws with regard to disposing of all the junk cleaned out of your home or even commercial place? If you don't, so you leave the fridge or even broken Tv set at the completely wrong place, you can find fined. specialists are familiarized with junk fingertips. Whether they allow you to load the18 wheeler or simply grab the dumpster you rented, they will know the correct final regenerating place for the items. In some cases, that will mean some sort of donation middle or a recycle facility--your trash might be another person's treasure! But that's only some of the benefit of dealing with junk haulers. You will also save constantly it would take you to drive items to the dump or recycle center by yourself. Instead, it will be easy to breathe some sort of sigh of alleviation when the vehicle or dumpster pulls away, realizing that your work is finished.
Please use the form below to contact us. We look forward to working with you and will get back to you as soon as possible. All fields are required

subset: commoncrawl


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The Grail Lords - Official Forum
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₁ In the beginning God created the heavens and the earth. ₂ The earth was without form, and void; and darkness was on the face of the deep. 653 more words
Tags » I Am
Ingested Announce U.S. Tour With Enterprise Earth, Bodysnatcher, I Declare War, Aethere, & I Am
Ingested have announced a U.S. tour with Enterprise Earth and Bodysnatcher. I Declare War, Aethere, and I Am will also perform on select dates.
Tour Dates: 213 more words
Don't Lose God
Morning Thought: This week I turned forty-three and I was encouraged that a couple of people shared Isaiah 43 with me. It's packed with promises. The Lord says, "I am with you." It's easy for us to lose God in the past. 126 more words
I AM -- "I am the Bread of Life" ~ Jesus
"I am the Bread of Life" (John 6:35) is one of the seven "I Am" statements of Jesus. Jesus used the same phrase "I AM" in seven declarations about Himself. 370 more words
The Journey Begins
I've been asked twice this week if I write a blog. I guess that means that some people are vaguely interested in my life and it's stories, and perhaps that I should in fact, start writing a blog. 291 more words
What is Mind? What is 'I'-thought?
August 15, 2018
I am part of a group which meets weekly to study and have dialogs about the spiritual development. Currently we are studying a book on Vedanta – The Essential Teaching – Updesa Sara by Bhagvan Raman Maharshi with commentary by Swami Tejomayananda of Chinmaya Mission. 1,189 more words


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Car Windshield Replacement Near Me Fountain Hill PA
We Can Arrive in Just a Couple Hours!
Get our professional technicians at your door within hours for most jobs.
We normally have a repair vehicle in the region, quite possibly directly in Fountain Hill or close by! Our service specialists are trained to operate on all makes and models of vehicles. We service Fountain Hill and all local communities in PA.
Our Services
- Why Choose Us?
- Our Auto Glass Services
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Windshield Repairs in Fountain Hill Pennsylvania
A lot of car components seem to be mysterious for many. Having said that, your car's windshield shouldn't be categorized in that grouping. Like other aspects in life, when your windshield is working properly, we do not contemplate it. Yet, when there is an issue, it becomes a serious concern.
Windshields are made using laminated glass. They are fabricated using a layering system. The outside layers are glass and the inner layer is a specific laminate.
The laminate normally is made from a style of vinyl plastic. The laminate functions as a sticking layer for the inner and outer layer of glass. This is the grounds of how laminated glass is produced. It will protect against a windshield from shattering into harmful glass shards.
Windshields installed in a manufacturing plant setting are done with robots, in a remarkably controlled manner. Electronic alignment and placement procedures ensure that both molding and windshield are accurately fitted. Learn more about Fountain Hill windshield replacement cost from your local repair professional.
Damaged windshields are a safety risk, therefore they have to be repaired once there are any hints of damage. Due the tight installation method as described previously, the most ideal strategy is to have the repair work done on the original windshield, in place. If the damage is a small chip or crack, this is feasible. This is not possible if the crack has lengthened, if the chip is in the driver's field of vision or the chip is larger that a coin.
Small chips or cracks can be repaired with any number of windshield repair kits that are available today. Although this is an option, we still strongly recommend that these simple patches be taken care of by an auto glass professional.
