Mechanisms of Ad-p53 induced apoptosis in human malignant glioma

Malignant brain tumors are one of the most challenging cancers affecting society today. In a recent survey, an estimated 17,000 annual cases were recorded with a staggering total of 13,300 deaths. A unique degree of heterogeneity typifies glial tumors and presents a challenge for solitary anti-neoplastic treatments. Tumors subsist as heterogeneous masses that progress through dysplasia to astrocytomas, mixed glioma and glioblastoma multiforme. Although traditional therapeutic approaches have provided increments of success, the median survival time remains 12 months. The urgency to improve upon current clinical protocols has encouraged alternative experimental strategies such as p53 adenoviral gene therapy (Ad-p53). This study addresses the efficacy of Ad-p53 for the treatment of glioma. Our model presents a tumor response that is unique among human cancers. Ad-p53 effectively induces apoptosis in mutant p53 expressing cells yet fails to do so in those with wildtype p53. In order to adopt Adp53 as a standard anti-cancer modality, we characterized the role of the tumor suppressor gene p53 in mediating apoptosis. We demonstrate that altering cellular p53 status through the introduction of a dominant negative mutant p53 (175H, 248W, 273H) sensitized cells to Ad-p53. We discovered that wild-type p53 expressing glioma cells retain the apoptotic machinery necessary to accomplish cell death, but have developed mechanisms that interfere with p53 signaling. Earlier studies have not addressed the mechanisms of Ad-p53 apoptosis nor the resistance exhibited by wild-type p53 glioma. To explain the divergent phenotypes, we identified apoptotic pathways activated and effectors of the response. We illustrated that modulation of the death receptor Fas/APO-1 is a principal means of Ad-p53 signaling that is impaired in wild-type p53 glioma. Moreover, the apoptotic response was found to be a multi-faceted process that engaged several caspases, most notably caspases -1, -3 and -8. Lastly, we assessed the ability of anti-apoptotic molecules Bcl-2 and CrmA to inhibit Ad-p53 apoptosis. These studies revealed that Ad-p53 is a powerful tool for inducing apoptosis that can be delayed but not inhibited by anti-apoptotic means. This work is critical for understanding the development of glioma and the phenotypic and genotypic alterations that account for tumor resistance. ^

Interventions to reduce sexual risk behavior in African American men

The purpose of this review was to describe characteristics of interventions that have been conducted for African American men and identify similarities and differences between interventions for subpopulations of African American men. Of the 473 studies identified through database searching, 8 studies met the eligibility criteria for this review. Target populations within these studies included heterosexual men, homosexual and bisexual men, persons with mental health problems, and injection and non-injection drug users. Little variation was found in the theories and methods used in interventions for different target populations. However, several different behavioral determinants were addressed within these interventions. Although interventions for drug users generally did not exclude individuals based on sexual orientation, these interventions were able to address HIV sexual risk behavior in heterosexual, homosexual, and bisexual-identified men. Given these findings, multi-faceted approaches to HIV prevention are recommended in order to reduce HIV risk in African American men.^

Refugees from Myanmar and their health care needs in the US: A qualitative study at a refugee-resettlement agency

In response to the recent rapid influx of refugees from Myanmar, Interfaith Ministries for Greater Houston (IM), a refugee resettlement agency, started to support them in June 2007. The study looked at the refugees' perspectives and identified the gaps in their understanding on US health care system, health seeking behaviors and challenges in utilizing health care in United States. The major issues identified were non-compliance with tuberculosis prevention medication due to barriers in obtaining medication refills, barriers in accessing specialty care services, transportation issues, written and oral language barrier, difficulties in the application for and use of Medicaid and Gold Card, misunderstanding of emergency health services, lack of resources for health education, self-treatment with Western medicine and income too low to buy private health insurance. In order to transform them to healthy citizens able to contribute to the US workforce, several multi-faceted and comprehensive approaches and better coordination among agencies are recommended. ^

