Sphingosine Kinase 1 Promotes Malignant Progression in Colon Cancer and Independently Predicts Survival of Patients With Colon Cancer by Competing Risk Approach in South Asian Population

OBJECTIVES: Sphingosine kinase 1 (SphK1) phosphorylates the membrane sphingolipid, sphingosine, to sphingosine-1-phosphate (S1P), an oncogenic mediator, which drives tumor cell growth and survival. Although SphK1 has gained increasing prominence as an oncogenic determinant in several cancers, its potential as a therapeutic target in colon cancer remains uncertain. We investigated the clinical relevance of SphK1 expression in colon cancer as well as its inhibitory effects in vitro.

METHODS: SphK1 expression in human colon tumor tissues was determined by immunohistochemistry and its clinicopathological significance was ascertained in 303 colon cancer cases. The effects of SphK1 inhibition on colon cancer cell viability and the phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway were investigated using a SphK1-selective inhibitor-compound 5c (5c). The cytotoxicity of a novel combination using SphK1 inhibition with the chemotherapeutic drug, 5-fluorouracil (5-FU), was also determined.

RESULTS: High SphK1 expression correlated with advanced tumor stages (AJCC classification). Using a competing risk analysis model to take into account disease recurrence, we found that SphK1 is a significant independent predictor for mortality in colon cancer patients. In vitro, the inhibition of SphK1 induced cell death in colon cancer cell lines and attenuated the serum-dependent PI3K/Akt signaling. Inhibition of SphK1 also enhanced the sensitivity of colon cancer cells to 5-FU.

CONCLUSION: Our findings highlight the impact of SphK1 in colon cancer progression and patient survival, and provide evidence supportive of further development in combination strategies that incorporate SphK1 inhibition with current chemotherapeutic agents to improve colon cancer outcomes.

LSQ14bdq: a type Ic Super-luminous Supernova with a double-peaked light curve

We present data for LSQ14bdq, a hydrogen-poor super-luminous supernova (SLSN) discovered by the La Silla QUEST survey and classified by the Public ESO Spectroscopic Survey of Transient Objects. The spectrum and light curve are very similar to slow-declining SLSNe such as PTF12dam. However, detections within ∼1 day after explosion show a bright and relatively fast initial peak, lasting for ∼15 days, prior to the usual slow rise to maximum light. The broader, main peak can be fit with either central engine or circumstellar interaction models. We discuss the implications of the precursor peak in the context of these models. It is too bright and narrow to be explained as a normal ⁵⁶Ni-powered SN, and we suggest that interaction models may struggle to fit the two peaks simultaneously. We propose that the initial peak may arise from the post-shock cooling of extended stellar material, and reheating by a central engine drives the second peak. In this picture, we show that an explosion energy of ∼2 × 10⁵² erg and a progenitor radius of a few hundred solar radii would be required to power the early emission. The competing engine models involve rapidly spinning magnetars (neutron stars) or fallback onto a central black hole. The prompt energy required may favor the black hole scenario. The bright initial peak may be difficult to reconcile with a compact Wolf-Rayet star as a progenitor since the inferred energies and ejected masses become unphysical.

An Investigation Into Improving Off-Design Performance in a Turbocharger Turbine Utilizing Non-Radial Blading

Off-design performance now plays a vital role in the design decisions made for automotive turbocharger turbines. Of particular interest is extracting more energy at high pressure ratios and lower rotational speeds. In this region of operation the U/C value will be low and the rotor will experience high values of positive incidence at the inlet. The positive incidence causes flow to separate on the suction surface and produces high blade loading at inlet, which drives tip leakage. A CFD analysis has been carried out on a number of automotive turbines utilizing non-radial fibred blading. To help improve secondary flows yet meet stress requirements a number of designs have been investigated. The inlet blade angle has been modified in a number of ways. Firstly, the blading has been adjusted as to provide a constant back swept angle in the span wise direction. Using the results of the constant back swept blading studies, the back swept blade angle was then varied in the span wise direction. In addition to this, in an attempt to avoid an increase in stress, the effect of varying the leading edge profile of the blade was investigated. It has been seen that off-design performance is improved by implementing back swept blading at the inlet. Varying the inlet angle in the span wise direction provided more freedom for meeting stress requirements and reduces the negative impact on blade performance at the design point. The blade leading edge profile was seen to offer small improvements during off-design operation with minimal effects on stress within the rotor. However, due to the more pointed nature of the leading edge, the rotor was less tolerant to flow misalignment at the design point.

