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During the stress response to intense exercise, the sympathetic nervous system (SNS) induces rapid catabolism of energy reserves through the release of catecholamines and subsequent activation of protein kinase A (PKA). Paradoxically, chronic administration of sympathomimetic drugs (β‐agonists) leads to anabolic adaptations in skeletal muscle, suggesting that sympathetic outflow also regulates myofiber remodeling. Here, we show that β‐agonists or catecholamines released during intense exercise induce Creb‐mediated transcriptional programs through activation of its obligate coactivators Crtc2 and Crtc3. In contrast to the catabolic activity normally associated with SNS function, activation of the Crtc/Creb transcriptional complex by conditional overexpression of Crtc2 in the skeletal muscle of transgenic mice fostered an anabolic state of energy and protein balance. Crtc2‐overexpressing mice have increased myofiber cross‐sectional area, greater intramuscular triglycerides and glycogen content. Moreover, maximal exercise capacity was enhanced after induction of Crtc2 expression in transgenic mice. Collectively these findings demonstrate that the SNS‐adrenergic signaling cascade coordinates a transient catabolic stress response during high‐intensity exercise, which is followed by transcriptional reprogramming that directs anabolic changes for recovery and that augments subsequent exercise performance.
The sympathetic nervous system coordinates catabolism of energy stores during exercise with anabolic responses post‐exercise by activating the Crtc/Creb transcriptional complex.
High‐intensity exercise activates the Crtc/Creb transcriptional complex to direct anabolism.
Adrenergic and cholinergic signaling converge on Crtc‐mediated transcription.
Sustained activation of the Crtc/Creb complex in skeletal muscle increases maximal exercise capacity.
The sympathetic nervous system (SNS) controls the "fight or flight" response by releasing energy stores and enhancing cardiovascular dynamics during high‐intensity exercise (HIE). Catecholamines released by the SNS bind and activate β‐adrenergic receptors (BARs), initiating a series of molecular events that increase intracellular cAMP, which in turn liberates the catalytic subunit of protein kinase A (PKA) to induce rapid signaling pathways (Altarejos & Montminy, 2011). In skeletal muscle, PKA initiates catabolism of glycogen and intramuscular triglyceride (IMTG) energy stores in the sarcoplasm by phosphorylating of the regulatory enzymes phosphorylase kinase and hormone‐sensitive lipase (Chesley et al, 1996; Jocken & Blaak, 2008). These SNS‐mediated catabolic effects are rapid and transient mechanisms for countering energetic stress.
β‐Adrenergic receptor agonists (β‐agonists) are used clinically as sympathomimetic drugs and in research as tool compounds to determine how skeletal muscle responds to sympathetic activation. When used acutely, β‐agonists parallel the ability of catecholamines to induce catabolism of energy reserves in skeletal muscle; however, prolonged administration of the same compounds induces an anabolic state and cause muscle hypertrophy (Choo et al, 1992; Mersmann, 1998; Ryall et al, 2007). It remains unclear whether the anabolic properties of β‐agonists are only a pharmacological effect or whether these observations suggest that sympathetic outflow also directs skeletal muscle anabolism.
Recently studies have suggested that the transcriptional arm of β‐adrenergic signaling has roles in regulating muscle hypertrophy. First, exercise or β‐agonists induce expression of multiple Pgc‐1α (Ppargc1a) splice variants in both skeletal muscle and cultured myocytes via activation of an alternative promoter located ~13 kb upstream of the proximal promoter (Baar et al, 2002; Miura et al, 2008; Norrbom et al, 2011; Ruas et al, 2012). Second, muscle‐specific overexpression of one of the isoforms, Pgc‐1α4, causes muscle hypertrophy in mice and primary myotubes, where silencing Pgc‐1α4 attenuates clenbuterol‐mediated hypertrophy of primary myotubes (Ruas et al, 2012). Third, mice having loss of BAR signaling via muscle‐specific Gα(s) deficiency have decreased total muscle mass and attenuated expression of total Pgc‐1α (Chen et al, 2009). Finally, genetic ablation of all BARs in mice also attenuates Pgc‐1α expression (Bachman et al, 2002). Thus, transcriptional responses to β‐adrenergic signaling and exercise promote muscle hypertrophy, but the mechanism of transcriptional control is unknown.
β‐Agonists such as clenbuterol or isoproterenol direct gene expression via the activation of the cAMP‐response‐element‐binding protein (Creb) transcription factor and associated co‐regulators, Creb‐regulated transcriptional coregulators (Crtc) and Creb‐binding protein (CBP) or its paralog p300 [reviewed in (Altarejos & Montminy, 2011)]. Disrupting assembly of the Creb transcriptional complex in skeletal muscle, by forced overexpression of a dominant‐negative Creb molecule (A‐Creb) that prevents Creb DNA binding, causes a severe dystrophic phenotype (Ahn et al, 1998; Berdeaux et al, 2007). However, neither Crtc coactivators nor Creb have been shown mediate hypertrophic responses by β‐agonists or exercise.
Herein, we report that Crtc/Creb‐directed transcription is initiated by β‐agonists and in response to catecholamines released during exercise. Further calcium and β‐adrenergic signaling is revealed to converge on the Crtc/Creb complex to increase their transcriptional output, providing a novel mechanism that integrates the level of cardiodynamic stress with the intensity of muscle contraction in working muscle. Moreover, overexpression of Ctrc2 or Crtc3 coactivators alone is shown to be sufficient to activate Creb‐dependent transcription without β‐adrenergic signaling. Remarkably, conditional expression of Crtc2 coactivators in the striated muscle of transgenic mice or in primary myocytes is sufficient to induce anabolic changes that drive myofiber hypertrophy, including increases in the levels of intramuscular glycogen and triglycerides. In contrast, acute PKA activation by β‐agonists or HIE increases catabolism and depletes intramuscular glycogen stores in Crtc‐expressing myotubes and mice. Collectively, these findings establish that the SNS governs anabolism in skeletal muscle as a mechanism of recovery and adaptation via the Crtc/Creb transcriptional complex.
Enforced expression of Crtc is sufficient to activate Creb signaling
There are three mammalian Creb‐regulated transcriptional coregulators – Crtc1, Crtc2 and Crtc3 – that have unique and sometimes overlapping expression patterns. The β‐agonists isoproterenol (Iso) triggered the dephosphorylation and rapid translocation of Crtc2 and Crtc3 to the nucleus in cultured primary myotubes and C2C12 myotubes, while Crtc1 was not detected by immunoblotting (Fig 1A–B). Absolute quantitation of transcripts of each coregulator in gastrocnemius, quadriceps and C2C12 myotubes confirmed that only Crtc2 and Crtc3 are expressed in skeletal myocytes (Supplementary Fig S1). Isoproterenol stimulation also increased phospho‐Creb and phospho‐Atf1 in a temporal manner, hallmarks of transcriptional activation (Fig 1A; Gonzalez & Montminy, 1989).
Source Data for Figure 1 A [embj201386145-SourceData-Fig1A.pdf]
Previous studies in other cell types have shown that overexpression of the Crtc coactivators activates Creb‐dependent transcription independent of PKA signaling (Conkright et al, 2003a; Screaton et al, 2004). This occurs by overwhelming the regulatory mechanisms that retain the coactivators in the cytoplasm, where nuclear localization is sufficient for transcriptional activation (Supplementary Fig S2) (Screaton et al, 2004). We used a luciferase reporter gene regulated by cAMP response elements (CRE) and having a minimal TATA core promoter element to assess the effects of clenbuterol or isoproterenol on Creb transcriptional activity in primary myocytes, with or without Crtc2 and Crtc3 overexpression. Overexpression of either Crtc2 or Crtc3 increased luciferase activity to levels seen with either β‐agonist (Fig 1C). Further, propranolol, a β‐adrenergic antagonist, abolished the action of the β‐agonists yet did not block downstream Crtc2‐ or Crtc3‐mediated transcription (Fig 1C). Crtc2‐ or Crtc3‐mediated transcription was Creb dependent, as the effects of Crtcs were attenuated by co‐expression of the dominant‐negative A‐Creb molecule (Fig 1C). Finally, primary myocytes stimulated with isoproterenol or transduced with adenovirus expressing Crtc2 or Crtc3 increased the relative number of transcriptions for the canonical Crtc/Creb‐responsive genes Nr4a1, Nr4a3 and Sik1 (Conkright et al, 2003a; Screaton et al, 2004; Kanzleiter et al, 2010; Pearen et al, 2012), similar to those found following stimulation with isoproterenol (Fig 1D). Thus, β‐agonists activate the Crtc/Creb transcriptional complex and overexpression of Crtc2 or Crtc3 mimics adrenergic‐dependent transcriptional activation without receptor activation.
The sympathetic nervous system activates the Crtc/Creb transcriptional complex
As β‐agonists activated the Crtc/Creb transcriptional complex, we next examined whether a physiological stimulus would parallel pharmacological activation. Catecholamines released by the SNS in response to HIE bind and activate BARs. As expected, mice exercised to exhaustion had significantly higher levels of epinephrine and norepinephrine in the quadriceps muscles and plasma spillover relative to rested controls, along with a commensurate increase in intracellular levels of cAMP (Fig 2A–B). HIE provoked increases in the levels of phospho‐Creb and phospho‐Atf1, while causing the dephosphorylation of Crtc2 and Crtc3, 30 min post‐exercise (Fig 2C), and led to increases in the mRNAs of the canonical Crtc/Creb‐responsive genes Nr4a1, Nr4a3, Ppargc1a (Pgc1‐α) and Sik1 (Herzig et al, 2001; Conkright et al, 2003a; Screaton et al, 2004; Kanzleiter et al, 2010; Pearen et al, 2012) in the quadriceps muscle (Fig 2D–E). An extended kinetic analysis showed that maximal induction of these transcripts occurred between 1 and 2 h post‐exercise and that transcript levels returned to resting levels after 4–8 h (Supplementary Fig S3A). Dephosphorylation and redistribution of Crtc2 followed a similar temporal pattern (Supplementary Fig S3B and C). Thus, in response to a single bout of intense exercise, the Crtc/Creb transcriptional complex activates skeletal muscle target genes in a prototypical fashion, where a burst phase is followed by an attenuation of transcription (Michael et al, 2000; Mayr & Montminy, 2001).
Source Data for Figure 2 C [embj201386145-SourceData-Fig2C.pdf]
If the Crtc/Creb transcriptional complex is indeed activated during HIE by the SNS/adrenergic signaling pathway, then administration of β‐blockers should block the transcriptional activation of Crtc/Creb‐dependent genes. Indeed, expression of Pgc‐1α and Sik1 was also markedly induced in the tibialis anterior muscle with exercise, and this response was suppressed by the administration of the β‐blocker propranolol (Fig 2E). Notably, electroporation of a Crtc3 expression construct directly into the tibialis anterior muscle was sufficient to override these effects of propranolol (Fig 2E). Thus, enforced Crtc expression circumvents upstream BAR signaling in vivo, and SNS release of catecholamines in response to the stress of exercise initiates Crtc/Creb‐mediated gene expression.
