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IL-10 is essential for inhibiting chronic and acute inflammation by decreasing the amounts of proinflammatory cytokines made by activated macrophages. IL-10 controls proinflammatory cytokine and chemokine production indirectly via the transcription factor Stat3. One of the most physiologically significant IL-10 targets is TNF-α, a potent proinflammatory mediator that is the target for multiple anti-TNF-α clinical strategies in Crohn's disease and rheumatoid arthritis. The anti-inflammatory effects of IL-10 seem to be mediated by several incompletely understood transcriptional and posttranscriptional mechanisms. In this study, we show that in LPS-activated bone marrow-derived murine macrophages, IL-10 reduces the mRNA and protein levels of TNF-α and IL-1α in part through the RNA destabilizing factor tristetraprolin (TTP). TTP is known for its central role in destabilizing mRNA molecules containing class II AU-rich elements in 3′ untranslated regions. We found that IL-10 initiates a Stat3-dependent increase of TTP expression accompanied by a delayed decrease of p38 MAPK activity. The reduction of p38 MAPK activity releases TTP from the p38 MAPK-mediated inhibition, thereby resulting in diminished mRNA and protein levels of proinflammatory cytokines. These findings establish that TTP is required for full responses of bone marrow-derived murine macrophages to IL-10.
One of the key players in immune homeostasis is IL-10, a cytokine that was discovered 18 years ago as a T cell-secreted factor that inhibited cytokine production by Th1 cells (1). Over the years, it became clear that IL-10 is produced by many cell types including T and B cells, macrophages, dendritic cells, mast cells, keratinocytes, or epithelial cells (2). It is generally considered that the main biological function of IL-10 is to limit or shut down inflammatory responses. This notion is supported by the phenotype of IL-10-deficient mice that develop severe inflammatory bowel disease due to spontaneous chronic inflammation and are susceptible to endotoxin treatment because of acute overproduction of proinflammatory cytokines (3, 4). Many of these phenotypes can be recapitulated by T cell-specific deletion of the IL-10 gene, indicating that T cell-derived IL-10 is primarily responsible for chronic inflammation (5). Under conditions of acute inflammation, the main source of IL-10 are macrophages and dendritic cells (6). On the cellular level, IL-10 inhibits production of proinflammatory cytokines and regulates differentiation and proliferation of various immune cells. These effects depend entirely on the activation of the transcription factor Stat3 by IL-10 (7, 8, 9, 10, 11). The events downstream of Stat3 activation that mediate the anti-inflammatory functions of IL-10 remain an area of active research. It is becoming increasingly clear that multiple mechanisms mediate the IL-10 function. On the one hand, IL-10 inhibits transcription of a subset of proinflammatory genes (12, 13). In a mouse model lacking 3′ untranslated regions (UTR)4 in the Tnf gene, the transcriptional mechanism was found to play a major role in IL-10 responses (13). On the other hand, IL-10 was also reported to act posttranscriptionally by increasing the rate of mRNA decay of inflammatory cytokines such as TNF-α or by inhibiting translation (12, 14, 15). The posttranscriptional regulation depends on 3′ UTR containing AU-rich elements (AREs) (16). However, far less is known about the IL-10-regulated effector genes that control the anti-inflammatory response. Several candidates have been described, but so far none have been shown to account for the majority of the anti-inflammatory effects (17). IL-10 was also demonstrated to up-regulate the dual-specificity phosphatase 1 (DUSP1) in LPS-stimulated macrophages. causing a more rapid inactivation of p38 MAPK (18). The reduction of p38 MAPK activity may lead to a decreased stability of ARE-containing mRNAs and/or reduced transcription by transcription factors that depend on p38 MAPK. Recently, the transcriptional repressor ETV3 and the corepressor SBNO2 were characterized as IL-10/Stat3-induced genes that may contribute to the anti-inflammatory IL-10 effects (19). An important aspect of the above-mentioned studies that remains to be resolved is how IL-10 inhibits specifically only a subset of inflammatory genes. These studies indicate that yet unknown IL-10/Stat3 target genes need to be discovered to complement the current knowledge about the anti-inflammatory effects of IL-10.
In this study, we demonstrate that IL-10-mediated reduction of TNF-α and IL-1α production by LPS-treated mouse bone marrow-derived macrophages (BMDMs) is less efficient in cells lacking the RNA-destabilizing factor tristetraprolin (TTP). TTP is known to bind and destabilize mRNAs of several proinflammatory cytokines (e.g., TNF-α) containing class II AREs in their 3′ UTRs (20). TTP facilitates degradation of the bound mRNA by initiating the assembly of RNA decay machinery (21, 22). The RNA degradation activity of TTP is negatively regulated by p38 MAPK-dependent signaling (23, 24, 25). Mice lacking TTP (encoded by the Zfp36 gene) develop multiple chronic inflammatory syndromes ranging from arthritis to cachexia to dermatitis that can all be relieved by reduction of TNF-α levels (26). By comparing LPS-treated wild-type and TTP-deficient BMDMs, we show that IL-10 accelerates, in a TTP-dependent way, the decay of TNF-α mRNA, resulting in a reduction of secreted TNF-α. Furthermore, IL-10 increases TTP expression in LPS-treated wild-type (WT) but not Stat3-deficient BMDMs. However, we show that the increased TTP levels are not sufficient to mediate the IL-10 effects. Instead, the IL-10- mediated reduction of p38 MAPK activity in LPS-treated BMDMs that is known to be caused by up-regulation of the p38 MAPK phosphatase DUSP1 (18) is required to act in concert with TTP to reduce mRNA levels of proinflammatory cytokines such as TNF-α and IL-1α. We propose that the sustained activation of Stat3 by IL-10 causes both an increased TTP expression and a reduction in p38 MAPK activity. The combination of these effects results in a reduction of mRNA stability and attenuation of cytokine production.
Materials and Methods
Stat3, p38 MAPK, and DUSP1 (sc-1102) Abs were from Santa Cruz Biotechnology, the ERK Ab was from BD Transduction Laboratories, and the phosphotyrosine-Stat3 Ab (pY-Stat3) was from Cell Signaling and New England Biolabs. Rabbit Ab to TTP was obtained by immunizing rabbits with 44 C-terminal amino acids of TTP fused to GST. IL-10 and IL-6 (Sigma-Aldrich) were used at a concentration of 10 ng/ml, LPS from Salmonella minnesota (Alexis) was used at a concentration of 5–10 ng/ml, and anisomycin and actinomycin D (both Sigma-Aldrich) were used at a concentration of 100 ng/ml and 5 μg/ml, respectively. SB203580 (SB; Sigma-Aldrich) was dissolved in DMSO and used at final concentration 4 μM. ATP (1 μM; Sigma-Aldrich) was added 1 h before collecting the samples.
Cell culture
Primary macrophages were grown in L cell-derived CSF-1 as previously described (27). Zfp36−/− and Dusp1−/− mice (26) were on the C57BL/6 background. The Zfp36 gene encodes TTP, which is the better known name and therefore is used throughout. For experiments with cells derived from TTP−/− and TTP+/+ mice, littermates originating from the TTP+/− colony were used. The LysMcre-Stat3fl/fl mice were obtained by crossing Stat3fl/fl mice (28) with LysMcre, strain B6.129P2-Lyzstml(cre)Ifo (The Jackson Laboratory), all on the C57BL/6 background. Mice, 8–12 wk old at the time of bone marrow collection, were housed under specific pathogen-free conditions. Mouse experiments were conducted in compliance with national laws. Mouse macrophage line RAW 264.7 was grown in DMEM supplemented with 10% FCS.
Inducible expression of TTP
The open reading frame of the mouse TTP was PCR-amplified from cDNA. The PCR was used to add Flag tag DYKDDDDK at the C terminus. The TTP-Flag fragment was cloned into the pGL2-basic (Promega) containing a tetracycline-responsive element (TRE) in the promoter. The resulting plasmid pTRE-TTPfl was transfected into HeLa-Tet-off cells (BD Clontech) using nucleofection (Amaxa). After transfection, the cells were incubated overnight in medium with (no TTP expression) or without (TTP expression) tetracycline (1 μg/ml).
For ELISA, BMDMs were seeded the day before use at 2 × 105 cells/well in a 24-well plate. Supernatants were diluted 1/8 in DMEM (for TNF-α) or 1/2 (for IL-1α) and cytokines were assayed using ELISA kits (R&D Systems) according to the manufacturer's instructions.
Quantitative Western blot
After treatment, whole cell extracts were prepared and assayed by Western blotting as described elsewhere (29). Detection and quantitation of signals were performed using the infrared imaging system Odyssey (LI-COR Biosciences).
Quantitation of gene expression by quantitative RT-PCR (qRT-PCR)
Total RNA was isolated using TRIzol reagent (Invitrogen). Reverse transcription was performed with Moloney murine leukemia virus reverse transcriptase (Fermentas). The following primers were used: for HPRT, the housekeeping gene used for normalization, HPRT forward (fwd) 5′-GGATTTGAATCACGTTTGTGTCAT-3′ and HPRT reverse (rev) 5′-ACACCTGCTAATTTTACTGGCAA-3′; for TTP, TTP fwd 5′-CTCTGCCATCTACGAGAGCC-3′ and TTP rev 5′-GATGGAGTCCGAGTTTATGTTCC-3′; for TNF-α, TNF-α fwd 5′-CAAAATTCGAGTGACAAGCCTG-3′ and TNF-α rev 5′-GAGATCCATGCCGTTGGC-3′; for suppressor of cytokine signaling (SOCS) 3, SOCS3 fwd 5′-GCTCCAAAAGCGAGTACCAGC-3′ and SOCS3 rev 5′-AGTAGAATCCGCTCTCCTGCAG-3′; and for TTP primary transcript, TTPpt fwd 5′-GACTGGCAAGCTCGTGAAGT-3′, pt-TTP-rev 5′-CAGTCAGGCGAGAGGTGA-3′. For determination of mRNA decay by qRT-PCR, the primers TNF-α fwd 5′-TTCTGTCTACTGAACTTCGGGGTGATCGGTCC-3′ and TNF-α rev 5′-GTATGAGATAGCAAATCGGCTGACGGTGTGGG-3′ and for IL-1α, the primer set QT00113505 from Qiagen was used. Amplification of DNA was monitored by SYBR Green (Molecular Probes (30).
