text:
Big Savings for the Long Holiday Weekend
Big Savings for the Long Holiday Weekend
10 cents Per Litre Off All Fuel Grades at Gull
Auckland, 23 January 2014 – Fuel savings ahead of the Auckland Anniversary weekend were announced today by Gull, New Zealand's only family owned fuel retailer.
The discount day starts at 7am Thursday 23 January, at participating Gull sites, and runs until midday Friday 24 January. Regular 91 will be priced at $1.999, well below most of the bigger players in the market.
Even bigger savings are possible at
Gull's manned sites, when paired with Countdown fuel
vouchers, says Graham Stirk, Gull New Zealand Retail
Business Manager.
"Gull is all about delivering value. We know that many families are still on holiday, enjoying a last long weekend before school starts for the year. We'd like our customers to spend as little on getting to and from their destination as possible, and have more money to spend on the family."
At the majority of Gull outlets where Gull controls retail prices, prices are as follows:
Fuel Grade
Unmanned Site
Manned Site
Regular (91 Octane)
Low Sulphur Diesel
Gull unmanned sites accept payment via EFTPOS or PIN
operated credit or debit card.


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subset: commoncrawl


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During development and in pathological contexts such as fibrosis and cancer progression, epithelial cells can initiate a complex transcriptional reprogramming, accompanied by dramatic morphological changes, in a process named 'epithelial-mesenchymal transition' (EMT). In this transition, epithelial cells lose their epithelial characteristics to acquire mesenchymal properties and increased motile and invasive behavior. Transforming growth factor-β (TGF-β) has emerged as a major inducer of EMT through activation of downstream signaling pathways, including Smad and non-Smad signaling pathways. Among the non-Smad pathways, increasing evidence is emerging that the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin axis plays a major role in TGF-β-induced EMT, notably through the regulation of translation and cell invasion. Pharmacological inhibitors of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin pathway may therefore represent an opportunity to selectively target essential aspects of TGF-β-induced EMT and provide an approach to prevent cancer cell dissemination toward metastasis, without the need to fully inactivate TGF-β signaling.
During development, in response to injury, inflammation and pathological conditions, epithelial cells show a remarkable differentiation plasticity. A manifestation of this plasticity is the process that has been named 'epithelial to mesenchymal transformation' or 'transdifferentiation', but is now more commonly referred to as 'epithelial-mesenchymal transition' (EMT). In EMT, the loss of epithelial characteristics, such as intercellular contacts and cell polarity, is complemented by the acquisition of mesenchymal characteristics and increased cell motility and invasion (fig. (fig.1).1). This transition involves a complex transcriptional reprogramming and non-transcriptional signaling events that contribute to major changes in cell morphology and behavior. Depending on the physiological and tissue contexts, cells that have undergone EMT can revert to reacquire their epithelial characteristics, thus leading to a mesenchymal-epithelial transition [Kalluri and Weinberg, 2009]. Over the last 15 years, transforming growth factor-β (TGF-β) has been shown to function as a potent inducer of EMT, with its signaling pathways intimately involved in the activation and progression of EMT [Moustakas and Heldin, 2007; Miyazono, 2009; Xu et al., 2009].
Three types of EMT with distinct functional consequences have been distinguished, depending on the developmental and physiological context [Kalluri and Weinberg, 2009]. Type 1 EMT is linked to developmental processes. During vertebrate embryonic development, EMT occurs in a precise and programmed spatiotemporal manner, starting as early as gastrulation, when it mediates the formation of the mesoderm. EMT is also a key process in the delamination of neural crest cells that disperse to give rise to a variety of cell types, including osteoblasts, chondrocytes and muscle cells. At later stages, an EMT-like process allows endothelial cells to transition into mesenchymal cells, e.g. in heart development. EMT is also involved in the fusion of the palatal shelves and in Müllerian duct regression [Acloque et al., 2009; Thiery et al., 2009]. The 2 other types of EMT are not involved in normal development, but occur in response to injury or inflammation and are at the basis of pathological processes. Type 2 EMT occurs in wound healing, tissue repair and regeneration and is also associated with inflammation-induced fibrosis. Such fibrosis involves a mesenchymal conversion of epithelial cells in addition to an infiltration and proliferation of fibroblasts [Iwano et al., 2002; Kalluri and Neilson, 2003]. Finally, during tumor progression, carcinoma cells can escape the environment of the primary tumor by initiating an EMT process, resulting in motility and invasive behavior which potentially leads to metastasis at distant sites. Once in the new loci, these cancer cells can then revert through mesenchymal-epithelial transition to form metastatic carcinomas. The EMT associated with cancer invasion and progression has been classified as type 3 EMT [Thiery and Sleeman, 2006; Kalluri and Weinberg, 2009; Klymkowsky and Savagner, 2009].
The transition from an epithelial to a mesenchymal phenotype involves dramatic changes in gene expression, as well as in cell morphology and behavior (fig. (fig.1).1). An early step in EMT is the dissolution of epithelial cell junction complexes that mediate cell-cell adhesion. These specialized junction complexes consist of transmembrane molecules that, through interactions with adaptor proteins beneath the plasma membrane, interact with the actin cytoskeleton, intermediate filaments or microtubules. Among these complexes, tight junctions contain occludin and claudins that bind zonula occludens proteins, adherens junctions are characterized by E-cadherin that binds to β- or p120-catenin, gap junctions contain connexins, and desmosomes consist of desmosal cadherins that bind proteins in the submembranous plaque. The rapid delocalization of these junctional proteins and the downregulation of their expression represent early steps in EMT that lead to the individualization of the cells [Thiery and Sleeman, 2006; Xu et al., 2009]. Concomitantly, the cells lose their apical-basal polarity and epithelial cell architecture. Two polarity complexes, one composed of Par3 and Par6, and the other one comprising Crumbs-3, localize predominantly to tight junctions and are disrupted when the tight junctions are disassembled [Moreno-Bueno et al., 2008]. Accompanying the disassembly of the junction complexes, the cortical actin cytoskeleton is reorganized through the activities of Rho-like GTPases (Rho, Rac and Cdc42) into stress fibers extending within lamellipodia and filopodia. In these stress fiber-enriched protrusions, actin can dynamically polymerize and depolymerize allowing for enhanced cell motility [Zavadil and Böttinger, 2005; Yilmaz and Christofori, 2009].
Since many of the junction complex proteins characterize epithelial cells, the dissolution of the junctions results in a loss of many epithelial marker proteins. Among them, decrease in E-cadherin expression has become a major indication of loss of epithelial characteristics. Further, the expression of other epithelial proteins, such as epithelial-specific cytokeratins, is also downregulated. In EMT, the loss of epithelial markers is accompanied by an induction of the expression of mesenchymal proteins, such as vimentin. In addition, expression of N-cadherin, a mesenchymal protein that promotes migration and invasion, increases while the expression of E-cadherin decreases. EMT is also marked by increased expression of matrix metalloproteinases, which degrade extracellular matrix, and extracellular matrix proteins such as fibronectin, collagens or laminin [Zavadil and Böttinger, 2005; Zeisberg and Neilson, 2009]. Together, loss of epithelial protein expression, changes in cell shape and expression of mesenchymal proteins result in a motile cell behavior that allows invasion into surrounding tissues with increased extracellular matrix turnover.
