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At least 55 records · Page 3

Human papillomavirus type 16 E6 inhibits p21{sup WAF1} transcription independently of p53 by inactivating p150{sup Sal2}

HPV16 E6 deregulates G1/S cell cycle progression through p53 degradation preventing transcription of the CDK inhibitor p21{sup WAF1}. However, additional mechanisms independent of p53 inactivation appear to exist. Here, we report that HPV16 E6 targets the cellular factor p150{sup Sal2}, which positively regulates p21{sup WAF1} transcription. HPV16 E6 associates with p150{sup Sal2}, inducing its functional inhibition by preventing its binding to cis elements on the p21{sup WAF1} promoter. A HPV16 E6 mutant, L110Q, which was unable to bind p150{sup Sal2}, did not affect the ability of the cellular protein to bind p21{sup WAF1} promoter, underlining the linkage between these events. These data describe a novel mechanism by which HPV16 E6 induces cell cycle deregulation with a p53-independent pathway. The viral oncoprotein targets p150{sup Sal2}, a positive transcription regulator of p21{sup WAF1} gene, preventing G1/S arrest and allowing cellular proliferation and efficient viral DNA replication.

60 APPLIED LIFE SCIENCES↗

A functional nuclear localization sequence in the VP1 capsid protein of coxsackievirus B3

The capsid proteins of some RNA viruses can translocate to the nucleus and interfere with cellular phenotypes. In this study we found that the VP1 capsid protein of coxsackievirus B3 (CVB3) was dominantly localized in the nucleus of the cells transfected with VP1-expressing plasmid. The VP1 nuclear localization also occurred in the cells infected with CVB3. Truncation analysis indicated that the VP1 nuclear localization sequence located near the C-terminal. The substitution of His220 with threonine completely abolished its translocation. The VP1 proteins of other CVB types might have the nuclear localization potential because this region was highly conserved. Moreover, the VP1 nuclear localization induced cell cycle deregulation, including a prolonged S phase and shortened G2-M phase. Besides these findings, we also found a domain between Ala72 and Phe106 that caused the VP1 truncates dotted distributed in the cytoplasm. Our results suggest a new pathogenic mechanism of CVB. - Highlights: Black-Right-Pointing-Pointer The VP1 protein of coxsackievirus B3 can specifically localize in the nucleus. Black-Right-Pointing-Pointer The nuclear localization signal of coxsackievirus B3 VP1 protein locates near its C-terminal. Black-Right-Pointing-Pointer The VP1 nuclear localization of coxsackievirus B3 can deregulate cell cycle. Black-Right-Pointing-Pointer There is a domain in the VP1 that determines it dotted distributed in the cytoplasm.

60 APPLIED LIFE SCIENCES↗

Transforming properties of Felis catus papillomavirus type 2 E6 and E7 putative oncogenes in vitro and their transcriptional activity in feline squamous cell carcinoma in vivo

Felis catus papillomavirus type 2 (FcaPV2) DNA is found in feline cutaneous squamous cell carcinomas (SCCs); however, its biological properties are still uncharacterized. In this study, we successfully expressed FcaPV2 E6 and E7 putative oncogenes in feline epithelial cells and demonstrated that FcaPV2 E6 binds to p53, impairing its protein level. In addition, E6 and E7 inhibited ultraviolet B (UVB)-triggered accumulation of p53, p21 and pro-apoptotic markers such as Cleaved Caspase3, Bax and Bak, suggesting a synergistic action of the virus with UV exposure in tumour pathogenesis. Furthermore, FcaPV2 E7 bound to feline pRb and impaired pRb levels, resulting in upregulation of the downstream pro-proliferative genes Cyclin A and Cdc2. Importantly, we demonstrated mRNA expression of FcaPV2 E2, E6 and E7 in feline SCC samples, strengthening the hypothesis of a causative role in the development of feline SCC. - Highlights: • FcaPV2 E6 binds to and deregulates feline p53 protein. • FcaPV2 E7 binds to and deregulates feline pRb protein. • FcaPV2 oncogenes inhibit UVB-induced apoptosis. • FcaPV2 E6E7 and E7 increase the lifespan of primary cells. • FcaPV2 E2, E6 and E7 are expressed at the mRNA level in feline SCC in vivo.