To prepare extracts, cells were washed with cold PBS and lysed in buffer containing 10 mM Tris-HCl (pH 7.5), 50 mM NaCl, 30 mM NaPPi, 50 mM NaF, 2 mM EDTA, 1% Triton X-100, and a protease inhibitor mixture (Roche). Extracts were cleared by centrifugation at 15,000 rpm. Twelve-microliter cell extracts (30 μg of protein) from RAW 264.7 cells or 5-μl cell extracts (15 μg of protein) from pTRE-TTPfl-transfected HeLa-Tet-off cells were incubated with 0.5 μl of poly(U) RNA (100 ng/μl), 0.5 μl of Cy5.5-labeled TNF-α ARE (1 pmol/μl), 1 μl of RiboLock RNase Inhibitor (Fermentas), and 2.5 μl of 5× Gelshift buffer (200 mM KCl, 5 mM MgCl2, 0.5 mM EGTA, 2.5 mM DTT, 100 mM HEPES-KOH (pH 7.9), and glycerin 50% (v/v)) for 20 min at room temperature. For supershift assays, 0.5 μl of TTP antiserum was added. Samples were then separated on a 6% polyacrylamide gel. The Cy5.5 signal was detected and quantified using the infrared imaging system Odyssey (LI-COR Biosciences). Poly(U) RNA and Cy5.5′-labeled TNF-α ARE RNA were purchased from Microsynth. The sequence for Cy5.5′-labeled TNF-α ARE was as follows: 5′-AUUAUUUAUUAUUUAUUUAUUAUUUA-3′.
Statistical analysis
Data from independent experiments were analyzed using univariate linear regression models and the SPSS program. For qRT-PCR normalized copy numbers and for ELISA pg/ml were log-transformed. Residuals were plotted, visually inspected, and tested for normality. Design matrices were specified such that the coefficients for the relevant comparisons could be calculated, e.g., between the baseline and induced states and between genotypes. Only the significance levels are reported.
IL-10 increases TTP expression in LPS-treated macrophages in a Stat3-dependent manner
TTP expression has been reported to be controlled by the transcription factors Stat1 (in response to IFNs) and Stat6 (in response to IL-4) (27, 31). Affymetrix analysis revealed that LPS-induced TTP expression is further enhanced by IL-10 (data not shown) at 30 min after treatment of Il10−/− BMDMs with IL-10 and LPS, suggesting that TTP may represent a Stat3 target gene involved in the anti-inflammatory responses to IL-10. To examine the effect of IL-10 on TTP expression in more detail, we investigated TTP gene expression in BMDMs conditionally deleted for Stat3 (LysMcre-Stat3fl/fl) and control LysMcre-Stat3 cells. LysMcre is known to delete loxP-flanked alleles in macrophage and neutrophil lineages with >90% efficiency (7). Treatment of BMDMs with IL-10 and LPS caused a 2- to 3-fold increase in TTP mRNA (Fig. 1,A) and protein levels (Fig. 1,B) compared with LPS treatment alone. The IL-10-mediated increase in TTP expression required Stat3 since in LysMcre-Stat3fl/fl cells the TTP levels remained unchanged upon IL-10 treatment. The expression of Stat3 was reduced by >90% in LysMcre-Stat3fl/fl cells (Fig. 1,B), thereby confirming the deletion efficiency by LysMcre. Analysis of TTP primary transcripts by PCR (Fig. 1 C) and nuclear run-on assays (data not shown) revealed that the IL-10-mediated induction of TTP was caused by increased transcription.
These findings document that IL-10-activated Stat3 increases expression of TTP in LPS-stimulated macrophages. IL-10 alone only weakly increased TTP transcription, and this induction was not sufficient to generate detectable levels of TTP protein. This way of regulation resembles that of IFN-induced TTP expression, which was shown to be activated by IFNs and the IFN-activated Stat1 only if p38 MAPK signaling (by e.g., LPS) is stimulated in parallel (27). p38 MAPK is known to increase by yet unclear mechanisms the transcriptional activity of several Stat members (32, 33, 34).
TTP is required for full inhibitory effect of IL-10 on TNF-α and IL-1α production
To test whether TTP was an effector of the IL-10 anti-inflammatory responses, we measured the amount of secreted TNF-α by ELISA in BMDMs from TTP−/− and control WT littermates that were treated with LPS with or without pretreatment with IL-10. We measured TNF-α production at 6, 8, and 10 h after LPS stimulation. After 10 h, TNF-α was diminished by IL-10 to ∼20% in control cells, whereas in TTP−/− cells only a reduction to 60% was achieved (Fig. 2,A). Similar results were obtained if cells were treated simultaneously with LPS and IL-10 (Fig. 2,B), although the contribution of TTP to the IL-10 response was higher in the pretreatment protocol (Fig. 2Α). These data show that TTP contributes to IL-10-mediated inhibition of TNF-α cytokine production.
To investigate whether the incomplete IL-10-mediated inhibition of TNF-α production in TTP−/− BMDMs resulted from differences in mRNA amounts or in mRNA decay, we analyzed the amounts of TNF-α mRNA in LPS-stimulated TTP−/− and control BMDMs with or without pretreatment with IL-10. In WT cells, IL-10 caused a reduction of TNF-α mRNA to 40% of the amount present in cells treated with LPS alone, whereas in TTP−/− cells IL-10 caused a reduction to only 80% of the level in cells treated with LPS alone (Fig. 2,C). In these experiments, TNF-α mRNA was measured after 2 h of LPS treatment since the amount of TNF-α mRNA peaks at this time point (Ref. 13 and data not shown). To further illustrate the role of TTP in IL-10-mediated decrease of TNF-α mRNA, we analyzed the rate of TNF-α mRNA decay in LPS-stimulated TTP−/− and WT BMDMs with or without IL-10 pretreatment. Transcription was stopped after 3 h of LPS stimulation by addition of actinomycin D, and the degradation of TNF-α mRNA was followed in 15- min intervals for a total of 45 min after imposing the transcriptional stop (Fig. 3,A). In LPS-treated control BMDMs, the decay rate of TNF-α mRNA was increased 2.5-fold by IL-10 treatment (half-life t½ without IL-10 = 32 min; t½ with IL-10 = 13 min). In LPS-treated TTP−/− BMDMs, the residual TNF-α mRNA decayed with a 2.5-fold longer half-life (t[1/2] = 82 min) compared with WT. This difference is similar to the one reported previously (35). Importantly, IL-10 treatment of LPS-stimulated TTP−/− cells did not increase the decay rate and the remnant mRNA levels were comparable to those in cells treated with LPS alone. LPS-stimulated macrophages produced endogenous IL-10 that is known to mask to some extent the effect of added IL-10 (see Ref. 18). Since TTP was recently shown to target IL-10 mRNA for degradation (36), we asked whether TTP−/− BMDMs produce more IL-10 after stimulation with LPS. Cytokine measurement revealed that TTP-deficient cells secrete 2- to 3-fold more IL-10 than the WT cells (supplemental Fig. S15). To assess the contribution of endogenous IL-10 to the IL-10-mediated TNF-α mRNA decay, we compared the TNF-α mRNA levels and decay rates in IL-10−/− and WT cells. IL-10−/− BMDMs expressed 2-fold more TNF-α than WT cells (Fig. 3,B). Importantly, the reduction of TNF-α mRNA by exogenous IL-10 was more pronounced in IL-10−/− cells compared with WT cells. The decay rate of TNF-α mRNA was not affected by IL-10 treatment of WT cells stimulated for 1 or 2 h with LPS (Fig. 3,C). However, IL-10 accelerated the decay rate in IL-10−/− cells treated for 2 h with LPS, but not for 1 h (Fig. 3,D). Therefore, endogenous IL-10 can mask to a certain extent the effect of exogenous IL-10 on the mRNA decay. In addition, the IL-10-mediated increase in mRNA decay rate becomes more apparent at later time points of LPS treatment, consistent with the need for new protein synthesis (e.g., TTP). Note that the duration of LPS treatment in Fig. 3,A was 3 h and that the differences in IL-10-imposed inhibition of TNF-α production in TTP−/− vs WT cells increased with time of LPS treatment (Fig. 2, A and B).
To further substantiate the role of TTP in the anti-inflammatory effects of IL-10, we measured the IL-10-mediated reduction of IL-1α protein and mRNA in TTP−/− and WT cells (Fig. 3, E and F). Efficient LPS-stimulated production of IL-1α, a known IL-10 target (13), depends on a second stimulus, such as ATP, that activates the IL-1-processing function of the inflammasome (37). Although IL-1α is not a direct substrate of caspase 1, production of mature IL-1α has been shown to be inflammasome/caspase 1 dependent (37). BMDMs from WT and TTP−/− animals were stimulated with LPS (10 h) and ATP (1 h before the collection of supernatants) in the presence or absence of IL-10. IL-10 caused a decrease of IL-1α protein to 20% of LPS plus ATP-treated WT cells, whereas in TTP−/− cells the IL-1α production was reduced only to 60% of the LPS plus ATP-treated samples (Fig. 3,E). Similar differences between WT and TTP−/− cells were determined also for the IL-10-mediated decrease in IL-1α mRNA (Fig. 3 F).
To rule out that the absence of TTP affected activation of Stat3 by IL-10 that might result in reduced IL-10 responsiveness of TTP−/− cells, the IL-10-induced tyrosine phosphorylation of Stat3 was determined in LPS-stimulated TTP−/− and WT BMDMs in the presence or absence of IL-10. The level of tyrosine-phosphorylated Stat3 was under all conditions comparable in both genotypes (supplemental Fig. S2A). In addition, the stimulatory effect of LPS was similar in TTP−/− and WT cells as judged by the activation of p38 MAPK (supplemental Fig. S2B). Thus, a different activation of the critical proinflammatory (p38 MAPK) and anti-inflammatory (Stat3) components in the WT and TTP−/− cells could be excluded as a reason for the observed differences in IL-10 responses.
These data establish that TTP plays an important role in IL-10-mediated down-regulation of two critical inflammatory cytokines (TNF-α and IL-1α).