Functional Characterization of AtxA, the Bacillus anthracis Virulence Regulator

Coordinated expression of virulence genes in Bacillus anthracis occurs via a multi-faceted signal transduction pathway that is dependent upon the AtxA protein. Intricate control of atxA gene transcription and AtxA protein function have become apparent from studies of AtxA-induced synthesis of the anthrax toxin proteins and the poly-D-glutamic acid capsule, two factors with important roles in B. anthracis pathogenesis. The amino-terminal region of the AtxA protein contains winged-helix (WH) and helix-turn-helix (HTH) motifs, structural features associated with DNA-binding. Using filter binding assays, I determined that AtxA interacted non-specifically at a low nanomolar affinity with a target promoter (Plef) and AtxA-independent promoters. AtxA also contains motifs associated with phosphoenolpyruvate: sugar phosphotransferase system (PTS) regulation. These PTS-regulated domains, PRD1 and PRD2, are within the central amino acid sequence. Specific histidines in the PRDs serve as sites of phosphorylation (H199 and H379). Phosphorylation of H199 increases AtxA activity; whereas, H379 phosphorylation decreases AtxA function. For my dissertation, I hypothesized that AtxA binds target promoters to activate transcription and that DNA-binding activity is regulated via structural changes within the PRDs and a carboxy-terminal EIIB-like motif that are induced by phosphorylation and ligand binding. I determined that AtxA has one large protease-inaccessible domain containing the PRDs and the carboxy-terminal end of the protein. These results suggest that AtxA has a domain that is distinct from the putative DNA-binding region of the protein. My data indicate that AtxA activity is associated with AtxA multimerization. Oligomeric AtxA was detected when co-affinity purification, non-denaturing gel electrophoresis, and bis(maleimido)hexane (BMH) cross-linking techniques were employed. I exploited the specificity of BMH for cysteine residues to show that AtxA was cross-linked at C402, implicating the carboxy-terminal EIIB-like region in protein-protein interactions. In addition, higher amounts of the cross-linked dimeric form of AtxA were observed when cells were cultured in conditions that promote toxin gene expression. Based on the results, I propose that AtxA multimerization requires the EIIB-like motif and multimerization of AtxA positively impacts function. I investigated the role of the PTS in the function of AtxA and the impact of phosphomimetic residues on AtxA multimerization. B. anthracis Enzyme I (EI) and HPr did not facilitate phosphorylation of AtxA in vitro. Moreover, markerless deletion of ptsHI in B. anthracis did not perturb AtxA function. Taken together, these results suggest that proteins other than the PTS phosphorylate AtxA. Point mutations mimicking phosphohistidine (H to D) and non-phosphorylated histidine (H to A) were tested for an impact on AtxA activity and multimerization. AtxA H199D, AtxA H199A, and AtxA H379A displayed multimerization phenotypes similar to that of the native protein, whereas AtxA H379D was not susceptible to BMH cross-linking or co-affinity purification with AtxA-His. These data suggest that phosphorylation of H379 may decrease AtxA activity by preventing AtxA multimerization. Overall, my data support the following model of AtxA function. AtxA binds to target gene promoters in an oligomeric state. AtxA activity is increased in response to the host-related signal bicarbonate/CO2 because this signal enhances AtxA multimerization. In contrast, AtxA activity is decreased by phosphorylation at H379 because multimerization is inhibited. Future studies will address the interplay between bicarbonate/CO2 signaling and phosphorylation on AtxA function.

Discreta regente, la austriaca o Doña Virtudes. Las imágenes de María Cristina de Habsburgo

Más allá del mito de la discreta regente de España, María Cristina de Habsburgo ofrece una imagen poliédrica que puede contribuir a calibrar la importancia política, cultural y social de la representación simbólica de la corona. Las imágenes —oficial, de la oposición y populares— de María Cristina son analizadas desde diversas perspectivas: la consolidación de una monarquía en crisis tras el fallecimiento de Alfonso XII pocos años después de la República, la creación de una identidad nacional todavía no afirmada y la conformación de los estereotipos de género en torno al discurso de la separación de esferas. Imágenes que daban respuestas muchas veces divergentes a las circunstancias que distinguían a Maria Cristina de otros monarcas: era regente y no reina por derecho propio, era extranjera pero ocupaba el trono español y era mujer pero desempeñaba la más alta magistratura del país.