A review of high magnetic moment thin films for microscale and nanotechnology applications

The creation of large magnetic fields is a necessary component in many technologies, ranging from magnetic resonance imaging, electric motors and generators, and magnetic hard disk drives in information storage. This is typically done by inserting a ferromagnetic pole piece with a large magnetisation density MS in a solenoid. In addition to large MS, it is usually required or desired that the ferromagnet is magnetically soft and has a Curie temperature well above the operating temperature of the device. A variety of ferromagnetic materials are currently in use, ranging from FeCo alloys in, for example, hard disk drives, to rare earth metals operating at cryogenic temperatures in superconducting solenoids. These latter can exceed the limit on MS for transition metal alloys given by the Slater-Pauling curve. This article reviews different materials and concepts in use or proposed for technological applications that require a large MS, with an emphasis on nanoscale material systems, such as thin and ultra-thin films. Attention is also paid to other requirements or properties, such as the Curie temperature and magnetic softness. In a final summary, we evaluate the actual applicability of the discussed materials for use as pole tips in electromagnets, in particular, in nanoscale magnetic hard disk drive read-write heads; the technological advancement of the latter has been a very strong driving force in the development of the field of nanomagnetism.

Maternal Risk Anxiety in Belfast: Claims, Evaluations, Responses

This paper considers the social logic of maternal anxiety about risks posed to children in segregated, post-conflict neighbourhoods. Focusing on qualitative research with mothers in Belfast’s impoverished and divided inner city, the paper draws on the interactionist perspective in the sociology of emotions to explore the ways in which maternal anxiety drives claims for recognition of good mothering, through orientations to these neighbourhoods. Drawing on Hirschman’s model of exit, loyalty and voice types of situated action, the paper examines the relationship between maternal risk anxiety and evaluations of neighbourhood safety. In arguing that emotions are important aspects of claims for social recognition, the paper demonstrates that anxiety provokes efforts to claim status, in this context through the explicit affirmation of non-sectarian mothering.

Going above and beyond: how sustainability culture and entrepreneurial orientation drive social sustainability supply chain practice adoption

Purpose
– This paper aims to examine what drives the adoption of different social sustainability supply chain practices. Research has shown that certain factors drive the adoption of environmental sustainability practices but few focus on social supply chain practices, delineate which practices are adopted or what drives their adoption.

Design/methodology/approach
– The authors examine the facilitative role of sustainability culture to explain the adoption of social sustainability supply chain practices: basic practices, consisting of monitoring and management systems and advanced practices, which are new product and process development and strategic redefinition. The authors then explore the role played by a firm’s entrepreneurial orientation in shaping and reinforcing the adoption of social sustainability supply chain practices. A survey of 156 supply chain managers in multiple industries in Ireland was conducted to test the relationship between the variables.

Findings
– The findings show that sustainability culture is positively related to all the practices, and entrepreneurial orientation impacts and moderates social sustainability culture in advanced social sustainability supply chain adoption.

Research limitations/implications
– As with any survey, this is a single point in time with a single respondent. Implications for managers include finding the right culture in the organisation to implement social sustainability supply chain management practices that go beyond monitoring to behavioural changes in the supply chain with implications beyond the dyad of buyer and supplier to lower tier suppliers and the community surrounding the supply chain.

Practical implications
– The implications for managers include developing and fostering cultural attributes in the organisation to implement social sustainability supply chain management practices that go beyond monitoring suppliers to behavioural changes in the supply chain with implications beyond the dyad of buyer and supplier to lower tier suppliers and the community surrounding the supply chain.

Originality/value
– This is the first time, to the authors’ knowledge, that cultural and entrepreneurial variables have been tested for social sustainability supply chain practices, giving them new insights into how and why social sustainability supply chain practices are adopted.

The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer

Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, beingsignificantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression.

A coactivator role of CARM1 in the dysregulation of β-catenin activity in colorectal cancer cell growth and gene expression

Aberrant activation of Wnt/β-catenin signaling, resulting in the expression of Wnt-regulated oncogenes, is recognized as a critical factor in the etiology of colorectal cancer. Occupancy of β-catenin at promoters of Wnt target genes drives transcription, but the mechanism of β-catenin action remains poorly understood. Here, we show that CARM1 (coactivator-associated arginine methyltransferase 1) interacts with β-catenin and positively modulates β-catenin-mediated gene expression. In colorectal cancer cells with constitutively high Wnt/β-catenin activity, depletion of CARM1 inhibits expression of endogenous Wnt/β-catenin target genes and suppresses clonal survival and anchorage-independent growth. We also identified a colorectal cancer cell line (RKO) with a low basal level of β-catenin, which is dramatically elevated by treatment with Wnt3a. Wnt3a also increased the expression of a subset of endogenous Wnt target genes, and CARM1 was required for the Wnt-induced expression of these target genes and the accompanying dimethylation of arginine 17 of histone H3. Depletion of β-catenin from RKO cells diminished the Wnt-induced occupancy of CARM1 on a Wnt target gene, indicating that CARM1 is recruited to Wnt target genes through its interaction with β-catenin and contributes to transcriptional activation by mediating events (including histone H3 methylation) that are downstream from the actions of β-catenin. Therefore, CARM1 is an important positive modulator of Wnt/β-catenin transcription and neoplastic transformation, and may thereby represent a novel target for therapeutic intervention in cancers involving aberrantly activated Wnt/β-catenin signaling.