TTP function in IL-10 responses depends on IL-10-mediated reduction of p38 MAPK activity at later phase of inflammation
IL-10 and IL-6 are both known to activate Stat3 yet only IL-10 exhibits anti-inflammatory properties (38, 39, 40). To examine whether and to what extent IL-6 was able to stimulate TTP expression, BMDMs were treated with LPS with or without IL-6. Interestingly, IL-6 was able to increase TTP expression in LPS-treated macrophages almost to the same extent as IL-10 (Fig. 4,A). Yet, consistent with the known properties of IL-6, IL-6 was not able to inhibit TNF-α (Fig. 4,B) and IL-1α (Fig. 4,C) in either WT or TTP−/− BMDMs. These data also implicate that the up-regulation of TTP expression by IL-10 cannot solely explain the role of TTP in the anti-inflammatory effects of this cytokine. We speculated that the role of TTP in IL-10 responses might be explained by an IL-10-dependent increase in TTP activity. TTP function is known to be negatively regulated by p38 MAPK and its downstream kinase MK2 (41). IL-10 has been reported to modestly inhibit p38 MAPK in the later phases of LPS treatment (18). The reduction of p38 MAPK activity is caused by the IL-10-mediated up-regulation of the dual-specificity phosphatase DUSP1 (Ref. 18 and Fig. 4,F). We reasoned that such a reduction in p38 MAPK could relieve the p38 MAPK-dependent inhibition of TTP, thereby increasing the ability of TTP to down-regulate its target mRNAs. To investigate whether IL-6 was also able to reduce p38 MAPK activity, BMDMs were stimulated with LPS alone or along with either IL-10 or IL-6 and p38 MAPK activity was monitored after 2, 4, and 6 h. Treatment of LPS-stimulated cells with IL-10 caused a modest (3-fold) but consistent inhibition of p38 MAPK at 2, 4, and 6 h compared with the samples treated with LPS alone (Fig. 4,D). To better document the IL-10 effect on p38 MAPK phosphorylation, the complete time course of IL-6- and IL-10-treated samples was run on a single gel (supplemental Fig. S3A). The LPS-induced activation of p38 MAPK at an early time point (30 min) was not affected by IL-10 cotreatment (Fig. 4,E). Importantly, p38 MAPK activity was not reduced by treatment with IL-6 at any time point examined (Fig. 4, D and E, and supplemental Fig. S3A). These findings are in agreement with the induction of mRNA for the MAPK phosphatase DUSP1 by IL-10 but not IL-6 in LPS-treated macrophages (18). To further support the role of DUSP1 in the IL-10-mediated effect on p38 MAPK activity, we examined p38 MAPK phosphorylation in DUSP1−/− BMDMs treated with LPS alone or along with either IL-10 or IL-6 for 4 h. In DUSP1−/− cells, IL-10 was no longer able to reduce p38 MAPK phosphorylation after treatment (Fig. 4 F). Consistent with the IL-10-mediated decrease in p38 MAPK phosphorylation, at the 4 h-time point, the induction of DUSP1 by IL-10 plus LPS compared with LPS alone was more apparent than after a shorter treatment (1 h; supplemental Fig. S3B). The different effect of IL-10 and IL-6 on p38 MAPK is in agreement with the anti-inflammatory properties that are exhibited by IL-10 but not IL-6. The difference between IL-10 and IL-6 with regard to their anti-inflammatory properties has been attributed to SOCS3 that, as part of the negative feedback loop, binds to the gp130 subunit of the IL-6 receptor but not to the IL-10 receptor (38, 39, 40). Thus, SOCS3, a Stat3 target gene, is able to inhibit signaling elicited by IL-6 but not by IL-10. Consequently, IL-10 induces a prolonged Stat3 activation, whereas IL-6-mediated Stat3 activation is rapidly shut down. Consistently, in LPS-treated BMDMs IL-10 and IL-6 caused a comparable Stat3 activation after 30 min of cytokine treatment, whereas after 2 h Stat3 remained active only in cells stimulated with IL-10 but not IL-6 (supplemental Fig. 3C). These data suggest that a sustained Stat3 activation is needed for inhibition of p38 MAPK.
Although p38 MAPK is needed for TTP expression and protein stability (24, 25, 42), the kinase negatively regulates TTP activity at least at two levels. First, phosphorylation of TTP at Ser52 and Ser178 by MAPK-activated protein kinase kinase 2 (MK2), a kinase downstream of p38 MAPK, provides binding sites for 14-3-3 proteins that reduce the destabilizing activity of TTP (23, 43). Second, phosphorylation of TTP by MK2 was reported to negatively regulate its binding to AREs (25). To show that the IL-10-mediated decrease in p38 MAPK activity was able to change TTP properties in terms of its phosphorylation and binding to AREs, we analyzed the mobility of TTP in SDS-PAGE and binding of TTP to AREs in EMSA experiments. TTP appears in SDS-PAGE in the form of multiple bands that reflect various degree of predominantly p38 MAPK-dependent phosphorylation (24). To demonstrate p38 MAPK effects on TTP phosphorylation and binding to AREs, we first used an inducible expression of TTP in HeLa-Tet-off cells. This system allows manipulation of p38 MAPK activity without affecting the transcription of the TTP gene that is known to require p38 MAPK activity (27, 42). Stimulation of HeLa-Tet-off cells expressing TTP (i.e., without tetracycline) with anisomycin (a p38 MAPK agonist (44)) resulted in a more pronounced appearance of a slower migrating hyperphosphorylated TTP band, whereas the p38 MAPK inhibitor SB reduced the amount of the hyperphosphorylated TTP and also the total TTP level due to TTP protein destabilization (Fig. 5,A). The analysis of the same extracts in a RNA EMSA experiment revealed that anisomycin reduced binding of TTP to the TNF-α ARE by 50% (Fig. 5,B), whereas inhibition of p38 MAPK resulted in a similar amount of ARE-bound TTP as in untreated cells (Fig. 5,B) despite a reduced TTP protein level present in that sample (compare SB-labeled lanes in Fig. 5,A and 5B). Consistent with the IL-10-mediated p38 MAPK inhibition, the treatment of BMDMs with LPS plus IL-10 resulted in a shift to less phosphorylated TTP bands in SDS-PAGE if compared with cells treated with LPS alone or with LPS plus IL-6 (Fig. 5,C). This shift to faster migrating TTP bands was more pronounced after 6 h of treatment. To address the IL-10 effect on TTP binding to AREs, we used the murine macrophage cell line RAW 264.7 since we were not able to detect TTP-ARE complexes in RNA EMSA experiments if BMDMs were used. LPS-stimulated RAW 264.7 cells express at least 3- to 5-fold more TTP than BMDMs (data not shown). Similar to BMDMs, LPS plus IL-10 treatment resulted in a more pronounced appearance of the hypophosphorylated TTP if compared with treatment with LPS alone or LPS plus IL-6 (Fig. 5,D). Consistently, LPS plus IL-10 treatment caused an ∼50–80% increase in the formation of TTP-ARE complexes in RNA EMSA experiments compared with LPS alone or LPS plus IL-6 treatments (Fig. 5,E). These data show that IL-10 decreases the phosphorylation of TTP and enhances the in vitro binding of TTP to TNF-α ARE in a manner similar to the pharmacological inhibition of p38 MAPK. These findings are in agreement with an increased TTP activity under conditions of reduced p38 MAPK activation as is the case in IL-10-treated cells. Interestingly, despite the reduced p38 MAPK activity and hence increased proteasome-mediated TTP degradation in IL-10-treated cells, the TTP protein levels were not diminished compared with LPS plus IL-6-treated cells (Fig. 5, C and D). We explain this observation by the sustained Stat3 activation and, hence, a strong Stat3-driven transcription of the TTP gene in IL-10-treated cells (supplemental Fig. 3C).
To test whether p38 MAPK activity protects mRNA from TTP-mediated decay, we examined the stability of TNF-α and IL-1α mRNAs in the presence of the p38 MAPK inhibitor SB in TTP−/− and control WT BMDMs. Two hours after LPS stimulation, SB was added in combination with actinomycin D. p38 MAPK inhibition caused a 4-fold decrease of mRNA stability of TNF-α (TNF-α without SB: t½ = 31 min; TNF-α with SB: t½ = 8 min) and an ∼8- to 10-fold decrease in IL-1α mRNA stability (IL-1α without SB: t½ >2 h; IL-1α with SB: t½ = 14 min; Fig. 6). In TTP−/− cells, the inhibition of p38 MAPK caused only a modest (2-fold) decrease in mRNA stability of TNF-α mRNA (TNF-α without SB: t½ = 80 min; TNF-α with SB: t½ = 37 min with SB) and no detectable decrease of IL-1α mRNA stability (IL-1α without SB: t½ = >2 h; IL-1α with SB: t½ = >2 h). These data indicate that the augmentation of mRNA decay by inhibition of p38 MAPK is to a large part TTP dependent. The contribution of TTP to the effects of p38 MAPK inhibition depends on the nature of the target mRNA.
We conclude that the IL-10-mediated reduction of p38 MAPK activity increases TTP-dependent mRNA decay. The combined effect of IL-10 on p38 MAPK activity and TTP expression contributes to the anti-inflammatory properties of IL-10.
This study provides evidence that the mRNA- destabilizing factor TTP plays an important role in anti-inflammatory effects of IL-10. BMDMs deficient in TTP show a strongly reduced anti-inflammatory response to IL-10. Two cytokines, TNF-α and IL-1α, were here demonstrated to be inhibited by IL-10 in a TTP-dependent manner. IL-10 appears to regulate TTP function in two ways (Fig. 7). First, IL-10 increases TTP expression in LPS-treated BMDMs. This augmented expression depends on Stat3, the key immediate effector of IL-10 effects. Second, IL-10 reduces at later time points the activity of p38 MAPK in LPS-treated BMDMs, hereby releasing TTP from the p38 MAPK-mediated inhibition. Since the increased expression of TTP is not sufficient to initiate an anti-inflammatory response (as demonstrated by IL-6-mediated up-regulation of TTP), we conclude that the TTP-dependent IL-10 effects can be best explained by the combination of higher TTP expression and reduction of p38 MAPK activity.
TTP is known for its mRNA-destabilizing activity most notably, but not exclusively, toward TNF-α mRNA via AREs in 3′ UTR. Thus, the IL-10-mediated rise in TNF-α decay rate is consistent with the elevated TTP levels and activity. In addition to TNF-α, our data suggest that IL-1α is also a TTP target. The 3′ UTR of the murine IL-1α (GenBank accession no. NM_010554; http://www. ncbi.nlm.nih.gov/GenBank/) contains three elements (UAUUUAUA, AUAUUUAU, and UAUUAUUUAU) with similar sequences as the nonameric canonical sequence (UUAUUUAUU) recognized by TTP (45, 46). IL-1α has so far not been described as TTP target despite of several recently published global screens for novel TTP targets (36, 47). However, these searches revealed that in such global screens important targets might be missed (e.g., TNF-α in the study of Stoecklin et al. (36)). In addition, the finding that TTP regulates also mRNAs with no obvious AREs in 3′ UTR adds another degree of complexity to searches for TTP targets (47). The role of TTP in IL-10 responses is also in agreement with a study reporting IL-10-mediated ARE-dependent destabilization of CXCL1 mRNA (16). Importantly, in that study, the IL-10-induced mRNA decay was not detectable before 2 h of LPS/IL-10 treatment. This time point correlates well with the appearance of TTP expression (42) and with our data showing that IL-10-mediated decay of TNF-α mRNA is not apparent before 2 h of LPS treatment.