Chip repair may look like such a small-scale concern, lots of car owners will ignore it. This is a bad tactic. Little chips can absolutely turn into larger issues that require a full replacement.
Fountain Hill Windshield Replacement
Significant damage to your windshield will require a complete replacement. In fact, your car will not pass PA inspection with crack, chips or significant damage. Windshields that have substantial damage, such as long cracks or chips that are spidering across the glass, will call for a replacement. Simply put, when the crack is too large to repaired, the windshield will have to be removed and new one will have to be installed. Learn more about best windshield repair company in Fountain Hill 18015 here. A brand-new windshield ultimately returns the functionality and safety back to your car. A new windshield is the only safe option.
Fountain Hill Emergency Auto Glass Repairs
A broken or cracked car window or windshield can be a significant nuisance. Also, the problems may so significant that your car is not lawfully driveable. We are the absolute best service for all of your car's glass repairs. Our repair men can make your repairs happen quickly with our emergency repair services.
Emergency Service You Want!
As a reputable glass service center in Fountain Hill, we pride ourselves on our careful approach to auto glass replacement. The repair is performed quickly and our standards are high. This ensures that you are given the finest quality glass repairs on your car. As a customer, your safety is our top priority, and we won't send you back out driving until we're certain that your car is in proper shape.
Windshield FAQ
Has Anyone Ever Ridden On Greyhound??????
How Is It, Is It Comfortable And Good Value To Travel Eight Hours On The Bus?
I don't live near a major airport so bus is what I choose a lot to get across the country. I have made quite a few trips: Texas to NY at least twice, Texas to DC, Texas to Iowa at least twice.
I have a car now so I think my bus days are over but still it isn't a bad way to go.
Some tips:
Get your tickets at least 10 days in advance if you are making a longer trip. You get a flat fare, I think it's 59 dollars one way. You may be able to get a plane fare cheaper, and it gets you there faster. If you can fly cheaper, go ahead...but not just because busses suck so bad you will do anything to stay off them.
When you ride, try to read your fellow passengers and your driver. Some don't want any hoohaa and don't want to get to know you, others will become your travel buddy and want to hear your life story. Play the game.
Take enough on board to get you through the ride but not so much as to crowd anyone out or clutter up your little spot. You might want a book, or something with headphones, and you want a small pillow and a sweater or small blanket, you also want some small snack items and nicotine replacement if you smoke. You also want a water bottle and a bottle of hand sanitizer, a toothbrush and some toothpaste, a travel roll of TP, and a travel packet of cleaning wipes for the bathroom because the water in the toilet sloshes around and splashes up and it does not flush, and there isn't much that can be done about that that isn't done already when they layover to clean the bus. A tiny toy or storybook carried with you to share or give away to a child on the bus will go a long way to making travel buddies, as well as distracting kids who are usually trying to be on their best behavior on a bus. Try to be patient and compassionate. Lots of single parents on busses and there's nothing going to change for the better by getting bent out of shape about it.
There will likely be times on your route where you will have to share seats, and other parts of your trip where you can spread out. They shouldn't fill the bus over capacity of 2 to a seat. The very back seat on the bus is a mixed blessing. You can usually spread out a little more, but in a pinch it is a three seater, not a two seater, as well as being the first one asked to share when the bus starts to fill up. It is also right next to the bathroom.
Re: safety, be mindful, not paranoid. The busses attract a mixed crowd but usually not people intent to commit crimes against you, they are just trying to get somewhere, just like you are. You need to keep important items like your driver's license, your plastic, and your cash, keys, phone, etc on your person, in your pocket so you don't leave it behind. Layovers in some places are scarier than others, and you can thank the locals for that, not the bus line.
Try to get your luggage on the same bus with you (it will be underneath), sometimes you can watch them loading and catch mistakes but all things considered they are pretty good about keeping you and your stuff together. There are other times when you are in a caravan of people going the same place in different busses and your stuff might be on the other bus. It's no big deal. As with flying, you want your very most important things with you in your carryon, and you want to pack light.
