text:
ADA Standards of Medical Care in Diabetes
Submit Cover Art
Exercise and Myocyte Enhancer Factor 2 Regulation in Human Skeletal Muscle
Sean L. McGee and
Mark Hargreaves
From the Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Australia
Address correspondence to Prof. Mark Hargreaves, School of Exercise and Nutrition Sciences, Deakin University, 221 Burwood Hwy., Burwood VIC 3125, Australia. E-mail: mharg{at}deakin.edu.au
Diabetes 2004 May; 53(5): 1208-1214. https://doi.org/10.2337/diabetes.53.5.1208
Overexpression of GLUT4 in skeletal muscle enhances whole-body insulin action. Exercise increases GLUT4 gene and protein expression, and a binding site for the myocyte enhancer factor 2 (MEF-2) is required on the GLUT4 promoter for this response. However, the molecular mechanisms involved remain elusive. In various cell systems, MEF-2 regulation is a balance between transcriptional repression by histone deacetylases (HDACs) and transcriptional activation by the nuclear factor of activated T-cells (NFAT), peroxisome proliferator-activated receptor-γ coactivator 1 (PGC-1), and the p38 mitogen-activated protein kinase. The purpose of this study was to determine if these same mechanisms regulate MEF-2 in contracting human skeletal muscle. Seven subjects performed 60 min of cycling at ∼70% of Vo2peak. After exercise, HDAC5 was dissociated from MEF-2 and exported from the nucleus, whereas nuclear PGC-1 was associated with MEF-2. Exercise increased total and nuclear p38 phosphorylation and association with MEF-2, without changes in total or nuclear p38 protein abundance. This result was associated with p38 sequence-specific phosphorylation of MEF-2 and an increase in GLUT4 mRNA. Finally, we found no role for NFAT in MEF-2 regulation. From these data, it appears that HDAC5, PGC-1, and p38 regulate MEF-2 and could be potential targets for modulating GLUT4 expression.
AMPK, AMP kinase
CaMK, calcium/calmodulin-dependent protein kinase
HAT, histone acetyltransferase
HDAC, histone deacetylase
MAPK, mitogen-activated protein kinase
MEF-2, myocyte enhancer factor 2
MKK, MAPK kinase
NFAT, nuclear factor of activated T-cells
PGC-1, peroxisome proliferator-activated receptor-γ coactivator 1
Skeletal muscle glucose transport is primarily mediated by the transmembrane glucose transporter GLUT4. The importance of this protein in maintaining glucose homeostasis is highlighted by studies disrupting skeletal muscle GLUT4, which results in severe insulin resistance and glucose intolerance (1). Furthermore, selective overexpression of GLUT4 in skeletal muscle improves whole-body insulin action and glucose homeostasis (2,3). As such, regulation of GLUT4 expression is seen as a potential therapeutic target for the management and treatment of insulin resistance in disorders such as type 2 diabetes. An acute bout of exercise increases GLUT4 transcription (4) and gene (5) and protein expression (6). A binding region on the GLUT4 promoter for the myocyte enhancer factor 2 (MEF-2) transcription factor is required for this response (7). Whereas stimuli such as increases in intracellular calcium and decreases in cellular energy balance have been implicated in the exercise-induced increase in GLUT4 (8), the molecular mechanisms regulating MEF-2 are unknown. In the basal state, DNA-bound MEF-2 is thought to be associated with, and inhibited by, the class II histone deacetylases (HDACs) (9). HDACs repress transcriptional activity by deacetylating the NH2-terminal tails of histone proteins, resulting in chromatin condensation, which tightens the electrostatic interactions between the positively charged histone tails and negatively charged DNA backbone. The tightened, condensed histones prevent transcriptional coactivators from accessing their respective DNA binding regions and other transcriptional activators, such as MEF-2, thereby repressing gene transcription. The association between HDACs and MEF-2 appears to be broken by the calcium/calmodulin-dependent protein kinase (CaMK)-IV. Multiple serine residues on the HDACs are phosphorylated by CaMK-IV, which provides a binding site for the intracellular chaperone 14-3-3 and also masks a nuclear localization sequence (10). This results in the nuclear export of the HDAC and 14-3-3. To reverse the acetylation state of the surrounding histones, coactivators possessing histone acetyltransferase (HAT) activity must associate with MEF-2 (9). It is unclear if this is mediated by the calcineurin/nuclear factor of activated T-cells (NFAT) pathway or the peroxisome proliferator-activated receptor-γ coactivator 1 (PGC-1) pathway. Calcineurin dephosphorylates serine residues on the NFAT NH2-terminus, unmasking two nuclear localization sequences, which results in NFAT nuclear translocation (11). Nuclear NFAT interacts with and recruits coactivators possessing intrinsic HAT activity to MEF-2, allowing MEF-2 dimerization and association with transcriptional coactivators such as MyoD (9). PGC-1 has been implicated in the expression of GLUT4 (12) and functions like NFAT in that it recruits coactivators with HAT activity to various transcription factors, including MEF-2 (13). Although MEF-2 dimerization and association with cofactors is sufficient to initiate MEF-2-mediated transcription, the rate of transcription dramatically increases after MEF-2 phosphorylation on its transcriptional activation domain, found toward the COOH-terminus (9). The p38 mitogen-activated protein kinase (MAPK) has been found to associate with and phosphorylate MEF-2 on various threonine residues in this domain, resulting in enhanced transcriptional activity (14). Although many studies have observed these individual mechanisms in a variety of cell systems, it is unclear if these same mechanisms occur in contracting human skeletal muscle to regulate MEF-2 and ultimately control GLUT4 expression. The aim of this study was to determine if HDAC5, CaMK-IV, NFAT, PGC-1, and p38 MAPK were involved in the regulation of MEF-2 in human skeletal muscle during exercise.
Seven male subjects (aged 27 ± 3 years, 83 ± 4 kg, Vo2peak 47 ± 2 ml · kg −1 · min−1) were recruited for the study after completing a medical questionnaire and giving their informed written consent. All experimental procedures were approved by the Deakin University Human Research Ethics Committee. At least 7 days before the experimental trial, all subjects performed an incremental cycling test (Lode, Groningen, the Netherlands) to fatigue to determine peak pulmonary oxygen uptake. This test was also used to select the power output for the experimental trial from the linear relationship between oxygen uptake and power output.
Subjects performed a single bout of cycling for 60 min at 74 ± 2% of Vo2peak after a 12-h overnight fast. Expired air was collected twice, between 15 and 20 min and 40 and 45 min to ensure that subjects were exercising at the expected exercise intensity.
Muscle biopsies.
Muscle samples were obtained from the vastus lateralis before and immediately after exercise using the percutaneous needle biopsy technique with suction (15). Muscle samples were immediately frozen in liquid nitrogen and stored for later analysis.
Protein extraction.
Nuclear proteins were isolated as previously described (16). For whole muscle proteins, ∼15 mg muscle were homogenized in 10 volumes of homogenization buffer (25 mmol/l Tris, pH 6.8, 1% Triton X-100, 5 mmol/l EGTA, 50 mmol/l NaF, 1 mmol/l Na orthovanidate, 10% glycerol, 1% phenylmethylsulfonyl fluoride, 10 μg/ml leupeptin, and 10 μg/ml aprotinin) for ∼30 s on ice. The homogenate was then spun in a centrifuge for 5 min at 1,000g at 4°C. The supernatant was extracted and stored for later analysis. Protein concentration was determined using the BCA method.
Co-immunoprecipitation.
Nuclear protein (500 μg) was made up to 500 μl in immunoprecipitation wash buffer (50 mmol/l Tris, pH 7.5, 1 mmol/l EDTA, 1 mmol/l EGTA, 10% glycerol, 1% Triton X-100, 50 mmol/l NaF, 5 mmol/l Na pyrophosphate, 1 mmol/l dithiothreitol, and 1 mmol/l phenylmethylsulfonyl fluoride). Samples were precleared with 50 μl protein A Sepharose beads (Amersham Biosciences, Castle Hill, Australia) before being incubated with 2 μl anti-MEF-2 (Santa Cruz Biotechnology, Santa Cruz, CA) antibody overnight at 4°C. Samples were again incubated with 50 μl protein A Sepharose beads for 2 h, while rotating at 4°C. The Sepharose-bound immune complex was pelleted by centrifugation and washed four times with 1 ml immunoprecipitation wash buffer. Immune complexes were then resolved by SDS-PAGE, and the amounts of HDAC5, PGC-1, p38, and phospho-p38 present in the complex were determined by probing with antibodies directed toward those proteins. MEF-2 threonine phosphorylation was analyzed by immunoprecipitating MEF-2 from 100 μg nuclear protein and probing with a threonine-proline phosphospecific antibody (Cell Signaling Technology, Beverly, MA). A control lane of beads only was included on all gels to ensure that the signals observed were specific to the immune complex and not the beads themselves. Membranes were reprobed with the MEF-2 antibody to ensure that equal amounts of MEF-2 protein had been pulled down.
Immunoblotting.
Proteins were separated and identified using SDS-PAGE. A total of 30 μg protein from the whole-cell homogenate and 50 μg nuclear protein from each sample were loaded onto 1.5-mm 8% acrylamide gels before undergoing electrophoresis for 75 min at 150 V. Proteins were wet transferred to a nitrocellulose membrane for 100 min at 100 V. Membranes were blocked for 1 h in blocking buffer (5% skim milk powder in Tris-buffered saline and 0.25% Tween) and exposed overnight, at 4°C, to primary antibodies for HDAC5 (Cell Signaling Technology), NFAT (Santa Cruz Biotechnology), PGC-1 (Chemicon, Temecula, CA), p38, and phospho-p38 (Cell Signaling Technology). Membranes were exposed to appropriate anti-species horseradish peroxidase-conjugated secondary antibodies at a concentration of 1 in 10,000 in blocking buffer for 60 min at room temperature. Antibody binding was viewed by incubating in enhanced chemiluminescence substrate (Pierce SuperSignal Chemiluminescent; Pierce Biotechnology, Rockford, IL) and exposing to a Kodak Image Station 440CF (NEN Life Science Products, Boston, MA). Bands were identified and quantified using Kodak 1D Image Analysis Software (Eastman Kodak, Rochester, NY).
Real-time RT-PCR.
Total RNA was extracted from ∼10 mg muscle using the acid guanidium thiocyanate-phenol-chloroform extraction technique with modifications (FastRNA Kit-Green; Qbiogene, Carlsbad, CA). Oligo dT single-stranded cDNA was synthesized using an AMV Reverse Transcriptase Kit (Promega A3500; Promega, Madison, WI). Forward and reverse primers complementary to the human GLUT4 gene (GenBank NM 001042) were designed using Primer Express software (Applied Biosystems, Foster City, CA). The GLUT4 forward primer sequence (5′ to 3′) was CTT CAT CAT TGG CAT GGG TTT, whereas the reverse primer sequence was AGG ACC GCA AAT AGA AGG AAG A. Real-time RT-PCR was performed using the GeneAmp 5700 sequence detector and software (Applied Biosystems, Scoresby, Australia). Changes in GLUT4 gene expression were normalized to the housekeeping gene cyclophilin.
Statistical analysis.
All data are means ± SE, with resting samples assigned the arbitrary value of 1.0 and postexercise samples expressed relative to rest. Resting and postexercise means were compared using a t test with a significance level of 0.05.
GLUT4 mRNA.
After exercise, GLUT4 mRNA was increased 2.1-fold (P < 0.05) when expressed as a ratio to the housekeeping gene cyclophilin. Cyclophilin mRNA expression did not change with exercise (data not shown).
HDAC5 association with MEF-2 and HDAC5 subcellular localization.
HDAC5 association with MEF-2 decreased 26% (P < 0.05) after exercise (Fig. 1). This was associated with a 54% decrease (P < 0.05) in nuclear HDAC5 after exercise (Fig. 1), whereas there was no change in total HDAC5 protein content (Fig. 1).
Nuclear CaMK-IV and CaMK-II.