The Crtc coactivators integrate SNS/adrenergic and cholinergic signaling
The systemic action of catecholamines that is manifest during exercise suggests that the SNS lacks the specificity needed to direct adaptive changes only to the worked muscle (Lambert et al, 2010; Roatta & Farina, 2010). However, Crtc2 functions as a coincidence regulator of cAMP and Ca2+ signaling pathways in many cell types (Screaton et al, 2004; Baxter et al, 2011; Ch'ng et al, 2012), and during HIE, cholinergic signaling is specific to the worked muscle. Here, acetylcholine depolarizes the membrane of myocytes and liberates calcium (Ca2+) stores from the endoplasmic reticulum, which can by mimicked by treatment with KCl (Macías et al, 2001). Thus, we tested whether calcium and cAMP signaling pathways converged on Crtc‐dependent gene transcription by co‐treating primary myocytes with isoproterenol and KCl. Isoproterenol activated Crtc/Creb‐dependent expression of Nr4a1 and Nr4a3, and this response was markedly augmented by co‐treatment with KCl (Fig 3A). Moreover, Crtc2 or Crtc3 overexpression was sufficient to induce Nr4a1 and Nr4a3 to levels induced by co‐stimulation of primary myocytes with isoproterenol and KCl (Fig 3B). The dependency of Creb and the Crtc coactivators was illustrated by attenuating the transcriptional response to co‐stimulation with Iso and KCl by the co‐expression of A‐Creb (Supplementary Fig S4). Further, increasing intracellular Ca2+ augmented the duration of beta‐agonist‐dependent phosphorylation of Creb and dephosphorylation Crtc2 (Fig 3C), which lengthens the duration of target gene activation, prolonging the burst phase of Creb‐mediated transcription (Michael et al, 2000; Mayr & Montminy, 2001). Thus, the two pathways that are simultaneously activated by HIE, the cholinergic and adrenergic‐dependent signaling pathways, are integrated by Crtc coactivators in working muscle, suggesting that Crtc coactivators may function as physiological drivers of the adaptive response to exercise.
Source Data for Figure 3 C [embj201386145-SourceData-Fig3C.pdf]
The Crtc coactivators induce skeletal myofiber hypertrophy
We reasoned that conditional expression of the CRTC coactivators in transgenic mice could be used as a genetic tool to separate the rapid non‐genomic effects of SNS/adrenergic signaling from the later transcriptional axis in a tissue‐specific manner. To this end, we generated double transgenic mice (DTg) that inducibly express a constitutively active form of Crtc2, Crtc2tm, in muscle when administered doxycycline (Dox). The TRE‐Crtc2tm transgenic mice contain an ORF with three point mutations (S171A, S275A and K625A) that increase the activity and stability of Crtc2 (Screaton et al, 2004; Dentin et al, 2007; Jansson et al, 2008), under the control of tetracycline‐responsive elements (TRE). Skeletal muscle specificity was conferred when this transgenic line was crossed with second mouse that harbors a transgene for the reverse tetracycline transactivator (rtTA) regulated by the 1256[3Emut] MCK promoter (Grill et al, 2003).
Doxycycline (Dox) administration to DTg mice induced Crtc2 transgene expression two‐ to fivefold relative to endogenous levels of Crtc2 mRNA expressed in striated, but not cardiac muscle (Supplementary Fig S5A). Increased accumulation of FLAG‐Crtc2 was also evident after 3–7 days of Dox administration of transgenic mice (Supplementary Fig S5B and C). In striated muscle, Crtc2 overexpression led to significant increases in the mass of the gastrocnemius and soleus muscle relative to age‐ and weight‐matched Dox‐treated wild‐type (WT) littermates (Fig 4A). Quantitative analysis of fiber size in histological sections of gastrocnemius muscle confirmed increased average cross‐sectional area (CSA) of the fibers (Fig 4B–C). The skeletal structure was similar between experimental groups as indicated by the similar tibia bone length and body weights (Fig 4D–E).
Fiber type transitions occur primarily during development and only to a limited extent in response to chronic training (Simoneau et al, 1985; d'Albis et al, 1989; Lynch et al, 1995; Fry, 2004); however, several studies have reported that extended administration of β‐agonists fosters a slow‐to‐fast muscle fiber transition (Maltin et al, 1986; Agbenyega & Wareham, 1990; Hayes & Williams, 1994). However, an alteration in the ratio of fiber types was not evident by myosin ATPase staining of gastrocnemius muscle of DTg mice treated with Dox (Fig 4F). We therefore tested whether forced overexpression of Crtc3 would also produce fiber hypertrophy using a second approach, electric‐pulse‐mediated gene transfer. Notably, electric transfer of a Crtc3 expression vector provoked marked increases in wet muscle weight or the tibialis anterior muscle compared with muscle pulsed with a control vector (Fig 4G). Thus, modest overexpression of either Crtc2 or Crtc3 drives hypertrophic phenotypes similar to those seen with administration of β‐agonists, but without receptor activation (Shi et al, 2007; Koopman et al, 2010).
Crtc/Creb coordinates signaling circuits that drive muscle cell anabolism and hypertrophy
To investigate the mechanisms by which activation of the Crtc/Creb complex induces fiber hypertrophy, mouse primary myotubes were transduced with adenovirus expressing either Crtc2 or Crtc3. As predicted, forced overexpression of Crtc2 or Crtc3 also provoked hypertrophy in cultured myotubes (Fig 5A and Supplementary Fig S6A), including elevated levels of MHC protein (Fig 5B). Myotubes expressing Crtc3 typically had a greater hypertrophic response, yet Crtc2 adenovirus co‐expresses GFP, which only allows examination of transduced myotube and the with use of fixatives that could affect fiber size. Finally, overexpression of either Crtc2 or Crtc3 caused a marked increases in the ratio of total protein to DNA in the myotube, establishing that hypertrophy rather that hyperplasia leads to increased fiber size (Fig 5C).
Source Data for Figure 5 B E F G [embj201386145-SourceData-Fig5BEFG.pdf]
Myotube hypertrophy triggered by forced expression of Crtc2 or Crtc3 was associated with the inhibition of the proteosomal degradation pathway. Specifically, overexpression of either Crtc coactivator in primary myocytes increased expression of Sik1 (Fig 5D), which phosphorylates and inactivates the class II histone deacetylases HDAC4, HDAC5 and HDAC7 by directing their export into the cytoplasm (Takemori et al, 2009). Indeed, expression of Crtc2 and Crtc3 triggered the phosphorylation and cytoplasmic localization of HDCA4, HDAC5 and HDCA7 (Fig 5E and F and Supplementary Fig S6B and C). In skeletal muscle, inactivation of HDACs attenuates protein degradative pathways by indirectly preventing the expression of myogenin and the E3 ubiquitin ligase MuRF1, which are required for the ubiquitylation step in the degradation of muscle protein (McKinsey et al, 2000). Suppression of myogenin and MuRF1 was evident by immunoblotting, demonstrating their control by Crtc/Creb signaling network (Fig 5G). The currently accepted model by which β‐agonists induce muscle hypertrophy is attributed to non‐canonical mechanisms of GPCR signaling that are not dependent of cAMP signaling or Creb‐dependent transcription (Lynch & Ryall, 2008). Specifically, β‐agonists signal through the Gβγ subunits of the G‐protein tetramer and have been proposed to increase PI3 kinase activity and potentiate phosphorylation and activation of Akt1 kinase (Chesley et al, 2000; Erbay & Chen, 2001; Schmidt et al, 2001; Park & Chen, 2005; Kline et al, 2007), which then increases protein synthesis in myofibers by regulating components of the mTOR signaling network (Cuenda & Cohen, 1999; Erbay & Chen, 2001; Sneddon et al, 2001; Park & Chen, 2005; Koopman et al, 2010). Our data rather indicate that the Crtc/Creb transcriptional complex stimulates muscle growth via Pgc‐1α4/Igf‐1/Akt1 signaling pathway. First, of the four known Pgc‐1α splice variants, muscle‐specific overexpression of the Pgc‐1α4 isoform induced Igf1 expression and hypertrophy in primary myocytes (Ruas et al, 2012). Here, enforced expression of Crtc2 or Crtc3 mimics exercise‐mediated induction of the Pgc‐1α4 splice variant (Fig 6A). While full‐length Pgc‐1α (Pgc‐1α1) is regulated by p38 MAP kinase phosporylation of ATF2 in skeletal muscle (Cao et al, 2004; Akimoto et al, 2005, 2008), the Pgc‐1α4 isoform is induced via activation of an alternative promoter located ~13 kb upstream of the proximal promoter. This distal promoter contains putative cAMP‐responsive elements (CREs) (Miura et al, 2008; Yoshioka et al, 2009; Ruas et al, 2012) and is regulated by exercise and by β‐agonists. We cloned 500‐bp fragments of the distal and proximal Pgc‐1α promoters to determine whether Creb and the Crtc coactivators selectively activated either promoter. Only the distal promoter was responsive to isoproterenol stimulation (Fig 6B). Further, chromatin immunoprecipitation (ChIP) analyses of the distal and proximal Pgc‐1α promoters, along with the Nr4a1 and Gapdh promoters as positive and negative controls, respectively, confirmed that endogenous Creb, Crtc2 and Crtc3 are enriched at the distal Pgc‐1α promoter relative to the proximal promoter following treatment of myocytes with isoproterenol (Fig 6C and Supplementary Fig S7A). Overexpression of Crtc2 preferentially increased RNA transcripts originating from the distal promoter (Supplementary Fig S7B and C), consistent with previous reports stimulating myocytes with either the adenylate cyclase agonist, forskolin or clenbuterol (Miura et al, 2008; Ruas et al, 2012).
Source Data for Figure 6 F G [embj201386145-SourceData-Fig6FG.pdf]
Second, as the Pgc‐1α4 isoform induces Igf1 expression, we examined the expression of Igf1, Pdpk1 (Pdk1) and Akt1 in primary myocytes and transgenic mice expressing Crtc2. Notably, there were marked increases in Igf1, Pdpk1 and Akt1 transcripts in primary myocytes overexpressing Crtc2 or Crtc3 (Fig 6D) and in the gastrocnemius muscle of Dox‐treated double transgenic mice (Fig 6E). Increased protein levels of the Akt1 activating kinase Pdpk1 were evident, yet despite a clear and reproducible induction in Akt1 transcripts, only a very marginal change in Akt1 protein was be detected in Crtc2 or Crtc3 overexpression (Fig 6F). However, Crtc3 overexpression triggered an increase in Akt phosphorylation, which is required for activation of Akt kinases (Fig 6G) (Alessi et al, 1997). Thus, the Crtc/Creb complex orchestrates muscle hypertrophy by coordinately regulating both the protein degradation and muscle growth pathways.
