Regulation of HPV 16-E7 by E2, Phosphorylation and the Proteasome

In order to ensure a productive life cycle, Human Papillomaviruses (HPVs) require fine regulation of their gene products. Uncontrolled activity of the viral oncoproteins, E6 and E7, results in the immortalisation of the infected epithelial cells and thus prevents the production of mature virions. Here, we investigate the regulation of HPV-16 E7 activities through its interaction with both viral and cellular gene products. First, we show that HPV-16 E7 and E2 can interact directly and the region mediating this interaction is defined on each protein. The expression of E2 inhibits some of E7 oncogenic activities including primary cell transformation, induction of centrosome abnormalities and pRB degradation. In addition, E2 can stabilise E7 and redirect its localisation where it can associate with some of E2’s activities such as transcriptional activation and mitotic chromosome binding. Secondly, we provide evidence that E7 can be phosphorylated by CDK2 in vitro preferentially on its N-terminal domain, and we hypothesise that this occurs on more than one residue on E7. In vivo, we show that the activity of CDK2, as well as CKII, is necessary for the stability of E7. Finally, we identified an interaction between HPV-16 E2 and E7 with the cellular oncoprotein, Mdm2. Mdm2 appears to destabilise E7 targeting it to proteasome-mediated degradation at PML bodies. The stability of E7 in cells that have reduced expression of Mdm2 is markedly increased indicating that the expression of Mdm2 indeed destabilises E7. In the case of the Mdm2 interaction with E2, we observe that E2 inhibits Mdm2 mediated degradation of p53 and pRB and that the expression of Mdm2 enhances E2’s transcriptional activity and induces its re-localisation at specific structures within the nucleus. Overall, our findings expand our knowledge of the regulation of virally encoded proteins both through direct protein-protein interactions between themselves and through their interactions with cellular proteins

Autophagy and autophagy-related pathways in cancer

Maintenance of protein homeostasis and organelle integrity and function is critical for cellular homeostasis and cell viability. Autophagy is the principal mechanism that mediates the delivery of various cellular cargoes to lysosomes for degradation and recycling. A myriad of studies demonstrate important protective roles for autophagy against disease. However, in cancer, seemingly opposing roles of autophagy are observed in the prevention of early tumour development versus the maintenance and metabolic adaptation of established and metastasizing tumours. Recent studies have addressed not only the tumour cell intrinsic functions of autophagy, but also the roles of autophagy in the tumour microenvironment and associated immune cells. In addition, various autophagy-related pathways have been described, which are distinct from classical autophagy, that utilize parts of the autophagic machinery and can potentially contribute to malignant disease. Growing evidence on how autophagy and related processes affect cancer development and progression has helped guide efforts to design anticancer treatments based on inhibition or promotion of autophagy. In this Review, we discuss and dissect these different functions of autophagy and autophagy-related processes during tumour development, maintenance and progression. We outline recent findings regarding the role of these processes in both the tumour cells and the tumour microenvironment and describe advances in therapy aimed at autophagy processes in cancer

Enterprise Business Alignment Using Quality Function Deployment, Multivariate Data Analysis And Business Modeling Tools

This dissertation proposes two novel ideas to enhance the business strategy alignment to customer needs. The proposed business alignment clock is a new illustration to the relationships between customer requirements, business strategies, capabilities and processes. To line up the clock and reach the needed alignment for the enterprise, a proposed clock mechanism is introduced. The mechanism integrates the Enterprise Business Architecture (EBA) with the House of Quality (HoQ). The relationship matrix inside the body of the house is defined using multivariate data analysis techniques to accurately measure the strength of the relationships rather than defining them subjectively. A statistical tool, multivariate data analysis, can be used to overcome the ambiguity in quantifying the relationships in the house of quality matrix. The framework is proposed in the basic conceptual model context of the EBA showing different levels of the enterprise architecture; the goals, the capabilities and the value stream architecture components. In the proposed framework, the goals and the capabilities are inputs to two houses of quality, in which the alignment between customer needs and business goals, and the alignment between business goals and capabilities are checked in the first house and the second house, respectively. The alignment between the business capabilities and the architecture components (workflows, events and environment) is checked in a third HoQ using the performance indicators of the value stream architecture components, which may result in infrastructure expansion, software development or process improvement to reach the needed alignment by the enterprise. The value of the model was demonstrated using the Accreditation Board of Engineering and Technology (ABET) process at the Industrial Engineering and Management Systems department at the University of Central Florida. The assessment of ABET criteria involves an evaluation of the extent to which the program outcomes are being achieved and results in decisions and actions to improve the Industrial Engineering program at the University of Central Florida. The proposed framework increases the accuracy of measuring the extent to which the program learning outcomes have been achieved at the department. The process of continuous alignment between the educational objectives and customer needs becomes more vital by the rapid change of customer requirements that are obtained from both internal and external constituents (students, faculty, alumni, and employers in the first place)