If you don't know what you are doing re: catching your connections, etc ASK someone but more importantly PAY attention when your driver tells you what's going on. Read your monitors and look for signs above doorways that list popular routes from that gate, and destinations on the bus windows to make sure you are on time and in the right lines. Don't ever fall asleep waiting for a bus in a depot. You could miss it and if you are in the middle of nowhere your next chance to make up the difference is likely 24 hours later. That's one hellish layover, and you won't have your luggage with you.
Here's one thing I love about the bus. I have a string of Greyhound stories, and I have never met anyone on a bus who was too good to be on a bus. Just regular everyday people. Mostly it has been fun, and when it wasn't, there were a few other people around to make the best of it. Be friendly, be respectful, be patient, and it usually comes back around.
Windscreen Chip... Did I Get Scammed?
Ok So I Went To A &Quot;Free&Quot; Windscreen Repair Booth Thingyo In My Local Shopping Center, The Man Told Me My Insrance Wouldnt Cover It, However He Would Do It If I Gave Him £20 On The Sly And Left The Car For Half An Hour, I Abliged..
Having Came Back The Chip In My Windscreen Looked Exactly The Same To Me, I Was Under The Inpression The Chip Would Compleantly Dissapear? The Guy Told Me That It Was Smooth From The Outside And Wouldnt Get Any Worse.. Thats What I Paid For, Thats What Its Supposed To Be Like.
Am I Daft And Got Scammed? Did He Just Charge Me £20 For Nothing?
anytime they fill the hole in with the filler they use you can always see the repair, I always just replace the windshield as I'm too picky about my cars and to me their repair is unsightly.
Where Can I Find A Cheap Gps For My Car?
Looking For An Inexpensive Model For My Car.
do you want one that sticks to your windshield or an in-dash one?
I bought 2 windshield mount gps for $99 each on black friday. they were on sale EVERYWHERE!
97 Camaro Z28 Wont Unlock With Remote Key?
I Checked Every Button On The Remote Key And The Car Responds To It But It Wont Open The Doors Also From The Inside The Unlock Button Dosent Work It Has To Be A Problem In The Car What Should I Do Or How Can This Be Fixed
Did the remote ever open the other doors, beside the driver's door?
Your note about the inside unlock button not working is important. There's a linkage inside the door connecting the interior manual unlock button with the lock mechanism and the electronic actuator that your remote triggers.
I've seen other cars' linkages (with remotes) get stuck. Sometimes, whether it's proper or not, in order to be able to remote unlock it, you need to have remote locked it (not manually locked it).
Regardless, you can remove the interior trim panel on the door itself and look directly at the mechanism. Something is likely either broken or worn out or needs lubricant. You need to see it, and fix it. Removing a door trim panel is not so hard. Check a manual if you want (even in the store). If you don't have power windows, first remove the window roll-up handle. Manual will tell how for different car makes. Remove the several screws often found in the door grips, handles and map slots. Then, on most cars you pry around the edge of the fabric and plastic interior panel. It's held on by those plastic snap-in anchors that look almost like a cheap screw. While you pry around the edge of the door panel, watch for where these anchors are attached. Once you spot them (often buried within a carpet-type covering), you can use a flat blade to pry them out. Could be 5-10 of them. Don't be afraid. Pry it off. You inevitably break a few of the anchors and the edge clips around the door edge. Just buy replacement ones at an auto parts store.
Don't be spooked at the prospect of driving the car a few days without that interior door's trim. You might need a couple days to get a part at a store, or make a trip to your nearest larger salvage yard. Call them in advance to ask if they have some cars in their yard that are similar enough to your make/model to be likely to have the part(s) you need.


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Uploaded by: MrHoopsta
Date: 22.10.2013
Image "HEX" Code: #2681506
We have more photo of Mini Mini in our gallery. If you interesting to view them, you can follow on links below.
Also you can see full gallery of Mini Mini on this page.
If you have your own good photos of Mini Mini, you can upload them on our website and become one of our authors.