The Crtc coactivators augment intramuscular energy storage
Repetitive exercise increases energy reserves by promoting the intramuscular storage of both neutral lipids and glycogen. Glycogen content in skeletal muscle is an excellent predictor of exercise capacity, and depletion of glycogen is a primary cause of muscle fatigue (Bergström et al, 1967; Green et al, 1995). In efforts to spare glycogen catabolism, both endurance exercise and high‐intensity exercise lead to increased storage of intramuscular triglycerides (IMTGs) (Stepto et al, 2002; Hawley et al, 2011). Crtc overexpression was sufficient to provoke this anabolic response in skeletal muscle of mice, and in cultured myotubes. The gastrocnemius muscle of DTg mice contained greater IMTGs relative to wild‐type mice following Dox treatment (Fig 7A–B). Diacylglycerol O‐acyltransferase 1 (Dgat1) catalyzes the committed step in triacylglycerol synthesis, and muscle‐specific transgenic mice overexpressing Dgat‐1 display increased IMTGs (Liu et al, 2009; 2007; Zhang et al, 2010). Dgat1 expression elevated in the gastrocnemius muscle of Dox‐treated DTg mice relative to wild‐type mice (Fig 7C). Similar to the transgenic mice, myotubes overexpressing Crtc3 esterified more fatty acids to triglycerides (Fig 7D–E), and there were robust increases in the levels of Dgat1 mRNA and protein in Crtc2‐ and Crtc3‐expressing myofibers (Fig 7F–G). Accordingly, myotubes ChIP analyses showed recruitment of the Crtc/Creb complex to the Dgat‐1 promoter in isoproterenol‐stimulated myocytes, comparable to that of canonical Creb/Crtc target such as Nr4a1 (Fig 7H and Supplementary Fig S8). Thus, Crtc‐mediated increases in Dgat1 are associated with the accumulation of intramuscular triglycerides in Crtc‐expressing myofibers.
Source Data for Figure 7 G [embj201386145-SourceData-Fig7G.pdf]
Exercise performance is dependent on glycogen stores as an energy source, and in the short‐term, PKA activation initiates glycogenesis (Galbo et al, 1975), as evidenced by the low glycogen content in the muscle of mice that were run to exhaustion (Fig 8A). Glycogen content is not only replenished during rest but can increase to supraphysiological levels prior to training as a mechanism of dampening the energetic stress of future bouts of exercise (Green et al, 1995). Notably, glycogen content was dramatically increased in the muscle of DTg mice expressing Crtc2, and in the tibialis anterior (TA) muscle of mice transiently expressing Crtc3 (Fig 8B and Supplementary Fig S9).
These opposing effects of the SNS/adrenergic signaling cascade suggested a model whereby rapid cAMP/PKA signaling mediates glycogen catabolism followed by the subsequent activation of Crtc/Creb transcriptional program during recovery, which mediates the adaptive anabolic response. In accord with this newly identified duality in SNS/adrenergic function, the anabolic action of Crtc2 or Crtc3 on glycogen accumulation was reversed after 30 min of clenbuterol stimulation as effectively as control adenovirus infected myotubes ex vivo (Fig 8C–D). Importantly, a bout of high‐intensity exercise after Crtc2 overexpression reversed the elevated glycogen levels in the skeletal muscle (Fig 8E).
Crtc2 reduces metabolic stress and improves exercise capacity in skeletal muscle
Since Crtc2 overexpression fosters many of the same phenotypic changes that occur in response to the onset of a new exercise regimen, we reasoned that DTg mice would experience less stress during forced exercise. Metabolic stress and exercise capacity were tested using continuous running with an escalating velocity protocol (Fig 9A). Mice were tested for exhaustion during three trials prior to induction of the Crtc2 transgene followed by an addition three trials 2 weeks after administration of Dox. Both groups displayed signs of a training or learning effect, but the DTg mice exhibited a significant increase in performance that did not occur with the wild‐type cohort (Fig 9B). Moreover, lower plasma lactate levels occurred after 20 min of exercise when the Crtc2 transgene was expressed, suggesting that the same amount of work induced less metabolic stress in these mice (Fig 9C).
β‐Adrenergic receptor (β‐AR) agonists induce skeletal muscle hypertrophy (Choo et al, 1992; Mersmann, 1998) and attenuate muscle atrophy due to sarcopenia (Ryall et al, 2007), denervation (Maltin et al, 1989; Hinkle et al, 2002) or neuromuscular‐induced dystrophy (Harcourt et al, 2007; Zeman et al, 2000). These studies and others have spawned enthusiasm in the therapeutic application of β‐agonists for muscle wasting (Ryall & Lynch, 2008). The precise mechanism by which β‐agonists activate the Akt signaling pathway to promote muscle hypertrophy is however unclear, despite the fact that some have suggested that the Gβγ subunits of the G‐protein tetramer activate PI3K to then activate Akt1 (Chesley et al, 2000; Erbay & Chen, 2001; Schmidt et al, 2001; Park & Chen, 2005; Kline et al, 2007). Rather, here we show that β‐agonists or exercise activate the Crtc/Creb transcription and, using genetic approaches, establish that initiating Crtc/Creb signaling without activation of the adrenergic receptor is sufficient to induce adaptive changes, including hypertrophy and increased exercise capacity. Several upstream activators of Akt1, including Igf1 and Pdpk1 (Musaró et al, 2001; Rommel et al, 2001), are upregulated by Crtc/Creb signaling, but whether the hypertrophy observed is dependent on their function is unclear.
Activation of the Crtc/Creb transcriptional complex also inhibited the proteasomal degradation pathway, and this likely also contributes to the phenotypes manifest in Crtc2 transgenic mice. In skeletal muscle, inactivation of class II HDACs impairs protein degradative pathways via effects on the expression of myogenin and the E3 ubiquitin ligase MuRF1, which are required for the ubiquitylation of muscle protein (McKinsey et al, 2000). Crtc2 or Crtc3 overexpression appears to inactivate the histone deacetylases HDAC4, HDAC5 and HDAC7 via their induction of Sik1, which phosphorylates these HDACs and directs their export into the cytoplasm (Berdeaux et al, 2007; Takemori et al, 2009). Accordingly, myogenin and MuRF1 expression was suppressed in primary myocytes and transgenic mice expressing Crtc2. Thus, the Crtc/Creb transcriptional complex sustains muscle hypertrophy by coordinating the signaling circuits that decrease protein degradation and those that promote protein synthesis.
Despite the clear pharmacological effects of β‐AR agonists, the SNS has not been previously thought to direct the anabolic adaptations fostered by exercise, largely due to the systemic effects of catecholamines. We show here that the Crtc/Creb transcriptional complex is activated in response to SNS cues, including high‐intensity exercise, and that the Crtc coactivators integrate signals from both calcium and catecholamine pathways in muscle cells ex vivo and in vivo. During exercise, acetylcholine depolarizes the membrane of the worked muscle, liberating Ca2+ stores from the ER into the sarcolemmal space. Calcium not only directs contraction, but also functions as a second messenger that regulates the protein phosphatase calcineurin, which dephosphorylates NFAT transcription factors (Bassel‐Duby & Olson, 2006). When catecholamines increase cAMP signaling in contracting myofibers, the two signaling pathways converge to activate the Crtc coactivators. This dual signaling integration is highly conserved, occurring in diverse tissues such as hippocampus (Ch'ng et al, 2012), cortex (Baxter et al, 2011) and islet cells (Screaton et al, 2004). The convergence of these two exercise‐induced signaling pathways provides a mechanism to direct the appropriate adaptation primarily to the working muscle.
Skeletal muscle exhibits remarkable plasticity to exercise, which consists of any infinite combination of intensity, duration and resistance; however, most exercise research focuses on effects of these extremes of training regimes. This is best exemplified by comparing the differences in adaptations that result from chronic aerobic training versus resistance training (Egan & Zierath, 2013). Our data unexpectedly show adaptations that occur in both of these modalities, which are generally thought to be mutually exclusive. For example, Crtc2 expression increases myofiber cross sectional area with elevated triglyceride and glycogen stores but also stimulated the expression of genes known to induce mitochondrial biogenesis, including Pgc‐1α and Nr4A3. Moreover, it is unlikely that the SNS has a major role in these classically studied modalities since catecholamine levels progressively decrease in response to the same stimulus when the absolute workload is held constant (Winder et al, 1978). If SNS/Crtc/Creb signaling coordinates an adaptive response to exercise, the question remains, in what context and time frame does this occur? The distinctive pattern of responses seen with Crtc/Creb activation reflects the unique role of catecholamines in coordinating the stress response to novel stimuli or high‐intensity training. In support of this concept, several studies have shown that the onset of aerobic exercise increases myofiber hypertrophy along with mitochondrial biogenesis. For example, mice provided free wheel running access for 2 weeks have a significant increase in mitochondrial enzyme expression and generally show hypertrophy of hindlimb muscle (Allen et al, 2001, 2002; Harrison et al, 2002; Konhilas et al, 2005). Moreover, 12 weeks of cycle ergometer training induces myofiber hypertrophy in untrained young men, older men and older women (Harber et al, 2009, 2012). Thus, Crtc/Creb coordinates a unique cohort of adaptive responses tailored to the novel and intense stimuli that activate the SNS, and as training continues, the role of the SNS in directing adaptations quickly diminishes as other signaling pathways predominate.
The data presented herein suggest new functions for the SNS in coordinating both the immediate catabolic response to mobilize resources and in the anabolic adaptive changes in exercised muscle. In our model, the rapid action and transcriptional components of the SNS‐adrenergic signaling cascade are regulated in a sequential, biphasic manner (Supplementary Fig S10), suggesting a revision of the current concept of the SNS as driving solely catabolism during exercise (Egan & Zierath, 2013). Specifically, although transient elevations in cAMP and PKA regulate catabolism of energy stores during exercise, following exercise activation of the Crtc/Creb transcriptional complex induces genes that direct structural and metabolic remodeling. In support of this model, elevated levels of glycogen induced by forced expression of Crtc2 or Crtc3 are reversible by acutely activating PKA with clenbuterol, or by a bout of HIE. These adaptive Crtc/Creb‐driven events during rest would thus prepare the muscle for the next repetitive bout of exertion and suggest that the Crtc/Creb transcriptional complex plays a specialized role in coordinating the adaptive response to the stress or intensity of exercise to restore homeostasis. Transgenic mice showed a clear improvement in maximal exercise capacity during treadmill‐based stress test after induction of the Crtc2 transgene. This is consistent with the well‐known fact that athletic performance is greatly enhanced by reintroduction of high‐intensity interval training and periodic changes in exercise routines (Fairbarn et al, 1991; Smith et al, 2003; Babraj et al, 2009; Richards et al, 2010). Thus, the SNS is exquisitely tailored to direct skeletal muscle adaptations that are proportional to the stress of the exercise, and our work challenges the current paradigm of SNS as primarily being mediator of rapid catabolic changes in skeletal muscle, as it clearly also controls adaptive anabolic responses via the Crtc/Creb complex.
Materials and Methods
Transgenic mice
TRE‐Crtc2tm mice were generated by cloning FLAG‐Crtc2 (S171A, S275A, K628R) into pTRE‐Tight. Oocyte injections were conducted into pseudopregnant C57Bl6 mice at the University of Cincinnati. Skeletal muscle specificity was conferred when this transgenic line was crossed with second mouse transgenic strain that harbors a transgene for the reverse tetracycline transactivator (rtTA) that is regulated by the 1256[3Emut] MCK promoter (Grill et al, 2003). For skeletal muscle‐specific expression, Crtc2tm DTg mice were treated with DOX (1.0 g/kg chow, Bio serv). Wild‐type littermates were used as controls and were treated with DOX in the same manner.