Evaluation of social impact of traffic noice in Amman, Jordan

Few road traffic studies were conducted in Jordan, but the issue is drawing an increasing attention due to its growing magnitude and various impacts as a result of the high increase in vehicular traffic. This study further investigates the issue with the aim of providing an understanding of its social impact on residents of Amman, the capital of Jordan. Traffic noise levels were measured at selected locations along urban arterials and a social survey was performed to examine the reactions and attitudes of the neighboring residents towards these levels of traffic noise. The survey included social characteristics of individuals, and their attitudes towards traffic noise, and how it impacted their daily activities. A predesigned questionnaire was used for this purpose which included questions to evaluate the awareness of respondents of the problem and its environmental and health impacts. The financial impact that residents perceive of noise and the need for attenuation measures were also addressed. The results of the study also revealed that the impact of traffic noise on people can cause annoyance while performing daily activities were 24% of respondents reported that they get annoyed by traffic while working, 49% while resting, 34% while talking to others, 31% while talking on the phone, 39% while reading, 38% while watching TV and 53% of respondents get annoyed while sleeping. The respondents have also pointed out the following effects of noise: twist in mood (53%), headache (36%), and difficulty in concentration (40%). About 57% of respondents think traffic noise reduces the value of their properties and a total of 31% are willing to sell their house at reduced cost. About 59% of respondents consider attenuation measures necessary, and in order to reduce the noise, about 54% of respondents were willing to pay for attenuation measures which reflects the public awareness of the issue magnitude. Keywords: traffic noise, noise level, survey, social impacts

Propensity to Participate in Brand Alliances: a Managerial Perspective

A review of the brand alliance literature indicates that while scholars have concentrated on understanding consumers' reactions to brand alliances, the antecedents of firm participation in brand alliances are still not well understood. The purpose of this research is to fill this gap by investigating brand alliance formation at the firm level. Therefore, based on a review of relevant literature, this research developed a conceptual framework of brand alliance formation and empirically test a subset of this framework focused on firm-level alliance capabilities (i.e., alliance competence) and brand-level attributes (i.e., product quality) as antecedents of firms' propensity to brand ally. In addition, this research attempts to empirically test the moderating effects of firm level motivational factors (e.g., market entry/penetration) and managerial attitudes (e.g., attitude toward brand alliances) on the proposed relationships. Research hypotheses were empirically tested with rigorous research methods on a national sample of senior marketing executives and brand managers. Results indicate a significant direct relationship between alliance experience and alliance competence. More importantly, valence of alliance experience was shown to exhibit a moderating influence on the relationship between alliance experience and alliance competence. That is, the more positive alliance experience is the stronger the relationship between alliance experience and alliance competence. In addition, results indicate that alliance competence positively influenced propensity to brand ally. Although attitude toward brand alliances didn't moderate the relationship between alliance competence and propensity to brand ally, it has a strong and positive direct influence on propensity to brand ally. The empirical findings failed to support part of the proposed model. More specifically, the proposed influence of brand quality on propensity to brand ally was not significant. Also, the interaction effects of the three brand motivational variables on the relationship between brand quality and propensity to brand ally and the relationship between alliance competence and propensity to brand ally were also not significant. Several potential explanations for the non-significant results were explored. Next, theoretical and practical implications of study results were discussed. Finally, research limitations and directions for future research were presented.Department of Marketin