TTP-deficient cells are known to produce 2- to 3-fold more TNF-α (both mRNA and cytokine) than WT cells (26, 48). At the same time, IL-10 mRNA was shown to be targeted by TTP for degradation (36) and we found that the TTP-deficient BMDMs produce more IL-10 cytokine (supplemental Fig. S1). Thus, TTP cells produce more of both the proinflammatory TNF-α and the anti-inflammatory IL-10. Yet, the TTP cells still respond to IL-10 treatment (by e.g., Stat3 activation) and LPS treatment (by e.g., p38 MAPK activation) similarly as the WT cells (Fig. 4). We conclude that despite the 2- to 3-fold higher production of pro- and anti-inflammatory cytokines the TTP-deficient cells display comparable immediate-early response to pro- (LPS) or anti-inflammatory (IL-10) stimuli as WT cells.
We were not able to detect any differences in the TTP expression or p38 MAPK activity, the two key factors influencing the TTP function, when we compared the two protocols for IL-10 treatment. Thus, the higher absolute contribution of TTP to IL-10 responses in the pretreatment protocol suggests that IL-10 induces a cofactor of TTP during the pretreatment period. TTP serves as an adaptor protein linking mRNA to the mRNA processing and degradation machinery located in stress granules and processing bodies (21, 22). Some of the components of these complexes may be up-regulated by IL-10 during the pretreatment phase to enhance TTP function. Alternatively, IL-10-activated Stat3 may increase transcription of micro-RNAs such as micro-R16 that was shown to assist TTP in degradation of ARE-containing mRNAs (49). The influence of the experimental protocol on the IL-10 effects may also partially explain the discrepancy between our study and the study of Kontoyiannis et al. (14) who found no evidence for a role of TTP in IL-10 responses in the simultaneous treatment protocol. Instead, they proposed a rapid (within 15 min of IL-10 treatment) inhibition of p38 MAPK as the main mechanism of IL-10 action. We did not detect any inhibition of p38 MAPK activity by IL-10 at early time points regardless of applied protocol for IL-10 treatment (supplemental Fig. S2, A and B). These data are in agreement with several other studies showing no effect of IL-10 on p38 MAPK activity at early time points (2, 12, 50, 51). In a kinetics analysis of p38 MAPK activity, IL-10 was found to exhibit a modest inhibitory effect on p38 MAPK activity at later time points (after 3 h of LPS plus IL-10 treatment) (18). The IL-10-mediated inhibition of p38 MAPK correlated with the induction of the dual-specificity phosphatase DUSP1, a MAPK phosphatase (18). We observed a similar reduction in p38 MAPK phosphorylation in terms of both, the magnitude and kinetics, and found that DUSP1 was required for this effect. The inhibition of p38 MAPK was caused specifically by IL-10 but not by IL-6 and correlated with the ability of IL-10 (but not IL-6) to induce sustained Stat3 activation. Consistently, IL-10 but not IL-6 was reported to increase expression of DUSP1 in LPS-treated macrophages (18). DUSP1 function as a critical p38 MAPK-inactivating enzyme provides the most likely explanation for the susceptibility of DUSP1−/− mice to LPS-mediated toxic shock (52, 53). We speculate that the inhibition of the proinflammatory p38 MAPK by IL-10 at the later stages of macrophage stimulation is a key factor in immune homeostasis since p38 MAPK influences inflammation-related transcription, RNA stability, translation, as well as secretion. To mimic the inhibition of p38 MAPK by IL-10 at the late phase of stimulation, we used the p38 MAPK inhibitor SB and examined the effect of p38 MAPK on the TTP-dependent decrease of target mRNA molecules. Interestingly, whereas in the case of TNF-α a different decay rate (i.e., different decay rate in TTP+/+ and TTP−/− cells) was observed also without p38 MAPK inhibition, for IL-1α mRNA the TTP-dependent decay was detectable only if p38 MAPK was inhibited (Fig. 5). A similar requirement for p38 MAPK inhibition has been recently described also for the TTP target CXCL1 (KC) mRNA (54). These findings indicate that the p38 MAPK-mediated control of TTP activity has a differential impact on target mRNAs. Although the TTP-dependent decay of some mRNAs (e.g., TNF-α) proceeds in the presence of p38 MAPK activity, the degradation of other mRNAs (e.g., IL-1α and CXCL1) is strongly dependent on the kinase inhibition. This mechanism may play an important role in the specificity of TTP-mediated RNA decay: depending on the activation status of p38 MAPK or other kinases implicated in regulation of TTP activity (e.g., ERK of MK2), TTP would discriminate between various targets. The critical role that p38 MAPK plays in TTP-mediated RNA decay also suggests that the time point that is taken to determine RNA stability has a decisive effect on the outcome of the assay. The activation/inactivation profile of p38 MAPK is likely to vary between different experimental settings (e.g., amount and quality of LPS, the use of primary or immortalized cells, the origin of primary cells such as bone marrow or peritoneum) so that this aspect may also contribute to the variability of published data. For example, we did not observe an IL-10-mediated increase in TNF-α mRNA decay in peritoneal-derived macrophages.
Suppression of inflammatory responses by IL-10 is one of the key features in immune homeostasis. Despite many years of research, the question of how a single cytokine can specifically inhibit various inflammatory reactions with such a high efficiency remains unresolved. Recent studies suggest that known as well as yet unknown IL-10 effectors interfere on different levels and by different mechanisms with the intracellular inflammatory networks. This multitasking system employed by IL-10 is likely to be essential for the efficiency and specificity of the anti-inflammatory properties of IL-10. For example, the efficient and dominant inhibition of Tnf gene transcription by IL-10 still requires the remaining TNF-α mRNA to be removed from the system, i.e., by TTP. Although the primary IL-10-elicited signaling events that involve the IL-10 receptor, Jak1 and Tyk2 kinases, as well as the transcription factor Stat3, are to a large part common to all cell types, the more complex effects downstream of Stat3 may be cell type dependent. Thus, the function and activity of the Stat3-induced IL-10 effectors may be regulated by the environment within the particular cell type, hereby helping to explain the still incoherent and sometimes contradictory studies of the anti-inflammatory effects of IL-10.
We thank S. Badelt for excellent technical help and Bristol-Myers Squibb for the permission to use Dusp1−/− mice.
The authors have no financial conflict of interest.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
This study was supported by Austrian Science Fund (Fonds zur Förderungder Wissenschaftlichen Forschung) Grants SFB F28 and P16726-B14, European Science Foundation Grant I27-B03 (to P.K.), Austrian Science Fund Fonds zur Förderungder Wissenschaftlichen Forschung Grant SFB F28 and the Austrian Federal Ministry for Science and Research Grant Bundesministerium für Wissenschaft und Forschung GZ200.112/1-VI/1/2004 (to M.M.), National Institutes of Health Grant AI062921 (to P.J.M.), and Deutsche Forschungsgemeinschaft Grants Sonderforschungsbereich 576/TP-A11 and LA1262/4-1 (to R.L.).
Abbreviations used in this paper: UTR, untranslated region; ARE, AU-rich element; DUSP1, dual-specificity phosphate 1; BMDM, bone marrow-derived macrophage; TTP, tristetraprolin; WT, wild type; qRT-PCR, quantitative RT-PCR; fwd, forward; rev, reverse; SOCS, suppressor of cytokine signaling; SB, SB203580.
The online version of this article contains supplemental material.


text:
I love being the CEO of a small company. It's the best job I've ever had. One of the biggest reason is the speed at which we operate. Having worked for three multi-national corporations and the U.S. military for 22 years, I have a lot of experience with the often-slow pace of large organizations.
It makes sense that big companies take longer to get things done. Based on their size and complexity, they need formal command-and-control processes to ensure local units carry out the wishes of the head office. While there is a lot of talk about empowerment in big companies, the truth is employees at lower levels still don't have a lot of authority.
In the past ten years, I observed a significant shift in authority from local units to headquarters of the large companies I worked for. It became harder and harder to get things done in the local units as we waited for approval from above. Even though I knew the importance of command-and-control, I became increasingly frustrated with the bureaucracy of big companies.
Running a small business for the past year has been a breath of fresh air. We seem to run at a pace that is ten times faster than the large companies I worked for. One example is implementing an on-line ordering system. I worked for six years in one company trying to get the approvals and support to implement a simple on-line ordering tool. At my new company, Peak Demand Inc., we got it done in six months.
Here are some times when small company thinking beats big company thinking:
1. Action vs. discussion. Big company thinking says we need to discuss the idea and present it to upper management for approval. Small company thinking says, "let's do it!" At my new company, we made the decision to hire a great employee in five minutes when we heard he was involved in a restructuring and was available.
2. External vs. internal focus. Big company thinking means spending a lot of time in business reviews and internal meetings. Small company thinking means spending more time with customers. At my new company, my time-on-task for customers is nearly 100%. With fewer internal meetings, I have more time to travel and spend time with my customers.
3. Trust vs. suspicion. In big company thinking, there's a tendency to question people's motives, especially if they are from a different department or business unit. In my big company experience, I spent countless hours in meetings working to resolve disputes between various units. Small company thinking says there is no time for that. In my new company, we work as a team and trust that each person will do his part for the overall success of the company.
4. Performance vs. politics. In big company thinking, it's about who you know, what you wear, who you went to school with, what type of car you drive, and what you say in front of senior management. It's about looking good not just being good. In a small company, performance is the most important measure of success. Limited budgets, limited resources, and critical deadlines means every employee must be action-oriented. Those that can't perform at a high level, won't make it, regardless of who they know.
5. Today vs. tomorrow. In big company thinking, there is always tomorrow. Decisions and approvals come at a glacial pace. I recall once working for over six months to get all the signatures necessary for a capital improvement project. Small company thinking says it must be done now. In my new company, we use an expression, "ship it." It's a simple phrase that says, I've reviewed your project, it looks good, you have all your bases covered, "go for it!"
The good news is that big companies can think and act like small companies. I saw it early in my career working in a large corporation that gave power and authority to local, autonomous business units. Each unit acted like a small company and was entirely responsible for their business. The result was strong performance, empowered employees, and quicker results.
Whether you work in a small company or a multi-national corporation, speed is essential in business today. Big company thinking can lead to endless meetings, internal focus, lack of trust, politics, and a glacial command-and-control process. This will erode the performance of any business.
How is the thinking in your business? Are you fast and nimble or are you slow and cumbersome? Do you empower and trust your people to make the right decisions or do you require approval for every activity? Do you spend countless hours in internal meetings or are you on the road visiting customers? Comment with your thoughts below.

subset: commoncrawl


text:
Why You Shouldn't Be Ashamed Of Your Wounds!