Electric‐pulse‐mediated gene transfer
Electric‐pulse‐mediated gene transfer was conducted with an ECM 830 square wave using non‐invasive platinum‐coated tweezertrodes according to the manufacturer's guidelines. Fifty micrograms of purified plasmid DNA was injected with a 29‐G needle in the tibialis anterior muscle. Immediately after the plasmid injection, four pulses of 40 mV lasting for 100 ms with an interval of 200 ms between pulses were applied. The polarity was then reversed and four additional pulses were performed.
Mouse exercise protocols
Eight‐week‐old male C57BL/6J mice were acclimated and pre‐trained on a treadmill for 2 weeks prior to high‐intensity exercise. Mice were run at 10 m/min for 15 min followed by an incremental increase of 1 m/min over the next 5 min until a speed of 20 m/min was reached. Mice were considered exhausted if they had an irregular gate or stayed on the shock grid for two continuous seconds. Mice were rested 30 min post‐exercise before euthanization and tissue biopsy.
Exercise capacity was determined utilizing a treadmill‐based exercise stress test that consisted of an escalating belt speed that increased by 2 m/min every 2 min at a 15‐degree incline after an initial warm‐up at 20 m/min for 5 min. The maximum speed achieved despite extra stimulus was recorded. Each mouse was evaluated in three independent tests separated by 1‐week intervals prior to the administration of Dox, followed by three additional tests after 2 weeks of Dox administration. All animal protocols were reviewed and approved by the Institutional Animal Care and Use (IACUC) of The Scripps Research Institute, Florida.
Primary myocyte isolation and cell culture
Primary myoblasts were isolated from P1 to P3 day old C57BL/6J pups as described (Springer et al, 1997) and cultured on collagen‐coated plates in expansion media consisting in 1:1 F‐10/DMEM (Invitrogen) with 20% fetal calf serum and 25 μg/ml of bFGF. Sub‐confluent myoblasts were differentiated into multinucleate myotubes using a 1:1 F‐10/5 mM glucose DMEM supplemented with 4% heat‐inactivated horse serum (Hyclone) for up to 5 days. C2C12 mouse myoblasts from American Type Collection were expanded in DMEM supplemented with 10% fetal calf serum.
Pharmacological agents
Isoproterenol 100 nM, clenbuterol 45 nM and propranolol 10 μM.
Transfections and luciferase assays
Mouse primary myoblasts were transfected with the using Lipofectamin LTX and plus reagent (Invitrogen) following the manufacturer's guidelines. Luciferase assays were carried out as described (Conkright et al, 2003b) using BrightGlo (Promega) reagent and an EnVision® Reader (PerkinElmer).
The control GFP‐expressing, Crtc2‐expressing and Crtc3‐expressing adenoviruses have been described (Koo et al, 2005; Wu et al, 2006). For all experiments, myotubes were infected after 72 h of differentiation with 4 × 108 viral particles per ml per well for 24–48 h.
Immunoblotting and subcellular fractionation
Immunoblot analysis was performed as described (Conkright et al, 2003a). Cytoplasmic and nuclear biochemical fractionation of the myotubes was performed using the Active Motif nuclear extract kit (Active Motif) following the manufacturer's protocol. Whole‐cell extracts were prepared in HEPES whole‐cell lysis buffer (20 mM HEPES, pH 7.4, 1% Triton X‐100, 1× phosphoSTOP complete inhibition cocktail tablets (Roche), and 1X Complete‐EDTA Free protease inhibitor cocktail (Roche). Frozen muscle tissue was homogenized in lysis buffer T‐PER® tissue protein extraction reagent (Thermo Scientific) by a polytron homogenizer and sonication. The protein concentration was determined using the protein assay reagent (Bio‐Rad). 60–80 μg of protein was separated by SDS–PAGE and transferred to nitrocellulose membranes for immunoblotting. The antibodies used in this study were as follows: CRTC3 (C35G4)Rb, CREB (48H2)Rb, pAKT(Thr308) (244f1)Rb and pAKT(Ser473) (971s) were from Cell Signaling Technology; PGC1α ab54481 Rb and PDPK1 ab31406 Rb were from Abcam; Nur77 #2518 Rb was from Novus Biological and Epitomics; and CRTC2 #A300‐638A Rb was from Bethyl Laboratories.
Tissue and cellular glycogen content
Glycogen concentration of primary myotubes was measured using an assay kit from Biovision.
Measurement of signaling molecules
Catecholamines were quantitated using the 2‐CAT (Epinephrine/Norepinephrine) Research ELISA™ Kit from Rocky Mountain Diagnostic. cAMP was quantitated with a LANCE assay from PerkinElmer following the manufacturer's protocol.
RNA and qRT‐PCR
Total RNA from tissue or cells was harvested using Rneasy RNA Kit (Qiagen) and cDNA prepared using Transcriptor High Fidelity cDNA Synthesis Kit (Roche). Relative abundance of cDNAs was determined a Roche LightCycler 480 and normalized the resulting data to Rpl‐23 ribosomal RNA as described (Conkright et al, 2003b). Primers used were Nr4a1 (5′‐ttctgctcaggcctggtact′, 5′‐gattctgcagctcttccacc‐3′); Nr4a3 (5′‐tcagcctttttggagctgtt′, 5′‐tgaagtcgatgcaggacaag‐3′); Sik1 (5′‐cccttattattccccctgga‐3′, 5′‐cttcacttgcagagaagggg‐3′); Dgat1 (5′‐tggttaacctggccacaatc‐3′, 5′‐ttggagtatgatgccagagca‐3′); Pdpk1 (5′‐tcacagattttggaacagcaa‐3′, 5′‐tgagcagctctggagaaaca‐3′); and Ppargc1a isoform 1 (5′‐atggcttgggacatg‐3′, 5′‐gttcaggaagatctgg‐3′). Ppargc1a isoform 4 (5′‐TCACACCAAACCCACAGAAA‐3′, 5′‐CTGGAAGATATGGCACAT‐3′), Igf1 (5′‐TTTTCGCCTCATTATCCCTG‐3′, 5′‐TCTCCTTTGCAGCTTCGTTT‐3′).
Dissected muscle tissue was mounted in OCT medium (TissueTek) and frozen in liquid‐nitrogen‐cooled isopentane. Tissue sections were stained with hematoxylin and eosin for overall morphology, or ATPase activity for fast and slow fiber by standard methods. The cross‐sectional area of muscle fibers was determined using ImageJ software.
Chromatin immunoprecipitation
C2C12 cells were stimulated with isoproterenol for 30 min before cross‐linking in 1% formaldehyde as described (Amelio et al, 2007). We performed 28 cycles of PCR with the primers flanking the CRE sites of each promoter: Dgat1 (5′‐GAACCGCAAGACGTCAGC ‐3′, 5′‐GAGGCTGCGATGCTGCGG‐3′); Nr4a1 (5′‐AAGAAATAGCAGGCTGGTTGGG‐3′, 5′‐CAGGTAAGAGAAAGGAAGGGGTATG‐3′); Gapdh (5′‐GAAAAGGAGATTGCTACG‐3′, 5′‐GCAAGAGGCTAGGGGC‐3′); and Ppargc1 distal promoter (5′‐TCATTGAGCAGTGACTCCCAGG‐3′, 5′‐CAAACCCCTACATACCAGCAGC‐3′).
Statistical analysis
Two‐tailed Student's t‐test was used to determine P‐values between datasets assuming Gaussian distribution. Data are reported as the mean ± s.e.m., along with calculated P‐values. One‐way ANOVA was applied to compare means of three or more groups followed by Tukey's post hoc test for comparing pairs of means. The calculated P‐values are represented by *P < 0.05, **P < 0.01 and ***P < 0.001.
Author contributions
NB and MDC initiated the research and planned all experiments. NB performed most of the experiments and supervised the assistance of KAK, RH and MBL with cell culture and immunoblotting. NB and KAK developed and characterized the transgenic mice. ALA conducted the ChIP experiments and cloned the Pgc‐1α promoter constructs. NB, NK and MDC interpreted the data. NB, KAK, KN and MDC contributed to the writing of the manuscript.
Conflict of interest
N.E. Bruno and M.D. Conkright declare a patent application related to this work. The remaining authors declare that they have no conflict of interest.
Supplementary Information
Supplementary Figure S1 [embj201386145-sup-0001-FigS1.pdf]
Supplementary Figure S2 [embj201386145-sup-0002-FigS2.pdf]
Supplementary Figure S3 [embj201386145-sup-0003-FigS3.pdf]
Supplementary Figure S4 [embj201386145-sup-0004-FigS4.pdf]
Supplementary Figure S5 [embj201386145-sup-0005-FigS5.pdf]
Supplementary Figure S6 [embj201386145-sup-0006-FigS6.pdf]
Supplementary Figure S7 [embj201386145-sup-0007-FigS7.pdf]
Supplementary Figure S8 [embj201386145-sup-0008-FigS8.pdf]
Supplementary Figure S9 [embj201386145-sup-0009-FigS9.pdf]
Supplementary Figure S10 [embj201386145-sup-0010-FigS10.pdf]
The authors would like to thank Dr. Zhidan Wu for providing adenovirus expressing Crtc3. In addition, we thank Drs. John Cleveland, Andrew Butler, Tim Tellinghuisen and Dr. Patrick Griffin for their scientific review and editing during the preparation of this manuscript. This work was supported by the National Institute Health grant R01 DK081491 (MDC) and by monies to Scripps Florida from the state of Florida.
FundingNational Institute Health R01 DK081491
- © 2014 The Authors


text:
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Your generous pledge supports the following local charities:
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subset: commoncrawl


text:
Onkyo A-8170
Integrated Stereo Amplifier (1987-89)
Power output: 80 watts per channel into 8Ω (stereo)
Frequency response: 2Hz to 50kHz
Total harmonic distortion: 0.008%
Damping factor: 50
Input sensitivity: 0.16mV (MC), 2.5mV (MM), 150mV (line)
Signal to noise ratio: 74dB (MC), 93dB (MM), 107dB (line)
Output: 150mV (line)
Dimensions: 435 x 147 x 388mm
Weight: 11.2kg
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Reviewed Jun 28th, 2016 by toaster999
Excellent build, sound and quality.
Reviewed Jan 25th, 2016 by eeriesme
Very solid well built integrated amplifier.
re: A-8170
Great 80s piece of gear. Got it from a lady whose husband died, had it in garage for 5 years!
Sounds exceptional!


text:
I'm Darrell Young and seeking re-election as Cannon County Sheriff. I am a life long resident of Cannon County living in the Short Mountain area. I am married to Rachel Young and have three children, Brian Young, Chasity Evans and Christopher Young.
My parents are Joy and the late Billy Jack Young. My grandparents are Willie Mae Young and the late Jim Young and the late Frank and Lola Henegar.
I am a graduate from Woodbury Central High School in 1973. I have been working in law enforcement here in Cannon County for the past 23 years. I started with the Sheriff's Department in 1991 as a deputy sheriff under former Sheriff Robert Simpson and a graduate of the Tennessee Law Enforcement Training Academy in 1991. I left in 1992 to take a position with the Woodbury Police Department where I was a patrolman, captain and Assistant Chief.
