Loss of Akt activity increases circulating soluble endoglin release in preeclampsia:identification of inter-dependency between Akt-1 and heme oxygenase-1

Aims - Endothelial dysfunction is a hallmark of preeclampsia. Desensitization of the phosphoinositide 3-kinase (PI3K)/Akt pathway underlies endothelial dysfunction and haeme oxygenase-1 (HO-1) is decreased in preeclampsia. To identify therapeutic targets, we sought to assess whether these two regulators act to suppress soluble endoglin (sEng), an antagonist of transforming growth factor-ß (TGF-ß) signalling, which is known to be elevated in preeclampsia. Methods and results - Vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor (FGF-2), angiopoietin-1 (Ang-1), and insulin, which all activate the PI3K/Akt pathway, inhibited the release of sEng from endothelial cells. Inhibition of the PI3K/Akt pathway, by overexpression of phosphatase and tensin homolog (PTEN) or a dominant-negative isoform of Akt (Aktdn) induced sEng release from endothelial cells and prevented the inhibitory effect of VEGF-A. Conversely, overexpression of a constitutively active Akt (Aktmyr) inhibited PTEN and cytokine-induced sEng release. Systemic delivery of Aktmyr to mice significantly reduced circulating sEng, whereas Aktdn promoted sEng release. Phosphorylation of Akt was reduced in preeclamptic placenta and this correlated with the elevated level of circulating sEng. Knock-down of Akt using siRNA prevented HO-1-mediated inhibition of sEng release and reduced HO-1 expression. Furthermore, HO-1 null mice have reduced phosphorylated Akt in their organs and overexpression of Aktmyr failed to suppress the elevated levels of sEng detected in HO-1 null mice, indicating that HO-1 is required for the Akt-mediated inhibition of sEng. Conclusion - The loss of PI3K/Akt and/or HO-1 activity promotes sEng release and positive manipulation of these pathways offers a strategy to circumvent endothelial dysfunction.

Information systems, inter-functional collaboration and innovation in Taiwanese high-tech manufacturing firms

This article investigates whether (1) cross-functional integration within a firm and the use of information systems (IS) that support information sharing with external parties can enhance integration across the supply chain and wider networks and (2) whether collaboration with customers, suppliers and other external parties leads to increased supply chain performance in terms of new product development and introduction of new processes. Data from a high-quality survey carried out in Taiwan in 2009 were used, and appropriate econometric models were applied. Results show that the adoption of IS that enhance information sharing is vital not only for the effective communication with suppliers and with wider network members, but their adoption also has a direct effect across a firm's innovative effort. Cross-functional integration appears to matter only for the introduction of an innovative process. Collaboration with customers and suppliers affected a product's design and its overall features and functionality, respectively. © 2013 Copyright Taylor and Francis Group, LLC.

Effect of zinc-alpha 2-glycoprotein (ZAG) on expression of uncoupling proteins in skeletal muscle and adipose tissue

The plasma protein zinc-α2-glycoprotein (ZAG) has been shown to be identical with a lipid mobilizing factor capable of inducing loss of adipose tissue in cancer cachexia through an increased lipid mobilization and utilization. The ability of ZAG to induce uncoupling protein (UCP) expression has been determined using in vitro models of adipose tissue and skeletal muscle. ZAG induced a concentration-dependent increase in the expression of UCP-1 in primary cultures of brown, but not white, adipose tissue, and this effect was attenuated by the β3-adrenergic receptor (β3-AR) antagonist SR59230A. A 6.5-fold increase in UCP-1 expression was found in brown adipose tissue after incubation with 0.58 μM ZAG. ZAG also increased UCP-2 expression 3.5-fold in C2C12 murine myotubes, and this effect was also attenuated by SR59230A and potentiated by isobutylmethylxanthine, suggesting a cyclic AMP-mediated process through interaction with a β3-AR. ZAG also produced a dose-dependent increase in UCP-3 in murine myotubes with a 2.5-fold increase at 0.58 μM ZAG. This effect was not mediated through the β3-AR, but instead appeared to require mitogen activated protein kinase. These results confirm the ability of ZAG to directly influence UCP expression, which may play an important role in lipid utilization during cancer cachexia. © 2004 Elsevier Ireland Ltd. All rights reserved.