We desire to hide our deepest wounds. And rightfully so. We've been taught that wounds equal failure. As parents we fear the words "I told you so," if we revealed our struggles on this journey. But what if our wounds didn't equal failure? What if they did something bigger than we could imagine?


text:
Posted at 11:59 PM in foreign affairs, Human rights, liberalism, U.S. History | Permalink | Comments (0) | TrackBack (0)
I am against the beatification, secular or otherwise of politicians past or present. But some politicians have a record of greatness, some a record of achievement, some no record of anything, others a record of which to be embarrassed. I believe that Franklin Delano Roosevelt has a record of greatness - not, not perfection, but greatness, that in part stems from his firm footing in the values of liberalism. Democracy, self-government by citizens, is a form of government that can further liberalism, so long as citizens and elected leaders appreciate the connection between each individual's autonomy, the need to permit others their autonomy, and the need to collaborate in the grand experiment of self-government. Franklin Delano Roosevelt appreciated these connections, recognizing the value and dignity of the individual. Roosevelt appreciated the state's affirmative obligation to do more than simply stave off threats to individual autonomy. He understood the state's role in ensuring a social safety network that enabled the exercise of autonomy. While he experimented with the means to keep American democracy liberal, his programs were consistently aimed against absolutism and in favor of individual self-determination.
The selections below come from an article printed originally in 1995 (emphases mine, the link takes you to the full article). I find them as apt today as they were then.
Posted at 05:10 PM in FDR, liberalism, U.S. History, U.S. Presidential politics | Permalink | Comments (0) | TrackBack (0)
We shall see whether Mr. Favreau can write Mr. Obama an inaugural address worthy of those delivered at other times of great concern for our country. Meanwhile, below are selections, with some emphases added, from Franklin Delano Roosevelt's First Inaugural Address:
President Hoover, Mr. Chief Justice, my friends. This is a day of national consecration.
And I am certain that on this day my fellow Americans expect that on my induction into the Presidency, I will address them with a candor and a decision which the present situation of our people impels. This is preeminently the time to speak the truth, the whole truth, frankly and boldly. Nor need we shrink from honestly facing conditions in our country today. ... So, first of all, let me assert my firm belief that the only thing we have to fear is fear itself — nameless, unreasoning, unjustified terror which paralyzes needed efforts to convert retreat into advance. In every dark hour of our national life, a leadership of frankness and of vigor has met with that understanding and support of the people themselves which is essential to victory. And I am convinced that you will again give that support to leadership in these critical days. In such a spirit on my part and on yours we face our common difficulties. They concern, thank God, only material things. Values have shrunk to fantastic levels; taxes have risen; our ability to pay has fallen; government of all kinds is faced by serious curtailment of income; the means of exchange are frozen in the currents of trade; the withered leaves of industrial enterprise lie on every side; farmers find no markets for their produce; and the savings of many years in thousands of families are gone. More important, a host of unemployed citizens face the grim problem of existence, and an equally great number toil with little return. Only a foolish optimist can deny the dark realities of the moment.
And yet our distress comes from no failure of substance. We are stricken by no plague of locusts. Compared with the perils which our forefathers conquered, because they believed and were not afraid, we have still much to be thankful for. Nature still offers her bounty and human efforts have multiplied it. Plenty is at our doorstep, but a generous use of it languishes in the very sight of the supply. Primarily, this is because the rulers of the exchange of mankind's goods have failed, through their own stubbornness and their own incompetence, have admitted their failure, and have abdicated. Practices of the unscrupulous money changers stand indicted in the court of public opinion, rejected by the hearts and minds of men. True, they have tried. But their efforts have been cast in the pattern of an outworn tradition. Faced by failure of credit, they have proposed only the lending of more money. Stripped of the lure of profit by which to induce our people to follow their false leadership, they have resorted to exhortations, pleading tearfully for restored confidence. They only know the rules of a generation of self-seekers. They have no vision, and when there is no vision the people perish.
These dark days, my friends, will be worth all they cost us if they teach us that our true destiny is not to be ministered unto but to minister to ourselves, to our fellow men. Recognition of that falsity of material wealth as the standard of success goes hand in hand with the abandonment of the false belief that public office and high political position are to be valued only by the standards of pride of place and personal profit; and there must be an end to a conduct in banking and in business which too often has given to a sacred trust the likeness of callous and selfish wrongdoing. Small wonder that confidence languishes, for it thrives only on honesty, on honor, on the sacredness of obligations, on faithful protection, and on unselfish performance; without them it cannot live.
Posted at 12:31 PM in Economic empowerment, FDR, U.S. History | Permalink | Comments (7) | TrackBack (0)
Whatever you thought during the election or the primaries, what matters is what you think now. If you believe that President-Elect Obama is unwilling or unable to be anything more than an empty suit, you better start organizing around an alternative for 2012 right now. Because President-elect Obama has been organizing his run for 2012 since at least June of 2008, and probably earlier, assuming he has planned on being twice nominated by the Democratic Party.
If you have tended to prefer Democrats, you must accept the extreme unlikelihood of Senator Clinton challenging Senator Obama for the nomination. So, you need to identify somebody who would be willing and possibly able to challenge President-elect Obama for the nomination. It will be hard to find a person willing to do this. The last time a Democrat launched a serious primary run against an incumbent was when Senator Edward Kennedy unsuccessfully challenged Jimmy Carter; of course, the only opportunities since then have been to challenge President Bill Clinton who was, at the end of his first term, so successful a President that he was renominated by acclimation.
If you are looking ahead to the general election in 2012 and are an Independent, a Republican, or a Democrat willing to vote Republican, you have to accept that, as far as I know, there is no potential Republican contender with a commitment to gay rights or reproductive rights who could also garner the support of the Republican Party base.
You also need to face the fact that third party candidates do not win.
There is some possibility that Barack Obama may turn out to be this century's Martin Van Buren. Van Buren faced an economy riddled with unsolvable problems, and that set up the Whigs for victory despite Van Buren's popularity. It is possible that President-elect Obama will face a similar problem.
Just to remind people of some basic history, with the fall of Van Buren, the country entered a period of rather underwhelming Presidencies:
Abraham Lincoln then came to power at a time of crisis for the Union - but not crises or problems of the sort confronting Barack Obama today. We do not face the prospect of Civil War. Lincoln's ability to offer moral leadership in the face of that prospect in his time was well established prior to his election to the presidency, going back at least to one of his first major public speeches, The Lyceum Address, given in 1838, a speech that shows his awareness of the potential for tyranny to creep up upon a democratic republic whose citizens fail to commit themselves to the rules of law and the democratic institutions it rests upon. From that speech, entitled The Perpetuation of Our Political Institutions:
Lincoln's address invite "his audience to into a discussion of the principles, tendencies, and sustenance of self-government. He concentrates on its vulnerabilities and the burdens they place upon self-governing citizens." (source: John Channing Briggs, Lincoln's Speeches Reconsidered, p. 55).
As we have learned, much to our cost, the pace of our current electoral politics means a president who takes office - however he or she wins it (e.g. consider Bush's 2000 victory) stands a high chance of being renominated by her or his party (again, consider Bush in 2004) and retaining the presidency even after doing dreadful things (Bush). I may be wrong about President-elect Obama's chances of being a good leader or being able to resolve problems that may well be beyond his control. Perhaps, come 2012 I will feel he has earned my vote. For me, that would take a lot, because I do not believe in rewarding people who take advantage of corrupted procedures to gain office in the first place (which is what happened in Denver in 2008). But people can learn, and perhaps President-elect Obama will.
Regardless of that the nature of contemporary presevidential politics seems to demand that President-elect Obama start his current term as if he is already running for his next one. Therefore, those of us who await an election where we do not feel there is no major party candidate for whom we can vote or an election where we are not choosing the lesser of two of evils, need to begin seeking and supporting an alternative now.
Serious ideas and suggestions welcome.
Posted at 12:25 PM in U.S. History, U.S. Presidential politics | Permalink | Comments (6) | TrackBack (0)
I have just one question about this. Did Rahm Emanuel mention all of his connections to Rod Blagojevich on the famous vetting questionnaire that the Obama team supposedly required all prospective staff to answer? Given the broad wording of the questionnaire and the fact that Blagojevich has been under investigation for years for all sorts of crimes and shenanigans, I would have thought the Obama administration would want to know the full extent of overlapping ties, even if Emanuel has not done one improper or illegal thing in connection with the Senate vacancy created by President-Elect Obama's resignation. The issue that President-Elect Obama seems to have is one that cost him some people's trust back in the primary season. The change many of us have been waiting for is not us. It is a change from the hypocrisy, corruption, and absurdity that have riddled the last eight years of this country's political leadership. If the Obama questionnaire was meant to do more than provide protection for President Obama, that is, if the questions it asked were asked in good faith, seeking full disclosure up front in the name of creating a culture of transparency and truthfulness, then Mr. Emanuel should have revealed all of his overlaps and ties to Gov. Blagojevich. If you deal with dirty politicians, however much out of necessity, disclose your dealings; and, if need be, put them in context so as to show why you should not be seen to be cut from the same cloth. If Mr. Emanuel only now explains himself - or rather if an explanation is supplied only on December 22, when the Obama-Biden transition team releases its "internal investigation (the one that it has already told us clears its members of any wrongdoing), that is a post-hoc effort at rationalization, which is not going to cut it with people who thought that President-elect Obama was coming to the Presidency to stop that sort of thing. Since the inception of the office the President of the United States of America has merited a great deal of public scrutiny. No, this did not just start with Bill Clinton. In his own time, President Ulysses S. Grant's drinking habits were subject of much speculation; whether he was or was not an alcoholic and how that affected his ability to serve his country remains a topic of historical study and debate. The question of whether Thomas Jefferson fathered children with Sally Hemmings came up during his first term as president. I have no particular view as to whether Grant's drinking or Jefferson's relationship with Hemmings mattered during their own eras or whether and how they should matter know. But I do have a view about Presidents who expect not to come under scrutiny. In anything like an egalitarian democracy, it is the right of citizens to question their public servants, especially those who enjoy great public power. It is their right to care about the precise relationship and connections between their President's chief of staff and an apparently crooked Governor from the President's home state. It is their right to care about who their President chooses to write the words he speaks; or who he chooses to bless his inauguration. It is not only unrealistic to bleat about how unfair it is for the public to care about these things. It is to forget that the American public has always cared about these sort of things, even if at times the press has been selective and inconsistent in its reporting on different Presidents and presidential candidates. Certainly, part of why people care is that they care about sensationalistic matters or matters that may have nothing to with a person's actual qualifications or ability to be a good President. But people also care because they want to decide for themselves whether what a President reads or who she or he puts into a kitchen cabinet relates to a President's qualifications and abilities. So, people care about how Rahm Emanuel answered question 63: "Please provide any other information, including information about other members of your family, that could suggest a conflict of interest or be a possible source of embarrassment to you, your family, or the president-elect." They care whether he had to answer the question; they care whether he discusses any of his dealings with Gov. Blagojevich. And they care not only because they voted for a change in our nation's political culture; they care because many of them voted for the candidate they did because they took his discussions of change to mean a change from low standards when it comes to corruption or even questionable dealings. People want to trust Barack Obama. Many react badly to people who criticize his integrity or trustworthiness. But again, to expect any President to be forever unscrutinized by the public is naive. And if a a candidate makes people believe he offers more integrity and truthfulness than any of his rivals, it is naive to suppose that President will not be watched closely to see if that President lives up to the standards he himself set.