While HDAC5 association with MEF-2 decreased after exercise and was associated with HDAC5 nuclear export, CaMK-IV was not detected in the nuclear fraction at either rest or after exercise (data not shown). Furthermore, the CaMK-IV detected in whole muscle homogenates was negligible (data not shown). Because we have recently found that CaMK-II activity is increased in contracting human skeletal muscle (17), we hypothesized that CaMK-II could possibly target nuclear HDACs. However, no CaMK-II was discovered in the nuclear fraction at either rest or after exercise (data not shown).
Nuclear NFAT.
Nuclear NFAT content after exercise was similar to resting levels (rest, 50.7 ± 6.3 vs. 60 min, 51.1 ± 4.6 arbitrary units).
PGC-1 association with MEF-2 and PGC-1 subcellular localization.
Exercise increased PGC-1 association with MEF-2 by 3.7-fold (P < 0.05; Fig. 2). However, exercise had no effect on total or nuclear PGC-1 abundance (Fig. 2).
p38 MAPK and phosphorylated p38 MAPK association with MEF-2 and subcellular localization.
Total muscle p38 phosphorylation increased 4.8-fold (P < 0.05) and nuclear p38 phosphorylation increased 1.8-fold (P < 0.05) after exercise. However, there was no change in the abundance of total or nuclear p38 protein (Fig. 3). Association of p38 protein with MEF-2 increased 2.7-fold (P < 0.05) after exercise, whereas association of phosphorylated p38 with MEF-2 increased 1.8-fold (P < 0.05; Fig. 4).
MEF-2 threonine-proline phosphorylation.
MEF-2 threonine-proline phosphorylation increased 2.7-fold (P < 0.05; Fig. 5) after exercise.
The initial step in the upregulation of MEF-2-mediated gene expression, including potentially that of GLUT4, is the dissociation of the class II HDACs from MEF-2 (9). It was found that HDAC5 association with MEF-2 significantly decreased 24% after exercise, suggesting that HDAC5 does regulate MEF-2 in human skeletal muscle and is sensitive to exercise. Also observed was a 54% decrease in nuclear HDAC5 protein, whereas there was no change in total HDAC5 protein, suggesting that HDAC5 was exported from the nucleus. Although the assays used to generate these data are semiquantitative and nonstoichiometric, it does appear that more HDAC5 was exported from the nucleus than was dissociated from MEF-2. This could imply that HDAC5 regulates other exercise-responsive transcription factors in addition to MEF-2 and that HDAC5 could be an integral component in the molecular mechanisms leading to adaptations in response to exercise, such as enhanced muscle oxidative capacity and insulin sensitivity. Various studies have found that all of the class II HDACs (4, 5, 7, and 9) dissociate from MEF-2 and are exported from the nucleus in response to a variety of stimuli (18–20). This could imply that HDAC4, -5, -7, and -9 might all be responsive to exercise. Despite exercise dissociating HDAC5 from MEF-2 and inducing HDAC5 nuclear export, CaMK-IV was not detected in the nuclear fraction of human skeletal muscle either at rest or after exercise. Although various studies have suggested a direct role for CaMK-IV in phosphorylating HDAC5 and thereby causing dissociation from MEF-2 (10,19,21), it seems likely that other kinases with substrate specificities similar to CaMK-IV are able to phosphorylate HDAC5. This is supported by experiments using specific inhibitors of a variety of different kinases that have failed to block the phosphorylation of the class II HDACs in an in vitro kinase assay (22). Under these conditions, a broad specificity kinase inhibitor is needed to antagonize HDAC phosphorylation. Whereas CaMK-I has also been identified as a kinase capable of phosphorylating HDAC5 (19), there is little evidence to suggest that CaMK-I is present in human skeletal muscle. We have recently found that CaMK-II activity increases during exercise in human skeletal muscle (17). It has also been suggested that CaMK-II can phosphorylate cytosolic HDAC5 in neurons (23). However, no CaMK-II was detected in the nuclear fraction either at rest or after exercise, suggesting that CaMK-II was not responsible for the exercise-induced dissociation of HDAC5 from MEF-2 and subsequent HDAC5 nuclear export. A potential HDAC5 kinase could be AMP kinase (AMPK), which has also been implicated in the expression of the GLUT4 gene (24) and shares similar substrate specificity to the CaMKs. Furthermore, we have found that AMPK translocates to the nucleus in response to the same exercise protocol used in this study (16). Identification of the kinases involved in phosphorylating HDAC5 during exercise will be important in linking the molecular events regulating MEF-2 and the GLUT4 gene to a specific cellular stimulus generated during exercise, such as changes in energy balance or intracellular calcium (8).
Both the calcineurin/NFAT pathway (25) and PGC-1 pathway (26) have been implicated in the regulation of the GLUT4 gene through recruitment of transcriptional coactivators possessing HAT activity to MEF-2. The critical regulatory step in the calcineurin pathway is the dephosphorylation and subsequent nuclear translocation of NFAT. Using an antibody specific for NFATc1 (NFAT2), the most abundant NFAT isoform in skeletal muscle (11), we found no nuclear translocation of NFAT after exercise. From these data, it appears that calcineurin does not regulate MEF-2 in humans during acute exercise. However, studies in mice have linked the calcineurin/NFAT pathway to MEF-2 activation in response to prolonged periods of contraction (27), and overexpression of constitutively active calcineurin results in many of the adaptations seen with exercise training (28), suggesting that calcineurin/NFAT might be more sensitive to prolonged exercise stimuli. It is also possible that an NFAT isoform other than NFATc1 could mediate effects of exercise on MEF-2. However, there is evidence that many signaling pathways activated during acute exercise are antagonistic to the calcineurin pathway, possibly supporting the data from the present study. Evidence exists that the p38 MAPK pathway is able to phosphorylate NFAT, retaining it to an extranuclear localization (29). Although the phosphorylation status of NFAT was not examined in the present study, p38 phosphorylation increased 4.8-fold after exercise. It has also been found that AMPK, which is activated during exercise of intensities >60% Vo2peak (30), is able to antagonize transcriptional coactivators that are downstream of NFAT (31). Thus, although it seems that chronic or prolonged exercise is associated with changes in gene expression due to calcineurin activation, there is mounting evidence that the calcineurin pathway does not influence gene expression during acute exercise. Somewhat supporting this is evidence that NFAT is present in the nucleus only in response to prolonged low-amplitude calcium transients and is insensitive to high-amplitude transients (32). Although calcineurin has been implicated in changes in gene expression associated with fiber-type transformations with exercise (33), it seems likely that this occurs in the postexercise period. This makes evolutionary sense in that fiber-type transitions are not an immediate priority during exercise, as opposed to expression of exercise-responsive genes such as GLUT4, which could be critical to cell survival during exercise and in the immediate postexercise period. Although calcineurin could influence GLUT4 expression by switching fiber type from a fast to slow phenotype, because GLUT4 is more abundantly expressed in type 1 fibers (34), it appears that calcineurin may not be involved in the acute regulation of GLUT4 with exercise.
In contrast, we found that PGC-1 association with MEF-2 increased 3.7-fold after exercise, suggesting that it is PGC-1, rather than NFAT, that is responsible for recruiting coactivators with HAT activity to MEF-2 during exercise. Because we found no change in total or nuclear PGC-1 abundance, it seems that it is endogenous nuclear PGC-1 that is recruited to MEF-2. Once bound to a transcription factor, PGC-1 undergoes a conformational change that allows recruitment and binding of transcriptional coactivators (35). Although the localization of NFAT appears to be critical for its activity, the activity of PGC-1 appears to be regulated through association with a repressor (36,37). This association and the repression of PGC-1 appears to be broken by p38 MAPK (36,37). Although this was not assessed in this study, we did find that nuclear p38 phosphorylation increased 1.8-fold after exercise. It is thought that PGC-1 is primarily recruited to the MEF-2 isoforms C and D (38), whereas GLUT4 expression is primarily mediated by MEF-2A (39). Although this discrepancy could suggest that PGC-1 is not functionally involved in GLUT4 expression, it has been found that MEF-2A is required to form a heterodimer with MEF-2D to drive GLUT4 expression (39,40). The function of the MEF-2A/D heterodimer has not been established, but it is possible that the role of MEF-2D is to recruit transcriptional coactivators such as PGC-1 to MEF-2A. Supporting a role for PGC-1 in GLUT4 expression are data showing that overexpression of PGC-1 in GLUT4-deficient L6 myotubes restores GLUT4 mRNA levels to those observed in vivo (12). However, a recent study overexpressing PGC-1 in the skeletal muscle of mice found a downregulation of GLUT4 mRNA (41). Although these conflicting results are confounded by the different methods used in each study, the functional significance of PGC-1 binding to MEF-2 in contracting human skeletal muscle remains to be determined. Recent studies have found that PGC-1 transcription, mRNA, and protein are elevated after an acute bout of exercise (26,42). Whereas the recruitment of PGC-1 to transcription factors could determine PGC-1 function during exercise, the increase in PGC-1 after exercise could be important for postexercise adaptations such as mitochondrial biogenesis.
In the present study, total muscle p38 phosphorylation increased after exercise. This was associated with no change in total p38 protein. These findings are consistent with previous research (43). However, for the first time, we have demonstrated an increase in nuclear p38 phosphorylation after exercise. This was associated with no significant change in nuclear p38 protein, suggesting that the increase in nuclear p38 phosphorylation was largely due to phosphorylation of the endogenous nuclear p38 protein. Although not examined in this study, there are many kinases upstream that are capable of phosphorylating p38. The MAPK kinases (MKK)3, -4, and -6 are able to phosphorylate p38 (43), and it has also been observed that AMPK is upstream of p38 (44). It is unclear which, if any, of these kinases are responsible for the increase in nuclear p38 phosphorylation seen in the present study. We also observed that MEF-2-associated p38 and phosphorylated p38 increased after exercise. It is recognized that a distinct MEF-2A binding region on p38 exists and is required for p38 phosphorylation of MEF-2 (45). This study also found a binding domain for MKK3, indicating that MEF-2A, p38, and MKK3 can exist in a complex, possibly suggesting that it is MKK3 that is phosphorylating MEF-2-associated p38. Once associated, p38 can phosphorylate MEF-2A on its transcriptional activation domain on threonines 312 and 319 (14). As both of these threonine residues are followed by a proline residue, we immunoprecipitated MEF-2 from the nuclear fraction and probed with an antibody that only recognizes phosphorylated threonine residues that are followed by proline residues. Using this method, MEF-2 phosphorylation was found to increase 2.7-fold. Phosphorylation of MEF-2 on these residues is associated with an increase in MEF-2-mediated transcription (14), thus providing a functional link between p38 and MEF-2 regulation. This also suggests a potential role for p38 MAPK in the regulation of the GLUT4 gene.