Recent automotive trends, reviews, test drives and the latest news from the world of cars.Read the news section.
The charge for the Citro?n strategy, Julien Montarnal revealed to website Automotive News Europe that the new C4 Cactus will cost 13,950 euros at its launch in France, 4900 euros cheaper than the entry level compact C4 traditional.
The Datsun, low cost brand resurrected by Nissan in 2012, took the Hall of New Delhi, India, to show the concept redi-GO. It is the preview of a model that will hit the Indian market and other developing countries.
Chevrolet used the Hall of New Delhi to present a new concept car, the crossover Adra. The model was fully developed by General Motors technical center in India, located in Bangalore.
The National Highway Traffic Safety Administration (NHTSA), which is responsible for matters relating to traffic safety in the United States, investigating 30,000 units of the Toyota Camry Hybrid.
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Established in 2004, Five Star Painting handles both commercial and residential jobs, providing interior and exterior expertise that enhances your lifestyle by adding colour to your world. Like all Neighbourly brands, we are locally owned and operated.
"The project was completed well in advance. Great paint job and great service. Thank you."- Danny Fung


text: WFC U19Full game: Finland – Czech Republic (semifinal, Div A) By Daniël Nicolai Posted on May 5, 2018 Share Tweet Share Share Email Watch the first semifinal of the tournament now, between Finland and the Czech Republic (U19 WFC, A division)! Join the Floorball Worldwide Facebook Group Floorball WorldwideFacebook-groep · 89 ledenLid wordenFor lovers of floorball worldwide! Here you find the latest news about floorball! Related Items:Czech Republic, finland, u19wfc Share Tweet Share Share EmailRecommended for you Highlights: Czech Republic – Singapore 23-0 (University WFC Women) Highlights: Finland – Japan 33-0 (University WFC Women) Highlights: Finland – Japan 29-0 (University WFC) Comments


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The IRC's Global Experience series asks, "What's your global story? Do you get the chance to share it?" Join the IRC as we get hands-on cooking instruction from our friends at the Thai Cultural Center of Greater Kansas City, an organizational member of the IRC. After the food is made, be sure to stick around to enjoy the fruits of your labor.
Please notify the IRC of any dietary restrictions no later than Tuesday, August 28. Due to kitchen regulations, attendance for this event is capped at 20 participants. Tickets are $40 (General Admission) and $35 (Member Rate). Registration will close on Tuesday, August 28.
Parking and Directions
Free parking will be available in the NourishKC lot. The kitchen and lot are located on the northwest corner of 8th and Paseo.
About the Thai Cultural Center
Founded in 2007, the Thai Cultural Center of Greater Kansas City was established to bridge the gap between Thai and American cultures, raise cultural awareness, and promote the development of Thai communities in the Greater Kansas City area.
Remember Me
8/17/2018 » 8/19/2018Visit the IRC at the Ethnic Enrichment Festival
9/4/2018Global Experience: Thai Cooking Class
9/13/2018An Evening with Sarah Margon: Washington Director of Human Rights Watch
10/16/2018Your Global Future
10/30/2018What Do You Owe The World?
8/8/2018Volunteers Needed for the Ethnic Enrichment Festival
8/1/2018August 1, 2018: Meet International Fashion Designers Next Week
7/25/2018July 25, 2018: Help High-Schoolers Discover What Makes a Global Career
7/18/2018July 18, 2018: Internship Applications Due Friday
7/11/2018July 11, 2018: Keep Cool with These Indoor International Events
International Relations Council
107 West 9th St., Second Floor
Kansas City, MO 64105
816.423.2501, Fax
email@example.com, E-mail


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MVW Complete Formulation Multivitamins were designed to meet the daily supplemental vitamin recommendations as outlined a) in the Cystic Fibrosis Foundation Nutrition Consensus Statement published in 2002, b) in the recommendations for vitamin D as described in the 2011 Endocrine Society Clinical Practice Guidelines and c) in the recommendations for vitamin K as recommended by the 2002 European CF Society Nutrition Consensus Report.