60 APPLIED LIFE SCIENCES↗

Claudin-1 promotes TNF-α-induced epithelial-mesenchymal transition and migration in colorectal adenocarcinoma cells

Epithelial-mesenchymal transition (EMT) is an important mechanism in cancer progression and malignancy including colorectal cancer (CRC). Importantly, inflammatory mediators are critical constituents of the local tumor environment and an intimate link between CRC progression and inflammation is now validated. We and others have reported key role of the deregulated claudin-1 expression in colon carcinogenesis including colitis-associated colon cancer (CAC). However, the causal association between claudin-1 expression and inflammation-induced colon cancer progression remains unclear. Here we demonstrate, TNF-α, a pro-inflammatory cytokine, regulates claudin-1 to modulate epithelial to mesenchymal transition (EMT) and migration in colon adenocarcinoma cells. Importantly, colon cancer cells cultured in the presence of TNF-α (10 ng/ml), demonstrated a sharp decrease in E-cadherin expression and an increase in vimentin expression (versus control cells). Interestingly, TNF-α treatment also upregulated (and delocalized) claudin-1 expression in a time-dependent manner accompanied by increase in proliferation and wound healing. Furthermore, similar to our previous observation that claudin-1 overexpression in CRC cells induces ERK1/2 and Src- activation, signaling associated with colon cancer cell survival and transformation, TNF-α-treatment induced upregulation of phospho-ERK1/2 and -Src expression. The shRNA-mediated inhibition of claudin-1 expression largely abrogated the TNF-α-induced changes in EMT, proliferation, migration, p-Erk and p-Src expression. Taken together, our data demonstrate TNF-α mediated regulation of claudin-1 and tumorigenic abilities of colon cancer cells and highlights a key role of deregulated claudin-1 expression in inflammation-induced colorectal cancer growth and progression, through the regulation of the ERK and Src-signaling.

60 APPLIED LIFE SCIENCES↗

SIRT1 and microRNAs: The role in breast, lung and prostate cancers

Highlights: • Breast, lung and prostate cancers are the most common and threatening cancers worldwide. • SIRT1 is elevated in human breast, lung and prostate cancers. • SIRT1 and microRNAs serve as a tumor promotor or tumor suppressor. • MicroRNAs and SIRT1 deregulation have been linked to cancer. Breast cancer and prostate cancer are the most common malignant tumors in female and men, respectively. Furthermore, lung cancer is the leading cause of cancer deaths worldwide. It is an emergency to develop a powerful strategy to treat these threatening cancers more effectively, because of low efficacy and high rates of chemotherapy effects. MicroRNAs (miRNAs), a class of small non-coding RNAs, are key regulators of gene expression via induction of translational repression or mRNA degradation. MiRNA deregulation has been linked to cancer initiation and progression. Silent Inflammation Regulator 2 (SIR2) proteins-sirtuins- are a family of histone deacetylases (HDACs) that catalyze deacetylation of both histone and non- histone lysine residues. SIRT1 can act as an oncogene. It plays a role in tumorigenesis by anti-apoptotic activity and is implicated in diverse cellular process including autophagy, senescence, apoptosis, proliferation, and aging. MicroRNAs and SIRT1 serve as tumor suppressors or tumor promotors depending on the oncogenic pathway specific to particular tumors. MicroRNAs modulate cancer development by targeting SIRT1. In this review, we underlie the specific mechanisms involved in these threatening cancers by microRNAs/SIRT1 pathways.

60 APPLIED LIFE SCIENCES↗

Automatic Regionalization Algorithm for Distributed State Estimation in Power Systems

The deregulation of the power system and the incorporation of generation from renewable energy sources recessitates faster state estimation in the smart grid. Distributed state estimation (DSE) has become a promising and scalable solution to this urgent demand. In this paper, we investigate the regionalization algorithms for the power system, a necessary step before distributed state estimation can be performed. To the best of the authors' knowledge, this is the first investigation on automatic regionalization (AR). We propose three spectral clustering based AR algorithms. Simulations show that our proposed algorithms outperform the two investigated manual regionalization cases. With the help of AR algorithms, we also show how the number of regions impacts the accuracy and convergence speed of the DSE and conclude that the number of regions needs to be chosen carefully to improve the convergence speed of DSEs.