The complex changes in gene expression that are at the basis of EMT result largely from the actions of 3 families of transcription factors, i.e. the Snail, ZEB and basic helix-loop-helix (bHLH) families, whose expression and activities are induced upon initiation of EMT [Peinado et al., 2007]. The Snail (Snail1, Snail2 and Snail3) and ZEB (ZEB1 and ZEB2) proteins represent 2 classes of zinc finger transcription factors whose expression increases during EMT and which bind E-box elements in regulatory promoter sequences. Snail1 and Snail2 can recruit corepressors such as histone deacetylases or C-terminal binding proteins, and in this way transcriptionally repress the expression of target genes, such as the gene encoding E-cadherin [Batlle et al., 2000; Cano et al., 2000; Barrallo-Gimeno and Nieto, 2005]. Similarly, the ZEB transcription factors also have the ability to recruit corepressors, such as C-terminal binding protein, and repress E-cadherin transcription [Comijn et al., 2001; Eger et al., 2005]. Together, Snail and ZEB proteins repress the expression of a number of genes encoding tight junction, adherens junction, desmosome and polarity complex proteins. Besides repressing the expression of epithelial markers, these transcription factors also participate in the increased expression of proteins that characterize the mesenchymal phenotype, such as fibronectin, vitronectin, collagen, N-cadherin and matrix metalloproteinases [Peinado et al., 2007]. bHLH transcription factors also play a role in the progression of EMT. Among these, Twist1 and Twist2 dimerize with another type of bHLH proteins, i.e. E-proteins. These heterodimers then bind to DNA and repress the expression of some epithelial genes such as the gene encoding E-cadherin, while activating the expression of some mesenchymal genes [Perez-Moreno et al., 2001; Yang et al., 2004]. Since inhibitor of DNA binding (Id) proteins inhibit the dimerization and function of Twist transcription factors through dominant negative interference, induction of EMT is accompanied by downregulation of Id protein expression [Ruzinova and Benezra, 2003; Perk et al., 2005]. Interestingly, Snail proteins orchestrate the induction of EMT by increasing the expression of ZEB and bHLH factors [Peinado et al., 2007]. A further level of control in the regulation of this transcription network is exerted by microRNAs. Indeed, members of the miR-200 family act as essential regulators of EMT. They were shown to target and repress the expression of ZEB1 and ZEB2, and, accordingly, their expression is downregulated in cells that undergo EMT, thus leading to a decrease in E-cadherin expression [Gregory et al., 2008].
Recent insights have revealed that signaling pathways, including those initiated by TGF-β, regulate the expression and activities of these transcription factors [Moustakas and Heldin, 2007; Xu et al., 2009]. The orchestration of these transcription pathways, in combination with non-transcription signaling responses, allows TGF-β to act as a potent inducer of EMT. Dissecting the mechanisms of the EMT response to TGF-β provides a paradigm for the cellular basis of epithelial plasticity.
A variety of studies have implicated TGF-β as an inducer or essential mediator of EMT in embryonic development, fibrosis and tumorigenesis. For example, during cardiac development, TGF-β1 and TGF-β2 are expressed in the atrioventricular canal and outflow tract tissue at the onset of EMT, permitting the formation of the heart valves [Nakajima et al., 2000]. TGF-β2 null mice present severe cardiac defects with abnormalities in these regions, and inhibition of TGF-β2 blocks EMT in mouse heart explant cultures [Azhar et al., 2003; Mercado-Pimentel and Runyan, 2007]. As another example, TGF-β3 expression is essential for palatal development and fusion. It is expressed at the site and time of fusion of the palatal shelves, when the epithelial cells undergo EMT, and targeted inactivation of the gene encoding TGF-β3 results in a cleft palate that correlates with the absence of EMT [Pelton et al., 1990; Nawshad et al., 2004].
Consistent with its ability to induce a strong fibrotic response when injected subcutaneously, TGF-β acts as a mediator of pathological fibrosis in a variety of tissues including the kidney, liver, lung and heart. While this response involves the attraction and proliferation of fibroblasts in response to TGF-β, increasing evidence is emerging that TGF-β is also involved in EMT leading to fibrosis. Accordingly, in mouse models and human patients, TGF-β1 expression is increased in chronic kidney disease prior to fibrosis [Schnaper et al., 2003]. Patients with liver disease progressing to hepatic fibrosis also show increased TGF-β1 expression in biliary epithelial cells, and increased TGF-β1 expression occurs in a mouse model of induced liver fibrosis, while blocking TGF-β1 signaling demonstrated significant antifibrotic effect in the liver [Gressner et al., 2002; Meindl-Beinker and Dooley, 2008]. Fibroblasts isolated from patients with pulmonary fibrosis show increased secretion of TGF-β resulting in hyperactive TGF-β signaling [Willis and Borok, 2007]. Further, lineage-tracing experiments in mouse models illustrate a role of EMT of alveolar epithelial cells in lung fibrosis. In the adult heart, an endothelial to mesenchymal transition process occurs in cardiac fibrosis. This process is controlled by TGF-β, and progression of cardiac fibrosis is inhibited in transgenic mice with impaired TGF-β signaling [Zeisberg et al., 2007]. These in vivo observations are complemented by cell culture experiments showing that TGF-β induces EMT in renal tubular epithelial cells, hepatic stellate cells and alveolar epithelial cells, as well as initiating endothelial to mesenchymal transition in endothelial cells [Gressner et al., 2002; Zeisberg et al., 2003; Willis and Borok, 2007; Zeisberg et al., 2007].
TGF-β-induced EMT may also play an important role in carcinoma progression. EMT is thought to be a prerequisite for the invasive behavior of carcinoma cells, leading to dissemination and metastasis [Thiery, 2003; Thiery and Sleeman, 2006; Kalluri and Weinberg, 2009]. Such a role for TGF-β is consistent with the increased production and activation of TGF-β by cancer cells and has been well validated by cell culture and mouse model studies [Bierie and Moses, 2006a]. In addition, in vivostudies confirmed a correlation between the conversion of squamous into more invasive spindle cell carcinomas and the expression of activated TGF-β1 [Cui et al., 1996; Portella et al., 1998; Akhurst, 2008]. Moreover, the increase in TGF-β expression and/or activity provides an advantage for tumor progression not only by inducing EMT, but also by creating an immunosuppressive environment and initiating angiogenesis [Padua and Massagué, 2009]. How important EMT, and more specifically TGF-β-induced EMT, is in human carcinoma progression, invasion and metastasis remains unclear. Nevertheless, research on the molecular mechanisms and the role of TGF-β in EMT and cancer progression has been greatly aided by the characterization of cell culture models for TGF-β-induced EMT. Among these, the normal murine mammary gland (NMuMG) epithelial cell line is perhaps the best studied cell system. In these cells, addition of TGF-β induces an EMT program in cell culture that is completed in 36 h [Miettinen et al., 1994].
Other members of the TGF-β family are also involved in regulating EMT events during development and in cancer, although the knowledge of their roles is currently poorly developed. Bone morphogenetic proteins are involved in EMT processes during gastrulation, neural crest delamination and atrioventricular cushion patterning [Kishigami and Mishina, 2005; Ma et al., 2005; Acloque et al., 2009], and the anti-Müllerian hormone is required for the second phase of Müllerian duct regression [Klattig and Englert, 2007]. In the pathological context, bone morphogenetic proteins have been linked to EMT and invasiveness of several types of cancer cells [Theriault et al., 2007; Gordon et al., 2009], while in other cases, they promote or may be involved in mesenchymal-epithelial transition [Zeisberg et al., 2005].
Discussion of the role of these members of the TGF-β family in EMT is beyond the scope of this overview.
TGF-β signals through a heterotetrameric complex of two TGF-β type II (TβRII) and two TGF-β type I (TβRI) transmembrane dual specificity kinase receptors. Upon TGF-β binding to the receptors, TβRII activates TβRI, which in turn phosphorylates and activates the intracellular mediators Smad2 and Smad3. Once activated, Smad2 and/or Smad3 dissociate from the receptor complex and combine with the common Smad, Smad4, to form trimeric complexes of Smad proteins. These translocate to the nucleus where they cooperate with other transcription factors, coactivators or corepressors, to regulate gene transcription (fig. (fig.2).2). The inhibitory Smad6 and Smad7 block the activation of Smad2 and Smad3 by preventing their interaction with TβRI. They do not serve as transcription activators, yet may function as transcription repressors [Shi and Massagué, 2003; Feng and Derynck, 2005]. Consistent with the role of TGF-β as inducer of EMT, these receptors and Smads were shown to play a role in EMT.