Angiotensin II directly induces muscle protein catabolism through the ubiquitin-proteasome proteolytic pathway and may play a role in cancer cachexia

The ability of angiotensin I (Ang I) and II (Ang II) to induce directly protein degradation in skeletal muscle has been studied in murine myotubes. Angiotensin I stimulated protein degradation with a parabolic dose-response curve and with a maximal effect between 0.05 and 0.1 μM. The effect was attenuated by coincubation with the angiotensin-converting enzyme (ACE) inhibitor imidaprilat, suggesting that angiotensin I stimulated protein degradation through conversion to Ang II. Angiotensin II also stimulated protein breakdown with a similar dose-response curve, and with a maximal effect between 1 and 2.5 μM. Total protein degradation, induced by both Ang I and Ang II, was attenuated by the proteasome inhibitors lactacystin (5 μM) and MG132 (10 μM), suggesting that the effect was mediated through upregulation of the ubiquitin-proteasome proteolytic pathway. Both Ang I and Ang II stimulated an increased proteasome 'chymotrypsin-like' enzyme activity as well as an increase in protein expression of 20S proteasome α-subunits, the 19S subunits MSSI and p42, at the same concentrations as those inducing protein degradation. The effect of Ang I was attenuated by imidaprilat, confirming that it arose from conversion to Ang II. These results suggest that Ang II stimulates protein degradation in myotubes through induction of the ubiquitin-proteasome pathway. Protein degradation induced by Ang II was inhibited by insulin-like growth factor and by the polyunsaturated fatty acid, eicosapentaenoic acid. These results suggest that Ang II has the potential to cause muscle atrophy through an increase in protein degradation. The highly lipophilic ACE inhibitor imidapril (Vitor™) (30 mg kg-1) attenuated the development of weight loss in mice bearing the MAC16 tumour, suggesting that Ang II may play a role in the development of cachexia in this model. © 2005 Cancer Research.

Phenol methylation over nanoparticulate Co2FeO4 inverse spinel catalysts:the effect of morphology on catalytic performance

A series of CoFe2O4 nanoparticles have been prepared via co-precipitation and controlled thermal sintering, with tunable diameters spanning 7–50 nm. XRD confirms that the inverse spinel structure is adopted by all samples, while XPS shows their surface compositions depend on calcination temperature and associated particle size. Small (<20 nm) particles expose Fe3+ enriched surfaces, whereas larger (∼50 nm) particles formed at higher temperatures possess Co:Fe surface compositions close to the expected 1:2 bulk ratio. A model is proposed in which smaller crystallites expose predominately (1 1 1) facets, preferentially terminated in tetrahedral Fe3+ surface sites, while sintering favours (1 1 0) and (1 0 0) facets and Co:Fe surface compositions closer to the bulk inverse spinel phase. All materials were active towards the gas-phase methylation of phenol to o-cresol at temperatures as low as 300 °C. Under these conditions, materials calcined at 450 and 750 °C exhibit o-cresol selectivities of ∼90% and 80%, respectively. Increasing either particle size or reaction temperature promotes methanol decomposition and the evolution of gaseous reductants (principally CO and H2), which may play a role in CoFe2O4 reduction and the concomitant respective dehydroxylation of phenol to benzene. The degree of methanol decomposition, and consequent H2 or CO evolution, appears to correlate with surface Co2+ content: larger CoFe2O4 nanoparticles have more Co rich surfaces and are more active towards methanol decomposition than their smaller counterparts. Reduction of the inverse spinel surface thus switches catalysis from the regio- and chemo-selective methylation of phenol to o-cresol, towards methanol decomposition and phenol dehydroxylation to benzene. At 300 °C sub-20 nm CoFe2O4 nanoparticles are less active for methanol decomposition and become less susceptible to reduction than their 50 nm counterparts, favouring a high selectivity towards methylation.

Comparative analysis of experimental and modelling of gas-solid flow hydrodynamics:effect of friction and interparticle cohesion forces

The effect of friction and interparticle cohesion forces on the gas-solid flow hydrodynamics was discussed. A proposed interparticle cohesion and frictional force terms have been tested in a continuum fully developed flow model to investigate their effect on the general hydrodynamic features of vertical duct flow. It was observed that both terms have direct effect on lowering the material carryover, which implies a reduced bed expansion in freely bubbling column. The parametric analysis shows that cohesion and frictional forces are high when compared to kinetic stress and hence it can play a major role in describing the hydrodynamics features of the flow.

