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Laura Llacuna and Montserrat Mari have contributed equally to the work.
Liver Biology and Pathobiology
Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury†
Article first published online: 29 AUG 2006
DOI: 10.1002/hep.21285
Copyright © 2006 American Association for the Study of Liver Diseases
Additional Information
How to Cite
Llacuna, L., Marí, M., Garcia-Ruiz, C., Fernandez-Checa, J. C. and Morales, A. (2006), Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury. Hepatology, 44: 561–572. doi: 10.1002/hep.21285
- †
Potential conflict of interest: Nothing to report.
Publication History
- Issue published online: 29 AUG 2006
- Article first published online: 29 AUG 2006
- Manuscript Accepted: 30 MAY 2006
- Manuscript Received: 26 JAN 2006
Funded by
- Research Center for Liver and Pancreatic Diseases. Grant Number: P50 AA 11999
- US National Institute on Alcohol Abuse and Alcoholism. Grant Number: 1R21 AA014135-01
- Plan Nacional de I+D. Grant Numbers: SAF 02-3564, 03-04974
- Red Temática de Investigación Cooperativa. Grant Number: G03/015
- Red de Centros. Grant Number: C03/02
- Instituto de Salud Carlos III. Grant Numbers: FIS 04/1039, 03/0426, 02/3057, 02/0339
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
The molecular mechanisms of hepatic ischemia/reperfusion (I/R) damage are incompletely understood. We investigated the role of ceramide in a murine model of warm hepatic I/R injury. This sphingolipid induces cell death and participates in tumor necrosis factor (TNF) signaling. Hepatic ceramide levels transiently increased after the reperfusion phase of the ischemic liver in mice, because of an early activation of acidic sphingomyelinase (ASMase) followed by acid ceramidase stimulation. In vivo administration of an ASMase inhibitor, imipramine, or ASMase knockdown by siRNA decreased ceramide generation during I/R, and attenuated serum ALT levels, hepatocellular necrosis, cytochrome c release, and caspase-3 activation. ASMase-induced ceramide generation activated JNK resulting in BimL phosphorylation and translocation to mitochondria, as the inhibition of ASMase by imipramine prevented these events. In contrast, blockade of ceramide catabolism by N-oleyolethanolamine (NOE), a ceramidase inhibitor, enhanced ceramide levels and potentiated I/R injury compared with vehicle-treated mice. Pentoxifylline treatment prevented TNF upregulation and ASMase activation. Furthermore, 9 of 11 mice treated with imipramine survived 7 days after total liver ischemia, compared with 4 of 12 vehicle-treated mice, whereas 8 of 8 NOE-treated mice died within 2 days of total liver ischemia. In conclusion, ceramide generated from ASMase plays a key role in I/R-induced liver damage, and its modulation may be of therapeutic relevance. (HEPATOLOGY 2006.)
Hepatic ischemia/reperfusion (I/R) damage, which can occur in diverse settings including liver transplantation, trauma, hemorrhagic shock, or liver surgery, is a serious clinical complication that may compromise liver function because of extensive hepatocellular loss. The mechanisms responsible for hepatic I/R injury are not well understood despite the identification of several intercellular and molecular mechanisms involved in the necrotic and apoptotic death of hepatocytes. For instance, recruitment and activation of inflammatory cells (CD4+ T lymphocytes), as well as Kupffer cells and platelet adhesion in the sinusoidal lining, have been involved in sinusoidal endothelial cell death and hepatic I/R injury.1–4 Molecular events include nuclear factor kappaB (NF-κB) activation, tumor necrosis factor (TNF) generation, JNK activation, mitochondrial permeability transition (MPT), and reactive oxygen species overproduction.5–8
Sphingolipids, ceramide in particular, have emerged as signaling lipid intermediates that play a role in the stress response, and as mediators of apoptosis and autophagic cell death (type II programmed cell death).9–12 Ceramide levels in cells can increase by de novo synthesis in the endoplasmic reticulum from the N-acylation and subsequent desaturation of sphinganine.13 However, early ceramide increases are often associated with sphingomyelinase (SMase) activation, which hydrolyzes sphingomyelin to yield ceramide.11 This pathway contributes to the rapid upregulation of ceramide and may promote specific microdomain formation in the plasma membrane, allowing oligomerization of certain cell surface proteins such as ligand receptors (TNF family).14 Several SMases have been characterized, of which the neutral SMase (NSMase), with an optimum pH at 7.5, Mg2+ dependent and membrane bound, and the acidic SMase (ASMase), with an optimum pH at 4.8, are of relevance in the signaling of diverse cell death stimuli.11, 15–18
Ceramide levels are tightly regulated in cells, and hence, its potential participation in death signaling can be modulated by metabolic pathways that transform ceramide in other derivatives. For instance, ceramide can be metabolized into complex glycosphingolipids by its glucosylation in the cytosolic surface of the Golgi catalyzed by the rate-limiting enzyme glucosylceramide synthase (GCS).19 In addition, ceramide can be transformed into sphingomyelin20 by sphingomyelin synthase (SMS) or deacylated by ceramidases (CDases) into sphingosine.17, 21 The phosphorylation of sphingosine by sphingosine kinase generates sphingosine-1-phosphate, a bioactive lipid with anti-apoptotic properties.17, 18, 22
Previous studies using mice deficient in TNF gene or TNF receptor 1 (TNFR1) have identified TNF as a critical mediator in warm hepatic I/R injury.5, 6, 23 Moreover, increased hepatic ceramide levels have been observed in cold ischemia and warm reperfusion,24 although its consequences and regulation were not further examined. Furthermore, the regulation of SMases has been reported in a rat model of I/R, with NSMase being stimulated during the reperfusion of the ischemic liver, as opposed to ASMase, whose activity decreased.25 However, their impact on ceramide regulation and contribution to hepatic I/R injury were not addressed. Because ceramide overgeneration by ASMase has been shown to contribute to TNF-induced hepatocellular cell death and liver injury,16, 26 the aims of this study were first to examine whether ASMase contributes to warm hepatic I/R injury, because this specific aim has not been previously reported, and second, to analyze the metabolic regulation of ceramide during I/R. We describe here a critical role for ceramide generation through ASMase activation in hepatic I/R injury, which may be of therapeutic relevance because its pharmacological inhibition or suppression by siRNA protects the liver from I/R-induced damage.
Materials and Methods
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
Reagents, Antibodies, and Cells.
See Supplementary Materials and Methods (Available at: http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html.)
Partial and Total Hepatic Ischemia and Treatments.
Animal studies were approved by the IDIBAPS Animal Care and Use Committee. ASMase knockout mice (C57BL/6 strain) were propagated using heterozygous breeding pairs and genotyped as described previously.16, 26 Hepatic partial warm ischemia was performed during 90 minutes in wild-type or ASMase−/− (8–12 weeks) mice as described previously.6 Animal survival was determined using a model of total hepatic ischemia in male wild-type mice (25–30 g), in which only the ischemic tissue is left in place.7 Control animals were sham operated. See Supplementary Materials and Methods for detailed protocols and treatments.
Enzyme Activities, Ceramide, Ganglioside, and TNF Determinations.
Mg2+-dependent NSMase and ASMase activities were determined from [N-methyl-14C]sphingomyelin (56.6 mCi/mmol, Amersham Biosciences, Piscataway, NJ) as described.27 CDase activities were measured using 5 μmol/L [14C]ceramide (55 mCi/mmol, ARC, St. Louis, MO) or C12-NBD ceramide (Molecular Probes, Eugene, OR) in 10 mmol/L Tris-HCl, pH 8.0 for the neutral/alkaline CDase or 0.5 mol/L acetate buffer, pH 4.5, for the acid CDase.21, 28 The GCS and SMS were determined as described previously.29 Cellular lipids were extracted, dried under N2, and subjected to mild alkaline hydrolysis (1N methanolic KOH, 1 hour, 37°C) to remove glycerol phospholipids. Ceramide levels were quantified from liver samples by the DG kinase assay.10 Sphingolipids were separated in LK6D gel 60A TLC plates using chloroform/acetic acid (90:10). Labeled spots were scraped and quantified using a scintillation counter or a Fuji BAS-2500 PhosphoImager system. Hepatic ganglioside levels during I/R were determined by high-performance thin-layer chromatography as described previously.16 Total TNF (bound and free) levels in serum and hepatic tissue were measured using a mouse-specific competitive enzyme immunoassay kit (Chemicon, Temecula, CA).
Liver Histology and Terminal Deoxynucleotidyl Transferase-Mediated Nick-End Labeling.
See Supplementary Materials and Methods.
Western Blotting and Caspase Activation.