Although many aspects of MEF-2 regulation were observed in this study, it was also found that GLUT4 mRNA was increased 2.1-fold after exercise, suggesting an increase in MEF-2 transcriptional activity. It is unclear if the dissociation of repressors, association of coactivators, and phosphorylation of MEF-2 are all required for enhanced MEF-2 transcriptional activity or whether each of these events are additive in nature. It is also unclear if regulation of MEF-2 through these mechanisms would increase MEF-2 DNA binding activity. Although increased MEF-2 DNA binding has been observed in humans after a marathon (46), studies investigating the class II HDACs found that the HDACs do not interfere with MEF-2 DNA binding, despite interacting with the DNA-binding MADS (MCMI, agamous, deficiens serum response factor) and MEF-2 domains of the MEF-2 proteins (10,47). Instead, these studies found that the HDACs repress MEF-2 transcriptional activity by inhibiting MEF-2 dimerization and associations with transcriptional coactivators. This could suggest that MEF-2 is DNA bound in the basal state. Furthermore, Wu and Olson (48) found that p38 activation is associated with enhanced MEF-2 transcriptional activity, without changes in MEF-2 DNA-binding activity. Additionally, others imply that MEF-2 DNA binding is a function of the abundance of the MEF-2 protein (7). In this study, we found that there was no change in the nuclear abundance of MEF-2 after exercise (data not shown). We have also conducted preliminary MEF-2 mobility shift assays on resting and exercised human skeletal muscle from this study and have been unable to detect differences in MEF-2 DNA binding. Whether this is a reflection of MEF-2 DNA binding in vivo or an issue with the sensitivity of the assay in our hands remains to be determined.
In conclusion, the results from the present study demonstrate that HDAC5, PGC-1, and p38 MAPK could regulate MEF-2 in response to exercise in human skeletal muscle, whereas we found no role for CaMK-IV, CaMK-II, and NFAT. These mechanisms could also regulate the expression of GLUT4 and other metabolic genes and might be therapeutic targets for the treatment and management of insulin resistance and type 2 diabetes.
A: Total and nuclear HDAC5 protein in response to exercise. B: MEF-2-associated HDAC5 in response to exercise. All values are calculated as the fold changes relative to rest and are reported as the means ± SE (n = 7). Significantly different from rest: *P = 0.006 and #P = 0.009. IB, immunoblot; IP, immunoprecipitate.
A: Total and nuclear PGC-1 protein in response to exercise. B: MEF-2-associated PGC-1 in response to exercise. All values are calculated as the fold changes relative to rest and are reported as the means ± SE (total n = 7; nuclear n = 6). Significantly different from rest: *P = 0.041. IB, immunoblot; IP, immunoprecipitate.
Total and nuclear p38 and phosphorylated p38 (p-p38) in response to exercise. All values are calculated as the fold changes relative to rest and are reported as the means ± SE (n = 7). Significantly different from rest: *P = 0.016 and #P = 0.013.
MEF-2-associated p38 and phosphorylated p38 (p-p38) in response to exercise. All values are calculated as the fold changes relative to rest and are reported as the means ± SE (n = 7). Significantly different from rest: *P = 0.032 and #P = 0.035. IB, immunoblot; IP, immunoprecipitate.
MEF-2 threonine-proline phosphorylation in response to exercise. All values are calculated as the fold changes relative to rest and are reported as the mean ± SE (n = 7). Significantly different from rest: *P = 0.039. IB, immunoblot; IP, immunoprecipitate.
We thank Laura Cluberton, Dr. Andrew Garnham, and Nick Kimber for their assistance during this study and Dr. Kirsten Howlett for technical advice on the coimmunoprecipitation techniques.
Accepted February 2, 2004.
Received October 9, 2003.
Zisman A, Peroni OD, Abel ED, Michael MD, Mauvais-Jarvis F, Lowell BB, Wojtaszewski JF, Hirshman MF, Virkamaki A, Goodyear LJ, Kahn CR, Kahn BB: Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med6 :924 –928,2000
Tsao TS, Burcelin R, Katz EB, Huang L, Charron MJ: Enhanced insulin action due to targeted GLUT4 overexpression exclusively in muscle. Diabetes45 :28 –36,1996
Leturque A, Loizeau M, Vaulont S, Salminen M, Girard J: Improvement of insulin action in diabetic transgenic mice selectively overexpressing GLUT4 in skeletal muscle. Diabetes45 :23 –27,1996
Neufer PD, Dohm GL: Exercise induces a transient increase in transcription of the GLUT-4 gene in skeletal muscle. Am J Physiol265 :C1597 –C1603,1993
Kraniou Y, Cameron-Smith D, Misso M, Collier G, Hargreaves M: Effects of exercise on GLUT-4 and glycogenin gene expression in human skeletal muscle. J Appl Physiol88 :794 –796,2000
Greiwe JS, Holloszy JO, Semenkovich CF: Exercise induces lipoprotein lipase and GLUT-4 protein in muscle independent of adrenergic-receptor signaling. J Appl Physiol89 :176 –181,2000
Thai MV, Guruswamy S, Cao KT, Pessin JE, Olson AL: Myocyte enhancer factor 2 (MEF2)-binding site is required for GLUT4 gene expression in transgenic mice: regulation of MEF2 DNA binding activity in insulin-deficient diabetes. J Biol Chem273 :14285 –14292,1998
Ojuka EO, Jones TE, Nolte LA, Chen M, Wamhoff BR, Sturek M, Holloszy JO: Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca(2+). Am J Physiol Endocrinol Metab282 :E1008 –E1013,2002
McKinsey TA, Zhang CL, Olson EN: MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem Sci27 :40 –47,2002
McKinsey TA, Zhang CL, Olson EN: Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5. Proc Natl Acad Sci U S A97 :14400 –14405,2000
Olson EN, Williams RS: Remodeling muscles with calcineurin. Bioessays22 :510 –519,2000
Michael LF, Wu Z, Cheatham RB, Puigserver P, Adelmant G, Lehman JJ, Kelly DP, Spiegelman BM: Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc Natl Acad Sci U S A98 :3820 –3825,2001
Scarpulla RC: Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochim Biophys Acta1576 :1 –14,2002
Zhao M, New L, Kravchenko VV, Kato Y, Gram H, di Padova F, Olson EN, Ulevitch RJ, Han J: Regulation of the MEF2 family of transcription factors by p38. Mol Cell Biol19 :21 –30,1999
Evans W, Phinney S, Young V: Suction applied to a muscle biopsy maximises sample size. Med Sci Sports Exer14 :101 –102,1986
McGee SL, Howlett KF, Starkie RL, Cameron-Smith D, Kemp BE, Hargreaves M: Exercise increases nuclear AMPK α2 in human skeletal muscle. Diabetes52 :926 –928,2003
Rose AJ, Hargreaves M: Exercise increases Ca2+-calmodulin-dependent protein kinase II activity in human skeletal muscle. J Physiol553 :303 –309,2003
Zhang CL, McKinsey TA, Olson EN: The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis. Proc Natl Acad Sci U S A98 :7354 –7359,2001
McKinsey T, Zhang C, Olson E: Signal-dependent nuclear export of a histone deactylase regulates muscle differentiation. Nature408 :106 –111,2000
Dressel U, Bailey PJ, Wang SC, Downes M, Evans RM, Muscat GE: A dynamic role for HDAC7 in MEF2-mediated muscle differentiation. J Biol Chem276 :17007 –17013,2001
McKinsey TA, Zhang CL, Olson EN: Identification of a signal-responsive nuclear export sequence in class II histone deacetylases. Mol Cell Biol21 :6312 –6321,2001
McKinsey TA, Zhang CL, Olson EN: Signaling chromatin to make muscle. Curr Opin Cell Biol14 :763 –772,2002
Linseman DA, Bartley CM, Le SS, Laessig TA, Bouchard RJ, Meintzer MK, Li M, Heidenreich KA: Inactivation of the myocyte enhancer factor-2 repressor histone deacetylase-5 by endogenous Ca2+/calmodulin-dependent kinase II promotes depolarization-mediated cerebellar granule neuron survival. J Biol Chem278 :41472 –41481,2003
Zheng D, MacLean PS, Pohnert SC, Knight JB, Olson AL, Winder WW, Dohm GL: Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase. J Appl Physiol91 :1073 –1083,2001
MacLean PS, Zheng D, Dohm GL: Muscle glucose transporter (GLUT 4) gene expression during exercise. Exerc Sport Sci Rev28 :148 –152,2000
Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, Kelly DP, Holloszy JO: Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J16 :1879 –1886,2002
Wu H, Rothermel B, Kanatous S, Rosenberg P, Naya FJ, Shelton JM, Hutcheson KA, DiMaio JM, Olson EN, Bassel-Duby R, Williams RS: Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway. EMBO J20 :6414 –6423,2001
Ryder JW, Bassel-Duby R, Olson EN, Zierath JR: Skeletal muscle reprogramming by activation of calcineurin improves insulin action on metabolic pathways. J Biol Chem278 :44298 –44304,2003
Braz JC, Bueno OF, Liang Q, Wilkins BJ, Dai YS, Parsons S, Braunwart J, Glascock BJ, Klevitsky R, Kimball TF, Hewett TE, Molkentin JD: Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. J Clin Invest111 :1475 –1486,2003
Chen ZP, Stephens TJ, Murthy S, Canny BJ, Hargreaves M, Witters LA, Kemp BE, McConell GK: Effect of exercise intensity on skeletal muscle AMPK signaling in humans. Diabetes52 :2205 –2212,2003
Yang W, Hong YH, Shen XQ, Frankowski C, Camp HS, Leff T: Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors. J Biol Chem276 :38341 –38344,2001
Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI: Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature386 :855 –858,1997
Kubis HP, Hanke N, Scheibe RJ, Meissner JD, Gros G: Ca2+-transients activate calcineurin/NFATc1 and initiate fast-to-slow transformation in a primary skeletal muscle culture. Am J Physiol Cell Physiol285 :C56 –C63,2003
Daugaard J, Nielsen J, Kristiansen S, Andersen J, Hargreaves M, Richter E: Fiber type-specific expression of GLUT4 in human skeletal muscle. Diabetes49 :1092 –1095,2000
Puigserver P, Adelmant G, Wu Z, Fan M, Xu J, O'Malley B, Spiegelman BM: Activation of PPARgamma coactivator-1 through transcription factor docking. Science286 :1368 –1371,1999
Ichida M, Nemoto S, Finkel T: Identification of a specific molecular repressor of the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha). J Biol Chem277 :50991 –50995,2002
Knutti D, Kressler D, Kralli A: Regulation of the transcriptional coactivator PGC-1 via MAPK-sensitive interaction with a repressor. Proc Natl Acad Sci U S A98 :9713 –9718,2001
Handschin C, Rhee J, Lin J, Tarr PT, Spiegelman BM: An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle. Proc Natl Acad Sci U S A100 :7111 –7116,2003
Mora S, Pessin JE: The MEF2A isoform is required for striated muscle-specific expression of the insulin-responsive GLUT4 glucose transporter. J Biol Chem275 :16323 –16328,2000
Santalucia T, Moreno H, Palacin M, Yacoub MH, Brand NJ, Zorzano A: A novel functional co-operation between MyoD, MEF2 and TRalpha1 is sufficient for the induction of GLUT4 gene transcription. J Mol Biol314 :195 –204,2001
Miura S, Kai Y, Ono M, Ezaki O: Overexpression of peroxisome proliferator-activated receptor gamma coactivator-1alpha down-regulates GLUT4 mRNA in skeletal muscles. J Biol Chem278 :31385 –31390,2003
Pilegaard H, Saltin B, Neufer PD: Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol546 :851 –858,2003
Widegren U, Ryder JW, Zierath JR: Mitogen-activated protein kinase signal transduction in skeletal muscle: effects of exercise and muscle contraction. Acta Physiol Scand172 :227 –238,2001
Xi X, Han J, Zhang JZ: Stimulation of glucose transport by AMP-activated protein kinase via activation of p38 mitogen-activated protein kinase. J Biol Chem276 :41029 –41034,2001
Chang CI, Xu BE, Akella R, Cobb MH, Goldsmith EJ: Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b. Mol Cell9 :1241 –1249,2002
Yu M, Blomstrand E, Chibalin AV, Krook A, Zierath JR: Marathon running increases ERK1/2 and p38 MAP kinase signaling to downstream targets in human skeletal muscle. J Physiol536 :273 –282,2001
Kao HY, Verdel A, Tsai CC, Simon C, Juguilon H, Khochbin S: Mechanism for nucleocytoplasmic shuttling of histone deacetylase 7. J Biol Chem276 :47496 –47507,2001
Wu H, Olson EN: Activation of the MEF2 transcription factor in skeletal muscles from myotonic mice. J Clin Invest109 :1327 –1333,2002
May 2004, 53(5)
Sign up to receive current issue alerts
View Selected Citations (0)
Thank you for your interest in spreading the word about Diabetes.
You are going to email the following Exercise and Myocyte Enhancer Factor 2 Regulation in Human Skeletal Muscle
Message Subject (Your Name) has forwarded a page to you from Diabetes
Message Body (Your Name) thought you would like to see this page from the Diabetes web site.
Sean L. McGee, Mark Hargreaves
Diabetes May 2004, 53 (5) 1208-1214; DOI: 10.2337/diabetes.53.5.1208
PDK4 Augments ER–Mitochondria Contact to Dampen Skeletal Muscle Insulin Signaling During Obesity
FoxO Transcription Factors Are Critical Regulators of Diabetes-Related Muscle Atrophy
Pygo2 Regulates Adiposity and Glucose Homeostasis via β-Catenin–Axin2–GSK3β Signaling Pathway
Show more Signal Transduction
© 2020 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.