24 POWER TRANSMISSION AND DISTRIBUTION↗

A Robust Gene Expression Prognostic Signature for Overall Survival in High-Grade Serous Ovarian Cancer

The objective of this research was to develop a robust gene expression-based prognostic signature and scoring system for predicting overall survival (OS) of patients with high-grade serous ovarian cancer (HGSOC). Transcriptomic data of HGSOC patients were obtained from six independent studies in the NCBI GEO database. Genes significantly deregulated and associated with OS in HGSOCs were selected using GEO2R and Kaplan–Meier analysis with log-rank testing, respectively. Enrichment analysis for biological processes and pathways was performed using Gene Ontology analysis. A resampling/cross-validation method with Cox regression analysis was used to identify a novel gene expression-based signature associated with OS, and a prognostic scoring system was developed and further validated in nine independent HGSOC datasets. We first identified 488 significantly deregulated genes in HGSOC patients, of which 232 were found to be significantly associated with their OS. These genes were significantly enriched for cell cycle division, epithelial cell differentiation, p53 signaling pathway, vasculature development, and other processes. A novel 11-gene prognostic signature was identified and a prognostic scoring system was developed, which robustly predicted OS in HGSOC patients in 100 sampling test sets. The scoring system was further validated successfully in nine additional HGSOC public datasets. In conclusion, our integrative bioinformatics study combining transcriptomic and clinical data established an 11-gene prognostic signature for robust and reproducible prediction of OS in HGSOC patients. This signature could be of clinical value for guiding therapeutic selection and individualized treatment.

60 APPLIED LIFE SCIENCES↗

miRNA Gene Promoters Are Frequent Targets of Aberrant DNA Methylation in Human Breast Cancer

miRNAs are important regulators of gene expression that are frequently deregulated in cancer, with aberrant DNA methylation being an epigenetic mechanism involved in this process. We previously identified miRNA promoter regions active in normal mammary cell types and here we analyzed which of these promoters are targets of aberrant DNA methylation in human breast cancer cell lines and breast tumor specimens. Using 5-methylcytosine immunoprecipitation coupled to miRNA tiling microarray hybridization, we performed comprehensive evaluation of DNA methylation of miRNA gene promoters in breast cancer. We found almost one third (55/167) of miRNA promoters were targets for aberrant methylation in breast cancer cell lines. Breast tumor specimens displayed DNA methylation of majority of these miRNA promoters, indicating that these changes in DNA methylation might be clinically relevant. Aberrantly methylated miRNA promoters were, similar to protein coding genes, enriched for promoters targeted by polycomb in normal cells. Detailed analysis of selected miRNA promoters revealed decreased expression of miRNA linked to increased promoter methylation for mir-31, mir-130a, let-7a-3/let-7b, mir-155, mir-137 and mir-34b/mir-34c genes. The proportion of miRNA promoters we found aberrantly methylated in breast cancer is several fold larger than that observed for protein coding genes, indicating an important role of DNA methylation in miRNA deregulation in cancer.

59 BASIC BIOLOGICAL SCIENCES↗

Risk and Cost Analysis of Utilizing FLEX Equipment for O&M Cost Reduction in Nuclear Power Plants