The release of mitochondrial proteins was monitored using cytochrome c (1:2000) and Smac/DIABLO (1:2000) antibodies30 and quantitated by scanning densitometry. JNK and AKT phosphorylation were analyzed in cell extracts using phospho-JNK (1:2500) and phospho-AKT (1:2000) antibodies. Mitochondrial fractions, obtained as previously indicated,10 were used to analyze Bim and phospho-Bim (1:1000) levels. Caspase-3 activation was monitored by immunohistochemistry with an active caspase-3 antibody (clone C92-605), whereas its activity was quantified as described.30
Real-time Polymerase Chain Reaction.
See Supplementary Materials and Methods.
In Vitro siRNA Transfection and In Vivo Treatment.
siRNA transfection into the murine hepatoma cell line H1c1c7 was accomplished with siPORTamine™ cationic solution (Ambion, Austin, TX). siRNA-mediated silencing of ASMase was verified at the enzyme level by measuring ASMase activity and at mRNA level by real-time polymerase chain reaction (PCR) as described in the supplementary Methods. For in vivo experiments, chemically synthesized siRNAs (Curevac, Tübingen, Germany) were delivered into mice using the hydrodynamic transfection method31, 32 by intravenously injecting 1 nmol scrambled or ASMase siRNAs in 1 mL phosphate-buffered saline into the tail vein 24 and 48 hours before surgery. For additional information, see Supplementary Materials and Methods.
Statistical Analyses.
Results were expressed as mean ± standard deviation with the number of individual experiments detailed in figure legends. Statistical significance of the mean values was established by the Student′s t test. Animal survival was evaluated using the Kaplan-Meier method and compared using the log-rank test.
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
Transient Accumulation of Ceramide by Sequential Activation of ASMase and Acid Ceramidase During I/R.
The levels of ceramide increased transiently during reperfusion compared with sham controls, with two peaks at 30 minutes and 6 hours post-reperfusion (Fig. 1A), returning to basal levels after 6 hours (not shown). Because ceramide levels reflect the balance between its generation and metabolism, we next analyzed the activity of the enzymes involved in ceramide regulation. As seen, only the activities of ASMase and acid ceramidase (ACDase) were stimulated during the reperfusion phase, without changes in NSMase, GCS or NCDase (Fig. 2A–E). The SMS activity, however, decreased between 1 and 3 hours after reperfusion (Fig. 2F). ASMase exhibited two peaks of activity, an early one by 10 to 30 minutes and a later peak by 6 hours after reperfusion (Fig. 2A). ACDase, however, displayed an activation window between 1 and 6 hours post-reperfusion (Fig. 2D). Because TNF activates ASMase,11, 16 we next determined the kinetics of serum TNF release during I/R (Fig. 1B). In agreement with previous findings,5 we observed an early increase by 10 to 15 minutes post-reperfusion that lasted for up to 8 hours (Fig. 1B). Similarly, TNF levels were enhanced in liver samples post-reperfusion (not shown). Moreover, pentoxifylline (PTX), a well-established inhibitor of TNF production in vivo, which prevented I/R-induced hepatic damage,6 suppressed the ASMase activation during I/R (Fig. 1C) and the subsequent increase in ceramide levels (not shown), indicating that TNF release during I/R mediates the activation of ASMase.
Pharmacological Regulation of Ceramide Modulates Hepatic I/R Injury.
To establish the relationship between ASMase/ACDase activation and hepatic ceramide accumulation, we tested the effect of inhibition of both enzymes in ceramide homeostasis during I/R. Imipramine, which prevents ASMase activation,16, 33 and N-oleoylethanolamine (NOE), a potent ACDase inhibitor,21, 34 were administered 30 minutes before surgery. Imipramine, which prevented the I/R-induced ASMase activation, decreased the peak of ceramide levels generated 30 minutes after reperfusion (Fig. 1D). As expected, NOE enhanced the accumulation of ceramide with respect to the group subjected to I/R (Fig. 1D). Neither imipramine nor NOE modulated hepatic ceramide levels of sham-operated mice. Furthermore, we examined the impact of ceramide regulation on hepatic I/R injury. As indicated, I/R caused hepatic injury reflected by serum alanine aminotransferase (ALT) levels and liver histology (Fig. 3A–B). In addition, we observed significant terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL)-positive hepatocytes after I/R (Fig. 3C), consistent with the coexistence of oncotic necrosis and apoptotic cell death.7, 8 Importantly, imipramine pretreatment protected the liver against I/R injury, as seen by ALT levels, histology, and TUNEL staining, whereas NOE enhanced the extent of hepatic injury (Fig. 3A–C). Imipramine pretreatment, however, did not affect the phosphorylation of Akt or the level of nuclear p65 measured in hepatic extracts after I/R (Fig. 3D), indicating that the protective effect of imipramine is unrelated to NF-κB signaling.
ASMase Down-Regulation by siRNA Protects the Liver Against I/R-Induced Damage.
To further verify the role of ASMase-induced ceramide generation in hepatic I/R damage and discard potential side effects of imipramine, we used two approaches. First we performed hepatic I/R in ASMase−/− mice. However, most (80%–90%) ASMase−/− mice died shortly after anesthesia during ischemia (not shown), because of severe pulmonary dysfunction as characterized previously.35 Therefore, we used an alternate loss-of-function approach using RNA interference, which has been used successfully in silencing gene expression in the liver.31, 32 siRNA efficacy to deplete ASMase mRNA levels was verified in Hepa1c1c7 cells by real time PCR (Fig. 4A), and was accompanied by the reduction of the endogenous ASMase activity (Fig. 4B), whereas the scrambled siRNA did not display any effect. In addition, ASMase-siRNA did not affect the endogenous activities of NSMase or GCS (Fig. 4B), or those of ACDase, NCDase, or SMS (not shown), leading us to examine its effects in vivo.
Double-stranded RNA duplexes may elicit immune responses via interactions with Toll-like receptors 3 and 9,36 and hence we investigated this possibility by examining the involvement of immnune responses in the potential effects of ASMase-siRNA on hepatic I/R in vivo. Interleukin-12 (IL-12) levels were measured in mice 2 hours after injection of ASMase-siRNA, scrambled siRNA, or saline with respect to mice treated with Poly I:C, an analog of dsRNA that is recognized by TLR3 and elicits immune responses in mice.36 As seen, in contrast to the effect observed after Poly I:C injection, no significant increase in IL-12 serum levels were detected in mice treated with ASMase-siRNA (Fig. 4C), consistent with recent reports using naked siRNAs.37 Next, mice were injected into the tail 2 consecutive days with either ASMase-siRNA or scrambled siRNA and then subjected to I/R the day after the last dose. ASMase-siRNA decreased hepatic ASMase mRNA levels (Fig. 4D) and inhibited ASMase activity translating in a reduction in the levels of ceramide after reperfusion (Fig. 4E). Importantly, ASMase-siRNA reduced the extent of I/R-induced hepatic damage monitored by serum ALT levels (Fig. 4F), histology, or TUNEL (not shown). These data establish a key role of ASMase in hepatic I/R injury.
Ceramide Regulation During I/R Modulates the Mitochondrial Cell Death Pathway.
Because ceramide is known to play a role in cell death pathways through mitochondria,10, 11 we next examined the mitochondrial release of cytochrome c and Smac/DIABLO during I/R. As seen, I/R caused the release of cytochrome c and Smac/DIABLO after I/R (Fig. 5A). This outcome was accompanied by active caspase 3 detected by fluorescence assay or immunohistochemistry (Fig. 5B–C). Of note, the number of positive cells observed were less than those stained with TUNEL (Fig. 3C). Next, we examined whether the regulatory role of ceramide on hepatic I/R damage was accompanied by appropriate changes in the apoptosome assembly. Although imipramine treatment reduced cytochrome c and Smac/DIABLO release from mitochondria by I/R, NOE enhanced the release of these apoptogenic proteins from mitochondria (Fig. 5A). In addition, caspase 3 activation induced by I/R was reduced or enhanced by imipramine or NOE pretreatment, respectively (Fig. 5B–C).
JNK Activation by I/R Is Suppressed by ASMase Inhibition.
To identify the potential downstream intermediates of ASMase-mediated hepatic I/R injury, we focus on complex glycosphingolipids and gangliosides because in cultured hepatocytes ganglioside GD3 mediates TNF-induced death.16 Gangliosides are synthesized from ceramide on its glucosylation by GCS, which is inhibited by d-threo-1-phenyl-2-decanoylamino-3-morpholino-propanol HCl (PDMP).16, 19 Unexpectedly, pretreatment with PDMP 30 minutes before surgery did not protect the liver against I/R injury (Fig. 6A), consistent with the lack of GCS activation during I/R (Fig. 2C). Moreover, no changes in the pattern of gangliosides were observed during I/R (not shown), thus further discarding a role for gangliosides in the hepatic I/R injury.