Posted at 11:30 AM in Barack Obama, Character in Politics, long term political reform, U.S. History, U.S. Presidential politics | Permalink | Comments (2) | TrackBack (0)
In 1972, here are just some of the items that were on President Nixon's plate that anybody - Nixon-hater, Democrat, liberal; Nixon-fan, Republican, conservative - who cared about welfare of the country would have thought the President should well have been concentrating on:
Then, there were these "distractions":
The distractions spilled over into 1973:
Of course, in 1973, there are matters that anybody would think deserved Presidential attention, including:
The point: being President in complex times - and the early 1970s were complex times - means coping with a variety of events. Some make the President's job easier, some make it harder. But just because the ones that make it harder do that, does not mean they should not be examined.
I hope that the matters that the pundits are dismissively trivializing as distractions do not in fact lead to the same sort of demise for President-elect Obama that the distraction of the early 1970s brought to Richard Nixon. The revelation that Richard Nixon was possibly more corrupt than his greatest detractors ever thought he was was not good for the country. But that does not mean it would have been better for the country if press and public just went ostrich-like and refused to consider the "distractions" because of the very real difficulties facing the U.S. and the country at large. Ridding the country of a thieving vice-president and a president who regarded the U.S. Consitution as an inconvenient constraint on his own power was good thing.
True, how troubling distractions are is a matter of degree. A plagiarizing Vice-President is not as troubling as one who is an income-tax evader. A Presdent whose staff may be involved in high level state corruption is less bothersome than a President who is personally directing violations of national and international law. A President who retains a misogynistic speech writer, keeping him out of sight, presumably in the hope that all will be forgotten is terribly bothersome.
But whatever the final truths we learn aout the current "distractions" facing President-elect Obama, we need to know the truth. After we get some information we can decide whether it disqualifies Mr. Obama from the presidency. But for now, we need to the press to take the heat and find out some truth for us.
It would also be helpful if the Obama administration's transition team would ditch the bunker mentality. Somebody has to begin the process of political disarmament in Washington D.C.
Posted at 05:47 PM in Barack Obama, Current Affairs, U.S. History | Permalink | Comments (2) | TrackBack (0)
Although only two women precede Senator Hillary Rodham Clinton as Secretary of State, scattered through American history are women in official diplomatic service. Ruth Bryan Owen stands out for a number of reasons, including the fact that she was elected to Congress before women could vote. (Typical, eh? A woman could serve her fellow citizens but not participate in electing her representatives.) Another woman diplomat, of rather different political views than Owen, was Clare Boothe Luce (as Owen was the first woman congressional representative from Florida, Luce was the first woman to represent Connecticut in the House; both served as ambassadors after their stints in Congress). One of Luce's greatest legacies: The Clare Boothe Luce Program. In her bequest (almost her entire estate),' she sought "to encourage women to enter, study, graduate, and teach" in science, mathematics and engineering.'
Despite the careers of women like Owen and Luce are impressive, the Department of State does not have a particularly woman-filled history.
Who were the first women in the Foreign Service?
Lucile Atcherson passed the Diplomatic Service examination in 1922 with the third-highest score, and was appointed a secretary in the Diplomatic Service on December 5, 1922. She was assigned as Third Secretary of the Legation in Berne, Switzerland, on April 11, 1925. She resigned September 19, 1927 in order to get married. Pattie H. Field was the first woman to enter the Foreign Service after passage of the Rogers Act. She was sworn in on April 20, 1925, served as a Vice Consul at Amsterdam, and resigned on June 27, 1929 to accept a job with the National Broadcasting Company.
Who was the first woman to be chief of a U.S. diplomatic mission?
Ruth Bryan Owen, daughter of William Jennings Bryan, was appointed Minister to Denmark on April 13, 1933. She presented her credentials on May 29, 1933 and served until June 27, 1936.
Who was the first woman to hold the rank of Ambassador?
Eugenie Moore Anderson was appointed Ambassador to Denmark on October 20, 1949. She presented her credentials on December 22, 1949, and served until January 19, 1953.
Who was the first woman Foreign Service Officer to become an Ambassador?
Frances E. Willis was appointed Ambassador to Switzerland on July 20, 1953, and presented her credentials on October 9. She served until May 5, 1957. She later served as Ambassador to Norway (1957-1961) and Ambassador to Ceylon (now Sri Lanka) (1961-1964). Willis was the third woman Foreign Service Officer, being appointed on August 29, 1927. She was appointed Career Ambassador on March 20, 1962.
Who was the first woman to become an Assistant Secretary of State?
Carol C. Laise was appointed Assistant Secretary of State for Public Affairs on September 20, 1973. She served until March 27, 1975. She then served as Director General of the Foreign Service from April 11, 1975 to December 26, 1977.
Who was the first woman to head one of the regional bureaus?
Rozanne L. Ridgway was appointed Assistant Secretary of State for European and Canadian Affairs on July 18, 1985. She served until June 30, 1989. She had also been the first woman to serve as Counselor of the Department of State (March 18, 1980-February 24, 1981).
Who was the first woman Under Secretary of State?
Lucy Wilson Benson was appointed Under Secretary of State for Security Assistance, Science, and Technology on March 23, 1977 and served until January 5, 1980. At the time of her appointment, she was the highest-ranking woman in the Department.
Posted at 09:00 PM in State Department, U.S. History, women in politics | Permalink | Comments (0) | TrackBack (0)
As I wrote in Part One, PERAB, President-elect Obama's new economic advisory board self-styles itself on Dwight Eisenhower's original PFIAB. So was the last Presidential economic advisory board, created by Ronald Reagan. Members of Ronald Reagan's President's Economic Policy Advisory Board:
As I wrote in Part One, PERAB, President-elect Obama's new economic advisory board self-styles itself on Dwight Eisenhower's original PFIAB. So was the last Presidential economic advisory board, created by Ronald Reagan. Members of Ronald Reagan's President's Economic Policy Advisory Board:
T. Lynn, managing partner, Jones, Day, Reavis, and Pogue; former
Director, Office of Management and Budget; and former Secretary of
Housing and Urban Development. George
Shultz will serve as Chairman of the Board. Martin Anderson, Assistant
to the President for Policy Development, will serve as Secretary to the
Paul McCracken, Edmund Ezra Day University Professor of Business Administration at the University of Michigan; former Chairman of the Council of Economic Advisers under President Nixon.
George Shultz, president, Bechtel Group, Inc.; former Secretary of the Treasury, Secretary of Labor, and Director of the Office of Management and Budget.
William E. Simon, former Secretary of the Treasury.
Thomas Sowell, senior fellow, the Hoover Institution.
Herbert Stein, senior fellow, American Enterprise Institute; former Chairman of the Council of Economic Advisers under President Nixon.
Charls E. Walker, chairman, Charls E. Walker Associates, Inc.; former Deputy Secretary of the Treasury.
Walter B. Wriston, chairman, Citibank/Citicorp.
T. Lynn, managing partner, Jones, Day, Reavis, and Pogue; former
Director, Office of Management and Budget; and former Secretary of
Housing and Urban Development.
George Shultz will serve as Chairman of the Board. Martin Anderson, Assistant to the President for Policy Development, will serve as Secretary to the Board.
Hmmm..lots of Nixonians, lots of Hoover Institute types, plenty of neo-classical economic thinkers. Not the sort of group that seems likely to have provided unbiased, nonpartisan advice. How will PERAB differ in this respect? We citizens need to know who the members will be sooner rather than later.
Hmmm..lots of Nixonians, lots of Hoover Institute types, plenty of neo-classical economic thinkers. Not the sort of group that seems likely to have provided unbiased, nonpartisan advice.
How will PERAB differ in this respect? We citizens need to know who the members will be sooner rather than later.
Posted at 10:03 AM in Economic empowerment, P(F)IAB, PEPAB, PERAB, presidential advisory boards, U.S. History | Permalink | Comments (1) | TrackBack (0)
Since reading about the new President's Economic Recovery Advisory Board ["PERAB"}, I have been curious about presidential advisory boards. I decided to check on how often they have been used and for what purposes. As it turns out, presidential advisory boards are not that uncommon, and the most recent President to use one dedicated to economic matters is Ronald Reagan. As for Eisenhower's Foreign Intelligence Advisory Board "PFIAB", it has been in operation since then under one name or another except under President Carter, who canceled it - Ronald Reagan reinstated it.
According to the White House webpage on The President's Intelligence Advisory Board and Intelligence Oversight Board (emphases mine):
The President's Intelligence Advisory Board and Intelligence Oversight Board (PIAB) provides advice to the President concerning the quality and adequacy of intelligence collection, of analysis and estimates, of counterintelligence, and of other intelligence activities. The PIAB, through its Intelligence Oversight Board, also advises the President on the legality of foreign intelligence activities.
The PIAB currently has 16 members selected from among distinguished citizens outside the government who are qualified on the basis of achievement, experience, independence, and integrity.
Unique within the government, the PIAB traditionally has been tasked with providing the President with an independent source of advice on the effectiveness with which the intelligence community is meeting the nation's intelligence needs and the vigor and insight with which the community plans for the future.
The Board was established in 1956 by President Eisenhower and was originally called the President's Board of Consultants on Foreign Intelligence Activities. It gained its current name under President Kennedy and it has served all Presidents since that time except for President Carter. A record of chairpersons is available.
For over four decades the PIAB has acted as a nonpartisan body offering the President objective, expert advice on the conduct of U.S. foreign intelligence. This role reflects the vital assistance that intelligence provides the President in meeting his executive responsibilities. The President must have ample, accurate and timely intelligence; and most recent Presidents have sought the assistance of a separate, unbiased group -- the PIAB -- to advise them on intelligence matters.