Several Nuclear Power Plant (NPP) operators in USA have announced to close their plants despite there are remaining years on their operating licenses. The cause of these closures is because the plant operators suffer financial losses. Approximately 80% of USA NPPs would have undergone financial losses if they were situated in a deregulated electricity market. In a deregulated market, electricity generators are independent entities separate from the transmission companies and Independent System Operator (ISO) which manages the market. NPPs in this market are termed merchant NPPs, and their profitability is determined solely from electricity generation revenues. Meanwhile, regulated and public power nuclear units’ profitability is determined by the regulatory process in place for each unit. Due to the complexity of differentiating each regulated and public power NPP’s regulations 36 NPPs are at an immediate risk of retiring early to stop losses, while 27 units will likely to follow in the long run. Today, cost is well-recognized and important factor in NPP decision-making that cannot be ignored. Therefore, it is essential to consider risk and cost together in decision-making to strengthen the position of the nuclear industry in an economically challenging energy market. With operational and maintenance (O&M) cost at 70% of the total operating expenditure of an NPP and some plants closing prematurely despite excellent safety record, there is an urgent need to address the high O&M cost. One of the novel entities that provide additional safety resulting in reduced risk of nuclear power plants is Flex equipment. Flex strategies were postulated by the US NRC in the wake of Fukushima Dai-chi accident to address beyond design-basis accidents and improve plant flexibility. Flex strategy comprise both onsite and off-site component storage for the provision of additional materials and equipment. This work explored innovative ways of utilizing the onsite Flex equipment during regular plant operation, for purposes in addition to the intended use of beyond design basis accidents. This report describes the risk and cost analysis of using Flex equipment during regular or unplanned maintenance.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

Multiple Hub Network Choice in the Liberalized European Market

A key question that so far has received relatively little attention in the germane literature is that of the changes at various airports as a result of the EU liberalization policies. That is, presently, most major European airports still benefit from the so-called home-carrier phenomenon where the country's publicly or semi-publicly owned carrier uses the country's main airport as its gateway hub and, consequently, the home-carrier is also the principal user of this airport (in terms of proportion of total aircraft movements, number of passengers transported, connections, slots ownership, etc.). The country's main airport has substantially benefited from these monopoly conditions of airline captivity, strongly determined by the bilateral system of international air transport regulation. Therefore, European major airports were used to operate in essentially different markets, compared to the increasingly competitive markets of their home based carriers. This partly explains relative stability of transport volumes and financial results of European major airports compared to the relatively volatile financial results of most European national airlines. However, the liberalization of European aviation is likely to change this situation. Market access is open now to all community carriers, i.e. carriers with majority ownership and effective control in the hands of EU citizens. Ticket prices are free, governments can only intervene in case of dumping or excessive pricing. A community airline can choose its seat in any of the 15 member states. Licensing procedures are harmonized between member states. In the last few months community carriers have had unrestricted route access within the EU. Most probably this development will be extended to countries inside and outside Europe. Last year the European Commission got the mandate to start negotiations with 10 other European countries. In the meantime the EC has also started negotiations with the USA on so-called soft rights. In the meantime, open skies agreements have been concluded between the USA and most of the EU member states to facilitate strategic alliances between airlines of the states involved. As a result of this on-going liberalization the model of the single 'national' carrier using the national home base as its single hub for the designated third, fourth and sixth freedom operations will stepwise disappear. Within the EU the concept of the national carrier has already been replaced by that of the community carrier. State ownership in more and more European carriers is reduced. On the longer run mergers or even bankruptcy will further undermine the "single national carrier - single national hub" model in Europe. In the meantime, strategic alliances between national carriers in Europe will already reduce the airlines' loyalty to a single airport. Profit maximization and accountability to share holders will supersede the loyalty of these newly emerging alliances, probably looking for the opportunities of a multiple hub network to adequately cover the whole European market. As a consequence, some European airports might see a substantial decline in arriving, departing and transfer traffic, thus in revenues and financial solvency, as well as in their connection to other inter-continental and intra-European destinations. At the same time, other airports might realize a significant increase in traffic as they will be sought after by the profit maximizing airlines as their major gateway hubs. Which will be the losing airports and which will be the winning ones? Can airports anticipate the actions of airlines in deregulated markets and utilize policies which will improve their relative position? If so, what should be these anticipatory policies? These questions become the more urgent, since an increasing number of major European airports will be privatized in the near future. Although increasing airport congestion in Europe will also be reflected in a growing demand pressure for airport slots, this is not a guarantee for a stable transport volume growth of individual airports. The more volatile the market is, the more vulnerable privatized airports become. Therefore, the main issue of this study is the analysis of the opportunities of major European airports to become a central hub as a result of the network choices made by the new European airlines in a completely liberalized market. In a previous study (Berechman and de Wit, 1996), we already explored the potential of Amsterdam Airport Schiphol of becoming the major West-European hub, once European aviation markets are deregulated. A major hindrance of that study was the use of a single hub-and-spoke network. For example that model could not analyze the viability of different combinations of European hubs within a multiple hub network of alternative airline alliances. In this study, we have formulated the model of a multi-hub network where two West-European airports are used for inter-continental and intra-European travel to enable a more realistic analysis of hub choice. Like the previous one also this multi-hub model is primarily used to assess the potential ability of Amsterdam Airport Schiphol for becoming a major West-European hub. Thus, in particular, the policy tests focus on this airport in a double hub network.