The verbal transformation effect and the perceptual organization of speech:influence of formant transitions and F0-contour continuity

This study explored the role of formant transitions and F0-contour continuity in binding together speech sounds into a coherent stream. Listening to a repeating recorded word produces verbal transformations to different forms; stream segregation contributes to this effect and so it can be used to measure changes in perceptual coherence. In experiment 1, monosyllables with strong formant transitions between the initial consonant and following vowel were monotonized; each monosyllable was paired with a weak-transitions counterpart. Further stimuli were derived by replacing the consonant-vowel transitions with samples from adjacent steady portions. Each stimulus was concatenated into a 3-min-long sequence. Listeners only reported more forms in the transitions-removed condition for strong-transitions words, for which formant-frequency discontinuities were substantial. In experiment 2, the F0 contour of all-voiced monosyllables was shaped to follow a rising or falling pattern, spanning one octave. Consecutive tokens either had the same contour, giving an abrupt F0 change between each token, or alternated, giving a continuous contour. Discontinuous sequences caused more transformations and forms, and shorter times to the first transformation. Overall, these findings support the notion that continuity cues provided by formant transitions and the F0 contour play an important role in maintaining the perceptual coherence of speech.

Motives for corporate cash holdings:the CEO optimism effect

We examine the chief executive officer (CEO) optimism effect on managerial motives for cash holdings and find that optimistic and non-optimistic managers have significantly dissimilar purposes for holding more cash. This is consistent with both theory and evidence that optimistic managers are reluctant to use external funds. Optimistic managers hoard cash for growth opportunities, use relatively more cash for capital expenditure and acquisitions, and save more cash in adverse conditions. By contrast, they hold fewer inventories and receivables and their precautionary demand for cash holdings is less than that of non-optimistic managers. In addition, we consider debt conservatism in our model and find no evidence that optimistic managers’ cash hoarding is related to their preference to use debt conservatively. We also document that optimistic managers hold more cash in bad times than non-optimistic managers do. Our work highlights the crucial role that CEO characteristics play in shaping corporate cash holding policy.

Placebo expectancy effect of consuming psychoactive beverages on cognition and mood

Energy drinks have become very popular over the past few years with over half the student population in colleges and universities consuming them at least once a month (Malinauskas et al., 2007). It has been reported that the most common reasons why students consume energy drinks are to maintain alertness, reduce symptoms of hangover, increase energy, to help with driving and to prevent sleepiness (Attila and Cakir, 2011; Malinauskas et al., 2007). Previous research has suggested that energy drinks enhance sensorimotor speed, behaviour, and reduce levels of fatigue (Alford et al., 2001; Horne and Reyner, 2001; Howard and Marczinski, 2010; Kennedy and Scholey, 2004; Smit et al., 2004). The two key ingredients found in energy drinks are caffeine and glucose which have been examined together and alone, which have indicated enhanced reaction times, improvement in both verbal memory and sustained attention and more recently there is evidence to show that expectancy may play a key role in predicting intentions of future consumption (Adan and serra-Grabulosa, 2010). According to Kirsch (1997) people have specific expectations when they consume psychoactive substances that trigger physiological and psychological reactions, which tend to be independent of the psychoactive substance ingested. The concept of expectancy effects can be unambiguous especially when the information provided to the participants prior to the experimental study is specific to a possible outcome response. This thesis investigated the extent of expectancy effect on cognition and mood when psychoactive drinks containing caffeine and glucose were consumed in comparison to non-psychoactive drinks. The investigation commenced with examining the independent effects of caffeine and glucose, followed by the combination of caffeine and glucose as an energy drink on mood and cognition. The investigation advanced by comparing drink presentation effects (i.e., consuming the experimental drink from a branded bottle versus from a glass) irrespective of drink content on mood and cognition. Finally, the investigation lead to exploring what factors may predict expectancy effects when participants’ consumed psychoactive drinks among healthy adults. This was done by applying the Theory of Planned Behaviour model (TPB) (Azjen, 1991) to explore the contribution of specific attitudes, subjective norms and perceived behavioural control to the extent of expectancy effects as well as to behavioural intention, with additional variables including; beliefs, habits, past-behaviour, selfidentity. Self-identity representing someone who drinks energy drinks regularly. The level of internal consistency for Cronbach’s alpha was conducted for each variable within the TPB model and for the additional variables included for test reliability. This thesis consisted of four studies, which found that consumption of caffeine and glucose independently and also in combination resulted in psychoactive effects on mood and cognition. Experiment 2 was the only study, which indicated an expectancy effect for immediate verbal recall task and the mood subscale tension. Conversely, for experiment 4 there was a reverse effect found for the immediate verbal recall task. However, there were significant expectancy and psychoactive effects found for mood subscales throughout the four studies. It was also found that the TPB model had two significant variables past-behaviour and self-identity predicted intentions suggesting that participants who regularly consume psychoactive beverages have salient beliefs about consuming psychoactive drinks and the TPB model can be utilised to predict their intentions. Furthermore, the Theory of planned behaviour model found that habit and self-identity significantly predicted participants’ expectancy effects on the vigour. Indicating consumers of energy drinks are familiar with expected outcome response. This model was unsuccessful in predicting expectancy response for cognitive performance. Thus, overall the findings from the four studies indicated that caffeine and glucose have cognitive enhancing properties, which also positively improve mood. However, expectancy effects have been identified for mood only, whereas the overall findings within this thesis were unable to identify significant predictors of expectancy effect and response.