JNK inhibition has been reported to protect the liver against I/R-induced apoptotic/necrotic cell death,7 and the apoptotic role of ceramide is exerted through JNK activation.38–40 Therefore, we evaluated whether the role of ceramide in hepatic I/R damage is mediated by JNK activation. I/R resulted in the phosphorylation of JNK (p46 and p54 isoforms, Fig. 6B), and this was accompanied by phosphorylation of c-Jun (not shown). JNK activation contributed to the hepatic damage induced by I/R since SP600125, a potent and specific JNK inhibitor,41 protected against I/R-induced hepatic damage as reflected by serum ALT levels (Fig. 6C) or histology (not shown). Importantly, imipramine pretreatment, which decreased ceramide generation and protected the liver against I/R (Figs. 1D and 3A), prevented JNK phosphorylation caused by I/R (Fig. 6B). SP600125, however, did not prevent the early increase in ceramide levels during the reperfusion phase, or ASMase activation (not shown), indicating that JNK activation is downstream of ASMase stimulation during I/R. In addition, because ceramide-induced phosphorylation and translocation of Bim to mitochondria are mediated by JNK,40 we analyzed its phosphorylation during I/R. As seen, BimL and its phosphorylated form both translocated to the mitochondria and, more importantly, imipramine and SP600125 suppressed these events (Fig. 6D).
Ceramide Regulation Modulates Survival After Total Hepatic I/R.
We next examined the survival rate in a model of total hepatic I/R in which survival depends on recovery of the ischemic liver after reperfusion. Mice (n = 8–12 per group) were subjected to 60 minutes of ischemia instead of the 90-minute period used in the partial ischemic experiments because this protocol killed all mice within 24 hours of total hepatic I/R. Under these conditions, 8 of 12 vehicle-treated mice subjected to total ischemia died within the first 72 hours post-reperfusion (Fig. 7A), with histological evaluation on autopsies showing massive necrosis in the liver (not shown), consistent with previous reports.7, 8 However, imipramine pretreatment markedly improved the survival rate with 9 of 11 treated mice surviving after 7 days post-reperfusion (Fig. 7A). In contrast, all NOE-treated mice (8 of 8) died within 48 hours postischemia, with 75% of animals dying within 24 hours of reperfusion (Fig. 7A). Thus, these data demonstrate the relevance of the pharmacological regulation of ceramide in hepatic I/R injury.
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
This study examines the role of ASMase in the homeostasis of ceramide and its contribution to hepatic I/R injury. Here we describe the transient generation of ceramide during I/R due to the sequential activation of ASMase followed by ACDase stimulation. Because ASMase generates ceramide from sphingomyelin hydrolysis whereas ACDase catabolyzes it, the time-dependent pattern in the activation of these ceramide-regulating enzymes accounts for the temporal window in which ceramide peaked during I/R. These observations raise several questions, namely, how these enzymes become stimulated in the liver during I/R and what would be the consequences of their activation for hepatic function in I/R?
TNF Release During I/R Activates ASMase.
TNF upregulation by activated Kupffer cells plays a key role in hepatic I/R injury,5, 6, 23 and TNF-induced hepatocellular death is mediated in part through ASMase activation.11, 16 During I/R we detected an early release of TNF and postulated that this cytokine may contribute to I/R-induced ASMase activation. PTX, a methylxantine inhibitor of TNF production in vivo,6, 42 prevented the activation of ASMase and the consequent increase in ceramide levels observed during I/R. The mechanism for ACDase stimulation by I/R is currently unknown. However, it has been reported that the overexpression of ACDase in human skin fibroblasts led to ASMase stimulation and that ASMase could be co-precipitated with ACDase using anti-ceramidase antibodies,43 suggesting the physical interaction between these acid pH optimum enzymes. Whether this outcome occurs in I/R remains to be established. Moreover, we did not address the role of the ACDase activation during I/R in modulating hepatic injury, although it can be expected that through ceramide deacylation, ACDase would generate sphingosine, which may be further metabolized to sphingosine 1-phosphate, a bioactive lipid with anti-apoptotic properties.17, 18, 22 In line with this, it has been shown that ACDase overexpression prevented TNF-induced death in L929 cells,21 whereas NCDase transfection protected rat hepatocytes from TNF-induced cell death through ASMase activation.44
Ceramide Generation Through ASMase Contributes to Hepatocellular Death.
The next question we addressed was whether ceramide signals hepatocellular death and whether hepatic I/R injury would be modulated by the generation of ceramide. Tissue damage during I/R can proceed through adenosine triphosphate–dependent necrosis or caspase-dependent apoptosis, two forms of cell death that are regulated by MPT.8, 45 The release of cytochrome c from mitochondria is a key event in caspase 3 activation through the apoptosome assembly. Although the release of cytochrome c in I/R we observed may seem modest, it closely correlated with the degree of caspase 3 activation. Even in the case of NOE pre-treatment in which the degree of liver injury estimated by ALT release and histology is rather substantial compared with vehicle-treated mice, the level of cytochrome c released into the cytosol is enhanced from twofold to approximately 3.5-fold. Although this increment is reflected in the activation of caspase 3, it suggests that the release of cytochrome c from mitochondria is highly regulated. Cytochrome c is anchored to the mitochondrial membrane through both electrostatic and hydrophobic interactions with acidic phospholipids, most notably cardiolipin, and recent observations indicated that the releasable pool of cytochrome c is determined by its interaction with cardiolipin, which undergoes a cytochrome c–mediated peroxidation.46 Whether cytochrome c release correlates with the loss of cardiolipin in hepatic I/R injury remains to be established. Accordingly, the contribution of apoptosis to hepatic I/R injury appears to be relatively minor as it normally occurs in isolated hepatocytes. In contrast, necrosis affects extensive areas of parenchymal cells consistent with the massive release of ALT in serum that reflects plasma membrane leakage, indicating that necrosis is the predominant form of liver injury during I/R.8 In line with this, recent studies in cyclophilin D null mice revealed a critical role of MPT in necrotic cell death in heart, liver, and brain.45
To examine the impact of ceramide in hepatic I/R injury, we inhibited ASMase and ACDase before surgery. Imipramine, a tricyclic antidepressant that inhibits the activity of ASMase due to the hydrolysis of the active ASMase form,16, 33 prevented the generation of ceramide post-reperfusion and decreased hepatocellular death. Although, unfortunately, the use of ASMase−/− mice was precluded because of pulmonary dysfunction and sensitivity to ischemia due to accumulation of sphingomyelin in their lungs,35 the suppression of ASMase in vivo by siRNA reduced the activation of ASMase, diminished ceramide generation, and protected the liver from I/R-induced damage, thus verifying the results observed with imipramine. Moreover, PTX, which has been reported to protect the liver against I/R injury,6 prevented the activation of ASMase and the consequent ceramide generation by I/R (Fig. 1C). In contrast, the inhibition of ACDase resulted in enhanced ceramide content and potentiation of the I/R-induced hepatic damage. Of potential clinical significance is the fact that in vivo pretreatment with imipramine extended the survival of mice subjected to total liver ischemia.
Mitochondrial Targeting by ASMase-Induced Ceramide.
Earlier studies in isolated mitochondria indicated that ceramide induced MPT and reactive oxygen species,10, 16 thus implying that the ceramide generation during I/R elicits MPT, with the phenotype of hepatocyte demise modulated by the extent of adenosine triphosphate depletion. The question that arises then is how ceramide targets mitochondria and regulates hepatocyte cell death during I/R. We discard the involvement of glucosylceramide and glycosphingolipids (such as GD3) generation in hepatic I/R injury. Consistent with these observations, I/R did not stimulate GCS, nor increased glucosylceramide or GD3 levels, and PDMP, a GCS inhibitor, failed to protect against I/R. These unexpected findings indicate that although the TNF-ASMase arm occurs in both isolated hepatocytes and hepatic I/R, the ASMase–GCS connection does not seem to occur in the latter. Whether this relates to differences in TNF dosage, signaling, or other factors requires further investigation.
We considered the possibility that ceramide targets mitochondria through activation of downstream effectors such as JNK.38, 39 Our data indicate first that I/R induced JNK phosphorylation, confirming previous findings,7 and second that imipramine prevented JNK activation. Thus, the contribution of JNK to hepatic I/R damage may be mediated through ASMase-induced ceramide formation (Fig. 7B). In agreement with these findings, the potent activation of JNK (eightfold) by exogenous ASMase47 has been reported in primary hepatocytes. Furthermore, the interaction of JNK with mitochondria has been reported during cell death,48, 49 opening the possibility that the role of JNK in hepatic I/R damage may be due to its interaction with mitochondria. However, the cytotoxic role of JNK may be attributable not only to its putative interaction with mitochondria but also to the activation of downstream targets, including BH3-only members of the Bcl-2 family such as Bim, which can be regulated by transcriptional and post-translational mechanisms.40, 50 Indeed, we have observed both the upregulation and phosphorylation of BimL, a Bim splice variant normally associated with microtubules through its interaction with the dynein light chain 1 that prevents its interaction with other Bcl-2 family members.50 The phosphorylation of BimL at threonine56 by JNK unleashes BimL from microtubules, allowing its redistribution and binding to Bcl-2.50 Consistent with this mechanism, we have observed the phosphorylation of BimL and its translocation to mitochondria during I/R, in agreement with previous findings in lung cancer cells,40 and this step was prevented by JNK inhibition (SP600125) or ASMase inhibition (imipramine) (Fig. 6D). Moreover, Bak has been involved in hepatic I/R injury in a JNK-dependent fashion,7 and hence we do not discard the participation of members of the Bcl-2 family of proteins. Thus, overall our findings indicate that the modulation of ceramide generation by ASMase during I/R regulates the mitochondrial pathway of hepatocellular death through JNK activation and subsequent mitochondrial translocation of BimL, suggesting that the modulation of ceramide may be a novel therapeutic approach to prevent post-ischemic liver injury.