Berechman, Joseph↗

The Conference Proceedings of the 1997 Air Transport Research Group (ATRG) of the WCTR Society

Topics included in the proceedings are: The effect of liberalized air transport bilaterals; cost competitiveness of major airlines; economic effects of duopoly competition in Korea; transforming Canada's aviation regulations; liberalization in Europe; airline labor cost in a liberalized Europe; noncooperative collusion; European air transport deregulation; public ownership and deregulation in the Scandanavian airline industry; airline competition between London and Amsterdam; and a banker's view of the European airline industry.

Oum, Tae Hoon↗

The Symposium Proceedings of the 1998 Air Transport Research Group (ATRG)

Contents include the following: airline deregulation in Australia: a medium term assessment; why can't Japan deregulate the airline industry and open the sky immediately?; toward a market-oriented air transport system?: present developments in Russian civil aviation performance and policy; the asian economic crisis and its implications for aviation policy in asia pacific: industry outlook approaching the next millennium; a tale of two airlines: the post privatization performance of two caribbean airlines: the role of capital productivity in British Airways' financial recovery; airline privatization: does it matter?; airfright demand: responding to new developments in logistics; and air cargo business relationships.

Reynolds-Feighan, Aisling↗

The Conference Proceedings of the 1997 Air Transport Research Group (ATRG) of the WCTR Society

The Aviation Institute University of Nebraska at Omaha (UNO) Monograph series has published the Conference Proceedings of the 1997 Air Transport Research Group (ATRG) of the World Conference on Transportation Research Society (WCTR) volume 1, number 3. The topics included in this document are: 1) Industrial Reform and Air Transport Development in China; 2) The Economic Effects of Airline Deregulation and the Open-Sky Policy of Korea; 3) The Economic Effects of Airline Deregulation and the Open-Sky Policy of Korea; 4) "Open Skies" in India-Is the policy succeeding? 5) The Japanese Domestic Air Fares under the Regulatory Regime: What will be expected after the revision of current charging system? 6) The Competitive Position of Airline Networks; and 7) Air Transport and Regional Economic Development in the European Union.

Own, Tae Hoon↗

EU Accession and Civil Aviation Regimes: Malta and Cyprus as a Case Study

Aviation deregulation is usually a challenging and demanding task and accession to the European Union requires that all candidate states should harmonize their legislation in the context of the European Common Aviation Area. Malta and Cyprus, the small Mediterranean island-states to join the EU in 2004, will have to abandon any protectionist policies in favour of their flag-carriers and let them survive in a liberal framework. The paper discusses the implications of this regime change for civil aviation in Malta and Cyprus and in addition to the airline industry, it examines the impacts on the complementary tourism sector. Unless carrying capacity limits are understood, the islands may become victims of successful airline liberalisation. The paper concludes by stressing the need for sustainable development and active policy making. Keywords: carrying capacity, Cyprus, air transport deregulation, Malta, tourism

Papatheodorou, Andreas↗

The Impact of Total Liberalization of Domestic Air Transport on the Social Welfare and on the Dynamic of Competition: Comparison Between the United States and the European Union