The Challenges of Irregular Maritime Migration. Jean Monnet Occasional Paper No. 4/2013

This contribution presents migrant smuggling by sea as a multi-faceted phenomenon. It juxtaposes State rights and duties, State security interests and protection of fundamental rights. Similarly, various branches of law, sometime contradictory, regulate irregular maritime migration. In view of these considerations, the argument is made that any effort to control the situation must lie in a cooperative initiative among States which considers migrant smuggling by sea in a holistic manner.

Does EU regulation hinder or stimulate innovation? CEPS Special Report No. 96, 19 November 2014

Introduction. One frequently hears the question posed in the title to this report, but there is little systematic analytical literature on the issue. Fragmented evidence or anecdotes dominate debates among EU regulatory decision-makers and in European business, insofar as there is a genuine debate at all. This CEPS Special Report focuses on the multi-faceted, ambiguous and complex relationship between (EU) regulation and innovation in the economy, and discusses the innovation-enhancing potential of certain regulatory approaches as well as factors that tend to reduce incentives to innovate. It adopts an 'ecosystem' approach to both regulation and innovation, and study the interactions between the two ecosystems. This general analysis and survey are complemented by seven case studies of EU regulation enabling and disabling innovation, two horizontal and five sectoral ones. The case studies are preceded by a broader contextual analysis of trends in EU regulation over the last three decades. These trends show the significant transformation of the nature as well as improvement of the quality of EU regulation, largely in the deepened internal market, which tend to have a favourable and lasting effect on the rate of innovation in the EU (other things being equal). Among the findings include the following: Regulation can at times be a powerful stimulus to innovation. EU regulation matters at all stages of the innovation process. Different types of regulation can be identified in terms of innovation impact: general or horizontal, innovation-specific and sector-specific regulation. More prescriptive regulation tends to hamper innovative activity, whereas the more flexible EU regulation is, the better innovation can be stimulated. Lower compliance and red-tape burdens have a positive effect on innovation. The authors recommend incorporating a specific test on innovation impacts in the ex-ante impact assessment of EU legislation as well as in ex-post evaluation. There is ample potential for fostering innovation by reviewing the EU regulatory acquis.

Why Do Some International Institutions Contain Strong Dispute Settlement Provisions: New Evidence from Preferential Trade Agreements

To understand why some international institutions have stronger dispute settlement mechanisms (DSMs) than others, we investigate the dispute settlement provisions of nearly 600 preferential trade agreements (PTAs), which possess several desirable case-selection features and are evoked more than is realized. We broaden the study of dispute settlement design beyond “legalization” and instead reorient theorizing around a multi-faceted conceptualization of the strength of DSMs. We posit that strong DSMs are first and foremost a rational response to features of agreements that require stronger dispute settlement, such as depth and large memberships. Multivariate empirical tests using a new data set on PTA design confirm these expectations and reveal that depth – the amount of policy change specified in an agreement – is the most powerful and consistent predictor of DSM strength, providing empirical support to a long-posited but controversial conjecture. Yet power also plays a sizeable role, since agreements among asymmetric members are more likely to have strong DSMs due to their mutual appeal, as are those involving the United States. Important regional differences also emerge, as PTAs across the Americas are designed with strong dispute settlement, as are Asian PTAs, which contradicts the conventional wisdom about Asian values and legalization. Our findings demonstrate that rationalism explains much of international institutional design, yet it can be enhanced by also incorporating power-based and regional explanations.