To dock a bike, line up the triangle at the front of the bike with the dock and push the bike firmly into the dock. The light on the dock will first show yellow. If it turns to green, it means you've docked the bike correctly and ended your ride.
If the light turns to red, it means that the bike was not docked correctly and is not locked. If no light appears at all, it means that the bike was not inserted correctly into the dock. If you get a red light or no light, remove the bike from the dock and push it back in to try again. If you're out on a ride and are having trouble docking a bike, please contact Divvy customer service, now supported by Lyft.
Annual Members can confirm that they've successfully docked a bike and ended a ride by checking their trip history in their account online. If you're not sure whether you ended a trip correctly, please return to the station and check to make sure it's secure. You are responsible for the bike until your trip is properly closed.


text:
import click

import papika.config
from papika.bridges.from_slack import BridgeFromSlack
from papika.bridges.to_slack import BridgeToSlack

@click.command()
def from_slack():
    config = papika.config.load_from_env_var_path()

    bridge = BridgeFromSlack(config)
    bridge.run()

@click.command()
def to_slack():
    config = papika.config.load_from_env_var_path()

    bridge = BridgeToSlack(config)
    bridge.run()

redpajama_set_name: RedPajamaGithub


text:
Majority of voters would rather have Brexit sorted than keep Northern Ireland in the Union
A mock checkpoint manned by actors dressed as customs officers constructed during an anti-Brexit rally at the Irish border near Carrickcarnan, Co Louth. Picture: PA/Brian Lawless
A majority of Remainers and Brexiteers would be prepared to see Northern Ireland leave the Union in order to achieve their preferred Brexit outcome, a survey has found.
Around four in 10 Britons said they cared little or not at all about the region.
Unionists in Belfast are opposed to prime minister Boris Johnson's proposed Brexit deal which they believe would create a regulatory border between Northern Ireland and the rest of the UK.
It would involve the region following some of the rules of the EU's single market to avoid a hard border on the island of Ireland but including a new regime for goods crossing the Irish Sea.
But while the matter of Northern Ireland has evoked passionate arguments on either side of the debate, a YouGov survey has found:
- Four in 10 Britons would not be concerned if Northern Ireland leaves the UK
- 41% said they cared little or not at all about Northern Ireland
- A majority would rather have their preferred Brexit outcome than see Northern Ireland stay in the Union; which was true for both Remainers and Leavers
- Even those who care a "great deal" about Northern Ireland, and want it to stay in the UK, would choose their Brexit preference over the Union remaining intact.
The organisation said: "New YouGov polling today exposes the weaknesses in the link between Northern Ireland and the rest of the UK.
"YouGov asked mainland Britons how much they care about Northern Ireland, how they'd feel if it left the Union and whether getting their own way on Brexit was more important than keeping the UK together."
It said its results showed that 41% say they "would not be bothered" if Northern Ireland left the UK.
A further 41% said they would be "upset" if it broke away, while only a minority of 9% would be "actively pleased to see them go".
The referendum divide does not make a difference, with 58% of Remain voters and 64% of Leave voters saying they'd rather have their own way on Brexit than see the Union preserved.
YouGov added: "As with so much, however, Brexit takes precedent.
"Given the choice between having their preferred outcome on Brexit and Northern Ireland staying in the Union, a majority of 58% chose the former and only 18% the latter."
The polling organisation added: "Even those Britons who say they want Northern Ireland to stay part of the UK tend to be willing to sacrifice it for the sake of Brexit.
"Almost half (47%) chose their preferred Brexit option, compared to 35% who chose the Union."

redpajama_set_name: RedPajamaCommonCrawl


DriveGLEAM is a software LED for your hard drives read/write activity in the system notification area (tray). It also supports output via parallel port so that you can have a red led for write and a green led for read access for example.
DriveGLEAM is a small tool that shows read / write activity for your hard drives in the system notification area (tray). DriveGLEAM also supports output via parallel port so that you can for example have a red led for write and a green led for read access.
DriveGLEAM can also be handy for system administrators who remotely log in to another computeres desktop. They can easily watch the system notification area (also known as system tray) for any activity on their harddrives.
DriveGLEAM uses very few resources and does not unlike other simmilar tools use hooks or other "tricks" to get the job done. Also please note that even if DriveGLEAM is know to be quite robust and if DriveGLEAM would crash it's designed to NOT cause any drives to freeze and cause corruption or loose data.
· Allows for CPU, RAM , VRAM usage display in tray.
· Keyboard scroll lock LED option.
· Standalone, does not require a install but uses inno setup for your convenience.
· Failure in DriveGLEAM can't "freeze" your drives.
· Does not install lots of files in your system.
All DriveGLEAM reviews, submitted ratings and written comments become the sole property of Windows 7 download. You acknowledge that you, not windows7download, are responsible for the contents of your submission. However, windows7download reserves the right to remove or refuse to post any submission for any reason.
Windows 7 Download periodically updates pricing and software information of DriveGLEAM full version from the publisher, but some information may be out-of-date. You should confirm all information.
Using warez version, crack, warez passwords, patches, serial numbers, registration codes, key generator, pirate key, keymaker or keygen for DriveGLEAM license key is illegal and prevent future development of DriveGLEAM. Download links are directly from our mirrors or publisher's website, DriveGLEAM torrent or shared files from free file sharing and free upload services, including Rapidshare, MegaUpload, YouSendIt, SendSpace, DepositFiles, DivShare, HellShare, HotFile, FileServe or MediaFire, are not used.