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
The authors thank Susana Núñez for expert technical assistance. M. Marí, and A. Morales are Ramón y Cajal investigators.
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
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- 3Kupffer cell activation and endothelial cell damage after storage of rat livers: effects of reperfusion. Hepatology 1991; 13: 83–95., , , , .
- 4Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury. J Clin Invest 2005; 115: 849–859., , , , , , et al.
- 5Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest 1990; 85: 1936–1943., , , , , .
- 6Tumor necrosis factor alpha, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver. Gastroenterology 2002; 122: 202–210., .
- 7JNK mediates hepatic ischemia reperfusion injury. J Hepatol 2005; 42: 850–859., , , , , , et al.
- 8Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury. Gastroenterology 2003; 125: 1246–1257., .
- 9Ceramide in the eukaryotic stress response. Trends Cell Biol 2000; 10: 73–80., .
- 10Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species: role of mitochondrial glutathione. J Biol Chem 1997; 272: 11369–11377., , , , .
- 11Regulation of ceramide production and apoptosis. Annu Rev Physiol 1998; 60: 643–665., .
- 12Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J Biol Chem 2004; 279: 18384–18391., , , , , , et al.
- 13De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J Biol Chem 2002; 277: 25843–25846..
- 14Role of sphingomyelinase and ceramide in modulating rafts: do biophysical properties determine biologic outcome? FEBS Lett 2002; 531: 47–53., , .
- 15Natural ceramide reverses Fas resistance of acid sphingomyelinase(−/−) hepatocytes. J Biol Chem 2001: 276: 8297–8305., , , , , , et al.
- 16Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice. J Clin Invest 2003; 111: 197–208., , , , , , et al.
- 17Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 2004; 4: 604–616., .
- 18Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy. Nat Med 2000; 6: 1109–1114., , , , , , et al.
- 19Glycosphingolipids and mitochondria: role in apoptosis and disease. Glycoconj J 2004; 20: 579–588., , , , .
- 20Sphingomyelin synthase as a potential target for D609-induced apoptosis in U937 human monocytic leukemia cells. Exp Cell Res 2004; 292: 385–392., , , , , , et al.
- 21Overexpression of acid ceramidase protects from tumor necrosis factor-induced cell death. J Exp Med 2000; 192: 601–612., , , , , , et al.
- 22Sphingosine kinase, sphingosine-1-phosphate, and apoptosis. Biochim Biophys Acta 2002; 1585: 193–201., , , .
- 23Dual role of tumor necrosis factor-alpha in hepatic ischemia-reperfusion injury: studies in tumor necrosis factor-alpha gene knockout mice. HEPATOLOGY 2004; 39: 412–421., , , .
- 24Reperfusion after liver transplantation in rats differentially activates the mitogen-activated protein kinases. HEPATOLOGY 1997; 25: 1128–1135., , , , , , et al.
- 25Role of tumor necrosis factor alpha and sphingomyelin cycle activation in the induction of apoptosis by ischemia/reperfusion of the liver. Biochemistry (Mosc) 2002; 67: 1347–1355., , , , , , et al.
- 26Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor-induced lethal hepatitis. J Clin Invest 2004; 113: 895–904., , , , , , et al.
- 27Human placenta sphingomyelinase, an exogenous acidic pH-optimum sphingomyelinase, induces oxidative stress, glutathione depletion, and apoptosis in rat hepatocytes. HEPATOLOGY 2000; 32: 56–65., , , , , .
- 28Bimodal regulation of ceramidase by interleukin-1beta. Implications for the regulation of cytochrome p450 2C11. J Biol Chem 1997; 272: 18718–18724., , , , .
- 29The absence of functional glucosylceramide synthase does not sensitize melanoma cells for anticancer drugs. FASEB J 2003; 17: 1144–1146., , , , , , et al.
- 30Ganglioside GD3 sensitizes human hepatoma cells to cancer therapy. J Biol Chem 2002; 277: 49870–49876., , , , , .
- 31RNA interference targeting Fas protects mice from fulminant hepatitis. Nat Med 2003; 9: 347–351., , , , , , et al.
- 32Caspase 8 small interfering RNA prevents acute liver failure in mice. Proc Natl Acad Sci U S A 2003; 100: 7797–7802., , , , , , et al.
- 33The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts. Biol Chem Hoppe Seyler 1994; 375: 447–450., , .
- 34Ceramidase and ceramide synthesis in human kidney and cerebellum: description of a new alkaline ceramidase. Biochim Biophys Acta 1975; 398: 125–31., , , .
- 35Alveolar lipoproteinosis in an acid sphingomyelinase-deficient mouse model of Niemann-Pick disease. Am J Physiol Lung Cell Mol Physiol 2003; 284: L518–L525., , .
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- 37Lack of interferon response in animals to naked siRNAs. Nat Biotechnol 2004; 22: 1579–1582., , , , .
- 38Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 1996; 380: 75–79., , , , , , et al.
- 39Ceramide activates the stress-activated protein kinases. J Biol Chem 1995; 270: 22689–22692., , , , .
- 40Ceramide promotes apoptosis in lung cancer-derived A549 cells by a mechanism involving c-Jun NH2-terminal kinase. Cancer Res 2004; 64: 7852–7856., , , , .
- 41SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A 2001; 98: 13681–13686., , , , , , et al.
- 42The regulation of tumor necrosis factor-alpha production in murine mast cells: pentoxyfilline or dexamethasone inhibits IgE-dependent production of TNF-alpha by distinct mechanisms. Cell Immunol 1996; 171: 140–146., , , , .
- 43Purification and characterization of recombinant, human acid ceramidase: catalytic reactions and interactions with acid sphingomyelinase. J Biol Chem 2003; 278: 32978–32986., , , , , , et al.
- 44Roles for C16-ceramide and sphingosine 1-phosphate in regulating hepatocyte apoptosis in response to tumor necrosis factor-alpha. J Biol Chem 2005; 280: 27879–27887., , , , , .
- 45Loss of cyclophilin D reveals a critical role of mitochondrial permeability transition in cell death. Nature 2005; 434: 658–662., , , , , , et al.
- 46Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors. Nat Chem Biol 2005; 1: 223–232., , , , , , et al.
- 47Deoxycholic acid activates c-Jun N-terminal Kinase pathway via FAS receptor activation in primary hepatocytes. J Biol Chem 2004; 279: 5821–5828., , , , , , et al.
- 48Direct activation of mitochondrial apoptosis machinery by c-Jun N-terminal kinase in adult cardiac myocytes. J Biol Chem 2002; 277: 10244–10250., , , , , , et al.
- 49Translocation of SAPK/JNK to mitochondria and interaction with Bcl-xL in response to DNA damage. J Biol Chem 2000; 275: 322–327., , , , , , et al.
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Supporting Information
- Top of page
- Abstract
- Materials and Methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
Supplementary material for this article can be found on the H EPATOLOGY website ( http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html ).
Filename | Format | Size | Description |
jws-hep.21285.mtd.doc | 29K | Supporting Information file jws-hep.21285.mtd.doc |
Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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Poll 3/11/14 The Bachelor Has Spoken — Did Juan Pablo Pick the Right Woman? After an emotional finale, Juan Pablo handed out his final rose. by Maggie Pehanick 178 Shares
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Town Square
Police hail Menlo Park woman's actions to catch suspect
Original post made on Apr 26, 2012
Read the full story here Web Link posted Thursday, April 26, 2012, 11:05 AM
Comments (1)
a resident of Menlo Park: The Willows
on Apr 26, 2012 at 3:09 pm
We sure could have used Kathy Barron's ever so vigilant eyes on that dark and sinister night last October when Mr. Bernstein's campaign sign for Virgina Chang Kiraly was vandalized.
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You can compare up to 3 cars
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Mario Paint lists
Wish List for Virtual Console Releases.0
This is a list of games that I would like to see on Virtual Console.
powermatt: Wishlist
konvikt: Collection
Psyael: Collection
Everygame I've Owned0
All the games that I have owned over the years.
My Top SNES Games.0
nintendoeats: Collection
Games of My Life0
LIST IS INCOMPLEATE Games that I remember playing, and have good memories of. Still working on this list.