Expression of a cytoplasmically truncated TβRII has been shown to block TGF-β-induced EMT in normal and cancer epithelial cells through dominant negative interference both in vitro and in vivo [Oft et al., 1998; Portella et al., 1998; Han et al., 2005]. In NMuMG cells, expression of a cytoplasmically truncated TβRI similarly inhibits TGF-β-induced EMT, whereas a constitutively active mutant of TβRI induces EMT in the absence of added TGF-β [Piek et al., 1999; Valcourt et al., 2005]. Similar to the effect of the dominant negative form of TβRI, a pharmacological inhibitor that represses the kinase activity of TβRI prevents TGF-β-induced EMT [Kondo et al., 2004; Lamouille and Derynck, 2007]. Downstream of the receptors, the Smad effectors mediate gene expression responses that are required for the induction of EMT upon TGF-β stimulation [Akhurst, 2008]. Indeed, expression of Smad2, Smad3 and Smad4 mutants that can interfere with Smad function, or downregulation of Smad4 expression using RNA interference, was also shown to inhibit the conversion from an epithelial to a mesenchymal phenotype [Valcourt et al., 2005; Deckers et al., 2006]. However, in some cell contexts, Smad2 was reported to act as an antagonist in TGF-β-induced EMT. For example, Smad2-deficient keratinocytes undergo EMT and promote skin tumor formation through enhanced activities of Smad3 and Smad4 [Hoot et al., 2008; see also Masszi and Kapus, 2011, this issue]. Finally, increased expression of the inhibitory Smad7 represses TGF-β-induced EMT in various epithelial cells [Valcourt et al., 2005; Zavadil and Böttinger, 2005].
The induction of EMT in response to TGF-β has been attributed in part to the Smad transcription complexes that regulate transcription of essential genes involved in this process. Notably, TGF-β signaling directly activates the expression of Snail proteins through Smads. Smad3 binds to regulatory promoter sequences of the gene encoding Snail1 and activates its transcription [Cho et al., 2007; Hoot et al., 2008]. In addition, Smad3 and Smad4 form a complex with Snail1 that binds to E-box and Smad-binding elements in the promoters of the genes encoding E-cadherin, occludin and the tight junction-associated cell adhesion molecule CAR, consequently repressing their transcription [Vincent et al., 2009]. In cells induced to undergo EMT, TGF-β also activates the expression of ZEB transcription factors through upregulation of the expression of the transcription factor Ets1, which then may cooperate with the bHLH transcription factor E47 [Shirakihara et al., 2007]. Moreover, the expression of the miR-200 microRNAs is downregulated in TGF-β-induced EMT, resulting in an increase in translation of the ZEB1 and ZEB2 mRNAs [Gregory et al., 2008]. In addition, expression of ZEB1 and ZEB2 directly represses the transcription of the miR-200 family through binding to ZEB-type E-box motifs in a compact region of the miR-200 family promoter [Bracken et al., 2008; Burk et al., 2008]. TGF-β signaling also regulates the activities of the bHLH family of transcription factors during EMT by repressing the expression of Id factors. In the case of Id1, a complex formed by Smad3, Smad4 and the transcription repressor ATF3, binds sequences in the Id1 promoter and represses its transcription [Kang et al., 2003]. The decrease in expression of Id factors then increases activity of E-proteins and Twist, resulting in transcriptional repression of the E-cadherin gene. Finally, the transcription factor HMGA2, whose expression increases during TGF-β-induced EMT through a Smad3/Smad4-dependent mechanism, has also emerged as an essential mediator in TGF-β-induced EMT by enhancing the expression of Snail and Twist proteins, and by repressing the expression of Id2 [Thuault et al., 2006].
In addition to Smad signaling, which directly targets transcriptional regulation, TGF-β initiates non-Smad signaling pathways (fig. (fig.2)2) [Derynck and Zhang, 2003; Moustakas and Heldin, 2005]. These pathways include the 3 mitogen-activated protein (MAP) kinase pathways that lead to activation of extracellular-regulated kinase (Erk), p38 and JNK. However, these pathways are generally more prominently activated by tyrosine kinase receptors, principally in response to growth factor stimulation. Activation of these pathways complements the Smad signaling responses to regulate essential aspects of TGF-β-induced EMT, such as cytoskeleton reorganization, and cell migration and invasion. Their synergy with TGF-β/Smad signaling in inducing EMT has been well illustrated through the cooperation of tyrosine kinase receptor activation with TGF-β signaling. For example, epidermal growth factor stimulates Ras and Erk MAP kinase signaling, which enhances TGF-β-induced EMT responses such as repression of E-cadherin expression and activation of Snail2, N-cadherin and matrix metalloproteinase expression [Grande et al., 2002; Schmidt et al., 2005; Uttamsingh et al., 2008]. Accordingly, pharmacological inhibition of MEK proteins, which activate Erk MAP kinase, prevents the EMT process induced by TGF-β [Xie et al., 2004]. Chemical inhibitors of p38 MAP kinase or JNK MAP kinase, and antisense oligonucleotides targeting JNK, have also been reported to block TGF-β-induced EMT as observed with morphological changes and epithelial versus mesenchymal marker regulation [Bakin et al., 2002; Yu et al., 2002; Santibanez, 2006; Alcorn et al., 2008].
TGF-β activates the Ras-Raf-MEK-Erk MAP kinase pathway through the association of ShcA with the TGF-β receptor complex and direct serine and threonine phosphorylation of ShcA by TβRI in response to TGF-β. The phosphorylated tyrosines on ShcA provide a docking site for the recruitment of Grb2 and Sos, and this complex initiates Ras activation leading to Erk MAP kinase signaling cascade [Lee et al., 2007]. TGF-β has been shown to induce p38 and JNK MAP kinase signaling through activation of TAK1 by the ubiquitin ligase TRAF6 that interacts with the TGF-β receptor complex [Sorrentino et al., 2008; Yamashita et al., 2008]. The recent characterization of how these MAP kinase pathways are activated in response to TGF-β should enable a dissection of their relative contributions to TGF-β-induced EMT.
TGF-β also regulates the activity of the small GTPase proteins Rho, Rac and Cdc42, which function as key signaling mediators in the reorganization of the actin cytoskeleton and the formation of lamellipodia and filopodia, actin protrusions that are required for cell migration [Bhowmick et al., 2001; Zavadil and Böttinger, 2005; Yilmaz and Christofori, 2009]. The mechanisms underlying regulation of the small GTPases by TGF-β receptor activation remain poorly characterized. In the early stage of TGF-β-induced EMT, the polarity molecule Par6 interacts at tight junctions with TβRI, and the phosphorylation of TβRI by TβRII recruits the E3 ubiquitin ligase Smurf1 which mediates the ubiquitination and consequently the degradation of RhoA during tight junction disruption [Ozdamar et al., 2005]. In addition, the microRNA miR-155 that targets RhoA expression is upregulated in TGF-β-induced EMT [Kong et al., 2008]. However, during EMT, TGF-β also activates RhoA and its downstream targets rho-associated coiled-coil containing protein kinase (ROCK) and LIM kinase, mediators of actin stress fiber formation [Vardouli et al., 2005; Pellegrin and Mellor, 2007]. Indeed, antisense oligonucleotides that downregulate the expression of ROCK or LIM kinase, and pharmacological inhibition of ROCK, inhibit the actin reorganization that accompanies TGF-β-induced EMT [Bhowmick et al., 2001; Tavares et al., 2006; Cho and Yoo, 2007].
Finally, TGF-β induces Akt activation through phosphoinositide 3 (PI3) kinase during EMT [Bakin et al., 2000; Lamouille and Derynck, 2007]. Once activated, Akt initiates signaling pathways such as the mammalian target of rapamycin (mTOR) pathway, that play roles in cell survival, growth, migration and invasion. The essential role of TGF-β-induced PI3 kinase-Akt-mTOR signaling in the context of EMT is discussed in the remainder of this review.