There I remained until August 2010 when I was elected as Sheriff of Cannon County. I and my staff have worked hard to make the citizens proud of the Sheriff's Department.
I will be hard to see everyone across the county so I would like to take this opportunity to again ask for your vote and support in the upcoming August 7, 2014 election.
Thank you,
Sheriff Darrell Young
Paid political advertising by Darrell Young


text:
|Dan Harasty
|Re: [Discuss-gnuradio] questions about USRP2 sink block and upconversion
|Wed, 03 Nov 2010 17:27:03 -0400
|Mozilla/5.0 (Windows; U; Windows NT 5.1; en-US; rv:18.104.22.168) Gecko/20101027 Lightning/1.0b2 Thunderbird/3.1.6
Marcus wrote:
It's usual in telecom systems for there to be some kind of AFC on the receive side to compensate for transmit-side frequency error.
Can't this problem also be solved with a transmit-side correction?If the "error" in this particular USPR2 LO is about 900MHz - 899.99701MHz = 0.00299 MHz, then won't telling the USPR2 to modulate to 900.00299 MHz pretty much get the tones to the right place?
I imagine the correction will change with device temperature and age, and also by intended "center frequency".
But as a first cut, won't that work? -- Dan Harasty On 11/3/2010 4:59 PM, Marcus D. Leech wrote:
On 11/03/2010 04:00 PM, Steve Mcmahon wrote:Hello: I am still somewhat new to GNU Radio. I am running GNU Radio 3.3.0 under openSUSE 11.2, and I have two USRP2 boards, each with a WBX daughterboard. I need some help understanding some fundamental things about GNU Radio and the USRP2 and upconversion. I am trying generate a tone at 900.001 MHz (900,001,000 Hz). I am using GRC to construct a simple flow graph where I have a signal source block generating a 1 khz cosine at a sample rate of 195.312 khz (=100e6/512), connected to a USRP2 sink block with the "decimation" parameter set to 512, and with the "frequency" parameter set to 900M. I then look at the output on a spectrum analyzer. My understanding was that I should see a clear spike at 900.001 MHz, but I don't. Instead I see a peak at 899.99701 MHz. What am I doing wrong? I'm using the internal USRP2 clock. Is this happening because the internal clock is good to only 7ppm?There are two sources of error--one, as you've observed is the precision of the reference clock on the USRP2. And the other is whatever residual measurement error your Spectrum Analyser has. Synthesized LOs are only as good as the reference clock, at least from a frequency-precision perspective. If you want to do better than that, then you can use an external 10MHz reference clock, such as a GPS frequency standard. This is entirely normal for synthesized RF gear. Measure just about any commercial radio out there with a precision measurement device, and there'll be some residual frequency error, unless you get lucky. It's usual in telecom systems for there to be some kind of AFC on the receive side to compensate for transmit-side frequency error.In general, how do I need to setup the frequency of a USRP2 source if I want to place tones in the spectrum? I thought it was simple upconversion. If I want to modulate a multitone signal (say with sine components 1 KHz, 3 khz, and 7 khz) to obtain an upconverted signal with tones at 901 MHz, 903 MHz, and 907 MHz, then I simply set the "frequency" parameter of the USRP2 sink to 900 MHz, right? How exactly does the USRP2 do the upconversion? What exactly does the "frequency" parameter do?The USRP2 takes your quadrature-sampled baseband signal, and interpolates it up to the required Tx-side sampling rate. It programs the Tx LO on the daughtercard to the desired frequency, and sends it on to the Tx mixer. Sometimes, due to LO frequency step size limitations on specific daughtercards, the USRP2 FPGA will use a DUC (Digital Up-converter) stage to get to exactly the desired frequency. I'm not sure whether you meant 901,903 and 907Mhz, or 900.001MHz, 900.003Mhz, and 900.007Mhz. For purposes of experiment, you can have 3 different signal generators, add their outputs, and send the resulting multi-tone baseband stream on to the USRP2.
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text:
woot woot... check it out!
how cute is this pic... it's my jorja and my friend chantelle's little boy caden... too cute!
Gosh they have grown up since then!
"savor the little things"
looking forward to the next case file ... CSI
and i have a couple of just because i can pages using lots of crate paper/maggie holmes and a bit of glitz too!
" you are my favorite girls"
"how lovely"
and i've been busy creating a few canvas's... hope you like!
this is on a 12" x 12" canvas
another 12" x 12" canvas
and this little cutie is on a 4" x 5" canvas
and i'm working on a couple more, that actually go into 3D frames to put up in my home!


text:
Google searches for Facebook fix
SAN FRANCISCO — Google is in hot water again.
Just weeks after setting off alarms with changes to its privacy policy, the company is under attack after The Wall Street Journal revealed that it's been bypassing Apple's privacy settings so that it can collect information on millions of iPhone users.
Story Continued Below
What's happened to the company that once vowed to "do no evil"?
One word: Facebook.
Sure, Facebook's $3.7 billion annual revenue pales compared to the whopping $8 billion Google brings in each quarter — right now. But Facebook's potential post-IPO trajectory puts it on a collision course for eyeballs and online advertising dollars and that's driving Google to make moves that anger lawmakers, provide fodder for an antitrust probe and prompt a lawsuit from a public interest group, analysts say.
"This is Google taking their lumps in the press in order to free themselves up to compete with Facebook on their social strategy," Ashkan Soltani, an independent privacy and security consultant and former technologist at the Federal Trade Commission's division of privacy and identity protection, said earlier this week.
Google recently unveiled a major change to its sacrosanct Google search to incorporate data from its fledgling social network Google+, which just so happens to place the Google+ data high in search results, analysts say.
Then, in one fell swoop, Google announced it was consolidating the privacy policies of more than 60 different products starting March 1.
In addition, the firm stated that it would begin viewing each user as one person and allow the sharing of user information between such products as search and YouTube.
That means users logged in with Google accounts — including users of Android phones — would be seen as one person by the different services. That's sort of like Facebook, which has increasingly optimized its service for mobile usage and is expected to roll out mobile ads soon.
Google's business moves to build a service that out-networks even Facebook have rankled some in Washington, where the company is already the subject of an antitrust probe and privacy scrutiny. "Of the privacy policy changes," Reps. Mary Bono Mack (R-Calif.) and G.K. Butterfield (D-N.C.) wrote to the company Thursday with a list of questions, "perhaps the most troubling is the intent to include in their profile Google search history captured when users are signed into their Google account for advertisement delivery."
The lawmakers wrote their letter before the latest revelation about Google. In a front-page story Friday, The Wall Street Journal reported that Google and other advertising companies were using "special computer code that tricks Apple's Safari Web-browsing software into letting them monitor" millions of iPhone users.
The Journal said Google stopped the practice after being contacted by the paper. Google told the paper it was mischaracterizing what happened and why.
In a statement to POLITICO, Rachel Whetstone, senior vice president for communications and public policy, said Friday, "The Journal mischaracterizes what happened and why. We used known Safari functionality to provide features that signed-in Google users had enabled. It's important to stress that these advertising cookies do not collect personal information."
Google explained that users of other browsers were not impacted. "Unlike other major browsers, Apple's Safari browser blocks third-party cookies by default. However, Safari enables many web features for its users that rely on third parties and third-party cookies, such as 'Like' buttons. Last year, we began using this functionality to enable features for signed-in Google users on Safari who had opted to see personalized ads and other content — such as the ability to '+1' things that interest them," Whetstone continued.
Google created a temporary link between the browsers and their servers "so that we could ascertain whether Safari users were also signed into Google, and had opted for this type of personalization. But we designed this so that the information passing between the user's Safari browser and Google's servers was anonymous — effectively creating a barrier between their personal information and the web content they browse," she said.
Instead, "the Safari browser contained functionality that then enabled other Google advertising cookies to be set on the browser. We didn't anticipate that this would happen, and we have now started removing these advertising cookies from Safari browsers," Whetstone added.


text:
St. Peter is a Catholic Faith Community called to be a beacon drawing others to Christ by proclaiming his Gospel. We invite you to stop in and visit us anytime.
Mass Schedule: Saturday 5:00 pm, Sunday 8:00 & 10:30 am
430 Main Street, Huron, Ohio 44839 419.433.5725
Diocese of Toledo Safe Environment Program in Full Compliance with USCCB Norms
Each year, the Diocese of Toledo is required to undergo an audit to ensure that it is in compliance with the articles of the United States Conference of Catholic Bishops Charter for the Protection of Children and Young People. Bishop Daniel Thomas is pleased to announce that, for the fiscal year 2017-2018, the Diocese was found to be in full compliance with the requirements in the Charter.
The Diocese of Toledo remains committed to ensuring the protection of children and providing a safe environment for all young people. If you have any knowledge of abuse that has been committed by a cleric, or any employee or volunteer of the Catholic Church, please report the abuse to your local police department, Child Protection Services, and Mr. Frank DiLallo, Diocesan Victim Assistance Coordinator. . Mr. DiLallo can be reached at (419) 214-4880 or by mail at 1933 Spielbusch Avenue, Toledo, Ohio 43604.
©2019 St. Peters Catholic Church Huron Ohio.
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text:
Community Ratification Vote of the Norway House Cree Nation Land Law
To many who read this article, it may seem rather detailed and focused only on Norway House Cree Nation (NHCN). While it is true that this is a purely NHCN initiative, First Nation Land Laws and First Nation's management of their own lands marks a significant step in self government, development and progress across the country. It moves us from a place where we are simply being 'wards' of the government of Canada and where our lands are managed by Indigenous and Northern Affairs Canada (INAC) under the Indian Act. With this initiative we are taking real and practical steps forward in self-government and local development.
For centuries prior to the Treaties, First Nations have taken the responsibility of taking care of their own territories and the resources that lay within, and it is time to take back this responsibility. This is true across the land. For communities that are subject to the mechanisms of INAC, progress is extremely bureaucratic, cumbersome and slow. So much so that one might question whether progress is happening at all. The Land Law as means for self-government is an important key to the future development and success of First Nations communities and economies.
In Manitoba for example, Opaskwayak Cree Nation, Chemawawin Cree Nation, Swan Lake First Nation, Brokenhead Ojibway Nation, Misipawistik Cree Nation, Long Plain First Nation and Nisichawayasihk Cree Nation have all implemented a community ratified Land Law. Nationally, 76 First Nations -42 in British Columbia, 9 in Saskatchewan, 7 in Manitoba, 14 in Ontario and 1 in Quebec- have successfully ratified their Land Codes. For these communities, the opportunities for development have been enhanced and they have become arguably stronger, more self reliant and more engaged in planning for their future development.
Norway House Cree Nation has now produced a final Land Law draft ready for community ratification that when approved, will give us the opportunity to realize our goal of self-determination. It is also important to understand that the Land Law does not affect our Treaty and Constitutional Rights.