My Top 100 Games of all Time0
This list is in no particular order. The list may change as time goes on, but its pretty accurate.
My SNES0
These are the games that I own0
95 of the first games that come to my mind0
I needed to make a huge list for one of the quests, so I figured I would just add the first 85 games that popped into my mind, and see who wins. ;)
100 Mario games.0
The only two games I'm including without Mario in the title of the game are Donkey Kong and Donkey Kong Jr. Only because these are the first games Mario appeared in. I won't be including Smash Bros. or any other game featuring him without his name in
... -
Obligatory List of Completed Games (With Unfunny Comments)0
Sometimes including unfunny comments! And yeah, some games have debatable meanings of "beaten" like fighting and rhythm games, but meh.
Games I've Beaten0
Games I've remember playing0
Just a list of games I remember playing. Keep in mind that I did not finish what's half of this list.
Games I have played0
I thought I'd make a list of all the games I've ever played. It seemed like the easiest way to hit a 95 item list.I must warn you, I'm over 20, and played some old/obscure stuff (some of it -- not all of it).I can't promise I finished all of them, o
... -
My SNES Collection0
My collection of Super Nintendo Entertainment System games
From The Beginning - Console games throughout the years0
---UNDER CONSTRUCTION--- The lists of lists. Every gamer has one and they are usually crazy huge. Mine is no exception. Unlike my other lists, I won't bother adding descriptions or Youtube videos. This list is mainly for myself so that one day I'll
... -
My all time favourite games OF ALL TIME!0
I figured just putting this list together would be interesting. I mean, what are my favourite games? *THIS LIST IS ONGOING* Horace, know that I got you covered.
My Favorite Retro Games0
Games that made me who I am0
Every Game I've Beaten (That I Remember)0
So somewhere in the darkness of the late 90s, I decided that the breadth of games that I had gone through merited a list. Perhaps for absurdity's sake, perhaps to try and convince myself to kick the "childish" habit; whatever the case, I now have pro
... -
My games.0
Title says it all... for some games I include a small description. these are all for my fudge load of consoles: http://www.giantbomb.com/profile/mariofreak1/my-consoles/46-56095/ lets just say i am a game collector. if you're wondering how i have
... -
My Gaming Collection0
I also list what console I own them for. Games I own for platforms they don't list: Cougar Boy: PuppetKnight, Dice Block, Bomb Disposer. Gameking: Starwars, Duckman, Brains, Catman. NOTE: I don't list games as Mac, so some of my PC games are Mac game
... -
Every game i've ever played0
PC Games0
April 5th, 2011 was a magical day indeed.
SNES Collection0
Ahhh, the Super Nintendo. My favorite console. Most likely my most complete colection with some factory sealed games! Pretty nice if I do say so myself...
Snesational SENS Games3
Nobody finds dyslexia as funny as I do. But I'd wager many people find SNES games as awesome as I do. Simply listing all the ones I've played would be a little extensive and probably (probably?) not that interesting to most, so here's an A-Z of SNES
... -
Slag: Collection
Games I used to own or have played0
This is a list of games I used to own or have played. Sad.
Games I've Played0
I barely have a life.
Xevabis' Collection
SNES/Super Famicom Collection0
The SNES was my first platform, as my dad had me playing MechWarrior when I was two. Naturally this would lead to may love of Mario World, F-Zero, Star Fox, and others.I have always loved the SNES so I figured I would by the Super Famicom to try it o
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Super Nintendo Collection0
This is the list of the Super Nintendo games that I currently own.
Every Single Mario Game to Date0
In honor of the release of New Super Mario Bros 2, I have decided to give a quick recap of the franchise from its origins to today by listing every single Mario game to date.
My SNES Collection0
This is the (ever growing) list of games I own for the SNES
My Physical Game Collection - SNES0
Need more dust covers
20+ years of video games.6
Man.... I've played a lot of games I guess.
Games I want in 20150


text:
The 12th-ranked Alabama baseball team suffered its first home series loss of the year, as the fifth-ranked Florida Gators defeated the Crimson Tide, 4-3, in a Southeastern Conference matchup on Saturday at Sewell-Thomas Stadium.
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No. 12 Alabama Baseball Falls to Florida 4-3 to Drop Series
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Rex Ryan signs a four-year deal, reportedly worth $11.6 million, to become New York Jets new head coach. Ryan replaces fired Eric Mangini.
Rex Ryan signs a four-year deal, reportedly worth $11.6 million, to become New York Jets new head coach. Ryan replaces fired Eric Mangini.
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Miami Dolphins Depth Chart Breakdown: Quarterbacks
Jets make it official: Todd Bowles to replace Rex Ryan as coach
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Jets Hire Todd Bowles As Next Head Coach
Story | Jan 14, 2015 | 6:52 PMNEW YORK — Todd Bowles is coming home and taking over as the New York Jets' head coach. The Jets hired the Arizona Cardinals defensive coordinator Wednesday to replace Rex Ryan, who was fired, along with general manager John Idzik, on Dec. 29 after... -
Brash and bold, Rex Ryan vows to build Buffalo Bills into bully
On The Fly: UConn's Cyle Larin Expected To Go Early In MLS Draft
People with knowledge of deal: Jets close to agreement to hire Cardinals' Todd Bowles as coach
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text:
The highly educated clinicians at The Peacemaker Center use their faith as true north when guiding clients to happier lives. Their counseling services cater to a wide array of issues, from those affecting the individual to ones eating away at families. And some zero in on more specific problems, such as eating disorders or drug and alcohol addictions.
Situated on the west end of Trolley Square, The Delaware Center of Horticulture unfurls as a fragrant oasis for plant life amid the urban bustle of Wilmington. The colorful gardens frame the DCH depression-era main building, which houses an art gallery and regular workshops for local green thumbs. Since 1977, the cooperative efforts of philanthropic earthworms and volunteers have driven the nonprofit organization's plethora of public works and outreach efforts designed to enrich the existence of humans through the power of plant life. One such initiative, the Parks and Public Spaces program, has introduced rich greenery to pavement-laden private and public urban landscapes throughout the state.
Giggles and the pitter-patter of tiny, sock-swathed feet echo off the walls of Pump It Up, where lilliputian guests pinball through a metropolis of inflatable slides and bouncy enclosures. During glow pop-in play, tykes frolic in the radiance of special lights, and in pirate-themed sessions, youngsters don costumes or just feel less self-conscious about the parrot permanently affixed to their shoulder. Small groups of ankle-biters tear through the facility during private parties, plummeting down slides, scaling plush ladders, and bounding off of springy floors.
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Boasting one of the area's only master goldsmiths, Stephen's Jewelers crams its displays with everything from watchstraps and batteries ($30–$60) to fine gold, silver, and platinum finery, as well as custom-designed pieces. The knowledgeable staff can help shoppers find something to cover naked appendages and pet bonsai trees in the boutique's selection of sterling-silver rings and pendants by Lilly Barrack, Sherry Tinsman, and Pam Ingersall ($75–$150). Custom rings, pendants, and other jewelry crafted in-house run the gamut from engagement-worthy bling to diamond-encrusted eye confections ($200+).


text:
Classic Double Room
Max Occupancy: 2 guests (up to 1 infant)Apartment, Annex Building
Max Occupancy: 4 guests (up to 1 infant)Deluxe Double Room
Max Occupancy: 3 guests (up to 1 infant)Deluxe Triple Room
Max Occupancy: 3 guests (up to 2 children, 2 infants)Family Room
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A restaurant, a bar/lounge, and a snack bar/deli are available at this inn. Free buffet breakfast, free WiFi in public areas, and free self parking are also provided. Additionally, dry cleaning, laundry facilities, and a 24-hour front desk are onsite.
Room Amenities
All 20 rooms feature thoughtful touches like bathrobes and slippers, plus minibars and LCD TVs with digital channels. Room service, coffee makers, and hair dryers are among the other amenities available to guests.
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Still 20 years old and has a great history in the cricketing field. But how many of Sri Lankans who love cricket know about this young spontaneous player? How many of us have at least bothered to go and check the background of him? More importantly how many of Sri Lankans actually know that this guy can be the next Mahela, Aravinda for Sri Lanka. He is a player who will bring pride to his alma mater Royal College Colombo without any doubt in the coming years through international cricket. The small breafing here is to introduce who Banuka is and what Banuka is capable of through what he has done till now in the arena.
Please visit : http://www.cricturf.com
Bhanuka Rajapaksa started turning heads in to his direction with a blistering 154 off 111 balls representing Sri Lanka u-19 team against Australia u-19 in Australia in 2009. Everyone who follows Sri Lankan cricket by heart sensed that next big star was born. They murmured that we have found next Sanath Jayasuriya.
Sri Lanka U-19 went to New Zealand for the u-19 world cup in 2010 having Bhanuka as the top gun, and he didn't disappoint his fans. He ended the tournament as the highest run getter for the country with 253 runs. In this tournament he brushed off any doubts people had regarding him as a dasher, he showed great temperament and excellent stroke play.