A variety of tyrosine kinase receptors for growth factors, such as epidermal growth factor, fibroblast growth factor, insulin-like growth factor-1 and insulin, activate signaling through the PI3 kinase-Akt pathway. Moreover, activation of PI3 kinase and Akt signaling has been detected in cells undergoing EMT [Larue and Bellacosa, 2005]. We and others have observed that TGF-β induces the PI3 kinase-Akt pathway in various cell types, including cells that undergo TGF-β-induced EMT [Bakin et al., 2000; Lee et al., 2004; Lien et al., 2006; Rodriguez-Barbero et al., 2006; Lamouille and Derynck, 2007; Lin et al., 2007; Yeh et al., 2008]. These observations raise the question as to what role the activation of PI3 kinase-Akt signaling plays in TGF-β-induced EMT.
Activation of PI3 kinase results in the generation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), which provides a phospholipid binding site for proteins that contain a pleckstrin homology domain, such as Akt. Once Akt is recruited to the plasma membrane, it is fully activated upon phosphorylation on a threonine by the kinase PDK1, and on a serine principally by mTOR in mTOR complex 2 (mTORC2). In some cell models, Akt may also be activated by integrin-linked kinase, a cytoplasmic kinase that relays signals between integrins and the actin cytoskeleton, and integrin-linked kinase function may be required for EMT [McDonald et al., 2008]. The 3 Akt kinases in mammalian cells (Akt1, Akt2 and Akt3) can phosphorylate a range of proteins that regulate physiological processes such as cell survival, growth, metabolism and migration. However, these Akt proteins display distinct functions, based on gene targeting studies [Gonzalez and McGraw, 2009]. In cell culture, downregulation of Akt2 expression blocks the phenotypical changes and cell migration increase that accompany insulin-like growth factor-1-dependent EMT, while downregulating Akt1 expression enhances this effect [Irie et al., 2005]. In the same epithelial cell model, decreased Akt1 expression promotes TGF-β-induced EMT through a decrease in abundance of the miR-200 family [Iliopoulos et al., 2009]. Interestingly, TGF-β2 selectively activates Akt2 but not Akt1 in NMuMG cells [Chaudhury et al., 2010]. However, the role of Akt in EMT, cell migration and invasion may differ depending on the TGF-β isoform and cell model used.
A downstream target of Akt proteins is glycogen synthase kinase-3β (GSK-3β), a kinase that binds to and phosphorylates Snail1, resulting in enhanced cytoplasmic retention and degradation of Snail1. Phosphorylation of GSK-3β by Akt results in its ubiquitination and degradation, leading to increased accumulation of Snail1 in the nucleus and repression of E-cadherin expression, consequently inducing EMT [Zhou et al., 2004; Bachelder et al., 2005]. In addition, Akt induces transcription of the Snail1 gene, through nuclear factor-κB activation, in squamous cell carcinoma lines that undergo EMT [Julien et al., 2007]. The nuclear factor-κB pathway can also promote EMT, invasion and metastasis in murine mammary cells transformed with H-Ras. Interestingly, interference with nuclear factor-κB activity in this cell model prevents TGF-β-induced EMT [Huber et al., 2004]. Akt also phosphorylates TSC2 in the TSC2-TSC1 complex, thus inhibiting its function as GTPase-activating protein toward the small GTPase protein Rheb. As a result, accumulation of Rheb-GTP activates the kinase mTOR in a complex called 'mTOR complex 1' (mTORC1) [Laplante and Sabatini, 2009]. Two major kinase targets of mTORC1 have been characterized: S6 kinases and 4E-BP1. The phosphorylation of S6 kinases 1 and 2 by mTORC1 regulates translation initiation and ribosome biogenesis, notably through activation of downstream targets such as the ribosomal protein S6 [Hay and Sonenberg, 2004; Holz et al., 2005]. Phosphorylation of 4E-BP1 by mTORC1 releases the eukaryotic translation initiation factor eIF4E from its interaction with 4E-BP1, thus initiating cap-dependent translation of mRNAs, such as the mRNA for cyclin D1, which is involved in cell cycle progression and proliferation [Hay and Sonenberg, 2004; Robert and Pelletier, 2009]. Therefore, activation of mTORC1 results in enhanced protein synthesis and, consequently, increased cell size. mTORC1 is activated not only in response to growth factors, but also responds to nutrients, amino acids and stress signals [Laplante and Sabatini, 2009].
Besides mTORC1 that comprises mTOR, mLST8 and Raptor, mTOR can also form a complex with mLST8, Rictor, mSin1 and Protor. The biology of this second complex named 'mTORC2' is less characterized when compared with mTORC1 [Laplante and Sabatini, 2009]. As mentioned already, mTORC2 mediates Akt phosphorylation, contributing to its full activation [Sarbassov et al., 2005]. It also phosphorylates protein kinase Cα and is believed to regulate the cytoskeletal organization by regulating Rho and Rac activities [Jacinto et al., 2004; Sarbassov et al., 2004]. Rapamycin acts as a specific inhibitor of mTORC1 activity and interferes with the recruitment and activation of mTORC1 targets, possibly by destabilizing the interaction of Raptor with mTOR. Rapamycin does not inhibit the activity of mTORC2, although prolonged rapamycin exposure can decrease mTORC2 activity by destabilizing the assembly of the regulatory components of this complex [Guertin and Sabatini, 2007].
We and others observed that TGF-β induces increases in cell size and protein content in various cell types, including epithelial cells that undergo EMT in response to TGF-β [Lamouille and Derynck, 2007; Das et al., 2008; Wu and Derynck, 2009]. These increases were apparent in 2 models of TGF-β-induced EMT, the murine mammary gland NMuMG cells and the human HaCaT keratinocytes. In these cells, we also detected a TGF-β-induced activation of mTOR resulting in phosphorylation of the 2 targets of mTORC1, S6 kinase 1 and 4E-BP1, through the activation of PI3 kinase and Akt (fig. (fig.3)3) [Lamouille and Derynck, 2007]. How TGF-β signaling links to activation of PI3 kinase is as yet unclear, although PI3 kinase has been found in association with the activated TGF-β receptor complex [Yi et al., 2005]. The increases in cell size and protein content in response to TGF-β are mediated by the activation of mTORC1, and accordingly, rapamycin inhibits the TGF-β-induced cell size and the protein content increases [Lamouille and Derynck, 2007]. The activation of S6 kinase 1 and 4E-BP1 is most likely responsible for the increased protein synthesis that occurs during TGF-β-induced EMT. These observations demonstrate that TGF-β regulates translation via PI3 kinase, Akt and mTORC1 during EMT. The activation of this translation pathway complements the transcriptional regulation through Smad signaling (fig. (fig.3).3). Whereas the activation of translation by mTORC1 in response to TGF-β may complement the increased Smad-mediated transcriptional responses, it may also allow for selective translational control of target genes that potentially play a role in the phenotype and behavior of cells that have undergone EMT. Interestingly, increased S6 kinase 1 activity enhances EMT and invasion in human ovarian cancer cells through induction of Snail1 expression at the transcriptional level, but the mechanism of such regulation remains unclear [Pon et al., 2008].