Through meetings with intelligence principals, substantive briefings, and visits to intelligence installations, the PIAB seeks to identify deficiencies in the collection, analysis, and reporting of intelligence; to eliminate unnecessary duplication and functional overlap; and to ensure that major programs are responsive to clearly perceived needs and that the technology employed represents the product of the best minds and technical capabilities available in the nation.
Independent of the intelligence community and free from any day-to-day management or operational responsibilities, the PIAB is able to render advice which reflects an objective view of the kinds of intelligence that will best serve the country and the organizational structure most likely to achieve this goal. The effect of the Board's recommendations over the years has been to influence the composition and structure of the intelligence community, the development of major intelligence systems, and the degree of collection and analytic emphasis that is given to substantive areas.
In carrying out their mandate, the members of the PIAB enjoy the confidence of the President and have access to all the information related to foreign intelligence that they need to fulfill their vital advisory role.
Assuming the P(F)IAB is really the model, I will quite curious to see who the additional 14 or so members of the new PERAB will be; how bipartisan it will be; what will ensure its objectivity and lack of bias; and what the full scope of its reviewing authority is going to be. Which Republicans will be serving? Will there be representatives from various economic schools of thought such as the Marxist School, the Institutionalist School, and the Keynesian School, just to name three of the major schools identified by the Federal Reserve Bank of San Francisco? Will the members of the committe be able to/be expected to review the FEC, the FTC, the Antitrust Division of the Justice Department, the Department of Commerce, the Treasury Department, the Department of Health and Human Services, the Pentagon, etc. to gather all information related to economic recovery?
As these questions indicate, if the model is PIAB, PERAB could be an extremely wide-ranging and influential body. Note it will operate independently of legislative oversight, reporting to the President and not to Congress. Maybe this is fine, maybe it is not - much depends on just how influential and wide-ranging President-elect Obama intends it to be. We citizens need some details about this newly minted Advisory Board.
Based on a quick survey of the literature, the last President to appoint an advisory board specifically dedicated to economic matters was Ronald Reagan, who created the President's Economic Policy Advisory Board ("PEPAB"). PEPAB is not currently in existence; it is unclear whether PERAB is modeled upon it.
According to Martin Anderson, a historian and Reagan domestic policy advisor, Reagan's economic policy board was also modeled on Eisenhower's PFIAB (remember Reagan reinstated PFIAB after Carter had discontinued it (see Anderson, Revolution: The Reagan Legacy, p. 261)). Anderson describes the formation of the PEPAB, and notes that it was meant to silence potential outside critics by bringing them "inside the Reagan Tent" (p. 262); it also served to empower Anderson, who mistrusted other Reagan administration team members such as David Stockman (pp. 262-64). PEPAB reported directly to the President to the consternation of the Treasury Department and, according to Anderson, to Don Regan. Anderson credit PEPAB with the creation and implementation of "Reaganomics" (p. 267).
Assuming Anderson is correct, and assuming that the new PERAB is intended to have the same force as the other self-styled economic descendant of Eisenhower's foreign intelligence advisory board, we citizens definitely need more details about President-elect Obama's intentions for PERAB.
Posted at 02:24 AM in Economic empowerment, P(F)IAB, PEPAB, PERAB, U.S. History | Permalink | Comments (0) | TrackBack (0)
Elizabeth Cady Stanton one of the staunchest fighters for the passage of the 16th Amendment absolutely understood that right in progressive political terms: as key to equality of opportunity underwritten by a government that considered itself responsible for providing it to the republic. I advise reading her entire speech, Solitude of Self, which she delivered to the Committee of the Judiciary of the United States Congress, Monday, January 18, 1892, when she was 77 years old.
Here are some passages worth special note (emphases mine):
Mr. Chairman and gentlemen of the committee: We have been speaking before Committees of the Judiciary for the last twenty years, and we have gone over all the arguments in favor of a sixteenth amendment which are familiar to all you gentlemen; therefore, it will not be necessary that I should repeat them again.
The point I wish plainly to bring before you on this occasion is the individuality of each human soul; [...] the right of individual conscience and judgment--our republican idea, individual citizenship. In discussing the rights of woman, we are to consider, first, what belongs to her as an individual, in a world of her own, the arbiter of her own destiny, an imaginary Robinson Crusoe with her woman Friday on a solitary island. Her rights under such circumstances are to use all her faculties for her own safety and happiness.
Secondly, if we consider her as a citizen, as a member of a great nation, she must have the same rights as all other members, according to the fundamental principles of our Government.
Thirdly, viewed as a woman, an equal factor in civilization, her rights and duties are still the same--individual happiness and development.
Fourthly, it is only the incidental relations of life, such as mother, wife, sister, daughter, that may involve some special duties and training. In the usual discussion in regard to woman's sphere, such as men as Herbert Spencer, Frederic Harrison, and Grant Allen uniformly subordinate her rights and duties as an individual, as a citizen, as a woman, to the necessities of these incidental relations, some of which a large class of woman may never assume. In discussing the sphere of man we do not decide his rights as an individual, as a citizen, as a man by his duties as a father, a husband, a brother, or a son, relations some of which he may never fill. Moreover he would be better fitted for these very relations and whatever special work he might choose to do to earn his bread by the complete development of all his faculties as an individual.
Just so with woman. The education that will fit her to discharge the duties in the largest sphere of human usefulness will best fit her for whatever special work she may be compelled to do.
The isolation of every human soul and the necessity of self-dependence must give each individual the right, to choose his own surroundings.
The strongest reason for giving woman all the opportunities for higher education, for the full development of her faculties, forces of mind and body; for giving her the most enlarged freedom of thought and action; a complete emancipation from all forms of bondage, of custom, dependence, superstition; from all the crippling influences of fear, is the solitude and personal responsibility of her own individual life. The strongest reason why we ask for woman a voice in the government under which she lives; in the religion she is asked to believe; equality in social life, where she is the chief factor; a place in the trades and professions, where she may earn her bread, is because of her birthright to self-sovereignty; because, as an individual, she must rely on herself. No matter how much women prefer to lean, to be protected and supported, nor how much men desire to have them do so, they must make the voyage of life alone, and for safety in an emergency they must know something of the laws of navigation. To guide our own craft, we must be captain, pilot, engineer; with chart and compass to stand at the wheel; to match the wind and waves and know when to take in the sail, and to read the signs in the firmament over all. It matters not whether the solitary voyager is man or woman.
To throw obstacle in the way of a complete education is like putting out the eyes; to deny the rights of property, like cutting off the hands. To deny political equality is to rob the ostracised of all self-respect; of credit in the market place; of recompense in the world of work; of a voice among those who make and administer the law; a choice in the jury before whom they are tried, and in the judge who decides their punishment. Shakespeare's play of Titus and Andronicus contains a terrible satire on woman's position in the nineteenth century--"Rude men" (the play tells us) "seized the king's daughter, cut out her tongue, out off her hands, and then bade her go call for water and wash her hands." What a picture of woman's position. Robbed of her natural rights, handicapped by law and custom at every turn, yet compelled to fight her own battles, and in the emergencies of life to fall back on herself for protection.
Such is individual life. Who, I ask you, can take, dare take, on himself the rights, the duties, the responsibilities of another human soul?
Posted at 10:00 AM in Economic empowerment, progressivism, U.S. History, women in politics | Permalink | Comments (1) | TrackBack (0)


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HERBANUM WASH AND BALM SETRegular price £105 Sale price £73
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500ml - 16.9 fl oz
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Aqua (Water), Cetearyl Alcohol, Glycerin, Vitis Vinifera (Grape) Seed Oil, Glyceryl Stearate SE, Butyrospermum Parkii (Shea) Butter, Cetearyl Olivate, Xanthan Gum, Sorbitan Olivate, Parfum (Natural Fragrance), Avena Sativa (Oat) Kernel Flour, Cucurbita Pepo (Pumpkin) Seed Oil, Salvia Hispanica (Chia) Seed Oil, Helianthus Annuus (Sunflower) Seed Oil, Beta-Carotene, Daucus Carota Sativa (Carrot) Root Extract, Daucus Carota Sativa (Carrot) Seed Oil, Ascorbyl Palmitate, Ethylhexylglycerin, Dehydroacetic Acid, Phenoxyethanol, Benzyl Alcohol, Coco-Caprylate/Caprate, Coconut Alkanes, Linalool+, Citral+ ,Limonene+, Geraniol+, Citronellol+.
+Naturally occurs in essential oil
This product contains oat flour which may contain gluten.
I9045 Aqua (Water), Cocamidopropyl Betaine, Sodium Cocoamphoacetate, Glycerin, Lauryl Glucoside, Xanthan Gum, Sodium Cocoyl Glutamate, Sodium Lauryl Glucose Carboxylate, Cucurbita Pepo (Pumpkin) Seed Oil, Salvia Hispanica (Chia) Seed Oil, Vitis Vinifera (Grape) Seed Oil, Parfum (Natural Fragrance), Sodium Chloride, Benzyl Alcohol, Coconut Acid, Ethylhexylglycerin, Citric Acid, Tocopherol, +Linalool, +Geraniol, +Citronellol, +Eugenol, +Citral, +Limonene.
+Naturally occurs in essential oil
VERDEN pH
VERDEN body products are carefully formulated to match the pH of your skin.
VERDEN Hand and Body Wash has a pH of 5.0-5.5.
VERDEN Hand and Body Balm has a pH of 5.0-5.5.
Do VERDEN products contain palm oil?
Palm oil derivatives are present within some ingredients used in the Balms and one ingredient used in the Wash. The ingredients we use are RSPO certified. We continue to work with all our suppliers to source only the most environmentally responsible ingredients in keeping with our vegan and cruelty-free status.
Do VERDEN products contain parabens or sulphates?
VERDEN products are free from parabens and free from SLS, ALS and SLES.
Are any VERDEN products free from fragrance allergens?
VERDEN roots itself in natural fragrance. Our products contain natural essential oils.
Do VERDEN products contain nut oil?
VERDEN products contain ingredients derived from coconut.
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However, VERDEN products are bottled in facilities which handle other products which may contain nut allergens.
For a full, detailed breakdown of what each VERDEN product contains, please consult the ingredients list on each product page of the website.
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VERDEN Washes and Bath Oils are gluten free and suitable for coeliacs.
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Can I use VERDEN if I have eczema, rosacea or psoriasis?
All skins are different and we suggest patch testing on a small area of your body over several days to see how your skin reacts. If you buy a VERDEN product and it does not suit your skin, you can return it to us within 28 days for a full refund. (*We do not refund the cost of postage.)
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Can VERDEN products be used during pregnancy?
VERDEN Bath Oils are not suitable for use in pregnancy. All VERDEN products contain 3% or less of essential oils. Some women prefer to avoid essential oils and fragrance completely during pregnancy. We always recommend checking with your health practitioner.