text:
Handyman Profession Revamp Info - 2017-08-02 17:00
Over the course of recent updates, you may or may not have noticed, but crafting has been undergoing lots of work since the start of the year. After the arrival of secure crafting and the equipment upgrades, we decided to rejuvenate the handyman profession.
This slightly hotchpotch profession has undergone a lot of changes here and there, to the point that it eventually diverged from its true goal: making furniture and decorations. So, we decided to make crafting decorations simpler by linking decorations' themes with their environments' resources as much as possible. That way, they'll be more consistent in terms of ingredients. Recipes will be divided into two categories: common and rare. The latter will be more difficult to create, but more rewarding in experience.
The difficulty in obtaining components will no longer vary from one craft to another, because all recipes of the same rarity will be aligned according to a single template. Decorations that are actually quite basic will no longer require you to put in too much effort to be crafted.
Don't worry if you notice that some decorations can no longer be crafted. In order to vary the ways in which they can be obtained, some decorations will be won after having defeated monsters! Certain sumptuous decorations will also be dropped by bosses and the new archmonsters.
Like the Pets revamp we announced two weeks ago, the changes on the Handyman profession will be applied to the game with the next major update.
Running on Wings
Ankama Takes a Calm Look Back…
An Explosion of Pack…
Get a Free Rubik's Cube Mystery Box!
My own suggestions
By Gerile3 the 18/01/2021 - 10:22
Hallo ^^
By pidaman22 the 18/01/2021 - 08:44
Other Languages 3
Srambad chapter one final quest bugged
By Stringy the 18/01/2021 - 07:39
1.70 Bug Reports 1
We want Pvp
By mwriot2 the 18/01/2021 - 06:06
HP Glitches with Conditioned gear
By YasaiTsume the 18/01/2021 - 02:42


text:
Lung Cancer Research Programs
A unifying approach to Non-small cell lung cancer therapy
Dr Joanna Woodcock; University of South Australia
The 14-3-3 proteins are closely associated with the severity and poor outcomes in many lung cancer patients and therefore represent a potential target for drug development. We already have experimental drugs that target 14-3-3 proteins and reduce tumour growth in experimental models.
Through your support, we will establish the role of 14-3-3 proteins in lung cancer and test how broadly effective 14-3-3-directed drugs would be in patients diagnosed with the disease.
From Big Data to Precision Medicine: Integrated analysis of clinical trial and electronic health record data in lung cancer
Professor Michael Sorich; Flinders University
Through the support provided by Cancer Council's Beat Cancer Project we will be able to develop online tools to help lung cancer patients and doctors to work through difficult decisions on whether to use an anti-cancer medicine.
We will do this by analysing a large amount of data available from previously completed studies of medicines along with data from real-world use of the medicines by patients. This analysis will allow predictions to be made regarding a patient's likely risk of benefits and harms from using a medicine and help them determine the right course of action moving forward.
Network (SACTN)—Clinical Trial Enhancement/SA Teletrial: Bringing Cancer Clinical Trials to the Country
Dr Dagmara Poprawski; Country Health SA
There are currently no cancer clinical trials offered outside of metropolitan Adelaide, meaning that patients from regional areas are required to travel in order to take part. The benefits of cancer patients participating in clinical trials are well recognised, particularly the ability to increase patient access to a full suite of therapy options including novel therapies.
Through your support, we will be able to look at the best way for patients in the South East to be recruited, treated and attend follow-up visits virtually from Mt Gambier hospital directly to sites like Flinders Medical Centre. This Teletrial model will utilise existing services, along with additional resources funded through this application, to establish regional cancer trial sites in the long term.
Even though we're at early stages, our hope is that the tele-clinical trial model will improve trial participation rates in non-metropolitan areas and ultimately, improve patient care.
Germline and Somatic Genetic Variation in Cancer
Professor Hamish Scott; University of South Australia
All diseases in humans have a genetic component, either inherited or caused by cell mutation. When we first started looking at haematological cancers such as lymphoma and leukaemia, it was thought that genetics didn't matter. Families with more than one case were just considered 'unlucky'. Now it is recognised that more than 10 per cent to 20 per cent of these cancers have a strong genetic component.
Through your support, we will be able to work on therapies that can address the genetic implications of some of these cancers, find better ways of treating and monitoring them, and ultimately save lives.
Improving the Management of Chemotherapy-Induced Nausea by Assessing and Treating Nausea as a Symptom Cluster
Professor Ian Olver; University of Adelaide
Current drug therapies can successfully prevent vomiting after chemotherapy; however, the majority of patients who undergo chemotherapy still suffer some form of nausea. Patients differ in what symptoms they label as nausea, all of which may need separate treatment.
Through your support, we will develop an App to find out what symptoms each patient reports as nausea and aim to see if we can improve it by treating each unique symptom. We will also monitor risk factors for nausea to see if we can prevent it occurring before chemotherapy treatment.
Clinical Cancer Registry
Associate Professor Caroline Miller and Professor David Roder; SAHMRI and University of South Australia
The South Australia Clinical Cancer Registry (SACCR) consists of four hospital-based clinical cancer registries and a central coordinating unit. The clinical registries provide information on cancer stage, grade, differentiation, treatments (surgery, radiotherapy, chemotherapy etc.), prognostic indicators, patient outcomes and other key indicators of quality cancer care that are needed to complement population incidence registries.
Data is limited to those who are treated at participating hospitals Flinders Medical Centre, The Queen Elizabeth Hospital, Lyell McEwin Health Service and the Royal Adelaide Hospital. Clinical registries provide clinicians and service planners with appropriate insight into current cancer trends and the impacts of changes to clinical practice and models of care on outcomes. There are over 300 data items potentially collected as defined by the South Australian minimum data set.
With the funding received through Cancer Council's Beat Cancer Project and other revenues, we will be able to continue collecting South Australian cancer-related data, enabling effective public health interventions and cancer incidence monitoring through sharing this data with clinicians and service planners.
Optimising Drug Therapy in Solid Tumours
Professor Ross McKinnon; Flinders University
My wife succumbed to breast cancer when aged 40. During the 15 months she lived with cancer, she experienced major drug toxicities and many ineffective drug treatments, many of which could have been avoided with better utilisation of biological markers and a higher level of pharmaceutical care. Her experience motivated me to optimise drug treatments for future generations, ensuring that others don't have to experience what she went through.
The ongoing support of Cancer Council's Beat Cancer Project will help us develop better and more effective drugs to treat cancer. We are researching across three main areas: using indigenous knowledge and Australia's remarkable marine biodiversity to identify new compounds with therapeutic potential in cancer and related conditions; using sophisticated statistical methods to determine if such biomarkers (biological indicators of disease) will be useful decision tools in cancer therapy; and studying the mechanisms by which cancer drugs are metabolised to determine ways to optimise drug strategies.
My message to donors is that drug discovery is difficult and challenging, but through a continuity of funding, we are getting closer to drug breakthroughs every day.
Improving Our Understanding of Cancer Biology, Diagnostics and Therapies
Professor Tim Hughes; University of Adelaide
Just over a decade ago, Chronic Myeloid Leukaemia (CML) was still considered a death sentence. This research has pioneered the use of tyrosine kinase inhibitors (TKIs) to treat a range of cancers including CML, which was once known as one of the most devastating forms of blood cancer. Through the use of TKIs and research into individualised therapies, we have seen significant breakthroughs, with some CML patients even achieving treatment free cancer remission. This in itself is a remarkable achievement considering that previously, only one in six CML patients survived eight years after their diagnosis.
Thanks to Cancer Council's Beat Cancer Project, my team has received ongoing funding to support our work since 2013. We're currently leading a global trial of a promising new therapy for CML, with results to be released later this year. Funding from the Cancer Council's Beat Cancer Project has enabled our team to lead this and other research projects in South Australia which will ultimately change lives.
Turning Research into Life-Saving Reality
Professor David Roder; University of South Australia
The primary aim of our unit is to develop more efficient and cost-effective services, especially related to cancer screening and treatment. With cancer impacting one in two Australians by the time they turn 85, our work is to benefit the whole Australian population, with the funding we receive from Cancer Council SA greatly increasing the reach of my work.
Through your support, our next step is to assist in the implementation of evidence-based health policies and evaluate their effectiveness. This work is ongoing, with a major emphasis on evaluating and improving outcomes of services for Aboriginal people. We are also working on assessing side effects of cancer therapies in order to improve the quality of life for those who survive their cancer diagnosis, and looking at service evaluation and policy development for breast and cervical screening and cancer treatment services.
SANT Datalink
Mr Andrew Stanley; SANT Datalink
South Australia has a range of data sets across health, education and social services. Once linked, data describing the health and experience of many thousands of individuals can be supplied to a researcher in a completely de-identified format. This intelligent linkage process strengthens privacy protection while giving researchers access to true population-based data relevant to many areas of research, including cancer prevalence, detection, treatment and outcomes.
Through your support, SANT DataLink is committed to contributing to a better understanding of cancer prevalence, factors contributing to this and improved treatments and outcomes for the community and individuals.
Immune Therapy to Treat Solid Cancers
Dr Tessa Gargett; University of South Australia
Immunotherapies that stimulate the immune system to attack and kill tumours represent an exciting new era in cancer treatment. The immune system contains cells that have the unique capacity to destroy cancer; however, tumours often develop ways to 'turn off' these cells and escape destruction. The most successful new immunotherapies work by blocking the tumour's method of escaping and allowing the immune system to kill cancerous cells. These therapies can be highly effective in solid tumours such as melanoma, with around 40 per cent of melanoma patients responding to therapy and some patients achieving a complete response where their tumours are eradicated. Despite these successes, approximately 60 per cent of melanoma patients do not respond. Other forms of solid cancers like brain cancers also fail to respond, and so these patients are completely missing out on these breakthrough treatments.
Through the support of Cancer Council's Beat Cancer Project, we plan to extend the promise of immunotherapy to all patients. We're testing brand new immune-based therapies specifically designed to boost the immune system in solid cancer patients. We have one clinical trial currently running at the Royal Adelaide Hospital which tests a personalised cell therapy in patients with melanoma. We will soon commence two new cell therapy clinical trials in patients with brain cancer. This project will help develop these trials and also follow patients receiving the new treatment to see how they respond, with the hope that the results can help inform treatments for all patients diagnosed with solid tumours.
Centre for Integrated Systems Biology
Professor Tim Hughes; SAHMRI / University of Adelaide
The ACRF Centre for Integrated Cancer Systems Biology (ACRF-CICSB) will be a state-of-the art facility providing new approaches to interrogate cancer biology. This facility will be located at SAHMRI and the University of Adelaide's newly constructed Adelaide Health and Medical Sciences (AHMS) Building (located adjacent to SAHMRI), in the newly established Adelaide BioMed City (ABMC) precinct.
South Australia has a strong national and international reputation for undertaking high quality research in cancer biology and treatment. Our translationally-focused research teams are already well supported by well-established enabling facilities located throughout Adelaide. Collectively, these facilities underpin many of the outstanding research discoveries from South Australian cancer researchers focused on understanding the intrinsic and extrinsic mechanisms of cancer initiation and progression, drug sensitivity and resistance and the mechanisms of cancer metastasis.
A data officer to support the familial cancer research of the Adult Genetics Unit
Dr Nicola Poplawski; CALHN
This application is for a three year salary for a 0.6 FTE ASO2 data officer to assist in the data management of the Adult Genetics Unit's KinTrak family database, improving the the opportunities for SA families to participate in familial cancer research.
When a client is referred to the AGU we collect and record family history information. The data is collated in KinTrak and clinical staff use the information to determine which cancer genes will be tested and provide an assessment of personal cancer risk.
If a genetic error is identified in a cancer gene, clinical staff use the information to manage risk notification and predictive genetic testing for current and future generations of the family; ensure relatives who do not have the genetic error avoid unnecessary cancer surveillance and provide relatives who do have the genetic error with gene specific risk management advice that lowers their cancer risk (prevention and risk reduction) and enhances detection of early stage cancer (surveillance).
Where ethically approved, research staff use the information to identify individuals/families who are eligible for recruitment to familial cancer research projects; identify individuals/families who are eligible for research or translational genetic testing and contribute data to local, national and international research initiatives relevant to familial cancer
Through support from Cancer Council's Beat Cancer Project we will be able to employ a data officer to take over these tasks and also support and contribute to AGU research activity; freeing clinical staff for research activities.
Beat Cancer Project Travel Grants
In addition to funding individual research projects, Cancer Council's Beat Cancer Project is proud to fund a number of travel grants, awarded to South Australian researchers across all the major research institutions. Funded through your generous donations, these grants help cover costs for researchers to travel to local, national and international events and conferences. It also gives them an opportunity to talk about their research with other experts, helping them to broaden their skills and learn from leading researchers.
Cancer Council SA's Behavioural Research Team
Cancer Council SA's Behavioural Research Team is based at our offices at Greenhill Road. Through your support, the team conducts monitoring, applied research and evaluation to inform the development of Cancer Council SA's cancer control programs and services. The Behavioural Research Team works closely with the Cancer Council SA Postdoctoral Fellow (Cancer Support) who is jointly based at the Flinders Centre for Innovation in Cancer. Together with two new postgraduate research students from Flinders University, they are interested in people's knowledge, attitude, behaviours and the decisions individuals make that may lead to healthy or unhealthy behaviours in the area of cancer control, as well as research into the psychosocial impact of cancer on those directly and indirectly affected by cancer.
Content printed from https://cancersa.org.au/get-involved/donate/donate-specifically/lung-cancer-fund/research