To further define the role of the activation of mTORC1 in TGF-β-induced EMT, we treated NMuMG and HaCaT cells with TGF-β to induce EMT, in the presence of rapamycin. While the cells did not increase in size and protein content, the inhibition of mTORC1 did not block the morphological changes associated with EMT. Accordingly, similar to cells in the absence of rapamycin, TGF-β induced cell shape changes, accompanied with cytoskeletal reorganization, dissolution of the junctions with delocalization of E-cadherin and zona occludens-1, and induction of mesenchymal markers such as fibronectin and N-cadherin. Besides the morphological and gene expression changes, EMT is accompanied by a change in cell behavior, specifically migration and invasion. However, when mTORC1 activity is blocked using rapamycin in cell culture, the cells that have undergone EMT do not show the increases in migration and invasion that normally accompany EMT [Lamouille and Derynck, 2007]. Perhaps the increased protein synthesis that follows mTORC1 activation may participate in the enhanced expression of specific proteins that act directly or indirectly in cell migration and invasion, such as matrix metalloproteinases. Therefore, activation of mTORC1 downstream of PI3 kinase-Akt and in response to TGF-β contributes to EMT in 2 ways. While it mediates the increase in protein synthesis and cell size during EMT, mTORC1 activity is also essential for the increased motility and invasion of cells that have undergone EMT. Since increased invasion plays a key role in cancer progression toward metastasis, these results highlight a role for Akt-mTOR signaling in cancer progression, independent of cell proliferation regulation. Therefore, rapamycin analogs or other inhibitors of mTOR activity may aid in preventing invasion, cancer progression and metastasis. In line with our observations, rapamycin has been found to inhibit the downregulation of E-cadherin expression in mesothelial cells that undergo TGF-β-induced EMT [Aguilera et al., 2005], and to block motility in some other cell models [Liu et al., 2006; Gulati et al., 2009]. On the other hand, the rapamycin-insensitive mTORC2 is believed to play a role in cytoskeleton arrangement through the regulation of Rho, Rac and protein kinase Cα activities [Jacinto et al., 2004; Sarbassov et al., 2004]. Therefore, it is conceivable that this complex could be involved in the process of actin cytoskeleton reorganization that occurs during TGF-β-induced EMT. Interestingly, decreased activity of mTORC2 inhibits the migratory behavior of breast cancer cells [Qiao et al., 2007]. Additional studies will be needed to decipher a possible implication of mTORC2 in EMT and the mechanisms that regulate its activation.
In epithelial cells, TGF-β signaling leads to inhibition of cell proliferation, which serves as an autocrine tumor suppressor function, while other signaling responses can promote the transition toward carcinoma cells and aid in cancer progression. An early event in the transition from epithelial to carcinoma cells is the inactivation of the tumor suppressor effect of TGF-β [Bierie and Moses, 2006b; Nguyen and Massagué, 2007]. Mutations in TβRII and TβRI receptors, as well as in TGF-β Smads, have been observed in carcinomas and inactivate the growth inhibitory activity of TGF-β. In addition, alterations in downstream components of Smad signaling have been shown to result in a similar effect without inactivating other TGF-β responses that are beneficial to the tumor cells [Bierie and Moses, 2006a]. As cancer cells often have increased expression and activation of TGF-β, the autocrine responses of carcinoma cells to TGF-β, in particular the loss of the epithelial phenotype and induction of EMT, are thought to play an important role in driving the invasive behavior of carcinoma cells and progression toward metastasis [Derynck et al., 2001; Nguyen and Massagué, 2007]. Accordingly, expression of dominant negative TβRII receptor in metastatic cell lines inhibits EMT in vitro and in vivo[Oft et al., 1998; Portella et al., 1998; Han et al., 2005]. Therefore, TGF-β-induced EMT correlates with tumor metastasis through an increase in cell-invasive characteristics.
The complexity of the TGF-β signaling responses, and the dual nature of their effects on epithelial cancer cells, i.e. tumor suppression versus cancer progression, has made the development of anti-cancer approaches based on inhibition of TGF-β signaling challenging. Nevertheless, TβRI kinase inhibitors, neutralizing TGF-β antibodies and the dimerized TβRII extracellular domain fused to human IgG Fc domain, are being evaluated in preclinical and clinical trials as inhibitors of cancer progression [Bonafoux and Lee, 2009]. Rather than developing approaches to block all TGF-β signaling and cellular responses, it is preferable to selectively target the TGF-β-induced promotion of invasion and metastasis of cancer cells, thereby avoiding an inactivation of the tumor suppression function of TGF-β. Our insights into the role of Akt-mTOR signaling in TGF-β-induced EMT, and in particular invasion, may provide a basis for such a targeted approach.
Deregulation and increased activities of PI3 kinase and Akt have been linked to tumorigenesis and cancer progression. The gene encoding the catalytic subunit p110α of PI3 kinase is frequently mutated in human tumors, resulting in increased PIP3 production and, consequently, increased Akt signaling. Mutations in the gene encoding the PI3 kinase regulatory subunit p85α have also been identified, and these lead to constitutive PI3 kinase activity [Liu et al., 2009]. Moreover, amplification of Akt genes or overexpression of Akt has been observed in a range of human tumors and is generally associated with poor prognosis. Recently, mutations in the pleckstrin homology domain of Akt1 that lead to growth factor-independent anchoring to the plasma membrane and increased Akt1 phosphorylation have been identified in several cancers [Gonzalez and McGraw, 2009]. Finally, loss of the tumor suppressor PTEN, a phosphatase that antagonizes PI3 kinase activity by dephosphorylating PIP3, is commonly observed in cancer progression [Liu et al., 2009]. These and many other findings link an increase in PI3 kinase and Akt signaling to tumorigenesis and to increased cell survival and decreased apoptosis.
Increased and deregulated mTORC1 and mTORC2 activities have also been observed in tumors and linked to cancer progression. In a tightly controlled manner, mTORC1 regulates the synthesis of proteins involved in cell cycle progression, apoptosis, invasion and angiogenesis. A deregulation of mTORC1-dependent translation initiation consequently allows for enhanced tumor growth and metastasis. Accordingly, increased levels and phosphorylation of downstream targets of mTORC1 have been correlated with tumor aggressiveness in various human malignancies [Guertin and Sabatini, 2007]. In addition, mTORC2 phosphorylates Akt, and this phosphorylation, together with the phosphorylation of Akt by PDK1, results in full Akt activation [Sarbassov et al., 2005]. Although the mechanism of mTORC2 activation requires further characterization, the elevated Akt phosphorylation observed in various human tumors may be explained by a hyperactivation of mTORC2. It has recently been shown that mTORC2 is required for tumor initiation in a model of prostate cancer cells in PTEN-deficient mouse [Guertin et al., 2009].
Because of the frequently observed deregulation in PI3 kinase-Akt-mTOR signaling in human cancers, and its link to increased cell proliferation and survival, the PI3 kinase-Akt-mTOR pathway has been extensively targeted in the development of cancer therapies. Wortmannin and LY294002 represented a first generation of PI3 kinase inhibitors, but their lack of selectivity and high toxicity made these drugs unsuitable for the treatment of cancers. Recently, more isoform-specific chemical inhibitors of PI3 kinase have been developed, with some also targeting the mTOR kinase. For example, PI-103 inhibits the activities of p110α and mTOR, and its use for cancer therapy is being explored [Liu et al., 2009]. With its central role, Akt is also considered an attractive therapeutic target. Accordingly, several Akt inhibitors are currently in clinical trials for cancer treatment. They comprise lipid-based phosphatidylinositol analogs that prevent the localization of Akt to the plasma membrane, ATP-competitive kinase inhibitors and allosteric inhibitors [Liu et al., 2009]. Rapamycin is a natural inhibitor of mTORC1 but its poor solubility led pharmaceutical companies to develop analogs with improved pharmacokinetic properties, some of which are already in clinical use [Guertin and Sabatini, 2009]. Whereas rapamycin inhibits the activity of mTORC1, it does not block the activities of mTORC2, although prolonged exposure to rapamycin can affect the assembly of mTORC2 components [Guertin and Sabatini, 2007]. However, mTORC2 activity has been shown to be enhanced following inhibition of mTORC1, as observed by Akt hyperphosphorylation following rapamycin treatment in several cell models. Therefore, it may be imperative to also target mTORC2. Consequently, pharmacological kinase inhibitors of mTOR that inhibit both mTORC1 and mTORC2 have recently been developed and are clinically evaluated as therapy to cancer progression [Guertin and Sabatini, 2009].