Central-Tapped Node Linked Modular Fault-Tolerance Topology for SRM Applications

Electric vehicles (EVs) and hybrid electric vehicles (HEVs) can reduce greenhouse gas emissions while switched reluctance motor (SRM) is one of the promising motor for such applications. This paper presents a novel SRM fault-diagnosis and fault-tolerance operation solution. Based on the traditional asymmetric half-bridge topology for the SRM driving, the central tapped winding of the SRM in modular half-bridge configuration are introduced to provide fault-diagnosis and fault-tolerance functions, which are set idle in normal conditions. The fault diagnosis can be achieved by detecting the characteristic of the excitation and demagnetization currents. An SRM fault-tolerance operation strategy is also realized by the proposed topology, which compensates for the missing phase torque under the open-circuit fault, and reduces the unbalanced phase current under the short-circuit fault due to the uncontrolled faulty phase. Furthermore, the current sensor placement strategy is also discussed to give two placement methods for low cost or modular structure. Simulation results in MATLAB/Simulink and experiments on a 750-W SRM validate the effectiveness of the proposed strategy, which may have significant implications and improve the reliability of EVs/HEVs.

A novel inhibitor of channel activating proteases: Putting the CAP on ENaC

Background: Excessive activation of epithelial sodium channels (ENaC) contributes to CF lung pathophysiology due to the resultant dehydration of the airway surface liquid (ASL) and impaired mucociliary clearance. Regulated proteolysis of the endogenous α and γ subunits of ENaC by apical membrane-bound Channel Activating Proteases (CAPs) is a fundamental regulatory mechanism for channel activity. In the CF lung a stark imbalance between the levels of CAPs and their natural inhibitors drives the activation of normally inactive ENaC. On this basis inhibition of CAPs-ENaC signalling represents a potential therapeutic intervention. To this end we have developed a novel cell impermeable active-site directed compound (QUB-TL1) designed to inactivate key trypsin-like CAPs highly relevant in this regard. Objectives & Methods: Utilize differentiated non-CF and CF human airway epithelial cells to assess the impact of QUB-TL1 on a range of parameters including surface CAP activities, ENaC subunit processing/channel activity, ASL height and mucociliary clearance. Results: Treatment of airway epithelial cells with QUB-TL1 results in the significant downregulation of key endogenous CAP activities found to be excessively active at the surface of CF cultures. QUB-TL1-mediated CAP inhibition subsequently causes the internalisation of a pool of processed (active) ENaCγ prominent at the apical surface of CF cultures which correlates with a decline in channel activity. This downregulation of ENaC activity results in an increase in ASL height and improved mucociliary clearance in CF cells. We further find QUB-TL1 uniquely inhibits the ENaC activating enzyme furin, which is in contrast to the alternate trypsin-like CAP inhibitors camostat mesylate and aprotinin. QUB-TL1-mediated furin inhibition correlates with a reduction in neutrophil elastase-induced ENaC activation. Moreover we find QUB-TL1 treatment protects CF cultures from Pseudomonas aeruginosa exotoxin A-induced cytotoxicity. Pseudomonas aeruginosa exotoxin A is a major toxic product activated by furin and positively associated with mortality. Conclusion: The novel inhibitor (QUB-TL1) dampens CAPs-ENaC signalling which improves hydration status mucociliary clearance in CF airway epithelial cell cultures. Moreover this compound provides additional benefit by preventing Pseudomonas aeruginosa exotoxin A-induced cytotoxicity.