text:
FSW Faculty Board and office
Mindfulness simply means being aware of the present moment. By noticing your thoughts, sensations and behavior, you learn to make conscious choices instead of reacting automatically. Living in the here and now requires practice, but it can be very beneficial. Among other things, you'll become aware of the signals your body gives you and you'll be able to discover your fixed patterns and habits.
Marleen Zwetsloot
The workload for this course amounts to 8 hours (5 hours of training and 3 hours of homework)
The automatic pilot
Focus and intention
Bodily signals, responding to stress
Thoughts as mental events
Mindful listening
Self care and compassion
Upon completion of this course, you: Know the theory behind mindfulness, trained your intention and internal motivation for the things you think are important and want to accomplish. In addition, you have more insight in your personal circle of influence, are more aware of your own (automatic) thoughts, sensations and behavior. Also, you are trained to pause and make use of your bodily signals to make more conscious choices and can recognize your personal stress signals in an earlier phase.
Finally, you will get familiar with short meditation practices to implement in your daily life.
This course will be spread over 5 weeks. Each week we will have one online group meeting in which we will discuss some theory, practice together and share experiences. Next to the group meetings we will work with an online module and you will be asked to do daily practices (about 15 minutes a day). We will work in smalls groups of 6 participants.
You can register for this course using the registration buttons on the right side of this page. Please note the difference between Staff (employee of Leiden University) and Extern/LUmc (e.g. extern, self-funded researchers or employee at LUmc).
18 January 2022 16:00 - 17:15 uur 25 January 2022 16:00 - 17:15 uur 1 February 2022 16:00 - 17:15 uur 8 February 2022 16:00 - 17:15 uur 15 February 2022 16:00 - 17:15 uur
Register: Staff
Register: Extern/LUmc
8 March 2022 16:00 - 17:15 uur 15 March 2022 16:00 - 17:15 uur 22 March 2022 16:00 - 17:15 uur 29 March 2022 16:00 - 17:15 uur 5 April 2022 16:00 - 17:15 uur
3 May 2022 16:00 - 17:15 uur 10 May 2022 16:00 - 17:15 uur 17 May 2022 16:00 - 17:15 uur 24 May 2022 16:00 - 17:15 uur 30 May 2022 16:00 - 17:15 uur
14 June 2022 16:00 - 17:15 uur 21 June 2022 16:00 - 17:15 uur 28 June 2022 16:00 - 17:15 uur 5 July 2022 16:00 - 17:15 uur 12 July 2022 16:00 - 17:15 uur
25 October 2022 16:00 - 17:15 uur 1 November 2022 16:00 - 17:15 uur 8 November 2022 16:00 - 17:15 uur 15 November 2022 16:00 - 17:15 uur 22 November 2022 16:00 - 17:15 uur


text:
Q: Ignore duplicate rows while adding to database with Blaze's Odo How can I ignore duplicate rows while storing a dataframe in a postgres DB with Blaze's Odo?
For example, I store the first 3 rows like this:
>>> odo(df[:3], 'postgresql:///my_db::my_table')

my_table has a column ID as a primary key. If I add a few more but this time including the previous last row, I want to skip that row and add others instead of getting that IntegrityError.
>>> odo(df[2:5], 'postgresql:///my_db::my_table')

    IntegrityError: (psycopg2.IntegrityError) duplicate key value violates unique constraint  ...

How can I do that? Loading ID values from DB and checking for duplicates seems expensive to me if the DB has millions of rows. Is there any better alternative?
Something like this:
INSERT...ON DUPLICATE KEY IGNORE

Blaze: 0.8.3, Postgres: 9.4.4, Psycopg2: 2.6.1

A: The data model for odo only supports appending, not merging. You'll need to either remove duplicates before passing it through odo, or use the database to remove the duplicates. Try adding an auto-increment field, and set it as the primary key. This will fix your IntegrityError problems on insertion, and you can remove the duplicates after that.