Since the lst of April 1997 date of the implementation of the third package of the liberalization, air transport, within the european Union has become totally liberalized. In the United States the deregulation of domestic air traffic was earlier and faster since it took place in October 1978 after the adoption of the only act of deregulation. This paper, in its first part, deals with the liberalization of the industry of air traffic in the european union. After a comparison with US system based on market demand, fare policy and network restrictions, we present our descriptive results coming from treatments on the OAG data. These results present several aspects such as the evolution of the competitive structure of the intra-european routes, the level of airport dominance and the growth of hub structure. The second part of the paper presents models of entry in the airline industry. As profitability" of route flown explains correctly decisions taken by airlines to serve or not a route, the paper focuses on the specification and the estimation of the determinants of city, pair profitability in the european union. Treatments done on the OAG data show a rapid development of leasing space agreement (partial and total) and code sharing practices between 1995 and 2000 in Europe that's why we differentiate first between the two type of competitive strategy of entry(direct entry and leasing space agreement) and second between the competitive strategy of entry and the alliance strategy of code sharing. So the estimation of model will be able to answer the question if the european air transport market is contestable and in case not to see if the decision of entry is more directed by the level of airport dominance (as in the domestic United States market)or essentially by the competitive structure of the routes. We try to explain the nature of entry(directleasing or code sharing) by the different levels of these two determinants.

Zbidi, Karim↗

Application of Core Theory to the Airline Industry

Competition in the airline industry has been fierce since the industry was deregulated in 1978. The proponents of deregulation believed that more competition would improve efficiency and reduce prices and bring overall benefits to the consumer. In this paper, a case is made based on core theory that under certain demand and cost conditions more competition can actually lead to harmful consequences for industries like the airline industry or cause an empty core problem. Practices like monopolies, cartels, price discrimination, which is considered inefficient allocation of resources in many other industries, can actually be beneficial in the case of the airline industry in bringing about an efficient equilibrium.

Raghavan, Sunder↗

Journal of Air Transportation, Volume 10, No. 2

Topics discussed include: Mitigation Alternatives for Carbon Dioxide Emissions by the Air Transport Industry in Brazil; Air Transport Regulation Under Transformation: The Case of Switzerland; An Estimation of Aircraft Emissions at Turkish Airports; Guide to the Implementation of Iso 14401 at Airports; The Impact of Constrained Future Scenarios on Aviation and Emissions; The Immediate Financial Impact of Transportation Deregulation on the Stockholders of the Airline Industry; Aviation Related Airport Marketing in an Overlapping Metropolitan Catchment Area: The Case of Milan's Three Airports; and Airport Pricing Systems and Airport Deregulation Effects on Welfare.

Bowen, Brent↗

miR-181a shows tumor suppressive effect against oral squamous cell carcinoma cells by downregulating K-ras

Research highlights: {yields} MicroRNA-181a (miR-181a) was frequently downregulated in oral squamous cell carcinoma (OSCC). {yields} Overexpression of miR-181a suppressed OSCC growth. {yields} K-ras is a novel target of miR-181a. {yields} Decreased miR-181a expression is attributed to its lower promoter activity in OSCC. -- Abstract: MicroRNAs (miRNAs) are epigenetic regulators of gene expression, and their deregulation plays an important role in human cancer, including oral squamous cell carcinoma (OSCC). Recently, we found that miRNA-181a (miR-181a) was upregulated during replicative senescence of normal human oral keratinocytes. Since senescence is considered as a tumor suppressive mechanism, we thus investigated the expression and biological role of miR-181a in OSCC. We found that miR-181a was frequently downregulated in OSCC. Ectopic expression of miR-181a suppressed proliferation and anchorage independent growth ability of OSCC. Moreover, miR-181a dramatically reduces the growth of OSCC on three dimensional organotypic raft culture. We also identified K-ras as a novel target of miR-181a. miR-181a decreased K-ras protein level as well as the luciferase activity of reporter vectors containing the 3'-untranslated region of K-ras gene. Finally, we defined a minimal regulatory region of miR-181a and found a positive correlation between its promoter activity and the level of miR-181a expression. In conclusion, miR-181a may function as an OSCC suppressor by targeting on K-ras oncogene. Thus, miR-181a should be considered for therapeutic application for OSCC.

60 APPLIED LIFE SCIENCES↗