Electron-impact excitation of Fe2: a comparison of intermediate coupling frame transformation, Breit-Pauli and Dirac R-matrix calculations

Modeling the spectral emission of low-charge iron group ions enables the diagnostic determination of the local physical conditions of many cool plasma environments such as those found in H II regions, planetary nebulae, active galactic nuclei etc. Electron-impact excitation drives the population of the emitting levels and, hence, their emissivities. By carrying-out Breit-Pauli and intermediate coupling frame transformation (ICFT) R-matrix calculations for the electron-impact excitation of Fe$^{2+}$ which both use the exact same atomic structure and the same close-coupling expansion, we demonstrate the validity of the application of the powerful ICFT method to low-charge iron group ions. This is in contradiction to the finding of Bautista et al. [Ap.J.Lett, 718, L189, (2010)] who carried-out ICFT and Dirac R-matrix calculations for the same ion. We discuss possible reasons.

Perceptual learning of acoustic noise generates memory-evoked potentials

Experience continuously imprints on the brain at all stages of life. The traces it leaves behind can produce perceptual learning [1], which drives adaptive behavior to previously encountered stimuli. Recently, it has been shown that even random noise, a type of sound devoid of acoustic structure, can trigger fast and robust perceptual learning after repeated exposure [2]. Here, by combining psychophysics, electroencephalography (EEG), and modeling, we show that the perceptual learning of noise is associated with evoked potentials, without any salient physical discontinuity or obvious acoustic landmark in the sound. Rather, the potentials appeared whenever a memory trace was observed behaviorally. Such memory-evoked potentials were characterized by early latencies and auditory topographies, consistent with a sensory origin. Furthermore, they were generated even on conditions of diverted attention. The EEG waveforms could be modeled as standard evoked responses to auditory events (N1-P2) [3], triggered by idiosyncratic perceptual features acquired through learning. Thus, we argue that the learning of noise is accompanied by the rapid formation of sharp neural selectivity to arbitrary and complex acoustic patterns, within sensory regions. Such a mechanism bridges the gap between the short-term and longer-term plasticity observed in the learning of noise [2, 4-6]. It could also be key to the processing of natural sounds within auditory cortices [7], suggesting that the neural code for sound source identification will be shaped by experience as well as by acoustics.

The role of environmental stress on protein synthesis fidelity

Estudos recentes estabelecem uma ligação entre erros na tradução do mRNA e cancro, envelhecimento e neurodegeneração. RNAs de transferência mutantes que introduzem aminoácidos em locais errados nas proteínas aumentam a produção de espécies reactivas de oxigénio e a expressão de genes que regulam autofagia, ribofagia, degradação de proteínas não-funcionais e protecção contra o stress oxidativo. Erros na tradução do mRNA estão portanto relacionados com stress proteotóxico. Sabe-se agora que o mecanismo de toxicidade do crómio está associado à diminuição da fidelidade de tradução e à agregação de proteínas com malformações que destabilizam a sua estrutura terciária. Desta forma, é possível que os efeitos do stress ambiental ao nível da degeneração celular possam estar relacionados com a alteração da integridade da maquinaria da tradução. Neste estudo procedeu-se a uma avaliação alargada do impacto do stress ambiental na fidelidade da síntese de proteínas, utilizando S. cerevisiae como um sistema modelo. Para isso recorreu-se a repórteres policistrónicos de luciferase que permitiram quantificar especificamente a supressão de codões de terminação e o erro na leitura do codão AUG em células exposta a concentações não letais de metais pesados, etanol, cafeína e H2O2. Os resultados sugerem que a maquinaria de tradução é na generalidade muito resistente ao stress ambiental, devido a uma conjugação de mecanismos de homeostase que muito eficientemente antagonizam o impacto negativo dos erros de tradução. A nossa abordagem quantitativa permitiu-nos a identificar genes regulados por uma resposta programada ao stress ambiental que são também essenciais para mitigar a ocorrência de erros de tradução, nomeadamente, HSP12, HSP104 e RPN4. A exposição prolongada ao stress ambiental conduz à saturação dos mecanismos de homeostase, contribuindo para a acumulação de proteínas contendo erros de tradução e diminuindo a disponibilidade de proteínas funcionais directamente envolvidas na manutenção da fidelidade de tradução e integridade celular. Ao contrário de outras Hsps, a Hsp12p adopta normalmente uma localização membranar em condições de stress, que pode modular a fluidez e estabilidade membranar, sugerindo que a membrana plasmática é um alvo preferencial da perda de fidelidade da tradução. Para melhor compreender as respostas celulares aos erros de tradução, células contendo deleções em genes codificadores das Hsps foram transformadas com tRNAs mutantes que introduzem alterações no proteoma. Os nossos resultados demonstram que para além da resposta geral ao stress, estes tRNAs induzem alterações a nível do metabolismo celular e um aumento de aminoacilação com Metionina em vários tRNAs, sugerindo um mecanismo de protecção contra espécies reactivas de oxigénio. Em conclusão, este estudo sugere um papel para os erros de tradução na gestão de recursos energéticos e na adaptação das células a ambientes desfavoráveis.