IRS-1 regulation in health and disease

The global incidence of diabetes is increasing at epidemic rates. Estimates suggest there are currently 150 million people with diabetes and this number is expected to double in the next 20 years. Type 2 diabetes accounts for 95% of all cases and is characterized in part by impaired sensitivity to insulin or 'insulin resistance'. Defects in the insulin signalling pathways underpin this resistance. In the current article we discuss the regulation of Insulin Receptor Substrate-1 (IRS-1), a protein that plays a pivotal role in insulin signalling and whose function is impaired in subjects with insulin resistance. Coordination of IRS-1 function is multi-faceted, involving phosphorylation of IRS-1 at multiple serine/threonine residues. This controls many aspects of IRS-1, including its interaction with the insulin receptor and subsequent tyrosine phosphorylation, as well as its subcellular distribution and targeting for degradation by the proteasome. Such tight control ensures appropriate transduction and attenuation of the insulin signal, thereby regulating insulin action in healthy individuals. Emerging evidence indicates that `diabetogenic factors' associated with insulin resistance, such as TNFalpha and elevated circulating fatty acids, impact on insulin signalling at the level of IRS-1 serine/threonine phosphorylation. The expression and/or activity of several kinases, such as IkappaB kinase beta (IKKbeta) and salt-induced kinase 2 (SIK2), and the phosphorylation of IRS-1 at key sites, such as Ser307 and Ser789, are increased in states of insulin resistance. Identifying the pathways by which such factors activate these and other kinases, and de. ning the precise roles of specific serine/threonine phosphorylation events in IRS-1 regulation, represent important goals which may eventually provide a rationale for therapeutic intervention.

Structure and activity in assessing antioxidant activity in vitro and in vivo:a critical appraisal illustrated with the flavonoids

Structure–activity relationships are indispensable to identify the most optimal antioxidants. The advantages of in vitro over in vivo experiments for obtaining these relationships are, that the structure is better defined in vitro, since less metabolism takes place. It is also the case that the concentration, a parameter that is directly linked to activity, is more accurately controlled. Moreover, the reactions that occur in vivo, including feed-back mechanisms, are often too multi-faceted and diverse to be compensated for during the assessment of a single structure–activity relationship. Pitfalls of in vitro antioxidant research include: (i) by definition, antioxidants are not stable and substantial amounts of oxidation products are formed and (ii) during the scavenging of reactive species, reaction products of the antioxidants accumulate. Another problem is that the maintenance of a defined concentration of antioxidants is subject to processes such as oxidation and the formation of reaction products during the actual antioxidant reaction, as well as the compartmentalization of the antioxidant and the reactive species in the in vitro test system. So determinations of in vitro structure-activity relationships are subject to many competing variables and they should always be evaluated critically. (c) 2005 Published by Elsevier B.V.

Beyond securitisation : Western Mediterranean international relations from a security perspective 1989-2002

Following the end of the Cold War and the ensuing changes to the international landscape, thinking about security has tended to become more discursive and interpretative in nature. What counts as security has increasingly derived from security discourses (that is, 'securitisation') and uncertainty about the multi-faceted future facing various countries and regions. Within this post-Cold War discourse, the Western Mediterranean has emerged as a region fraught with latent and manifest threats in the economic, political, societal and military sectors. Improved access to EU markets for Maghrebi exports; the security of energy supplies to the EU from Algeria and Libya; lack of democracy and the advance of political Islam; the flow of northward migration and worries about law and order in France, Italy and Spain; the growth in military expenditure and weapons proliferation in the Maghreb; all have been central to the securitisation agenda. However, this agenda has often lacked credibility especially when inter-linkages have purportedly been established between economic underdevelopment and political instability, between the advance of political Islam and the threat to energy supplies, or between immigration and the threat to national identity. Such inter-sectoral linkages distract from the credibility of those 'securitisation instances' which correspond to reality; the former linkages have often been exploited by extremist politicians in south-west European countries as well as by regimes in the Maghreb to advance their respective interests. Thus, securitisation may defeat its main purpose; it may generate responses out of keeping with the aims proclaimed at the outset, aims centred on the countering of real threats and the ensuring of greater stability.