The realization that TGF-β activates signaling through the PI3 kinase-Akt-mTOR axis and that this pathway is required for EMT and invasion now opens several opportunities, yet also leads to new questions. Our current data suggest that, in TGF-β-induced EMT, activation of mTOR signaling is required for motility and invasion, raising the possibility that inhibition of mTOR activity may prevent cancer dissemination. While such an approach may not block the cell morphological changes of EMT, inhibiting the invasion process at the very basis of cancer progression may represent an avenue of selectively inhibiting the cancer-promoting effects of TGF-β without the concern of relieving the tumor suppressor activity of TGF-β. The current findings also raise a number of new questions about the molecular mechanisms and functions associated with TGF-β-induced PI3 kinase-Akt-mTOR signaling. How activation of the TGF-β receptor complex leads to activation of PI3 kinase-Akt-mTOR signaling is currently unclear, nor do we know which PI3 kinase or Akt proteins are involved. Inhibition of mTORC1 represents an attractive approach for the prevention of EMT-associated cell motility and invasion, and in uncovering novel effectors of this process which lie under mTORC1 selective translational regulation. Such a strategy should provide insight into the link between TGF-β-induced EMT and the mechanisms underlying cancer progression.
We are grateful to J. Smyth and J. Xu for their critical review of the manuscript. This research was supported by grants RO1-CA136690 and PO1-HL60231 (project III) to R. Derynck, a postdoctoral fellowship grant (grant 5566-07) from the Leukemia and Lymphoma Society and a scientist development grant (grant 09SDG2280008) from the American Heart Association to S. Lamouille.
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The Prime Minister is encouraging New Zealand and Australian supermarkets to purchase Australasian products, rather than from their own country exclusively.
John Key was in Australia over the weekend, where he met with Prime Minister Tony Abbott.
Mr Key says he raised the issue of two of Australia's biggest supermarkets using products for their home brands only from Australian sources.
"It's important to remember these issues aren't simple. New Zealand supermarkets also procure some products exclusively from New Zealand suppliers.
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Mr Key says consumers understand that an open economy works well for both countries, so supermarkets should buy Australasian made.


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Three British teams were in action in the first night of this season's Champions League.
Wayne Rooney was back in the Manchester United team as they took on Scottish champions Rangers at Old Trafford.
United had the best chances to score, but Rangers defended well and the game finished 0-0.
There was bad news for United when Antonio Valencia seriously injured his ankle. The midfielder had to get stretchered off in the second half.
Tottenham also drew against German side Werder Bremen. Spurs went 2-0 up after an own-goal and a great header from Peter Crouch.
But the German side got two goals back to level the match. Even so, Spurs manager Harry Redknapp said he was "delighted" with his team's overall performance.


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Walking contradictions : Latina lesbianas, immigration and citizenship López, Candace (2010-12)In immigration and sexuality research there is new and emerging literature that understands the convergence of these two topics. However, scholarship primarily examining Latina lesbian immigrants is not as visible. This ...


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David Beckham Stuffed His Man Junk for Underwear Ad?
Rumor has it that David Beckham's Super Bowl commercial for H&M was apparently fake and was enhanced… his crotch was stuffed in the photos! That's what a stylist on the underwear ad is saying! David's rep denies it and says "it's all natural."
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About Special Collections
Using Archives: A Guide For Researchers
Step 1 - What is an Archive?
Step 2 - Planning Your Research
Step 3 - Contacting the Archive
Step 4 - Visiting the Archive
Rules and Regulations
Step 5 - Completing Your Visit
Step 1 - What is an Archive?
An archive is a repository for unique records of enduring value. Records housed in archives are often one of a kind or at least are very difficult to replace if lost, stolen, or destroyed. It is not necessarily the age of the records that give them their value; rather, it is the content and research potential of the documents that warrant their preservation in an archive. Archives are designed to provide users with access to the records while maintaining a stable environment for their protection.
Records are often kept in collections which are a grouping of related material that are most often created by a single individual or organization. Documents from two or more collections on similar subjects are never mixed and the original order the collection arrived in is maintained in most circumstances. Collections can range in size from a single sheet of paper to thousands of feet of material. The media and formats of the records vary as well. information can be stored on paper, magnetic tape, CD Rom, photographs, videotape, sketches, maps, and architectural drawings. Thus, a visit to an archive can prove to be a multifaceted experience.
Step 2 - Planning Your Research
As many archives do not loan their materials and do not have extended hours past 5 o'clock, the time a researcher needs to locate and study records can be constrained. Thus, it is beneficial to know the most about your subject before you enter an archive. Through the use of secondary sources such as books, encyclopedias and journal articles, a wider knowledge and greater focus on the subject can be attained. Key information such as names, places, dates and events can serve as appropriate leads in archival collections. With this background, you can enter an archive with specific questions and details that will help the archivist find the records you need without using up your precious time. An archivist may also be able to direct you to other materials related to your topic that you may not be aware of if they are provided with enough information.
There are literally thousands of archives in North America that are maintained by a number of unique organizations such as federal, state/county and municipal governments, churches, businesses, historical associations, universities, and military branches. Hence, knowing where to begin your search for records may seem daunting. There are ways, however, that can help you find the suitable archives for your research. While you conduct your background research from secondary sources, make note of where the authors found their information. Often footnotes, endnotes, bibliographies, and the narrative itself will refer to the archives and collections used. Talking with colleagues, professors, and others who are knowledgeable in your topic may help. As well, there are published guides and directories that are available at many libraries, if not directly, at least by inter-library loan. And finally, more and more archives are creating web pages that give details to their holdings. Some even have online finding aids to their collections that can be browsed by electronic searches.
Step 3 - Contacting the Archive
It is wise to contact an archive before making your first visit. Some archives are open to the public only at specific times and days and some collections are restricted from the public without written permission from the owner of the records or the archive/organization. Contacting the archive will save you time in the long run and will give you an opportunity to find out if the archive can realistically help your research or give you an estimate of how long your research will take.
Sometimes the archival repository with the materials you require may be a far distance from where you live making a visit problematic. To avoid long and expensive traveling, you may contact the archive and inquire about three options. First, some archives make their most frequently used materials available as on microfilm which can be sent to a closer library or archive on request. Second, many archives will conduct a limited amount of research on your behalf and sometimes at an hourly fee. When taking this option, be sure that you know what you are looking for and be as specific as possible. An undefined search may cause the archivist to view the search as too lengthy to perform as they will be taken away from their other duties. If these options are not feasible and the distance is too great, the archive should be able to provide you with a list of professional researchers that work in the area, which is the third option.
To find out about these options or to make a request, contact the archive by typed letter, telephone, or e-mail. Most archivists prefer requests in writing, as letters and e-mail tend to display information in a clearer manner which lessens the need to contact the researcher on numerous occasions. Reserve telephone messages for simple reference questions and inquiries about the archive's holdings. When you write, be sure to describe your request as succinctly as you can including names, dates, places, and specific documents. Please allow at least four to six week for a reply from the archives.
Step 4 - Visiting the Archive
This next section deals specifically with the procedures at the UTSA Special Collections.
Upon entering the Reading Room, you will be asked to fill out a Researcher Registration Form (PDF format; 30 KB) which will ask for your name and address, the title of the collection desired and a picture ID so that we can photocopy it. This document ensures that researchers are familiar with the archives policies on copyright, restrictions, and photocopying.
Rules and Regulations
Patrons will be asked to read and sign the following rules governing the Reading Rooms of Special Collections:
- The first time any researcher visits the Archives or Special Collections s/he must complete the Researcher Registration Form (PDF format; 30 KB) and show appropriate identification. On each subsequent visit the researcher will be asked to read through the rules.
- Visitors must sign the registration book each time they visit the Reading Room.
- ALL personal belongings are to be stored in lockers.
Allowed in Reading Room:
- Pencils
- Paper, must be stamped by a staff member
- Laptop and notebooks, will be inspected
- Digital camera (no flash), must sign user agreement
Not allowed in Reading Room:
- Pens, markers or ink of any kind
- Food, drink, candy (including chewing gum) and tobacco products
- Researchers are to remain reasonably quiet to avoid distracting others.