Bhanuka had a superb career as a schoolboy at Royal college, and he continued that in the international U-19 level, one can only hope that he would become what people want him to be; a legend.
In 2011, Bhanuka became only the third individual to be adjudged as the 'Schoolboy Cricketer of the Year' twice in the country's premier school sector awarding ceremony 'Observer-Mobitel Schoolboy Cricketer of the year'. He plays his domestic cricket for Sinhalese Sports Club and as well wishers to the Sri Lankan Cricket we want him to be the match winner that he promises to be.
Something interesting we found while going through some figures and facts of Bhanuka in comparison with Dinesh Chandimal and Lahiru Thirimanne who are two young players in the national site at their U-19 international level was that Bhanuka has a very high average and a strike rate. Chandimal in U19 International 50 overs has an Average of 26.04 with a Strike Rate of 74 and Lahiru has an Average of 35.86 with a Strike Rate of 67. However, the highlighting factor is Bhanuka has an Average of 35.86 and a huge Strike Rate of 99.8 which again proves he is the perfect material for an attacker. And at the moment, entire country is thinking of Chandimal and Thirimanna and how great these two batsmen can be in future. But looking at the above records it shows how good Bhanuka can be if he does this way of performance in the national side.
" In U19 International 50 overs : Dinesh Chandimal : Ave 26.04 || SR 74 , Bhanuka Rajapakse : Ave 35.86 || SR 99.8, Lahiru Thirimanne : Ave 25.28 || SR 67 "
Also, during the U19 WC 2010, the popular Cricket commentator Sanjay Manjrekar told in his commentary that Bhanuka reminds him of young Sachin Tendulkar. This is not an easy complement to get from him and especially from an Indian where the country prays Sachin as a god.
" He (Bhanuka) reminds me Sachin Tendulkar in his age. Bats, bowls and always in the game. " (01-24-2010)
Please visit : http://www.cricturf.com
Finally, the brief chat we had with Bhanuka showed us his eager and the hope filled eyes that are waiting to play for the National side to make the country proud. An exclusive interview with Bhanuka will be carried out in few days by Cricturf and we hope our fans will wait for it


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All of our Custom and Made-to-Order Corsets are non-refundable and non-returnable. Please fill out our custom measurements form and contact us with any questions. We are happy to help!
We highly recommend calling (1-888-5-CORSET) or emailing us your measurementsor submitting your measurements online BEFORE buying to help you find a corset that will fit you AND make you feel fabulous! You can also check out our blogon selecting the right corset.
This satin corset with lace trim offers extreme waist reduction. Fluted panels emphasize the feminine shape and flatten the tummy. This corset is best for figures that are full in the hips. For narrower hips style #20-c220 may be a better fit. Front length is 11.5". Steel boning and busk, back lacing. Fully lined. Front length is 11". Corset Sizes:18-30" / 46-76cm, Front Length: 11.5" / 29cm.
Corsets should, on average, be ordered 4-6 inches below your natural waist size. Every corset that we sell is made according to its own unique pattern, and each corset style is designed to fit a particular figure type. If you have any questions regarding the fit of the corset you would like to order, please submit your measurements.
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**Made to order, non-returnable item. Please submit your measurements to ensure the right fit.


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Dubai: An American human rights activist, who intended to observe a protest-related trial in Bahrain, was denied entry into Bahrain on Sunday despite authorities' pledge of transparency.
US rights activist denied entry into Bahrain
Sollom wanted to be present at the trial of doctors and nurses who treated injured protesters
Richard Sollom, deputy president of the US-based Physicians for Human Rights, told The Associated Press that Bahraini airport authorities gave no reason for their refusal to allow him into the country.
Sollom charged that Bahrain authorities do not want international observers at the trial of doctors and nurses who treated injured protesters, which was scheduled for yesterday. International human rights organisations have harshly criticised the prosecution of the health professionals who were working at the state-run Salmaniya Medical Centre during the massive protests in February and March.
"I am quite stunned. This was the first time a member of an international rights organisation came to Bahrain after authorities promised to respect human rights and told us we can come and see for ourselves," Sollom said in a telephone interview after he landed in Dubai Sunday evening.
"We can see now that not much has changed," he added. Bahraini authorities could not immediately be reached for comment.
Anti-state crimes
Sollom holds a US passport. He arrived in Bahrain on Sunday morning with a five-year, multiple entry visa. He said he wanted to observe yesterday's retrial of 21 doctors and nurses who were convicted last year of anti-state crimes and received lengthy prison sentences from a special security court.
The government has accused the medics of participating in efforts to overthrow the ruling Al Khalifa family.
In November, independent investigators tasked by Bahrain's king to probe the unrest were highly critical of the special security court that has tried the medics, opposition leaders and activists behind closed doors. A 500-page report by the Bahrain Independent Commission of Inquiry said the court has issued harsh sentences — including life in prison and death penalties — and "denied most defendants elementary fair trial guarantees".
The document also spotlighted abuses at the Salmaniya hospital.
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100 views, 9 favourites, 13 July 2013
Featured in THE WORLD AS WE SEE IT OR AS WE MISSED IT! on 22 June 2013 and in HIGH QUALITY IMAGES on 9 July 2013
These two beautiful roses would have to share the prize, if they were in a beauty contest for flowers! Growing in our garden in the North-East of England and captured with my Canon PowerShot SX40 HS camera in Macro mode.
My life is divided between teaching Music and Photography. The instruments I play are organ, piano, clarinet and saxophone. I taught German and Spanish before my retirement, but since I got my digital camera no longer have time for them!
View Full ProfileA wonderful capture.
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– BlueMoonRose
lovely Roses, xx
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– BlueMoonRose
Very nice capture
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– BlueMoonRose
A wonderful capture,lovely roses!
Thank you, dear Ana.
– BlueMoonRose
Gorgeous capture!!
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These roses are gorgeous… fantastic capture !!! ☺♥
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lovely roses
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– BlueMoonRose


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Genre/Form: | Diaries |
Named Person: | Henry Hollister; Annie Lane; Elizabeth Sears |
Document Type: | Archival Material |
All Authors / Contributors: | Shakers. |
OCLC Number: | 155494836 |
Description: | 2 v. |
One volume probably kept by Henry Hollister with description of land purchases, erection of buildings, and severe freezes, 1890-1895; and one volume written by Annie Lane and Elizabeth Sears concerning the founding of the Narcoossee community, 1895-1900.
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Photo SpecialSurprise! We're Married!
From secret ceremonies to whirlwind romances, see the couples (Chad & Sarah! Cameron & Benji!) whose weddings took the world by surprise
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It's always the battery
I own HTC phones since 2008. I started with the HTC HD2. That was an incredible phone. The whole world changed for me. Later I switched to a HTC HD7, another great mobile. Later on I felt in love with the HTC Titan and I own this phone nowadays. In the meantime I had a HTC 8x. My first dissapointment with HTC. Now, I've got this HTC ONE XL. I don't have the money to buy the HTC ONE, so let's wait a little longer. With this phone and every phone from HTC I'm having a great experience. Excellent build quality, the screen is piece of art. But just like every smartphone today (including S4, Iphones etc), the battery just won't last for a whole day. Since I'm used to charge my phones everyday for the last 5 years, I'm giving a 5 All Star Rating for this phone.


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Burial Life Insurance
Final Expense Life Insurance Highlights
- Specialized life insurance policy used for funeral expenses or to provide money for family.
- Easy underwriting and NO medical exam
- Death benefits as low as $1,000 and can exceed $100,000+ depending upon a family's needs.
- Premiums won't increase & Benefits won't decrease with most policies


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Vanessa: I still have a couple of questions for you my info shows Zacharias children but no Soloman. Where does Soloman show up on your grup sheets. I have Zachariah and Anna having five children Johann Christofel (1720-1727) Unnamed infant (1721-1721) Johann Wilhelm (1723-1794) Anna Margaretha (1726-1785) and Johann Gerhardt (1728-1789). Where is our Soloman. I sure appreciate your help with this and hope that you can give me a little more info. thanks Sharron
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© 2007 The Generations Network |


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Business Communications Blog
- October 21, 2013
- VPN: A Powerful Tool for Tough Security Issues and Maintaining Compliance
With cyber threats becoming increasingly common, do you want a secure yet flexible way to access your corporate data and applications from outside the office? You need a VPN. A VPN (Virtual Private Network) secures a user's Internet connection by encrypting all data that is sent and received.
- By Melinda Gaw
- Comments(0)
- October 14, 2013
- Your Business Backup Plan - Managed Broadband Failover
If your business can't afford even a minimal service disruption, you should consider a cost-effective failover solution to maintain critical operations.