The resource conservation effect of recycling in a dynamic Leontief model

The aim of the paper is to investigate the impact of recycling on the use of non-renewable resources in the economy. The paper tries to generalize the classical dynamic input–output model. In this regard we extend the standard Leontief model with the balance equation of recycled products, and we establish some properties of this augmented model. We investigate how recycling extends the availability of non-renewable natural resources for the next generations in an inter-industry framework. Supposing a balanced growth both for production and consumption, we examine the existence of the balanced growth path of this model and compare the results to the classical Leontief model. We try to answer the question whether recycling/reuse increases the growth possibility of an economy. Finally, we illustrate our results with a simple numerical example. Thus, we analyze a possible sustainable development of the economy on the basis of the product recovery management of industries.

Investigating the effect of geographical distances and cultural proximity on the Hungarian wine trade

Wine is a very special product from an economic, cultural, and sociological point of view. Wine culture and wine trade play an important role in Hungary. The effect of cultural and geographical proximity on international trade has already been proven in the international trade literature. The size of bilateral trade flows between any two countries can be approximated by the gravity theory of trade. The gravity model provides empirical evidence of the relationship between the size of the economies, the distances between them, and their trade. This paper seeks to analyse the effect of cultural and geographical proximity on Hungary’s bilateral wine trade between 2000 and 2012, employing the gravity equation. The analysis is based on data from the World Bank WITS, WDI, as well as CEPII, and WTO databases. I apply OLS, Random Effects, Poisson, Pseudo-Poisson-Maximum-Likelihood and Heckman two stage estimators to calculate the gravity regression. The results show that in the case of Hungary, cultural similarity and trade liberalisation have a positive impact, while geographical distance, landlockedness, and contiguity have a negative impact on Hungarian wine exports.

Effect of blood flow patterns on localized platelet adhesion under physiologic flow conditions using two-dimensional and three-dimensional stent models: An experimental and computational approach

This dissertation presents dynamic flow experiments with fluorescently labeled platelets to allow for spatial observation of wall attachment in inter-strut spacings, to investigate their relationship to flow patterns. Human blood with fluorescently labeled platelets was circulated through an in vitro system that produced physiologic pulsatile flow in (1) a parallel plate blow chamber that contained two-dimensional (2D) stents that feature completely recirculating flow, partially recirculating flow, and completely reattached flow, and (2) a three-dimensional (3D) cylindrical tube that contained stents of various geometric designs. ^ Flow detachment and reattachment points exhibited very low platelet deposition. Platelet deposition was very low in the recirculation regions in the 3D stents unlike the 2D stents. Deposition distal to a strut was always high in 2D and 3D stents. Spirally recirculating regions were found in 3D unlike in 2D stents, where the deposition was higher than at well-separated regions of recirculation. ^

The Effect of Natural Products and Small Gtpases in Adipogenesis

Insulin signaling is one of the main initiators of adipogenesis, the conversion from pre-adipocyte to adipocyte or lipid droplet. Rab proteins are the master regulator of intracellular trafficking and endosome fusion in endocytosis, making them potential regulators of insulin signaling in adipogenesis. Pre-adipocytes 3T3-Ll cells expressing several Rab5 constructs were used to examine the effect of dehydroleucodine (DhL ), a sesquiterpene lactone isolated from aerial parts of Artemisia douglasiana Besser. The results obtained identify Rab5 deactivation as a key step for adipogenesis by forming signaling endosomes. The addition of DhL significantly inhibited the lipid droplet accumulation in a dose-dependent manner and dramatically attenuated the synthesis of adipogenic transcriptional factors, C/EBPa and PPARy. Activation of AMPKa, Erk and Akt during adipocytic differentiation was not inhibited by treatment with DhL. This data suggest that DhL has an important role in Rab5 dependent adipogenesis by regulating several transcriptional factors including PP ARy expression, which is known to play an essential role during fat formation.