- Cell phone ringers must be set to silent. Calls may not be taken in the reading room.
- Access to stacks areas of Special Collections is not allowed.
- Notify a staff member when your visit ends. Present laptops and notebooks for inspection. Special Collections staff reserve the right to inspect all research materials and personal articles before a researcher leaves.
- Failure to follow these rules may lead to your removal and/or banning from the Special Collections reading rooms.
Patrons will be asked to read and sign the following rules governing the use of Special Collections Materials:
- Archival materials may only be consulted in the Reading Room under the supervision of Archives staff. Archival material may not be removed from the Archives.
- Researchers may request up to 3 boxes of material at a time. Only one box may be on the study table at a time. Only one folder may be removed from a box at a time. Use orange Out Cards to mark your place when removing folders from boxes.
- Keep material in the order in which you receive it even if you cannot discern a meaningful order. Use orange Out Cards to mark your place when removing items from folders.
- Archival materials must remain in clear view of Archives staff at all times.
- Cotton gloves must be worn when handling photographic materials. Gloves will be provided. Please avoid touching the surface of photographic materials, even while wearing gloves.
- Do not mark, fold or use post-it notes on materials. Respect the fragile nature of archival materials and handle with care. Archival materials must remain flat on the table.
- Do not exert pressure on material used, such as by taking notes on top of or resting an arm on archival material.
- Book cradles will be provided for the viewing of bound materials.
Proper credit must be given in citations.
- Archival citations: see "preferred citation" for each collection (ex. [Identification of item], MS ##, Collection Name, Special Collections, University of Texas at San Antonio Library).
- Special Collections citations: Proper credit must be given for original (non-published) material. Sample citation: Special Collections, University of Texas at San Antonio Library. Published books need not cite UTSA Library. If unsure, consult staff.
Photocopy Requests:
- Complete a photocopy request form. Not all materials can be photocopied, due to physical conditions or restrictions.
- Consult staff for additional information about photocopies.
- Use purple flags to mark material for photocopying. Do not separate material to be photocopied.
- Photocopies are not done one demand. Turnaround may take several business days, depending on the quantity ordered and the volume of orders.
- If you find materials that are torn, marked, out of order, or in any way seem damaged, please notify a staff member immediately.
- All materials must be returned to a staff member before leaving the Archives for more than 15 minutes.
Failure to comply with these rules may result in denial of access to the collections. Theft or mutilation of the holdings is a crime that may be prosecuted.
Step 5 - Completing Your Visit
When you are finished with you materials or are ready to leave, it is wise to make note of any information that will be of use during future visits. Return folders to their appropriate boxes and either leave the materials at the table or give them to a staff member. Be sure to let the staff know that you are leaving the archive.


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Yesterday, I Black Friday'd an S3 to replace an HTC Evo 4G (not LTE) that was getting a bit long in the tooth. While there is much to like, there are two things so far that bug me.
The first one is really minor: The stock weather app never updates unless I click on it. It went roughly 24 hours before it dawned on me that the weather bore no relation to what the screen said. By contrast, the stock HTC weather app would update all the time. I don't really need to know much more than the outside temp and if it is going to rain soon. Is there a way to make the stock app work better?
The second problem is far more annoying. Ahh, never mind. I just figured out why three different browsers all refused to go into landscape mode.


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CP7912 not starting
Unanswered Question
User Badges:
I have a CP-7912G that is not starting when connected to the network. The red/green lights come on, but then nothing else happens. I've done several searches on this forum and through TAC online and have not found any other references/fixes for this problem. Suggestions?
I have this problem too.
0 votes


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PACLARIO-L ArchivesArchiver > PACLARIO > 2009-05 > 1241790610
From: "Ellis Weller" <>
Subject: [PACLARIO] Obituaries, The Derrick, May 8, 2009
Date: Sat, 9 May 2009 09:50:58 -0400
The Derrick, May 8, 2009:
Lawrence E. Goble, Franklin Street, Clarion
Betty A. Scherder, Allegheny Township, Parker
Mildred N. Shofestall, Shofestall Road, Clarion
Evelyn Thompson, Thompson Drive, Lucinda
Jay Elias Wenner, 702 E. Third St., Oil City
Lt. Col. Frank D. Williams, 21 Oakwood Drive, Oil City
Lawrence E. Goble, 93, of Franklin Street, Clarion, died May 7, 2009
at Clarion Hospital.
Born July 12, 1915, in Clarion, he was the son of Benjamin F. Goble
and Belle Laura Simpson Goble, who both preceded him in death. He was
the oldest child of three.
He was married in 1943 to Catherine Minns of DuBois and she preceded
him in death in 1993.
On April 25, 1994, he married Helen Hedrick Shea, and she survives.
Larry was a 1933 graduate of Clarion High School. In 1933 he helped
start the Decorating Department at O-I Glass Plant in Clarion.
He served in the Army during World War II, moved to DuBois in 1946 and
worked as a restaurateur until 1955. He then moved to Concord, Calif.,
where he worked in electrical advertising until his retirement.
In 1994 he moved back to Clarion where he joined the First United
Methodist Church.
He enjoyed gardening, painting portraits and landscapes, and liked
wood working in his well-equipped shop.
In addition to his wife, Helen, he is survived by a son, Robert L.
Goble of Magalia, Cali.; a daughter, Kay Marini of San Leandro, Cali.;
two grandchildren, Mark Allen Goble of Martinez, Cali., and
Christopher Marini of Las Vegas, Nev.; a step-son, Brian Shea of
Phoenix, Ariz.; a step-daughter, Helen Marie Fox of Erie; and two
In addition to his parents and first wife, he was preceded in death by
a brother, Gerald Goble; and a sister, Dorothy Trunk.
Visitation will be held from 2 to 4 and 7 to 9 p.m. Sunday at the
Goble Funeral Home & Crematory, 330 Wood St., Clarion.
Funeral services will be held at 11 a.m. Monday at the First United
Methodist Church in Clarion with the Rev. Dr. Deryl Larsen
Interment will be in the Oakmont Cemetery of Layfette, Cali.
Memorials may be made to the First United Methodist Church in Clarion
or the Clarion-Forest VNA.
Online condolences may be sent at www.goblefh.net
Betty A. Scherder, 85, of Allegheny Township, Parker, died late Sunday
May 3, 2009, at Butler Memorial Hospital. Among her survivors is a
daughter, Jean Blauser of Parker, with whom she made her home.
Mildred N. Shofestall, 66, of Shofestall Road, Corsica, died
unexpectedly Thursday morning, May 7, 2009, at Brookville Hospital.
The Robert V. Burns Funeral Home in Clarion is handling arrangements,
which are incomplete.
A complete obituary will be published Saturday in The Derrick.
Evelyn Thompson, 92, of Thompson Drive, Lucinda, died Wednesday, May
6, 2009, at Golden Living Center in Shippenville.
Born March 4, 1917, in Leeper, she was the daughter of John Johnston
and Julia Slocum Johnston, both of whom preceded her in death.
She was married Oct. 3, 1940, to Fred F. Thompson, who preceded her in
death May 16, 1983.
She was a homemaker and was retired from the Sheraton Inn in Clarion.
Mrs. Thompson was a member of Scotch Hill United Methodist Church.
She enjoyed quilting, reading, gardening and her grandchildren.
Mrs Thompson is survived by two sons, Vern Thompson and Roger
Thompson, both of Lucinda; four daughters, Susanne Kelsch and her
husband, Joe, of Pittsburgh, Kathleen Hansen of Lucinda, Marian
Horwedel and her husband, Jim, of Tidioute, and Cindy Thompson of
Bonaire, Ga.; 16 grandchildren; three great-grandsons and a
son-in-law, Bob Maxwell, of Miola.
In addition to her parents and husband, she was preceded in death by a
daughter, Teresa Maxwell; a son, Patrick Thompson; a
great-granddaughter, Lily Krajewski; four brothers and one sister.