- By MegaPath Marketing
- Comments(0)
- October 7, 2013
- Asymmetrical Ethernet Advantages Over Cable
You've probably heard cable Internet services touted as business-ready. Although these services are appropriate for some situations, they often do not qualify as business-class. When you are choosing an Internet Service Provider for your business, look for one that has built its services around the needs of businesses and offers a range of fast, reliable access services.
- By MegaPath Marketing
- Comments(0)
- September 30, 2013
- 5 Ways Businesses are Streamlining Communications and Cutting Costs
Let's examine 5 ways businesses are streamlining communications and cutting costs by moving to a Hosted Voice over IP (VoIP) solution.
- By MegaPath Marketing
- Comments(1)
- August 26, 2013
- Is Cable Internet Access Really Right for Your Business?
If you've heard the hype about cable Internet for business, here are three important questions to ask the provider first.
- By Pasha Mohammed
- Comments(0)


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Mayor Todd Strange welcomes the Bassmaster Elite Series to Montgomery, Ala., for the second half of 2010 Toyota Trucks Championship Week.
Mayor Todd Strange welcomes the Bassmaster Elite Series to Montgomery, Ala., for the second half of 2010 Toyota Trucks Championship Week.
Russ Lane won the first leg of the 2010 Toyota Trucks Championship Week, held on Lake Jordan in Wetumpka, Ala. Aaron Martens finished a very close 2nd.
Cliff Pace, Greg Hackney, and John Crews visited about the upcoming tournament on the Alabama River.
Anglers arrive for Media Day in downtown Montgomery, Ala.
Members of the media begin to arrive and prepare their cameras for interviews.
Elite Series competitors and assembled media enjoyed lunch.
Skeet Reese does an interview with a local television station.
Dynamic Sponsorship's Alan McGuckin interviews Elite Series veteran Tommy Biffle.
Terry Butcher pens his autograph to a poster that includes all the anglers that qualified for the 2010 Toyota Trucks Championship Week.
John Crews autographs a set of cards with a photo of him holding one of his best fish caught during his win this year on the California Delta.
Russ Lane does an interview with a Montgomery, Ala., television station.
Kevin VanDam was a popular interview during Media Day.
On an off day from tournament fishing, Elite anglers traveled to the Bass Pro Shop in Prattville, Ala., to meet and greet fishing fans.
One of the more popular items noticed by the Elite Series pros was a rack of chilly pads, which they thought might help beat the Alabama heat.
Fishing fans line up for a chance to meet their favorite Elite Series pro.
Anglers take a seat to sign autographs and visit with fishing fans.
Kevin VanDam and Aaron Martens sign caps for two young fishing fans.
BASS, in conjunction with Hope For The Warriors, invited 12 wounded heroes to fish with the Elite Series pros on a private lake on Tuesday.
Russ Lane will be paired on Tuesday with John Lightsey.
Tommy Biffle was all smiles about fishing with Ryan Anderson.
Aaron Martens greets his fishing partner for Tuesday, Robert Hawkins.
Jake Keeslar has limited experience fishing, but will have one of the best to learn from, Kevin VanDam.
Timothy Murray was happy to be paired with Elite Series pro Edwin Evers.
After being paired with their Elite Series fishing partners, the wounded veterans were treated to a $200 Bass Pro Shops gift card in the Prattville Bass Pro Shop.
Edwin Evers helps Timothy Murray choose a rod and reel combination.
After leaving the Prattsville Bass Pro Shop, Russ Lane was hustled to the home field of the Montgomery Biscuits to throw out the first pitch.
Russ Lane waits to throw out the first pitch in a game pairing the home team, Montgomery Biscuits, against the Carolina Mudbugs.
Russ Lane's family, Elite Series anglers, and BASS staff watched Russ Lane throw out the first pitch from a skybox above the field.
Russ Lane with the ball he would use to deliver the first pitch.
Elite Series pro Terry Butcher and BASS Tournament Director Trip Weldon had a great seat to watch the Biscuits defend their home field.
Isolated rain showers begin to gather in the distance during the early innings of the game.
A temporary rain delay was the only glitch in a day off for the Elite Series pros competing in the Toyota Trucks Championship Week.


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Air Jordan 1 "Chinese New Year" Customs by The Remade by Patrick Johnson 3 Comments
April 23, 2013 BY Brendan Dunne / 6 c
If you're not a Zig Zag user and Raw papers are more your thing, then this Sab-One custom is for you. The pair uses the Air Jordan 1 as its base and slaps on a crisp brown colorway inspired by your favorite organic papers for do-it-yourself "cigarette" making. The pair even gets the hemp fiber aspect in there via the rugged looking laces. We've seen Nike SB come with some 4/20 nods from time to time, but we all know that Jordan Brand is never going to take it that far so we're glad to see a custom creaiton fill the void. Reconvene after the jump to see extra shots of the Air Jordan 1 "Raw" customs and tell us how dope these are in the comments.
Photos: PoT
Filed under: Air Jordan Customs
Tags: Air Jordan 1 Sab-one
Air Jordan 1 Mid "Hare" – New Images by Patrick Johnson 12 Comments
Dover Street Market x Air Jordan 1 by John Kim 13 Comments


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University of Missouri
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The 2014 Farm Bill contains several provisions that enable farmers and landowners to make decisions regarding their involvement in federal farm programs. Landowners will have the opportunity to reallocate base acres on individual farms as well as update yield information that is used to determine some farm program payments. Additionally, farmers will have the opportunity to elect to participate in the new commodity programs - Price Loss Coverage (PLC) and Agriculture Risk Coverage (ARC). To provide information on the new farm bill and assist landowners and farmers in making program decision, University of Missouri Extension and USDA Farm Service Agency are teaming up to host educational meetings. To see a list of some of these meetings near Johnson County, click here.
Dedra Thomas is the newest member to the Extension office. Dedra is a Family Financial Education Specialist. Information her program covers is planning, implementing and evaluating educational programs in financial literacy, money management, estate planning, food resource management, debt management and consumer issues for low income audiences. For more information or to set up an appointment to meet with Dedra, please call the office at 660-747-3193.
We are excited to announce Missouri 4-H Center for Youth Development is transitioning enrollment to Missouri 4HOnline beginning today! Please log on at http://mo.4honline.com. A link to the detailed, step-by-step instructions is included on the login screen, but we think you will find the system very easy to navigate.
In order to assist families with this transition, the University of Missouri Extension Johnson County office will be open at the following times for families to receive assistance setting up their accounts and ask any questions.
Monday through Friday, 8:30 am to 4:30 pm.
We look forward to a great year and appreciate your support and patience as we work together to Make the Best Better for Johnson County 4-H!
Master Gardeners are adults of all ages and all gardening skills who enjoy gardening. They are interested in lawns, shrubs, trees, flowers, vegetable gardens and caring for the environment. They are also interested in learning from each other and sharing what they know with other Master Gardeners and their community friends and neighbors. A Master Gardener Trainee can be anyone who wants to learn more about gardening, lawn, and shrub care, and sustaining the environment. You do not have to be an expert to join. You will not have to take exams or give presentations in class. You must, however, have a desire to learn, make a commitment to complete 30 hours of volunteer community service the first year, and to complete 2- hours of service each successive year to remain active in the program. The 12 session training starts February 3rd through April 28th on Tuesday nights from 6 pm to 9 pm. All classes are held in Grinstead Hall, University of Central Missouri. The one-time program fees are $130 for individuals and $225 per couple. The fee covers all class training materials. Couples receive only one set of materials. For more information, contact Master Gardener Maggie Stone, 660-747-7715.
Registration Form
As a Small Farm Outreach Worker, Phillip Boydston helps provide information and assistance to both rural and urban farmers and ranchers, with an emphasis on underserved and socially disadvantaged populations. Farm Outreach Workers (FOWs) provide information on ways to better manage your resources, reduce expenses and increase income. They also provide information on other available programs and resources that may improve your farm management practices and income. At your request, an FOW will make an appointment to visit with you and your family on your farm and discuss goals and plans. For more information or to set up an appointment, contact Phillip at 816-726-7720 or email@example.com
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Gamecocks Practice Monday Night
Aug. 27, 2012 COACH MANGUS POST-PRACTICE COMMENTS
August 27, 2012 FEATURED VIDEOS
Junior quarterback Connor Shaw missed a practice last week with back spasms, but is deemed ready to go for Thursday. "Connor's the starting quarterback right now," said quarterbacks coach G.A. Mangus. "We expect him to go out there and play well." Mangus was asked about the Commodore defense. "Vanderbilt is aggressive, very aggressive, sound, smart. They've been that way all along. They're in their right spots and make you execute. They've traditionally had good secondary players and they've got a couple returning that are good players. They'll be ready to play. We're looking forward to it." Mangus, who has been a key recruiter in the New Jersey area for the Gamecocks, has seen two of his recruits depart this fall in redshirt freshmen Tanner McEvoy and Sheldon Royster. "It happens all the time. It's just coincidence," said Mangus. "It happens that guys leave all the time around college football. We wish them well. Sometimes it works out and sometimes it doesn't." Mangus went on to say that it would not deter him from continuing to recruit that area of the country. The Gamecocks will return to the practice fields on Tuesday afternoon at 4 p.m. Head coach Steve Spurrier will host his weekly radio show on Tuesday night at 7 p.m. from Wild Wings Café in the Vista.