For NHCN members
What changes and opportunities will come to land management and land use at NHCN with a 'YES' vote? We would take control of all of the activities that take place on our lands that are no longer overseen by INAC. We would have the ability to internally develop commercial infrastructure and other types of leases. We can approve business licenses for NHCN members and non- members. We can develop our own land use and occupancy laws based on the needs of our nation. We can pass environmental laws for the protection of NHCN lands. We can issue permits and licenses and negotiate our own land designations. We would have the ability to create and enforce our own land laws, conduct land administration and enforce our own laws. We would be in a better position to attract businesses and negotiate leases for improved good and services for our membership. We would be able to make decisions pertaining to lands in a timely manner in shorter time frames than INAC that often takes years. We can survey our own lands and establish lots for residential, commercial, industrial and other purposes. We would have the ability to identify, document and protect traditional land holdings.
The significance of ratifying the Land Law is that it will give us the ability, for the first time in generations, to manage our own lands and realize the protections and benefits of self-governed land development.
This is an important and historic vote. Please take the time and let your voice be heard.


text:
David Alvarez Discusses Goals For First Year In Office
Tuesday, January 4, 2011
What will David Alvarez bring to the San Diego City Council? We speak to Councilmember Alvarez about his goals for District 8, and we discuss how he thinks the council should go about cutting the city's $73 million budget deficit.
What will David Alvarez bring to the San Diego City Council? We speak to Councilmember Alvarez about his goals for District 8, and we discuss how he thinks the council should go about cutting the city's $73 million budget deficit.
David Alvarez, San Diego City Councilmember representing District 8
Read Transcript
MAUREEN CAVANAUGH: I'm Maureen Cavanaugh and you're listening to These Days on KPBS. San Diego City Council member David Alvarez has been on the job just about a month now. He's taken his seat representing district eight, and he has cast his first votes. New City Council president Tony Young says he plans to conduct meetings differently this year with an unrelenting focus on fixing San Diego's structural deficit. Councilman David Alvarez is here to talk about his ideas for closing that deficit and his goals for District 8. It's a pressure to welcome David Alvarez back to These Days. Good morning, David.
ALVAREZ: Good morning, thank you for having me.
MAUREEN CAVANAUGH: We invite our listen ares to call with questions and comments for couple Alvarez. The number is 1-888-895-5727. That's 1-888-895-KPBS.
So how have your first weeks in office gone?
ALVAREZ: You know, it's been -- it's been exciting, it's been a lot of activity. Only a month into the job but on my first day, we had to make some really important decisions on a couple of issues at the city. And so it's -- I had to hit the ground running. And it's been exciting of it's been a learning insurance as well. Getting to learn a lot of the departments and a lot of the personnel at the city, to learn about the work that they're doing and it's been a good month.
MAUREEN CAVANAUGH: I'm wondering as you cast your first votes, what does that feel like after having, you know, battled so long to get to this council seat, and there you are sitting on the council, what is the feeling like? Is it one of responsibility?
ALVAREZ: Intense responsibility, and wanting to make sure you do the right thing, that you listen to all the facts and you make the decision based on those facts. So I got my agenda a couple days before my first meeting. So I had to hit and read through all the documents and read through all the factual evidence, and then make sure that you listen to all the public to make sure that you've got all the information to make that choice to cast that vote.
MAUREEN CAVANAUGH: So what are your goals on the council this year.
ALVAREZ: Well, there are several goals that I have for my district, but then also as a city, we've got many challenges, so maybe if I could first start with my district.
THE COURT: Please do, yeah.
ALVAREZ: The district is actually, I think, one of the most exciting in the City of San Diego 678 we've got everything from a border with Mexico from in the southern portion in San Ysidro and Otay, we've got agricultural land in the River Valley area, we've got bayfront both down in the south, and also in the Barrio Logan part of town, we've got historic neighborhood, in Barrio Logan and the northern portion of the district. Then we've got bran new communities in Bay Side and in Ocean View Hills. And so it's a very diverse district. So I'm really, really excited about the opportunities and challenges that that brings. But I think the three things that I want to focus on is on maintaining public safety in owl of our neighborhoods. I think that's a priority for people. It's been shown in surveys, and in study it is, time and time again, that's what people want from their city government, so that's a priority for me. Economic activity and development opportunities for people to have jobs or people to open up businesses and to run businesses in San Diego that are successful. And economic revitalization in some of the historic neighborhoods, some of the older neighborhoods where we can brick in some innovation, 134 redevelopment, some activity that's gonna bring November into some of these neighborhoods that really need a lot of infrastructure projects to make them go forward. But I think that ultimately as our counsel president pointed out in his first meeting as president, getting a grasp and a handle on our budget and solving a structural budget, our structural been deficit is a priority for me, and I think it is for the rest of the council, and that's where all of our energies really should be focused. That's where we're gonna be spending a lot of time, as the president said, almost as many meetings as possible, talking about that, and I think that it is where the priority should be. That's where we're gonna find out whether we can continue to provide the services that people want in the city or not.
MAUREEN CAVANAUGH: I'm speaking with San Diego City counsel member David Alvarez, he represents district 80, and he was just sworn into office early last month. And just to follow up on one of the things you said about your prior -- your goals for District 8, we've heard so much that in the southern part of San Diego, the foreclosure crisis has hit particularly hard. And I'm wondering, is there anything that you as a city councilman can ask the city council to do to try to mitigate that in some way or try to ease that pain a little bit?
ALVAREZ: Well, one of the things that we can do is work with our partners in the federal government to make sure that our credit agencies, our banks, our institutions, that loan money for people who are going through some difficult times are willing to work with the homeowners. So we could do things, like, for example, hold workshops, foreclosure prevention workshops, housing workshops, where we can bringing in the resources into the community so people can go and directly access, rather than having to call these 800 numbers that sometimes don't get answered or you never get a chance to actually speak to someone to make your case as to why you perhaps need to get a loan remodification. Or something of that sort. So bringing those types of resources to the city. A couple of years ago, when president Obama came into office, there was some funding that was created through the American recovery act for housing, and so making sure that those dollars are getting out there, that they're getting used in a way that's appropriate not only for new housing projects but also to prevent those foreclosures to allow people to stay in their homes is gonna be really, really critical. And you're right. The rate of foreclosure some of the Zip Codes in our communities of District 8 are way too high.
MAUREEN CAVANAUGH: As I say, I'm speaking with city City Council member David Alvarez. A caller is on the line. Oh, we had a caller on the line. But he had a very interesting question for you, and it goes along with the topic that I'm getting to, and that is the structure 58 deficit that we spoke about and that council Perez Kent wants to focus on, to fixate on hike a laser beam, I think he said. And I'm wondering, you said that public safety is a primary goal for you in representing District 8. But there have been ideas that since we have this $73 million deficit that we're facing this year in the City of San Diego, that there are going to have to be cuts to public safety services. What do you know now that you didn't not when you were running for the council that might have changed your attitude about that at all S&L.
ALVAREZ: Well, I still think that keeping cuts away from public safety should be a priority. However, given the massive deficit that we have and the percentage in terms of our budget in terms of how much goes to our public safety departments, police and fire primarily, and life guard services, that's over 50 percent of our budget, approximately 50 percent of our budget. So you can continue to cut in all the other areas like eliminating and closing libraries and parks and recreation centers and things like that, in order to maintain public safety. But at some time, you start to damage that infrastructure that we've created in our great city, in what we all believe is our great city, and you start focussing on some of the very, very core issues that are important, but some of these peripheral services like parks and recs and libraries, particularly in districts like mine where access to information is sometimes only obtained through libraries or the library system, where recreation opportunities and opportunities for kids to go out and have an opportunity to have some activities only occur 234 rec centers and parks, those are also important. And so we're gonna have to balance that. We're gonna have to find a way to be able to balance all of the needs that we have. And the needs are different in different parts of the district. We're gonna have to learn to prioritize where we really need to put in our dollars for public safety, where are the high crime rate areas and we're gonna need to start doing things a little bit differently, and again, prioritize what services are needed in which neighborhoods.
MAUREEN CAVANAUGH: Councilman Alvarez, the caller who couldn't stay on the line wanted to know what you thought about the City of San Diego declaring bankruptcy.
ALVAREZ: I think that's an option that's been presented by a few. I haven't had the opportunity to see how that option would play out. I think that there have been some talks and I think other City Council members have mentioned some ideas that sort of borrow on the idea of bankruptcy. But I'm not sure that we're ready to do that yet. I've seen -- I'm waiting for the mayor to propose a budget this next year to see how drastic these cuts are going to be. And once we have that information, because we haven't been able to receive that information yet, I want to make my decision based on that. And so I want to make sure that I have all the information before I make a decision on any of that.
MAUREEN CAVANAUGH: Have you come to any sort of conclusion about the budget proposal that was put out by Carl DeMaio which relied heavily on reforming the pension and, excuse me, outsourcing city departments? What is your take on that?
ALVAREZ: Well, a lot of those ideas are probably ideas we should look at and consider. I think that some of the numbers might -- might vary. Of they might not exactly equate to the number that we need to get to. And so in order to really move forward on the proposal, I think we've gotta have a really grasp on what it exactly means. We're gonna be going through a process of managed competition. Of and probably some of the services that we provide as a city will be outsourced. But how much that's gonna be and how much in savings we're gonna achieve, we will not know until a bidder comes in and provides a bid with an actual number of what it's gonna cost us. And so we can't really -- we can sort of estimate, but we cannot say precisely how much money we're gonna be saving by outsourcing. There is some money to be saved but how much that is, we don't know.
MAUREEN CAVANAUGH: You know, when you took your oath of office, council machine Alvarez, you shared with the public some very moving family history. And that is the fact that your family was basically dislocated by the construction of Petco Park downtown. And I'm wondering, not only is something to share with people to let them know that you know what city decisions can do to people because you know that very personally, it made me wonder about what it makes you think about the other construction projects that are proposed downtown, a new Chargers stadium, the push to expand the convention center. Does this personal history inform the way you think about these new projects?
ALVAREZ: Absolutely. I think everybody's personal history helps them decide, make decisions. And the fact that gentrification did occur in some of the neighborhoods that are adjacent to the downtown area, not only in Barrio Logan, Logan Heights and Sherman heights, that's gonna help me be able to make a better policy choice in terms of what the effects of those types of projects will be. And so when we are talking about building a new Chargers stadium, if that's where we decide to go, then we need to talk about what some of the ramifications of that are, and some of the impacts that that's gonna be have some of the neighboring communities on the downtown community, and how we're dona close those as well. Not just acknowledge that there are impacts but also how we're gonna be able to address those.
MAUREEN CAVANAUGH: We have a caller on the line, that is, James is calling from San Diego. Good morning, James, welcome to These Days.
NEW SPEAKER: Good morning, and happy new year to both of you.
MAUREEN CAVANAUGH: Thank you.
ALVAREZ: Thank you.
NEW SPEAKER: And I live in District 8. And just wanted to thank David for being our representative. And you know, the streets in our neighborhoods have really deteriorated over the years, especially like in Sherman heights issue it's know older neighborhood. And with the recent rains they've become even worse. I was wondering if there's any funding available to repair some of the streets and pot holes that have developed recently.
MAUREEN CAVANAUGH: James, thanks for the call. And pot holes, boy, are you all on the council gonna be hearing a lot about that.
ALVAREZ: Yeah, that's all we hear about. Of at least on the campaign trail, you hear about that a lot.
MAUREEN CAVANAUGH: Well, everywhere you look now, that's a pot hole.