redpajama_set_name: RedPajamaStackExchange


text:
'The Roar - The Latest News From the Coburg Football Club. Click here to register and receive
#WeAreCoburg
Club Song
Past Players and Officials Association
Team of the century
Best and Fairest Winners
Captains and Coaches
AFL Draftees
Representative Players
Premiership Teams
CLUB PARTNERS 2019
Coburg JFC
Coburg Auskick
Coburg FIDA Program
Coburg Superules
Calder Cannons
Fitzroy Stars
WINTERTHUR LIONS AFC
North London Lions
Lyon Lions
Another twelve re-sign for 2016!
in Featured Stories, Latest News
Ahead of the Christmas break of the pre-season, Coburg are pleased to announce that another twelve players have committed for the 2016 season - Lech Featherstone, Dion Hill, Mark Orr, Lachlan Johns, Rory Lehmann, Tom Goodwin, Josh Cauchi, Richard Bamblett, Jackson Clarke, Brandon Bailey, Cameron Holdsworth and Jesse Corigliano have all signed to go round again in 2016.
After his superb debut season in 2014 where he was named at centre half forward in the VFL team of the year and came within lengths of winning the Frosty Miller Medal, Lech's 2015 season was hampered by injury following a limited pre-season. While his 2015 got off to a promising start, we are looking forward to see what he can do when fit in 2016.
Dion impressed in his debut season in 2014, after a stint in the development league he managed 16 goals in the last six matches to finish with 22 goals for the season.
Mark managed 13 out of the Lions 18 senior matches in 2015, a fantastic result for the former Western Jets leadership group member. A promising key position player who can also play in the ruck, Mark also managed five goals, which included a four goal effort in the big win over reigning premiers Footscray in round fifteen.
Recruited from Eastern Football League powerhouse Vermont, Lachlan managed 13 goals in seven matches from the midfield after struggling with a persistent ankle injury early on in the season. Lachlan was eligible for the finals in the development league and was awarded as the clubs best finals player, and played in the AFL Victoria Young Guns game.
Also recruited from Vermont, Rory managed twelve senior games in 2015 holding a key defensive post for the majority of the season. With Michael Hartley being drafted to Essendon, Rory will again be crucial to the side's backline in 2016.
After stints with the Port Adelaide Magpies and the Box Hill Hawks, Tom was a crucial component in the ruck for the Lions throughout 2015. Tom managed 16 senior games in his first full season of senior football which also consisted of 398 hit outs for the season, including 49 against Frankston late in the season.
From the Calder Cannons, Josh managed 17 goals from 14 matches in his first season at VFL level as a small forward. His form was impressive early on, especially in the sides early season wins over Richmond and Frankston. Josh will be looking to make further strides in 2016.
After two years in the wilderness, Richie returned to Coburg following a stint with Essendon's VFL side. A premiership player with the development side in 2012, Richie managed the opening two senior games in 2015. However he battled injuries and struggled to win his spot back in the senior side and spent the rest of the season in the development league.
A product of Wangaratta and the Murray Bushrangers, Jackson managed to make his senior debut late in the season as 23rd man having struggled earlier in the season with injury. Having tasted senior football in 2015, the talented midfielder will be looking to further build on his 2015 experiences.
After starring for Gippsland League side Morwell in 2014, Brandon managed 14 games in the development side in 2015 often in the midfield or on the wing.
Recruited from the Western Jets, Cameron managed fifteen games in the development side during 2015, and was equally adept in
all positions either down back or up forward, and even as a pinch hitter in the ruck.
Also from the Calder Cannons, Jesse managed 9 development matches in 2015, mainly off half back with his best performance being in the Queen's Birthday match against the Northern Blues.
We are pleased to have these twelve players at Piranha Park again in 2016.
tags: Brandon Bailey Cameron Holdsworth Dion Hill Jackson Clarke Jesse Corigliano Josh Cauchi Lachlan Johns Lech Featherstone Mark Orr Richard Bamblett Rory Lehmann Tom Goodwin
Vale Jack Rogan.
Featured Stories Latest News
Coburg FC AGM Results~ 2015
Coburg FC NAIDOC Jumpers available for purchase!
High flying Bombers outgun Lions
Lions in Focus – Josh Guthrie
Match Preview: Coburg vs Essendon
Lions look to go back to back
Local League Lions Round 13
info@coburgfc.com.au
Piranha Park, Cnr Harding & Russell Streets, COBURG, VIC 3058
Lions named to take on North Melbourne
Cannon Browning added to Lions List
Local League Lions: Round 15
Coburg celebrates its history and welcome 14 new Life Members
©2018 coburg FC All rights reserved.Flexart.com.au


text:
Q: Number pad does not work in vim and less I am working from an iMac running Yosemite and using this keyboard.  The number pad works in the terminal, but when I open vim or less it does not.
For example using less, if I type for the number 8, I get ESCOx, not an 8.  In vim 7.2 (in command mode), it inserts an x.  How do I fix this behavior? I got this keyboard specifically for the number pad.

A: If you are using Terminal (not iTerm or others), there is a setting that might help. Turn off this setting (sorry, it's in german. But the location should be the same):

If you are using iTerm, there is at least a fix for vim: You can remap the keys to get this to work. Just add the following lines to your ~/.vimrc (Create it, if it doesn't exist.)
inoremap <Esc>Oq 1
inoremap <Esc>Or 2
inoremap <Esc>Os 3
inoremap <Esc>Ot 4
inoremap <Esc>Ou 5
inoremap <Esc>Ov 6
inoremap <Esc>Ow 7
inoremap <Esc>Ox 8
inoremap <Esc>Oy 9
inoremap <Esc>Op 0
inoremap <Esc>On .
inoremap <Esc>OQ /
inoremap <Esc>OR *
inoremap <Esc>Ol +
inoremap <Esc>OS -
inoremap <Esc>OM <Enter>

Source: a comment in the vim wiki.

A: If you're using iTerm and I correctly understood your question, in iTerm2 there is an appropriate preference:
http://www.twistermc.com/39930/use-number-pad-vim-iterm2/


At 15 min from Cabourg, in a village along the marsh of Dives : this is a lovely house is situated where Christine will warmly welcome you. Each bedroom has a pleasant atmosphere with an harmonious decoration. Families with children are welcome. Christine will be glad to advise you about places to discover. This is an address you won't forget ! In the owner house, on the ground floor: 1 bedroom sleepint 2 (a 160cm x200cm bed), private shower room and toilet. Independent entrance. Upstairs : 1 large bedroom sleeping 3 pers (a 160x200cm bed, 1 90x190cm bed), private shower room and toilet, 1 bedroom sleeping 2 (a 140x190cm bed), private shower and toilet. Extra bedroom for children on prior request. Baby equipment. Garden furniture. On previous request : table d'hôtes (dinner) or kitchen at disposal.


text:
Talkin' Out the Side of My Neck
I was denied entrance to the Power & Light District last night.
The inner sanctum of the entertainment area had reached its capacity of 3,500 for a free concert by Cameo. I stood among more than 1,000 disappointed people who were also shut out. After listening to the brilliant band for about twenty minutes as I verified that all external doors were locked and that every security guard took his job seriously, I dropped into the RecordBar.
Johnny Hamil led a "gawdy cartoonnoirjazz" (his words and stylization) band for a handful of fans, friends and family members. After marveling at the blood moon from the venue's smoking patio, I moved a few blocks west on Westport Road.
An adorably sincere little punk show at Records With Merritt provided me with the thrill I'd been seeking. Rather than feeling self-conscious about being the oldest member of the audience by at least twenty years, I took pleasure in knowing that I was the only listener who had attended performances by Sonic Youth and Cameo thirty years ago.
I'm featured in Sylvia Maria Gross' otherwise outstanding examination of The Popper's "I'm KC."
I previewed Vince Staples' concert at the Granada for Ink magazine.
I previewed Ernest James Zydeco's album release party for KCUR.
I reviewed Many a New Day: Karrin Allyson Sings Rodgers and Hammerstein at Plastic Sax.
Tech N9ne has a new video for "No K".
I've long adored K.T. Oslin. Even so, I can't tell if Simply, a brief album of remakes, is a last gasp or a welcome comeback.
Labels: Cameo, Ernest James Zydeco, Johnny Hamil, K.T. Oslin, Kansas City, Karrin Allyson, music, Records With Merritt, Sonic Youth, Tech N9ne, The Popper, Vince Staples
Album Review: Christian Scott- Stretch Music
I'm no longer crestfallen that Christian Scott isn't performing in Kansas City on his current tour. I expected his new release to expand on the exciting advances he made on Christian aTunde Adjuah, my #2 album of 2012. Instead, it's a tedious retrenchment.
Stretch Music is billed as "a genre-blind musical form that stretches the rhythmic, melodic and harmonic conventions of jazz to encompass as many musical forms, languages, thought processes and cultures as possible."
The project reeks of unflattering me-too-ism. Scott seems to be trying to unnecessarily prove that hip-hop, rock and jazz can coexist. He's merely rehashing the work of Flying Lotus, Nicholas Payton, Miles Davis and Gil Evans.
I expect Scott to be a leader. He's opted to be a follower. Unless Frank Ocean or Kanye West stumbles, Stretch Music will be the most disappointing album of 2015.
I reviewed Citizen Cope's concert at Crossroads KC.
Here are the weekly music previews I write for The Kansas City Star.
I spotlighted Making Movies' Carnaval for Ink magazine.
I contributed a Local Listen segment about Making Movies to KCUR.
Bobby Watson and his touring band thrilled me at the Folly Theater on Friday. Here's my review.
A man seated near me softly snored through much of the Kansas City Symphony's concert on Sunday afternoon. The tiresome program didn't excite me either. I'm more of a Berg: Lyric Suite; Wellesz: Sonnets By Elizabeth Barrett-Browning guy. Here's the intriguing EPK for the new collaboration between the Emerson String Quartet and Renée Fleming.
I assume that Shannon and the Clams and the critics who extol the band are trolling. Gone By the Dawn is dismal. RIYL: The Shaggs, the first rehearsal of an unpromising garage-rock band, Jonathan Richman at his most insufferable.
The subtleties of The Evolution of Oneself initially eluded me. Repeated listens have revealed that the trio of Orrin Evans, Christian McBride and Karriem Riggins have created one of the year's best jazz albums. Recommended to people who appreciate both Ray Brown and the Wu-Tang Clan.
I love everything about Windhand's Grief's Infernal Flower. RIYL: Slayer, cemeteries, Pallbearer.
Mary Halvorson's Meltframe does nothing for me. RIYL: Robert Fripp, dissertations about music theory, Bill Frisell.
I don't have anything bad to say about Keith Richards' Crosseyed Heart. RIYL: Ian McLagan, lions in the winter, Chuck Berry.
Steve Van Zandt's maximalist production of Introducing Darlene Love is too much for me. Here's the overblown "Forbidden Nights".
Labels: Bobby Watson, Christian Scott, Citizen Cope, Darlene Love, Kansas City, Kansas City Symphony, Keith Richards, Making Movies, Mary Halvorson, music, Orrin Evans, Shannon and the Clams
Una Copita de Ron
I'm beginning to suspect that I'm on the wrong continent. The joy I felt on a recent trip to Chile and at a concert by a cumbia band on Friday has me rethinking my place on the planet.
My Spanish may be atrocious, but most everything else feels right about a potential move to the south.
I didn't understand what a member of the dynamic show band Tropicalísimo Apache said when he pointed me out during Friday's free concert at Barney Allis Plaza. If he was encouraging a brave woman to dance with me, his request went unheeded.
No matter. I was so enthralled with the expertise with which the Mexican band played the music of Columbia that I'm "Una Copita de Ron" away from buying a one-way ticket to Bogotá or Santiago.
Here are my most recent weekly music picks for The Kansas City Star and Ink.
I previewed the Crossroads Music Fest for Ink and contributed to a review of the event for The Kansas City Star.
An item about Second Hand King is among my recent contributions to KCUR.
I caught a portion of the Prairie Village Jazz Festival at Plastic Sax. Here are my notes.
A vibrant mix of Afrobeat, soukous, rock and electronica, Mbongwana Star's From Kinshasa is stunning. Here's "Malukayi" (Tip via Big Steve.)
I'm unable to resist the Go! Team's charms. Listening to The Scene Between gives me the same feeling I had when I was seven years old and watching a new episode of my favorite Saturday morning cartoon. RIYL: the Magnetic Fields, Sid and Marty Krofft, the Crystals. Here's the title track.
I didn't catch last year's Chick Corea/Bela Fleck tour. The concert document Two indicates that you had to be there.
Live in Cuba, the Jazz at Lincoln Center Orchestra's new 137-minute album, alternately thrilled and bored me. RIYL: certain Grammy winners, Wynton, big bands.
Anne-Sophie Mutter gets it. The Club Album is everything it's meant to be. RIYL: populism (of a sort), Vivaldi, marketing genius.
Labels: Anne-Sophie Mutter, Crossroads Music Fest, Jazz at Lincoln Center Orchestra, Kansas City, Mbongwana Star, music, Second Hand King, the Go! Team, Tropicalisimo Apache
Funky Céilí
I planned on spending all day at the KC Irish Fest when I forked over $18 to gain admission to the popular event on Saturday. Succumbing to crankiness rooted in heat and sobriety, I left after just a few hours.
A solo set by Larry Kirwan of Black 47 was the highlight of my experience. His strident political songs were balanced by old favorites like "40 Shades of Blue" and the minor 1991 hit "Funky Céilí (Bridie's Song)".
Only one of the five additional performances I witnessed is worth mentioning. Kiana Weber, the fiddler of Gaelic Storm, led a session titled Transatlantic Unplugged with Kiana. The largely acoustic jam included guests from the festival's top acts such as Socks in the Frying Pan, We Banjos 3, the Elders and Flashpoint.
The lively collaborations provided a nice survey of everything I wasn't willing to stick around to hear.
I previewed Lee "Scratch" Perry's show at the Riot Room for Ink.
I reviewed Michael Pagán's The Ottawa Sesions album at Plastic Sax.
Rico Rodriguez has died.
Ruby Amanfu's Standing Still is the best Chris Isaak album I've heard in years. I'm down with anyone who covers both Bob Dylan and Kanye West. Her interpretation of the Wilco/Bragg/Guthrie gem "One By One" is magnificent. Here's a nice interview/performance video.
I purchased a batch of Bryan Ferry solo albums as cutouts in the early '80s. The posh atmosphere of those elegant recordings was foreign to me. I still can't relate more than 30 years later. Although Dan Bejar doesn't have much of a voice, Destroyer's Poison Season reminds me of those Ferry albums. RIYL: Belle and Sebastian, ennui, Gerry Rafferty.
Skullduggery, a 2014 collaboration between Joe McPhee and Universal Indian, is a treat. RIYL: Albert Ayler, skronk, Archie Shepp.
Myrkur's M has a lot of great moments. RIYL: Trio Mediaeval, angels and demons, Celtic Frost.
Much of Ghost B.C.'s Meloria sounds more like the Moody Blues than Black Sabbath. Not my thing.
Fidlar's Too is just as engaging as the skeezy punk band's first album. RIYL: Blink-182, intoxicants, Dead Milkmen. Here's "West Coast".
I have only one thing to say about Motörhead's Bad Magic album.
Jacob Fred Jazz Odyssey's The Battle For Earth is RIYL: Augustus Pablo, freaky jamz, Galactic. Here's "Appropriation Song".
George Clinton and affiliates like Bootsy Collins sounded cool when they rambled about the cosmic virtues of funk in the 1970s. When Dâm-Funk and his cohorts do the same on his new album Invite the Light, they comes across as dorks. Invite the Light is really good when no one's talking or singing. RIYL: 1975, Junie Morrison, funkateers.
(Original image of the Dublin band Tupelo at the KC Irish Fest by There Stands the Glass.)
Labels: Black 47, Dam Funk, Destroyer, Fidlar, Ghost B.C., Jacob Fred Jazzy Odyssey, Joe McPhee, Kansas City, KC Irish Fest, Kiana Weber, Larry Kirwan, Lee Scratch Perry, Michael Pagan, Motorhead, music, Myrkur, Ruby Amanfu