O género e o uso das tecnologias da comunicação no ensino superior público português: as questões de género na perceção e avaliação das tecnologias da comunicação usadas para suporte à aprendizagem

O processo de convergência europeu da educação superior, mais conhecido por Processo de Bolonha, tem promovido mudanças profundas ao nível do Ensino Superior (ES). Entre as várias diretrizes propostas, destaca-se a necessidade de se usarem Tecnologias da Informação e Comunicação (TIC), no sentido de promover uma participação mais ativa, participativa e autónoma dos estudantes nos processos de aprendizagem. No entanto, a escassez de estudos abrangentes não permite a construção de uma visão fundamentada do uso de Tecnologias da Comunicação (TC) ao nível do ES. Surge assim a necessidade de se identificar e caracterizar o uso de TC, numa tentativa de construir uma imagem atual sobre quais as TC que são usadas, em que contextos, com que finalidades e como é que o seu uso é percecionado pelos estudantes. A tese aqui apresentada tem, assim, como objetivo principal procurar contribuir para uma compreensão mais alargada do uso de TC no Ensino Superior Público Português (ESPP), partindo das perceções dos estudantes e dando especial enfoque ao estudo da influência do género na perceção e avaliação do uso dessas tecnologias para suporte à aprendizagem. Para a prossecução dos objetivos propostos e, tendo presente a questão de investigação, desenvolveu-se um estudo nacional de cariz descritivo e exploratório, tendo os dados sido recolhidos e tratados com recurso a métodos quantitativos e, posteriormente, interpretados de forma mais qualitativa. A recolha de dados decorreu entre 27 de outubro de 2010 e 11 fevereiro de 2011, período em que esteve disponível para participação um questionário online dirigido a todos os estudantes do ESPP. Durante este período foram levadas a cabo diversas ações de divulgação que visaram, sobretudo, fomentar uma participação elevada neste estudo, o que se traduziu num total de 2.207 respostas validadas. Apesar das limitações identificadas, considera-se que as conclusões deste estudo são significativas sobre as características da realidade atual sobre o uso de TC por parte dos estudantes do ESPP, no sentido em que existiu uma elevada participação no questionário, a maioria das IESPP estão representadas, bem como se identificam muitas semelhanças entre os participantes e o universo em estudo. Os resultados alcançados permitem, assim, conhecer as TC usadas pelos estudantes e identificar diferenças de género na perceção desse uso, com especial evidência na perceção das atitudes, benefícios e problemas, bem como nas atividades e competências para o uso de TC. Conclui-se, ainda, que os alunos reveem utilidade nas TC que utilizam, exprimem grande concordância em relação aos benefícios e têm uma perceção positiva face aos impactos associados ao uso dessas TC.

Determinants of online travel purchase intentions: a holistic approach

Online travel shopping has attracted researchers due to its significant growth and there is a growing body of literature in this field. However, research on what drives consumers to purchase travel online has typically been fragmented. In fact, existing studies have largely concentrated on examining consumers’ online travel purchases either grounded on Davis’s Technology Acceptance Model, on the Theory of Reasoned Action and its extension, the Theory of Planned Behaviour or on Roger’s model of perceived innovation attributes, the Innovation Diffusion Theory. A thorough literature review has revealed that there is a lack of studies that integrate all theories to better understand online travel shopping. Therefore, based on relevant literature in tourism and consumer behaviour, this study proposes and tests an integrated model to explore which factors affect intentions to purchase travel online. Furthermore, it proposes a new construct, termed social media involvement, defined as a person’s level of interest or emotional attachment with social media, and examines its relationship with intentions to purchase travel online. To test the 18 hypotheses, a quantitative approach was followed by first collecting data through an online survey. With a sample of 1,532 Worldwide Internet users, Partial Least Squares analysis was than conducted to assess the validity and reliability of the data and empirically test the hypothesized relationships between the constructs. The results indicate that intentions to purchase travel online is mostly determined by attitude towards online shopping, which is influenced by perceived relative advantages of online travel shopping and trust in online travel shopping. In addition, the findings indicate that the second most important predictor of intentions to purchase travel online is compatibility, an attribute from the Innovation Diffusion Theory. Furthermore, even though online shopping is nowadays a common practice, perceived risk continues to negatively affect intentions to purchase travel online. The most surprising finding of this study was that Internet users more involved with social media for travel purposes did not have higher intentions to purchase travel online. The theoretical contributions of this study and the practical implications are discussed and future research directions are detailed.