ALVAREZ: And thank you, James, for the phone call. You know streets is a -- and infrastructure in general, in District 8, and some of the older neighborhoods like I mentioned and Sherman heights definitely is an older neighborhood. And that is it a concern to people. And the rains did make that problem, I think, possibly worse. . And so today the City Council, we will be ratifying the mayor's declaration of an emergency for the City of San Diego. And we are hoping that with that, after all the assessments are done by state and federal officials that we will be able to receive some money to help off set some of the costs that occurred in some of the neighborhoods. No, whether or not that can go directly to resurfacing streets or fixing pot holes, I don't know, that's a good question that I will be asking. But it's something that we need to start focusing on. And that's something that people want to see -- aside from public safety, that's where people want to see the city's money going to. Of and I know the mayor introduced earlier last year, I believe it was in April, a $103 million project to resurface and work on streets. So I want to make sure that the priority of that money goes to some of the neighborhoods that really, really desperately need those. And a lot of my neighborhoods in District 8 rank last. And they have some of the poorest state of streets. So we gotta prioritize where our funding's gonna go to our city, to the communities that need them the most. Not only when it comes to street money, but all the other needs that they have.
MAUREEN CAVANAUGH: We're just about out of time, but I just want to ask you one quick question. When council woman Donny fry was leaving the office, she basically asked all the new City Council members, all the remaining City Council members to be more civil, to try to deal with each other in a good way, in a positive way, and maintain a sense of civil discourse. What is your feeling on that? What is the atmosphere at the council like when you deal with these problems?
ALVAREZ: Yeah. You know, Donna Frye's gonna be missed a lot. She had a lot of good leadership qualities that she brought to the council. And that was one of them, the way she conducted business as a public official. And I feel that my personality and just who I am is someone who will also try to make sure that we have that type of relationship on the council. I think I mentioned in my inaugural remarks that we're in this together, and if we're gonna survive issue we're gonna do it together. So there's a huge spirit of cooperation right now in the council. And that just gives me a lot of optimism. And there's a lot of hope on the tenth floor at city hall right now, because people are willing to work together, and we've extended that hand. And I look forward to working with all of my colleagues because they each have their own unique skill set and their own ideas that I think are good and that will make the city a better place. So I'm really looking forward to that.
MAUREEN CAVANAUGH: David Alvarez, thank you.
ALVAREZ: Thank you very much.
MAUREEN CAVANAUGH: And if you would like to comment, please go on-line, KPBS.org/These Days. Coming up, big issues facing San Diego schools this year of that's as These Days continues right here on KPBS.
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R. Buckminster Fuller died at his wife Anne's bedside on Friday, July 1, 1983, 11 days short of putting in 88 years on this planet. Thirty-six hours later, Anne Hewlett Fuller—Bucky's companion and most ardent supporter for over 65 years—passed away, never having regained consciousness from the coma that brought her husband to her side at Good Samaritan Hospital in Los Angeles.
To capsulize Fuller's achievements and ideas in a few hundred words would be an impossible task. Over two dozen books and 25 U.S. patents attest to the seemingly boundless energy he put forth through even his later years (his most recent book, Grunch of Giants, was published just this year).
We hope those of you who are familiar with Fuller's work will find that the following short examples rekindle your enthusiasm for Bucky's far-reaching vision, and, if you're a relative newcomer to his ideas, we hope that our sampling will encourage you to delve deeper.
Bucky was born on July 12, 1895, in Milton, Massachusetts, and his ancestors included the transcendentalist Margaret Fuller, the first publisher (in her literary magazine Dial) of Ralph Waldo Emerson and Henry David Thoreau. At age six, Bucky (as he preferred to be called) designed the tetrahedronal octet truss, using toothpicks and dried peas, but it took another 60 years for him to patent the design as the Octetruss.
In 1917 Buckminster Fuller took Anne Hewlett's hand in marriage. The couple's first child, Alexandra, was born in 1918, and—in an important way—Bucky's observation of, and love for, his daughter helped form his concepts of the perfection of childhood and of humanity's untapped potential. Alexandra's death, in 1922, precipitated the worst period in Bucky's life, and a catharsis that would eventually lead to a complete revision of his way of thinking.
On a windy winter night on the Chicago shore of Lake Michigan, while on the verge of suicide, he reasoned: "You do not have the right to eliminate yourself; you do not belong to you. You belong to the universe."
Through 1926 and 1927, Fuller gave up speaking to anyone other than his new baby, Allegra, and sought to purge his mind of the precepts he'd developed in his first 30 years. In short, he attempted to become "the most unlearned person in the world."
"If I am to be 50 years ahead of my time I shall be safe. No one will interfere with me because I'll be so far ahead that I will pose no threat to all the people who have a vested interest in opposing progress. They'll just call me a nut."
In 1927 Fuller designed the 4D house, for which the name Dymaxion (dynamic, maximum, and ion) was given by Waldo Warren, a public relations man with Marshall Field's department store. Among its features were the following:
- A round design meant to reduce the vacuum Bucky theorized must develop behind a building in the wind
- A gray-water filtering and reuse system
- Solid-waste recycling for fertilizer
- Solar energy for heat
- A low-flow shower head that was called a "fogger"
- Air-filled beds
- Weight so low that Fuller hoped it could be moved by air (something he didn't see happen until 1954).
On March 4, 1933, Bucky began building the Dymaxion car, which, in his mind at least, was to serve as a developmental prototype for a more ambitious aircraft. The first working model was an aluminum-skinned three-wheeler, with an aerodynamic teardrop shape that allowed it to travel at 120 MPH with a 90-HP Ford V-8. (At the time' most cars required at least 300 HP to reach that speed.)
The Dymaxion car received a great deal of publicity, and investors and workers alike anticipated a bright economic future. But Bucky had learned what he needed from the development of his theories and—in the face of considerable resistance from others—cast the project aside.
"I learned very early and painfully that you have to decide at the outset whether you're trying to make money or to make sense, as they are mutually exclusive.' "
Fuller's first book, Nine Chains to the Moon, was finished in 1937, but J. B. Lippincott refused to publish it because of a chapter devoted to Einstein's relativity theory. The noted physicist had claimed that there were only eight people in the world who were capable of understanding his theories, and Bucky's name wasn't on the list.
The aspiring author then requested that Lippincott forward a copy of the manuscript to Einstein, to see if that gentleman would be willing to expand his list. The reply came in the form of a request from Einstein to meet Fuller. After giving his approval of the disputed chapter, the respected scientist said:
"Young man, you amaze me. I cannot conceive of anything I have ever done as having the slightest practical application. I evolved all this in the hope that it might be of use to cosmogonists and astrophysicists in gaining a better understanding of the universe, but you appear to have found practical applications for it."
During the late 1940's, Bucky was busy working out the calculations for what would be his most famous invention, the geodesic dome. At Black Mountain College, not far from MOTHER's home, the first successful dome was built in 1949. By the mid-1950's, the Harvard dropout was receiving honorary degrees right and left, and was much in demand as a lecturer.
Bucky and Anne were able to build their own geodesic home in Carbondale, Illinois, and the sometimes-poet dedicated this humorous take-off on "Home on the Range" to it:
Let architects sing of aesthetics that bring
Rich clients in hordes to their knees
Just give me a home in a great circle dome
Where the stresses and strains are at ease.
Roam home to a dome, where
Gothic and Roman once stood
Now chemical bonds alone guard our blondes
And even the plumbing looks good.
The late 1960's turmoil eventually led to Bucky's leaving Carbondale, and he resisted becoming a part of the political upheaval of the time. As always, he abhorred the role of guru. His concern for the world grew more strident, though, as expressed in the volumes Critical Path and Grunch (Gross Universal Cash Heist) of Giants.
In those works, Bucky expressed his opinion that free enterprise works by "ruthless, but often polite, decimation of the unsupportable fractions [of humanity], or leaving the unsupportable fractions to their unhappy fate."
Socialism, on the other hand, he saw as "the theory of austerity for all and sharing of inadequacy with slow mutual approach to certain, untimely demise."
"Every child is born a genius. It is my conviction, from having watched a great many babies grow up, that all humanity is born a genius and then becomes de-geniused very rapidly by unfavorable circumstances and by the frustration of all their built-in capabilities."
"We say sunset…but there is no sunset…if you back up and look at earth you see the earth turns."


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SCADA Success Stories
View all Sessions
SCADA and Industrial Control System security is becoming more important in the wake of Stuxnet and increasing signs of cyberwar. Organizations are faced with the challenges of securing SCADA and industrial networks, yet approaches are different and with varying success. This birds-of-a-feather discussion will focus on what works and what doesn't when developing an industrial security plan.
Peter Lunk VP Marketing, Wurldtech


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President-elect Barack Obama's newly appointed chief of staff, Rahm Emanuel, served on the board of directors of the federal mortgage firm Freddie Mac at a time when scandal was brewing at the troubled agency and the board failed to spot "red flags," according to government reports reviewed by ABCNews.com.
According to a complaint later filed by the Securities and Exchange Commission, Freddie Mac, known formally as the Federal Home Loan Mortgage Corporation, misreported profits by billions of dollars in order to deceive investors between the years 2000 and 2002.
Our President Elects new Chief of Staff of Staff was appointed to this board by Bill Clinton in 2000 when scandal was going on from within Freddie Mac. He was later accused, as well as the rest of the board, by the Office of Federal Housing Enterprise Oversight of having "failed in its duty to follow up on matters brought to its attention."
During the years 2000, 2001 and 2002, according to the SEC, Freddie Mac substantially misrepresented its income to "present investors with the image of a company that would continue to generate predictable and growing earnings."
I don't think that republicans are going to pursue this, but I know if it was a republican in the situation the Media would be all over this. With some economists saying that Freddie Mac may have been the start to the whole economic problem we have been having recently. Do we really want this guy running any part of our country.


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This file contains 41 entries. All entries are arranged by main entry, title, and date of publication.
Oakeshott, J. F., (Joseph Francis). A Democratic Budget. Fabian Tract; No. 39. London: Fabian Society, 1892. 15 pp. Pamphlet O11 .D4 1892p. PDF
---. The Humanizing of the Poor Law. Fabian Tract; No.54. London: The Fabian Society, 1897. 23 pp. Pamphlet O11 .H8 1897p. PDF
O'Brien, John Robert. The Constitution of the United States from the Worker's Viewpoint. Racine, Wisconsin: the Author, <n.d.>. 48 pp. Pamphlet O13 .C6p.
---. The Field Which We Must Combat: A Survey of the Entire Radical Movement in America. Racine, Wis.: The Soap-Box University, c1921. 21 pp. Pamphlet O13 .F5 1921p. PDF
O'Connor, Tom. The Truth About Anti-Semitism in the Soviet Union: Exposing the Fraud Perpetrated on the American People. New York: American Committee of Jewish Writers, Artists & Scientists, <1949>. 24 pp. Pamphlet O18 .T7 1949p.
O'Hagan, Walter. Why a Catholic Should Be a Socialist. New York: Socialist Party, <1941-?> 8 pp. Pamphlet O36.3 .W5 1940p.