BagilaGod . Ali9009. Amanda96. SmileNikki.
tammy1chrisAngieMilenaGomezMillenaGAndyGarrets .MelissaJonesKevinHLexxyXXXOdriu .CammrynnPrettyDorymufflonSexyAngelsex90 .BestBlueXXLKevinHBrandyRoyceAmanda96 .FlirtyBigAmberLatiinBoiisGymYourLittleElizaLatiinBoiisGym .BdsmLeaderszzBAGIRAzzBestBlueXXL1DeliciousDoll .AlfredoBrown1LexxyXXXJennyJazzALiliana .MelanzzBAGIRAzzzzBAGIRAzzEmmaLoverr .AndyGarretsSensualNicolleLJAniceLaddyDarylPark1 .SecretMadywildpanthersDeliciousHotBodyBdsmLeaders .CominaFaustJennyJazzdaemonloveTramboliko .
SmileNikki00AidenMuscleOkksannaMissMura .KevinHpusseeaterxxoSecretMadyXSEXYeyesTSX .JennyJazzAndreiiiytammy1chrisScarletRosh .LatiinBoiisGymEmilySamH0TBoyAustinLexxyXXX .AfroditaBigTittsAli9009YourLittleElizaKeiraThomson .pituna69AngieMilenaGomezYourBrightStarAlfredoBrown1 .StuartBullMarryStealMsrBlackIrineLillitt .NinaBondSensualNicolleLJEmmaLoverrOhmore .JennyJazzNinaBondKevinHBestBlueXXL .DaisyGomezmufflonMistressFANTASYcamisanchez .wildpantherspituna69EllenStarMissMura .


text:
Cop 20: UN climate change conference | Lima
Brazil should take lead on climate, not just broker talks
Country's efforts to keep negotiations moving towards a global agreement should be backed by robust action on cutting emissions and embracing renewables
Carlos Rittl
Thu 4 Dec 2014 11.02 EST Last modified on Wed 14 Feb 2018 13.10 EST
Smoke from a brush fire lingers over a deforested section of the Amazon in Maranhao state, Brazil. Deforestation of the Amazon rainforest is on the rise. Photograph: Mario Tama/Getty Images
Over the past two decades, Brazil has developed a tradition for helping move international climate negotiations forward at critical moments. However, in the face of climate emergency, lack of ambition and a set of shy measures towards carbon emission reductions can neutralise the best ideas and great diplomatic role played by the country.
At the time of the Kyoto protocol, Brazil came up with the idea of a clean development fund, now the clean development mechanism, for helping developing countries engage in cutting emissions . It has also put on the table a bold, if controversial, proposal for burden-sharing based on historical responsibilities for the warming we've seen so far.
At the Copenhagen climate summit in 2009, Brazil showcased a significant voluntary target that delivered real CO2 reductions from controlling deforestation. In Durban, Brazilian diplomats used a smart twist of phrase to break a deadlock over the legal form of the 2015 climate agreement.
Brazil's newest diplomatic contraption was submitted to the UN shortly before the Lima climate conference, which opened on Monday. It is a mechanism called "concentric differentiation", which allows for every country to collaborate in the effort towards the target of limiting temperature rises to 2C above pre-industrial levels.
Its graphic representation consists of a series of three circles, the innermost of which should be occupied by developed countries with absolute, economy-wide targets; the middle one, by emerging economies, with intensity, per capita or relative reduction targets; and the outer circle, by other developing countries, with non-economy-wide targets. Every country should move towards the centre in time, according to its respective capabilities.
Brazil's 'concentric differentiation' approach to emission reductions. Photograph: UNFCCC
While the proposal is certainly interesting for differentiating among developing countries, it still may leave major emitters such as Brazil and China off the hook, by allowing them to set targets that are not measured in absolute reductions for the post-2020 period. That would be a tragedy for the climate and also detrimental to the Brazilian economy.
Brazil is far from being an innocent bystander of climate change – even by its own metric of historical responsibility. According to a recent peer-reviewed study, thanks to deforestation in the latter 20th century, the Latin American country is probably the fourth top contributor to the observed global warming, responding for about 7% of the total temperature change. Therefore, while still a developing country, it is among the nations that should deliver ambitious emissions pledges ('nationally determined contributions' in the UN jargon) for a post-2020 climate agreement.
There are reasons to believe that the emission cuts the country has achieved over the past decade may now be waning. According to data released by the Climate Observatory, a coalition formed by Brazilian civil society organisations, Brazil's greenhouse gas emissions have grown 7.8% in 2013 in spite of a very low economic growth, with major contributions coming from land use and energy.
Deforestation control is no longer taken for granted. Last year there was a 29% increase in the rate of forest clearing in the Amazon, and the 2015 data is pointing towards another increase.
The country's energy mix is also getting dirtier: 70% of the planned investments on energy will go to fossil fuel in the next 10 years. After swearing off coal a few years back, the Brazilian government has helped it stage a comeback last month, by awarding a contract for its first new coal power plant in nine years. If Brazil is serious about the 2C goal, then it must revert to its former pathway on coal.
The Climate Observatory's assessment for an equity-based 2030 climate target suggests that Brazilian non-land use emissions should peak well before 2025, and overall emissions should decline to significantly less than 1bn tons of CO2 equivalent per year by 2030. Achieving that would not be too hard for the country and can even be done while the economy grows – in fact, it can help set Brazil's struggling economy back to a growth trajectory.
In 2008, the country committed itself to zero net deforestation by 2015. It could increase its planted forests area from 7m to 17m hectares by 2025. Just by implementing measures that are already in place, it could also cut emissions in the agricultural sector by one-third in 2020 – or even reach zero emissions from farming and cattle ranching if the Low Carbon Agriculture plan could be expanded to the whole set of yearly investments in agriculture.
Brazil could also double its ethanol production by 2020 just by providing clear policies for the sector while reviewing its current policy of gasoline subsidies. With solar photovoltaic energy faring nearly as cheap as coal in the latest bids, and wind energy much cheaper than any fossil fuel, there is no reason for Brazil not to become again a renewables superpower. It actually might be helped in such quest by the current oil supply shock, which drove prices down and made Brazilian ultra-deep-water oil unattractive.
While other big emitters, such as the EU, China and the US, start showing their cards on the climate table and betting big on renewables, Brazil seems to be holding itself back.
Carlos Rittl is the executive secretary of the Brazilian Climate Observatory, a network of NGOs working on climate change
Global climate talks
Copenhagen climate change conference 2009