Visitation will be from 2 to 4 and 7 to 9 p.m Friday at the Goble
Funeral Home & Crematory, 330 Wood St, Clarion.
Funeral services will be held at 11 a.m. Saturday in the funeral home
with the Rev. Boyd Edmondson officiating.
Interment will be in Scotch Hill Cemetery.
Memorials contributions may be made to Scotch Hill United Methodist
Online condolences may be sent to www.goblefh.net.
Jay Elias Wenner, 78, of 702 E. Third St., Oil City, died at 8:20 p.m.
Wednesday, May 6, 2009, at home surrounded by his family.
He was born Jan. 31, 1931, in Van, and was the son of the late LeRoy
Wenner and Cecil Whitling Wenner.
Mr. Wenner had lived in Oil City for more than 42 years and had worked
as a truck driver for Pennland Tankers and Hanna Transfer Co. He last
drove for Mushroom Trucking until he was forced to retire due to
injuries sustained while serving in Korea.
Mr. Wenner served in the U.S. Army during the Korean Conflict from
1950 to 1953, and he was honorably discharged with the rank of
corporal. During his service he was wounded three times and received
the Purple Heart Medal with two Oak Leaf Clusters, the Korean Service
Medal with five Bronze Service Stars and the Combat Infantryman Badge
while serving in Company F of the 7th Calvary Regiment of the 1st
Calvary Division.
After his service in Korea he met and married Elizabeth "Betty"
O'Brien on June 9, 1956, at St. Michael Church in Emlenton, and she
Mr. Wenner was a member of St. Stephen Church in Oil City, and his
hobbies included hunting, fishing, gardening, woodworking and spending
time with his grandchildren. He also raised and bred hunting dogs.
Mr. Wenner also managed the local Stubler's AA baseball team from
1985-1990, leading them to four league titles.
In addition to his wife, Mr. Wenner is survived by a daughter, Debra
Ellen Schreffler and her husband, Mike; two sons, Robert J. Wenner and
his wife, Karen, and Jeff Wenner and his wife, Brenda, all of Oil
City; and eight grandchildren, Jason Wenner, Kaity Wenner, Chelsea
Wenner, Carlee Wenner, Bobby J. Wenner, Dana Wenner, Maddie Wenner and
Jacob Wenner, all of Oil City.
Also surviving are a great-grandson, Jason "J.J." Wenner Jr.; two
sisters-in-law, Roberta Wenner of Van and Doris Wenner of Florida; a
brother-in-law, Duane "Bud" Sweet of New Mexico; and numerous nieces
and nephews.
Mr. Wenner was the last surviving member of his immediate family and
was preceded in death along with his parents by his stepmother,
Dorothy Wenner; five brothers, Gerald Wenner, D.O. Wenner, Richard
Wenner, Harry Wenner and Tom Wenner; and three sisters, Romaine
Wenner, Irene Wenner and Ellen Sweet.
Friends will be received from 2 to 4 and 7 to 9 p.m. today at the
Hutchinson Funeral Home, 201 Bissell Ave., Oil City.
Mass of Christian Burial will be celebrated at 9 a.m. Saturday at St.
Stephen Church in Oil City with the Rev. Matthew Reyuchan, St. Stephen
pastor, as celebrant.
Mr. Wenner will be laid to rest with full military honors at Rockland
Memorial contributions can be made to the VNA Hospice of Venango
County, 491 Allegheny Blvd., Franklin, 16323.
Lt. Col. Frank D. Williams, United States Air Force, retired, 86, of
21 Oakwood Drive, Oil City, died at 1:15 a.m. Thursday, May 7, 2009,
at the Oil City Presbyterian Home.
Born Oct. 27, 1922, in West Monterey, he was a son of the late Frank
Leslie and Mable Elizabeth Buzard Williams.
After graduating from high school and college, he enlisted in the Air
Force, where he completed flight school, pilot training, in November
1943. He was a B-17 pilot during World War II.
Lt. Col. Williams was stationed in England and completed 20 missions
before being shot down over Germany on his 21st mission. He was a
prisoner of war for 13 months.
During his service he received the European-African Campaign Medal,
the Air Commendation Medal with Oak Leaf Cluster 2 , the World War II
Victory Medal, the Air Force Achievement Medal, the National Defense
Service Medal and the Air Force Outstanding Unit Award.
When he retired after 24 years, he was director of personnel
management at Dow Air Force Base in Bangor, Maine.
Lt. Col. Williams was a member of St. Paul Lutheran Church in Knox and
belonged to the Masons.
He enjoyed the outdoors, nature and fishing.
On July 25, 1945, he married Marilouise Freeman, who preceded him in
death on Feb. 17, 2009.
He is survived by one daughter, Laura E. Sekula and her fiance, James
Green, of Manassas, Va.; two grandsons, Nathan Michael Sekula and Ian
William Sekula, both of Manassas, Va; and several nieces and nephews.
In addition to his parents and wife, he was preceded in death by six
siblings, Edith Zula Daubenspeck, Anna Leeora Foringer, Marie
Elizabeth Mong, Paul Leslie Williams, Mabel Grace Trill and Nancy Jane
The Morrison Funeral Home in Oil City is in charge of arrangements.
There will be no visitation, and services will be held at the
convenience of the family.
Interment will be in Sunset Hill Memorial Gardens.
In lieu of flowers, it is suggested memorials be made to the American
Cancer Society.
This thread:
|[PACLARIO] Obituaries, The Derrick, May 8, 2009 by "Ellis Weller" <>


text: fan - Unregistered June 18, 2012 11:55 AM Go Honda!! the power of Dreams Still cannot believe that they beat the horde of Nissans in lmp2 . So stoked! I heard rumours during eurosport that Honda will have a factory LMp1 hybrid in 2013??? jeesus...cant wait if its true 2 agree 1 disagree


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text:
Bands Cover The Beatles' 'Ob-La-Di, Ob-La-Da' [VIDEO]
Recording a cover of any Beatles song isn't an easy feat, but performers from the Rock & Workshop Roadshow 2011 appear to have done just that. MercyMe, Jars of Clay, Matt Maher, Thousand Foot Krutch, The Afters and Lecrae formed together to do their own take on the Beatles' "Ob-La-Di, Ob-La-Da," complete with a one-take music video that is already going viral. Enjoy, after the jump.
Subscribe to Cars 108 on


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A plan to stay vital, productive and healthy for a lifetime
Saturday, October 1, 2016
Buck Institute for Research on Aging
A video of this event is now available
Much can be done to nurture and protect your gray matter as you age – and this is the event that can help you do that! Dr. Ram Rao of the Buck Institute has spent more than 15 years studying age-related neurodegeneration with a special emphasis on Alzheimer's disease. Dr. John Arden has over 40 years of experience providing psychological services and directing mental health programs and is the author of several books, including The Brain Bible.
Rammohan Rao, PhD is an Associate Research Professor interested in neuronal cell death and mechanisms of age-associated neurodegenerative diseases. He has published extensively in peer-reviewed scientific journals including a recent study that highlighted genes associated with increased risk for Alzheimer's. Dr. Rao has applied his research to develop tips for reversing memory loss. He is also a certified Clinical Ayurvedic Specialist and is a dedicated Yoga practitioner and teacher.
John B. Arden, PhD, is the Chief Academic Officer for the Institute for Brain Potential. His study of neuropsychology has inspired him to integrate neuroscience and psychotherapy, synthesizing the biological and psychological into a new vision for psychotherapy: Brain-Based Therapy. He conducts seminars throughout the U.S. and the world. His system incorporates current brain science with psychotherapy research, mindfulness, nutritional neuroscience and social intelligence.
Presentation: 10:30 am – 12:00 noon
Doors open at 10:00 am
Parking for this event will be onsite at the Buck Institute
To register, contact us at: firstname.lastname@example.com, 415.209.2045
Complimentary admission
Suggested donation: $10
This Community Seminar is generously supported by the Levy Family in Memory of Dr. S. William Levy.