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|The Library of Congress
The Library of Congress presents these documents as part of the record of the past. These primary historical documents reflect the attitudes, perspectives, and beliefs of different times. The Library of Congress and the University of North Carolina at Chapel Hill do not endorse the views expressed in these collections, which may contain materials offensive to some readers.
|Understanding the Collection
Working with the Collection
Building the Digital Collection
The digitization and presentation of these materials by the Academic Affairs Library of the University of North Carolina at Chapel Hill*, as part of the digital library project Documenting the American South*, was supported by an award from the Library of Congress/Ameritech National Digital Library Competition. Links marked * are to web pages mounted at the awardee institution. The digital reproductions of the narratives are also mounted at the awardee institution.
The source materials for this collection are housed in Libraries at the University of North Carolina at Chapel Hill.* Please contact the library at the University of North Carolina at Chapel Hill with any questions or information about the original materials or requests for reproductions.


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by Vernon Fitch
© copyright Vernon Fitch / The Pink Floyd Archives
Any comments, corrections or additions to this discography are appreciated.
Title: Oldies Collection - De Pre Historie 1980
Record Company: BMG-Ariola Records
Catalog Number: 261.780
Bar Code: 4 007192 617807
Release Information: A Belgian CD sampler that includes the Pink Floyd song, Another Brick in the Wall, part 2. Also includes music by Abba, Blondie, Leo Sayer, Madness, Pat Benatar, Godley & Creme, Electric Light Orchestra, Kool & the Gang, Diana Ross, Captain & Tenille, Garland Jeffreys, Marianne Faithfull, Orchestral Maneuvres in the Dark, and Peter Gabriel. Cover says "Printed in Germany."
Cover: Title cover.
Label: Silver label.


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Thousands of people all over the world are managing their weight with OGX
"I got on the scale in June of 2016 and found my weight was the highest it had ever been. I was 58, overweight, exhausted, and discouraged. I committed that day to start making changes. I started exercising and drinking more water. By pure chance, I was introduced to FENIX during that first week and I welcomed the opportunity to try it. I lost 3 kilos in the first week, drinking two shakes a day in place of two meals. The shakes were easy and convenient and travelled everywhere with me. I started walking, slowly at first, and as the pounds came off, I was able to walk further and faster. For the first time in many years, I got my bicycle out and starting biking on the parkway that runs along a river by our home. I lost 21 kilos in 5 months. The energy that I have now is unbelievable.
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Henrico County, Virginia, USA
Aurora, CO USA – Merrick & Company, a world leader in LiDAR, digital ortho imaging, photogrammetry, and geospatial solutions began a $580,000 contract with Henrico County, Virginia this week. This project is an update to geospatial data compilation contracts performed by Merrick in 1998 and 2003 and includes LiDAR data collection for the first time. The County will take final delivery in October 2008 of digital aerial photography, planimetric features, breaklines, a DTM, and 2-foot contours generated for the entire County using the new LiDAR data.
Merrick won this contract in a qualifications based competition. According to Alfredo Frauenfelder, Geographic Information Systems Coordinator for Henrico County, "Merrick proposed simultaneous LiDAR and digital orthophotography collection using multiple sensors on a single aircraft. This approach offers significant flight mission cost savings in comparison to performing two separate flights."
Gary Outlaw, explains, "Merrick is able to provide the County with more data at a higher quality for less cost when compared to traditional approaches for this project."
Henrico County is part of the Richmond, Virginia metropolitan area and is experiencing increased urbanization and suburban growth. New housing, retail space, offices, and government services required to support the growing population are changing the landscape and driving the need for new and updated geospatial data. County departments such as planning, finance, public works, and utilities access and maintain their respective data on an enterprise GIS server administered by the Henrico County GIS Office.
Visit Henrico County on the web at www.co.henrico.va.us.
About Merrick & Company
Founded in Denver in 1955, Merrick & Company is a world-leading geospatial solutions, surveying, multidisciplinary engineering, architectural, and construction management firm. The employee-owned company provides these services to municipal, state, federal, and private-sector clients. With approximately 400 employees, Merrick has offices in Aurora and Colorado Springs, CO; Los Alamos and Albuquerque, NM; Atlanta, GA, Ottawa, Canada; Mexico City and Guadalajara, Mexico; Bogota, Colombia.


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25. (WIP) Falkor by Kitty at Let's Buzz, Norway – fresh in the pic, from February. Continuing soon!
24. New tat in spirit of spooktober Nice Ink PA done by Angela she did all of them on my leg.
23. 15 hours of black work by Boris Bianchi @ Grit n Glory in NYC
22. Tattoo done today! My 4th one, done by Gee at Phoenix tattoo studio, Trowbridge uk
21. Anyone have an idea how much this would cost?
20. Healed Roses by Gabriel Martin @ Venom Art – Adelaide, South Australia
19. Stars on my feet – done by Erik Espinoza at Dark Age Tattoo Studio in Denton TX Sept 2019
18. Ink by Ian McCusker owner of 7 Seas Tattoo in Buffalo NY
17. Sleeve tattoo done by Daniel armitag from bowmanville, ontario at no love lost tattoo
16. "Impossible Triangle" thigh piece by Charlie Girl at Electric Hand Tattoo in Nashville, TN [6 months healed: Tattooed 9/28/19]
15. Probably 10,000th SPN Tattoo Posted Here, but I'm Proud of It. (Done by Brian Brewer, Hungry Eye Tattoo Co., Okeechobee, Fl.)
14. Healed crystal tattoo by Sarah at eternal tattoo Springfield MO
13. My healed elephant – done in 2013 by Jon Hanna at Living Art Studio
12. Healed Dumbo Tattoo by Jen Danger at Enchanted Tattoo in Edmonton, Alberta. Just under a year old.
11. Orchidmantis by Miki Kim at Highline Tattoo (NYC) healed
10. Done September 2019. My shell serotonin (shell-otonin) done by Luke at Absolute Tattoo in Reno, NV.
09. Healed (about 4 months) lady face, skull, flowers by Krish Trece – 10 Thousand Foxes, NYC
08. Stark Direwolf done by Frank Ball Jr @ WelcomeToHeavens, Echo Park, CA
07. nerf this! booty heart D.Va tattoo done by Isasha at Black Rabbit Tattoo, Richmond VA
06. Breathe Andrew John Smith at Good Fight Tattoo, London, 4 months
05. HEALED Foo dog and now what of part of my sleeve. …… Reigning Ink Tattoo Designs, Nicholasville, Kentucky……Was done over a year ago.
04. The Bison Healed Robert @ Monument Tattoos in Tallahasssee Florida
03. Taro from Harvest Moon 64! Done in January by Brittany at Pensacola Tattoo Studio. Pensacola, Fl
02. Healed Trash Panda. Mary Madsen @ Fox Runner Tattoo, Edmonton, Alberta
01. Finished and Fabulous! Healed and reworked backpiece by Elizabeth at Tattoo Noir, Shanghai.


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This week on Good, Bad, or Bull$#*! Beau, Michael, and Crofton give themselves license in a brand new debate about Product Licensing! Is Product Licensing a great way to enjoy a cultural touchstone through other mediums and products, or, is it a depraved exploitation designed to bilk people of their cash by "adding value" to otherwise benign merchandise and preying on their enthusiasm for art and culture?
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Bee Removal
Let's get one thing straight. We all love bees and the work they do for us. But not when they build their hives near humans. That's when bees become a problem that requires the help of the certified and insured pest control experts at Shoreline Turf & Pest Control Inc. We will safely remove the beehive from your property, and if possible, transport it to a new location. We are proud to offer bee relocation services to home and business owners throughout the region.
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First, we will perform an inspection of your property and the hive in particular. We need to determine its exact location, accessibility, and size. With these factors in mind, we will then create a plan for the removal of the hive.
Although we try to preserve the bees as much as possible, the inspection may show that it's not possible to relocate the hive safely. In these cases, we will have to find another strategy—one that you are happy with as well. Finally, we will draft a quote for the services you require that are competitive and market-driven.
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Environmentally-Friendly Bee Relocation Services
Ideally, we will be able to remove and relocate the problem hive. Our goal is to preserve the health of wild bees and allow them to continue their process of pollination—something that our agricultural industry depends on. We strive to offer clients ecologically conscious alternatives to pest control that satisfy their need for safety and ethics at the same time.
Often we will deliver the swarms of bees to a local apiary where they can thrive as a colony in safety while also providing essential pollinating services to the local environment. It's a careful balancing act, but one that's important for the success of our community.
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If the beehive is not located in an accessible area, we may not be able to remove and relocate it. If it is posing a danger to humans, we will take a different approach to bee removal. Our experienced bee control team will carefully, but efficiently, eliminate the hive at the source.
Although bee extermination may be the last resort, sometimes it is necessary. We take every precaution to ensure the safety and security of those in close proximity.
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Bee Removal Clean-Up and Follow-Up
To ensure the successful completion of the removal, we will perform a full clean-up and inspection of the property. This is an important step to prevent attracting other pests like wasps, mice, rates, etc. We will collect:
- Honeycomb
- Honey
- Dead bees
- Parts of the nest
- Larvae
Call the Best Bee Removal Service
If you are having problems with bees on your property, contact the pest control company that will get the job done quickly, efficiently, and environmentally. Where possible, we work to support the thriving bee population in our region. Protect yourself and protect your community by hiring Shoreline Turf & Pest Control Inc for bee removal.
Call now.


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More and more modern cameras allow shooting in 4K. Of course, it gives you better video quality, but there's more to 4K than just high resolution. If you still prefer shooting in 1080p, Peter McKinnon gives you several reasons why you should switch to 4K.
To properly experience a 4K video, you need to have a screen that supports it. However, many of us still watch videos in 1080p because we don't have the 4K monitor. If this is a reason why you don't shoot in 4K, it shouldn't be. Even if your video will be viewed in 1080p, when you downsample a 4K footage to 1080p, it will look much better. And of course, you can also have the 4K version for those whose monitor supports it.
Another advantage of 4K is that it allows you more control over the video in post processing. If you don't have the second camera, you can play with the 4K footage. You can zoom in the frames and still keep the high quality. 4K gives you more room to stabilize the footage in post, and you can even mimic dolly movement by zooming and moving the frame.
As far as I know, for many filmmaking enthusiasts (and not to mention pros), 4K video is even a deal breaker when choosing the camera. But if there are still those like me, who couldn't care less whether their camera shoots 1080p or 4K, these are some of the reasons why you should embrace the higher resolution.
[4K VS 1080p – What's the big deal? | Peter McKinnon]