Theoretical Investigation of Intra- and Inter-cellular Spatiotemporal Calcium Patterns in Microcirculation

Microcirculatory vessels are lined by endothelial cells (ECs) which are surrounded by a single or multiple layer of smooth muscle cells (SMCs). Spontaneous and agonist induced spatiotemporal calcium (Ca2+) events are generated in ECs and SMCs, and regulated by complex bi-directional signaling between the two layers which ultimately determines the vessel tone. The contractile state of microcirculatory vessels is an important factor in the determination of vascular resistance, blood flow and blood pressure. This dissertation presents theoretical insights into some of the important and currently unresolved phenomena in microvascular tone regulation. Compartmental and continuum models of isolated EC and SMC, coupled EC-SMC and a multi-cellular vessel segment with deterministic and stochastic descriptions of the cellular components were developed, and the intra- and inter-cellular spatiotemporal Ca2+ mobilization was examined. Coupled EC-SMC model simulations captured the experimentally observed localized subcellular EC Ca2+ events arising from the opening of EC transient receptor vanilloid 4 (TRPV4) channels and inositol triphosphate receptors (IP3Rs). These localized EC Ca2+ events result in endothelium-derived hyperpolarization (EDH) and Nitric Oxide (NO) production which transmit to the adjacent SMCs to ultimately result in vasodilation. The model examined the effect of heterogeneous distribution of cellular components and channel gating kinetics in determination of the amplitude and spread of the Ca2+ events. The simulations suggested the necessity of co-localization of certain cellular components for modulation of EDH and NO responses. Isolated EC and SMC models captured intracellular Ca2+ wave like activity and predicted the necessity of non-uniform distribution of cellular components for the generation of Ca2+ waves. The simulations also suggested the role of membrane potential dynamics in regulating Ca2+ wave velocity. The multi-cellular vessel segment model examined the underlying mechanisms for the intercellular synchronization of spontaneous oscillatory Ca2+ waves in individual SMC. From local subcellular events to integrated macro-scale behavior at the vessel level, the developed multi-scale models captured basic features of vascular Ca2+ signaling and provide insights for their physiological relevance. The models provide a theoretical framework for assisting investigations on the regulation of vascular tone in health and disease.

Papel do município e relações federativas: atuação de municípios cearenses nas políticas de formação continuada de alfabetizadores

The investigation analyze s the role of the municipalities in the ongoing development of literacy teachers, having as a field of study the municipalities of Jaguaruana and Palhano, both in the State of Ceará. The political - educational space adopted as a sample of the study is the p eriod between the years 2003 and 2006, when the emphasis on cooperative action among the federated entities is observed in the Government’s guidelines and Brazilian educational policies, showing the municipal presence in the implementation and execution of these policies. T he historical - dialectical materialistic perspective, understood as an analysis of the social reality as historical elaboration and product of the human praxis, is expressed as the required theoretical - methodological path. The investigatio n is operationalized through interconnected stages: one that involves bibliographical and documental analysis, in which the theoretical input of the research is added, as well as the Federal, State and M unicipal documents accessed ; and another, regarding t he field work, studying the specific character of the object and its mutual rela tionships in the municipalities . The research brings the notion of intergovernmental relationships and cooperative mechanisms as central theoretical tools and, dialoguing with them, ideas such as decentralization, municipalization and municipal autonomy are inserted into a theoretical/practical body, through which the historical and logical aspects of the object are detailed. The study describes and interprets the policies of on going development of literacy teachers with focus on the national guidelines formulated since the 1990’s and on the govern mental incorporation in the national and subnational spaces. In this sense, the analysis is based on the comprehension of the interrel ationship between the municipal policies and the p olicies created by the S tate or Federal G overnments in order to offer ongoing development of literacy teachers. Considering the investigated sample, it shows how the municipal role and the relationships bet ween the State and municipalities of Ceará have emerged, as well as their characteristics regarding the education management policies, taking into account the practices of municipalization and cooperation between the State and municipalities in their histo rical composition. It shows the practices which aim at the ongoing development of literacy teachers observed in the researched municipalities, pointing out the realities and specific marks left by municipal presence in the area, demonstrating the assigned role and the role played. Based on the points of view of the managers interviewed in the municipalities of Jaguaruana e Palhano, it is possible to note the meaning and effectiveness of the policies carried out. With such elements, it discusses the municipa l asymmetries in their homogeneities and heterogeneities rega rding the execution of their federative role. The analysis shows that th e role of the municipalities vary according to the historical, political and social interventions in each municipality. In the fields of formulation and execution of educational policies, the actions of the municipal governments, situated and with expressive interferences, reveal asymmetries in the sense that some municipalities have bigger autonomy and participate more effect ively in the production and distribution of policies than others. In terms of the researched realities, the study shows that taking care of the policies of ongoing development of literacy teachers is not a task that should be assigned exclusively to the mu nicipalities, nonetheless it is a role that they play with varying degrees of success. This role is in fact a joint competence of the federated entities, in the scope the Brazilian cooperative federalism.