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Hartford Sd Car Show
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The important thing to keep in mind about dumpster rental fees is to shop around. You don't want to wind up paying for something don't need and eventually won't utilize.
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You can certainly rent a next day dumpster in Maryland. It should be as easy as making a quick phone call to plan your rental.
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When you are for a cheapest price, the company usually has to cut crevices somewhere. This can be in paying out employees lower wages or even keeping much less dumpsters on hand. They may also sit and think delivering as well as picking up dumpsters so that they can make issues fit their particular schedule rather than customer's.
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The unique design of this Natural Wood Plank and Galvanized Metal C-Table will provide your living room with a touch of functional modern farmhouse flair! This versatile piece is perfect for providing an extra place to rest a drink.
- Table measures 26H x 18 in. in diameter
- Crafted of wood and metal
- Black frame finish
- Natural wood plank tabletop finish
- Tabletop features galvanized metal edge
- Not intended for commercial use
- Care: Dust with a soft, dry cloth.
Contact your local Kirkland's store for availability. Quantities and selection may vary by location.
Natural Wood Plank and Galvanized Metal C-Table is rated 4.9 out of 5 by 18.
Rated 5 out of 5 by SonyWine from Perfect Size Love this little round table that matches our decor perfectly and slides under our couch nicely. It's the perfect size to put drinks, your electronic items or even have a meal for one.
Date published: 2018-05-27
Rated 5 out of 5 by tish01 from justperfet for what i neeed it for y my chair and doesnt take up a lot of spae and matches my decor I bought this item at Brooksville mall located by spring hill, fl. the employee donna the sale clerk was friendly and helpful
Date published: 2018-06-28
Rated 5 out of 5 by Dancer84 from Cute! Love this table! So functional and looks great with our decor. Good quality and value.
Date published: 2018-05-20
Rated 5 out of 5 by Joejoe from Natural Wood Plank and Galvanized Metal C-Table Used as nightstands and is the perfect height and price as well.
Date published: 2018-06-21
Rated 5 out of 5 by BevGil from Great rustic look! Beautifully crafted. Rustic look. A little pricey but nice!
Date published: 2018-06-03
Rated 5 out of 5 by Amuch18 from Simple great product Product is simple but makes a big statement in guess room.
Date published: 2018-06-23
Rated 5 out of 5 by EliseW from C-Table This C-table is a wonderful, useable, versatile table on the chaise part of my couch. Great value, good quality, and looks great! Have gotten so many compliments on it! Great purchase!!!
Date published: 2018-05-04
Rated 5 out of 5 by Goodtogo from Perfect We were looking for "unique" tables for our new sectional and these are perfect. I wish they made some other furniture so we could get matching end tables though.
Date published: 2017-12-10
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Anyone know the weight or how stable Kirkland C or T tables are? Thank you.
Asked by: CC17
It is very lightweight, maybe 3lbs. Very stable!
Answered by: EliseW
Date published: 2018-07-07
What is the distance from the floor to the underside of the tabletop? Need to be sure it will fit over the arm of our loveseat.
Asked by: MountainMama
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The New Adventures of Batman Batman and Batgirl Pan Production Cel (Filmation, 1977). ...Click the image to load the highest resolution version.
DescriptionThe New Adventures of Batman Batman and Batgirl Pan Production Cel (Filmation, 1977). When Super Friends had Batman on ABC on Saturday morning, Filmation countered with The New Adventures of Batman on CBS, featuring the voices of the 1966 live action TV series stars Adam West and Burt Ward. This is an outstanding hand-painted pan cel of a full figure Batman and Batgirl running with capes flying; image sizes are 6" and 8". The cel is on a print background for presentation purposes, and a Filmation seal is on the cel. Matted with an opening size of 18" x 9", framed with Plexiglas for an overall size of 26.5" x 15.5". As a bonus, the cel is hand-signed by Mr. Bob Kane (1915 - 1998). Mr. Kane wrote for this series during its first season in 1968. Fine condition.
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