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Spring Cleaning, Carpet and Ceramic Tile Cleaning, Wood Floor Cleaning & Restoration
Read More..
Around the country, several Jani-King regional offices and franchisees have partnered with the corporate hospitality team to add new hotel and resort clients during the past few months. In Los Angeles alone, three new hotels have been signed while, just up the coast in San Francisco, Jani-King has also signed a luxury boutique property, Hotel Milano. Read More..
According to a new IFA survey, more than 50,000 veterans have found employment in the franchise industry over the past year and more than 400 veterans have become local franchise business owners. Since 2011, the franchise industry has hired and recruited more than 203,890 veterans, military spouses and wounded warriors — including 5,608 new veteran franchisees. Read More..
The Jani-King PGA Tour Professionals are Making Their 2015 Debut at The Sony Open Read More..
In March, Jani-King reported on several major account signings within the Environmental Services division. Read More..
Jani-King's corporate office, regional offices and franchisees took advantage of terrific opportunities over the last year to grow their businesses. For instance, Jani-King was rated the top commercial cleaning franchise by Franchise Direct, hotel business was hot, Austin went to space, Dallas prepared for Ebola and regions across the globe created their own success stories. Let's take a look back at some of the highlights that occurred in Jani-King in 2014. Read More..


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Dr. Craig I. Title, MD
Family Medicine, New York Center For Medical Weight Control
- 200 W 57th St Ste 401
New York, NY 10019 - 1 Office Location
- (212) 581-9532
Dr. Craig I. Title graduated from the Boston University School of Medicine in 1996. He works in New York, NY and specializes in Family Medicine and Bariatrics. Dr. Title speaks English and Spanish.
Gender: Male
Years in Practice: 19 Years
Languages Spoken: English, Spanish
Medical School: Boston University School of Medicine
Graduation Date: 1996
Hospital Affiliations: Not Available
Specialties: Family Medicine, Bariatrics


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Cars > stroker461's Garage
About stroker461's Garage
About me and my passion for cars
well my passion for cars when i was young, my best friend david bought a 73' Nova SS he built anawsome motor for it, all that had was the little s-10 blazer didn't have a built motor but did have the loudest stereo system around town extra battery's to run it, it was built for competition use, then i bought my 74' bird it didn't have the original 400 in it but did have a built 455 man that thing was quick i would run anything that pulled up next to me and rarely lost, anyways it was bad lol.
My first car
84 s-10 blazer
Car I wish I still had
still have it my 74' formula 400 firebird
My dream car
im building it now my 74' with a 70' front end on it, i like the 74' tail lights better than the 70' but the 70' front end better, yea i know its not original but im buildin what i want not what others want thats the whole point of building a car for yourself right????
Car clubs I'm in
none but i would like to start one with all of my friends and hit up the car shows when ever i get my car back on the road...
- Type of racing: drag racing
- Driver: ME
- Driving song: anything metallica
- Car movie: smokey and the bandit
- Car book: how to build high performance pontiac's
- Car magazine: hot rod and high performance pontiac
- Car game: full auto
— Profile last updated: Nov 27, 2011
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Next Generation Air Transportation System:
FAA Has Made Some Progress in Implementation, but Delays Threaten to Impact Costs and Benefits
GAO-12-141T: Published: Oct 5, 2011. Publicly Released: Oct 5, 2011.
Additional Materials:
- Full Report:
- Accessible Text:
(202) 512-4803
Office of Public Affairs
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This testimony discusses the current progress toward implementing the Next Generation Air Transportation System (NextGen). NextGen will impact nearly every aspect of air transportation and will transform the way in which the air transportation system operates today. It will do so, in part, by (1) using satellite-based surveillance as opposed to ground-based radars, (2) using performance-based navigation instead of cumbersome step-by-step procedures, (3) replacing routine voice communications with data transmissions, and (4) organizing and merging the disjointed data that pilots, controllers, airports, airlines, and others currently rely on to operate the system. The Federal Aviation Administration (FAA) has been planning and developing NextGen since 2003, and is now implementing near-term (through 2012) and mid-term (through 2018) capabilities. Over the years, concerns have been raised by the Congress and other stakeholders that despite years of effort and billions of dollars spent, FAA has not made sufficient progress in deploying systems and producing benefits. In past reports, we have made a number of recommendations to FAA to address delays in development and acquisitions, improve its processes, and focus on accountability and performance. Others have also made recommendations to FAA to improve its implementation of NextGen. For example, the Department of Transportation's Office of the Inspector General recently made recommendations regarding specific NextGen programs, and the NextGen Midterm Implementation Task Force--whose creation was requested by FAA--resulted in consensus recommendations from industry on specific capabilities FAA should prioritize. Over the last 2 years, FAA has taken several steps and instituted many changes to address several of these issues. This statement today discusses (1) the results of NextGen programs and improvements to date and (2) ongoing issues that will affect NextGen implementation. This statement today is based on our NextGen-related reports and testimonies over the last 2 years; ongoing work for this subcommittee that includes our analysis of selected NextGen acquisitions and our analysis of FAA's efforts to harmonize NextGen with air traffic control modernization efforts in Europe; our review of FAA's 2025 Strategic Plan, 2011 NextGen Implementation Plan, 2012 Budget Submission, and other documents; and selected program updates from FAA officials.
In summary, FAA has improved its efforts to implement NextGen and is continuing its work to address critical issues that we, stakeholders, and others have identified over the years. In some areas, FAA has implemented NextGen capabilities that have demonstrated measurable benefits for system users, such as fuel savings. FAA has also made progress in streamlining its processes, improving its capacity to develop new flight procedures, and focusing its efforts on specific procedures that are needed in key metropolitan areas. Furthermore, we found that several NextGen-related acquisitions are generally on time and on budget. However, some acquisitions have been delayed, which has impacted the timelines of other dependent systems, and the potential exists for other acquisitions to also encounter delays. These delays have resulted in increased costs and reduced benefits. Going forward, FAA must focus on delivering systems and capabilities in a timely fashion to maintain its credibility with industry stakeholders, whose adoption of key technologies is crucial to NextGen's success. FAA must also continue to monitor how delays will affect international harmonization issues, focus on human factors issues, streamline environmental approvals, mitigate environmental impacts, and focus on improving management and governance.
Jan 21, 2015
Aviation Safety:
Issues Related to Domestic Certification and Foreign Approval of U.S. Aviation ProductsGAO-15-327T: Published: Jan 21, 2015. Publicly Released: Jan 21, 2015.
Jan 16, 2015
Surface Transportation:
DOT Is Progressing toward a Performance-Based Approach, but States and Grantees Report Potential Implementation ChallengesGAO-15-217: Published: Jan 16, 2015. Publicly Released: Jan 16, 2015.
Jan 12, 2015
Commercial Aviation:
Raising Passenger Facility Charges Would Increase Airport Funding, but Other Effects Less CertainGAO-15-107: Published: Dec 11, 2014. Publicly Released: Jan 12, 2015.
Jan 9, 2015
Transportation Disadvantaged Populations:
Nonemergency Medical Transportation Not Well Coordinated, and Additional Federal Leadership NeededGAO-15-110: Published: Dec 10, 2014. Publicly Released: Jan 9, 2015.
Dec 19, 2014
Airport Privatization:
Limited Interest despite FAA's Pilot ProgramGAO-15-42: Published: Nov 19, 2014. Publicly Released: Dec 19, 2014.
Dec 10, 2014
Public Transit:
Federal and Transit Agencies Taking Steps to Build Transit Systems' Resilience but Face ChallengesGAO-15-159: Published: Dec 10, 2014. Publicly Released: Dec 10, 2014. -
Transportation for Older Adults:
Measuring Results Could Help Determine If Coordination Efforts Improve MobilityGAO-15-158: Published: Dec 10, 2014. Publicly Released: Dec 10, 2014. -
Unmanned Aerial Systems:
Efforts Made toward Integration into the National Airspace Continue, but Many Actions Still RequiredGAO-15-254T: Published: Dec 10, 2014. Publicly Released: Dec 10, 2014.
Nov 18, 2014
Highway Projects:
Many Federal and State Environmental Review Requirements Are Similar, and Little Duplication of Effort OccursGAO-15-71: Published: Nov 18, 2014. Publicly Released: Nov 18, 2014. -
Public Transportation:
Multiple Factors Influence Extent of Transit-Oriented DevelopmentGAO-15-70: Published: Nov 18, 2014. Publicly Released: Nov 18, 2014.
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