O'Hare, Kate Richards. Crime and Criminals. Kate O'Hare Booklets; No. 4. Girard, Kan.: Frank P. O'Hare, <1921>. 31 pp. Pamphlet O36 .C7 1921p. PDF
---. In Prison; Being a Report. St. Louis, Mo.: F. P. O'Hare, 1920. 64 pp. Pamphlet O36 .I5 1920p. PDF
---. Law and the White Slaver. Rip-Saw Series; No. 1. Saint Louis, Mo.: National Ripsaw Publishing Company, 1911. 32 pp. Pamphlet O36 .L3 1911p. PDF
---. Socialism and the World War. Kate O'Hare Booklets; No. 1. St. Louis: Frank P. O'Hare, 1919. 30 pp. Pamphlet O36 .S6 1919p. PDF
---. "Nigger" Equality. St. Louis, MO: National Rip-Saw, <19-->. 8 pp. Pamphlet O36 .N5 1900p. PDF
Olgin, Moissaye J., (Moissaye Joseph). Capitalism Defends Itself Through the Socialist Labor Party. New York: Workers Library Publishers, 1932. 40 pp. Pamphlet O45.5 .C3 1932p.
---. Life and Teachings of Friedrich Engels. New York: Workers Library Publishers, <1935>. 39 pp. Pamphlet O45.5 .L5 1935p.
Olney, Richard. In the Supreme Court of the United States, October Term, 1894. Chicago?: s.n., <1894>. 22 pp. Pamphlet O51.5 .I5 1894p. PDF
On the Question of Stalin; Comment on the Open Letter of the Central Committee of the CPSU (II) by the Editorial Departments of Renmin Ribao (People's Daily) and Hongqi (Red Flag), September 13, 1963. Peking: Foreign Languages Press, 1963. 23 pp. Pamphlet S782.5 .O5 1963p.
On the Revolutionary "Three-in-One" Combination. Peking: Foreign Languages Press, 1968. 37 pp. Pamphlet J51 .O5 1968p.
One World--Or None. <Cleveland: United World Federalists of Ohio, 1949>. 36 pp. Pamphlet U58.89 .O5 1949p.
Oneal, James. An American Labor Party: An Interpretation. New York: Rand School Press, <1936>. 14 pp. Pamphlet O58 .A5 1936p.
---. The Austrian Civil War. New York: Rand School Press, <1934>. 31 pp. Pamphlet O58 .A9 1934p.
---. Labor and the Next War: A Study of American Imperialism and Its Effect Upon the Workers. Chicago: Socialist Party of the United States, <192-?>. 40 pp. Pamphlet O58 .L3 1920p. PDF
---. Labor in England and America: A Significant Contrast. Chicago, Ill.: National Office, Socialist Party, <1925>. 19 pp. Pamphlet O58 .L33 1925p.
---. Militant Socialism. Rip-saw Series; No. 11. Saint Louis, Mo.: National Rip-Saw Publishing Co., 1912. 33 pp. Pamphlet O58 .M5 1912p. PDF
---. The Next Emancipation. 2nd ed. New York: Emancipation Publishing Co., 1922. 31 pp. Pamphlet O58 .N4 1922p. PDF
---. "Resolved: That the Terms of the Third International Are Inacceptable to the Revolutionary Socialists of the World": Being the Report of a Debate, Held in Star Casino, New York City. . . January Sixteenth, 1921. N.C.Y. <i.e. N.Y.C.>: The Academy Press, 1921. 31, <1> pp. Pamphlet O58 .R4 1921p. PDF
---. Sabotage: Or, Socialism Vs. Syndicalism, a Critical Study of Theories and Methods. Rip-saw Series; No. 20. Saint Louis, Mo.: National Rip-Saw Publishing Co., 1913. 32 pp. Pamphlet O58 .S2 1913p. PDF
---. Socialism Versus Bolshevism. New York: Rand School Press, 1935. 27 pp. Pamphlet O58 .S6 1935p.
---. Socialism's New Beginning. New York: Gene Debs People's Forum Foundation, 1958. 37 pp. Pamphlet O58 .S63 1958p.
---. The Workers in American History. 2nd ed. Terre Haute, Ind.: J. Oneal, 1910. 136 pp. Pamphlet O58 .W6 1910p. PDF
Oneida, Ltd. Oneida Community: 1848-1901. <Oneida, N.Y.?: Oneida Ltd.?, 1901?> 8 pp. Pamphlet O58.2 .O5 1901p. PDF
Openshaw, Keith. The Remoter Rural Areas. Fabian Research Series; 253. London: Fabian Society, 1966. 25 pp. Pamphlet O61 .R4 1966p.
Oppenheimer, Moses. Outlawing Socialism. Chicago: Socialist Party of the United States, 1920. 44 pp. Pamphlet O62 .O9 1920p. PDF
Oppenheimer, Ralph. Whatever Will Happen to the National Plan? Young Fabian Pamphlet; 12. London: Fabian Society, 1966. 24 pp. Pamphlet O62.3 .W5 1966p.
<Order Form>. London: Published by the Labour Party, <1849>. 3 pp. Pamphlet O65 .O7 1949p.
Orear, Leslie F. Out of the Jungle; the Packinghouse Workers Fight for Justice and Equality, by Leslie F. Orear and Stephen H. Diamond. <n.p.>: Hyde Park Press, 1968. 1 vol. (unpaged). Pamphlet O66 .O9 1968p.
The Origin and Development of the Differences Between the Leaderships of CPSU and Ourselves: Comment on the Open Letter of the Central Committee of the CPSU. Peking: Foreign Language Press, 1963. 99 pp. Pamphlet J51 .O7 1963p.
Orr, Charles Andrew. Stalin's Slave Camps: An Indictment of Modern Slavery. Brussels: International Confederation of Free Trade Unions, 1951. 104, <1> pp. Pamphlet O75 .S7 1951p.
Osborne, James B. The Truth About Socialism: An Analysis of the Philosophy Enunciated in the Declaration of American Independence, as Compared with the Philosophy of Social Democracy. Oakland, Calif.: International Press, 1912. 31 pp. Pamphlet O81 .T7 1912p. PDF
Out of Their Own Mouths: A Documentary Study of the New Line of the Comintern on War. New York: Young People's Socialist League, Greater New York Federation, <1936?> 39 pp. Pamphlet O94 .O9 1936p.
Overseas Socialist Hostels Society. British and Overseas Socialists Unite in This Appeal for Funds to Establish Residential Centres for Overseas Comrades Temporarily Resident in the United Kingdom. London: Overseas Socialist Hostels Society, <1957>. 4 pp. Pamphlet O96.3 .B7 1957p.
---. International Socialist Hostel Appeal. <London: Overseas Socialist Hostels Society, 1957?> 1 folded sheet (4 pp.) Pamphlet O96.3 .I5 1957p.
Overstreet, H. A., (Harry Allen). What We Must Know About Communism. New York: Alumni Publications, 1959. 14 pp. Pamphlet O96 .W5 1959p.
Owen, David Elystan. Social Services for All? Part Four. Fabian Tract; 385. London: Fabian Society, 1968. 122 pp. Pamphlet O97 .S6 1968p.


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Yukihiro Masuda, President of WiLLiFE organizes a "Tree Planting Tour" to Mongolia every year. Normally, various people from the Tri-Wall Group participate in the tour, but this year, due to schedule conflicts, only Masuda-san and Himematsu-san, a funeral service consultant, went to Selenge Province to plant trees and to check the condition of trees planted in past years. Due to forest fires and other natural phenomenon, seedling survival is only 50%. Realizing that, Masuda-san admitted, "To be honest, I was a little scared to see the site where we had planted. However, when I saw the greens in the field, spontaneously I made a wish to each tree. Please grow bigger and bigger and become a forest for saving our earth…"
Believing in continuance and habit can deliver results, Masuda-san says, "It would be great if we can continue these activities with the support of the Tri-Wall Group for years to come and leave this forest to future generations."


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This series is inspired by the Northern Lights only visible a handful of nights in Northern Minnesota each year. The hand-blown top is made from Pyrex glass making it extremely durable and the bottle stopper is made from high-grade stainless steel. This means that they will not corrode like cheap, chrome-based stoppers when exposed to acidic red wine.
*Please note that while we do our best to create a cohesive series, not every piece will be identical as it is all handmade and subject to variations.
~1" wide x 4" long
Three lampworked glass beads in various color combinations are suspended from a handmade sterling silver square. A sterling silver snake chain runs through the square. The pendant from the top of...
The Anchor Pendant is an iconic symbol of the boating lifestyle. This pendant makes the perfect gift for those who long for the open waters of Lake Superior and beyond. *Please note...
Dan Neff uses dichroic images to create the shimmering vision of calendars long forgotten on these glittering paper weights.


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21 Jul 2015
Merino for the Sun -Reason 5 Travel Light
Whether you are going on holiday, having a day out with the family or hiking with a back pack, space comes at a premium. This is where Merino wool comes in handy.
Merino garments will not need washing every day, even after a day of hard activities. Merino wool naturally contains Lanolin which has antibacterial properties and stops any odour, keeping your Merino garments fresher for longer.
From our other posts, you will also see how efficient Merino is at regulating your temperature, keeping you cool when you are active and warm during rest periods.
You will therefore need to pack less clothing which is especially great if travelling on budget airlines or if you need to fit everything in to a back pack.
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Hello, I have started making a more romantic style of earring, this is just a taster of a few photos that I have taken (that have been converted from RAW files, this take me a little while when sorting out my jewellery photos!)
Sets of four stud earrings come complete in a gift box and the long dangle earrings feature vintage glass drop beads. I have some of these dangle earrings in lovely bright Frida Kahlo style colours! I'll keep you posted to when these appear on Etsy!


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Alisa's Wish is a program of Community Services
Community Services is a reputable, strong, multi-service non-profit organization with over 40 years of experience in the social service sector. Community Services is accredited through the Council of Accreditation and offers a wide variety of programs.
These include: Victim Services, Community Law Services, Aboriginal Services, Clinical Counselling, Child and Youth Mental Health, Family Strengthening Services, Outreach Services to Children, Youth and Families, Out of Care Options, Community Living Services for Children, Youth and Families, Youth and Family Confliction Intervention Services and Volunteer Centre with over 60 member organizations.
Alisa's Wish is a Community Initiative
Our Multi-Disciplinary Team
Ministry of Children and Family Development
Community Based Victim Services
ACT 2 Child and Family Services
Cythera Transition House Society
School District 42 Safe and Caring Schools
School District 42 Aboriginal Education
For many years, Maple Ridge and Pitt Meadows RCMP, Ministry of Children and Family Development and Community Service Organizations helped children, youth, and supporting families who were victims of abuse. They knew there had to be a better way.
These community leaders had a vision – bringing help to the victims and supporting families 'under one roof' with Alisa's Wish Child and Youth Advocacy Centre. This would:
- Improve the chances of successfully convicting abusers using quality interviews from The Centre
- Speed up the access and understanding of support services to victims by having the Child and Youth Counsellor explain and help navigate the system with the victims
- Improve chances of healing in a healthy way by having the Child and Youth Counsellor work with the victims as soon as they walk through The Centre's doors and staying with them through their healing journey