An exploration of female leadership language:case studies of senior women in Bahrain

This is a multiple case study of the leadership language of three senior women working in a large corporation in Bahrain. The study’s main aim is to explore the linguistic practices the women leaders use with their colleagues and subordinates in corporate meetings. Adopting a Foucauldian (1972) notion of ‘discourses’ as social practices and a view of gender as socially constructed and discursively performed (Butler 1990), this research aims to unveil the competing discourses which may shape the leadership language of senior women in their communities of practice. The research is situated within the broader field of Sociolinguistics and the specific field of Language and Gender. To address the research aim, a case study approach incorporating multiple methods of qualitative data collection (observation, interviews, and shadowing) was utilised to gather information about the three women leaders and produce a rich description of their use of language in and out of meeting contexts. For analysis, principles of Qualitative Data Analysis (QDA) were used to organise and sort the large amount of data. Also, Feminist Post- Structuralist Discourse Analysis (FPDA) was adopted to produce a multi-faceted analysis of the subjects, their language leadership, power relations, and competing discourses in the context. It was found that the three senior women enact leadership differently making variable use of a repertoire of conventionally masculine and feminine linguistic practices. However, they all appear to have limited language resources and even more limiting subject positions; and they all have to exercise considerable linguistic expertise to police and modify their language in order to avoid the ‘double bind’. Yet, the extent of this limitation and constraints depends on the community of practice with its prevailing discourses, which appear to have their roots in Islamic and cultural practices as well as some Western influences acquired throughout the company’s history. It is concluded that it may be particularly challenging for Middle Eastern women to achieve any degree of equality with men in the workplace because discourses of Gender difference lie at the core of Islamic teaching and ideology.

Technology adoption in small and medium-sized logistics providers

Purpose - The main aim of the research is to shed light on the role of information and communication technology (ICT) in the logistics innovation process of small and medium-sized third party logistics providers (3PLs). Design/methodology/approach - A triangulated research strategy was designed using a combination of quantitative and qualitative methods. The former involved the use of a questionnaire survey of small and medium-sized Italian 3PLs with 153 usable responses received. The latter comprised a series of focus groups and the use of seven case studies. Findings - There is a relatively low level of ICT expenditure with few companies adopting formal technology investment strategies. The findings highlight the strategic importance of supply chain integration for 3PLs with companies that have embarked on an expansion of their service portfolios showing a higher level of both ICT usage and information integration. Lack of technology skills in the workforce is a major constraint on ICT adoption. Given the proliferation of logistics-related ICT tools and applications in recent years it has been difficult for small and medium-sized 3PLs to select appropriate applications. Research limitations/implications - The paper provides practical guidelines to researchers in the effective use of mixed-methods research based on the concept of methodological triangulation. In particular, it shows how questionnaire surveys, focus groups and case study analysis can be used in combination to provide insights into multi-faceted supply chain phenomena. It also identifies several potentially fruitful avenues for future research in this specific field. Practical implications - The paper's findings provide useful guidance for practitioners on the effective adoption of ICT as part of the logistics innovation process. The findings also provide support for ICT vendors in the design of ICT solutions that are aligned to the needs of small 3PLs. Originality/value - There is currently a paucity of research into the drivers and inhibitors of ICT in the innovation processes of small and medium-sized 3PLs. This paper fills this gap by exploring the issue using a range of complementary research approaches. Copyright © 2013 Emerald Group Publishing Limited. All rights reserved.

Evaluation of vulnerability factors for cyclones : the case of Patuakhali, Bangladesh

Tropical cyclones are considered as the most severe natural disasters in Bangladesh; they cause extensive damage, create losses in the country׳s economy, and affect social settings. The impact of natural disasters has been further intensified due to various vulnerability factors within the Bangladeshi community such as low income; shortages of food; lack of assets such as land and permanent housing; dense population, illiteracy. This study evaluates the vulnerability factors for cyclones in the community based in the Patuakhali region of south western Bangladesh. The bottom-up research approach was adopted for the study, whereby the local community was consulted for their viewpoints by using focus group interviews and semi-structured interviews. Different community groups and social categories including both men and women, from different age groups and livelihoods, participated in the study. The study revealed how the community׳s vulnerability to cyclones has been further aggravated by socio-economic factors such as social status, political influences and economic conditions. The majority of the community in Patuakhali has been “knowingly” vulnerable to cyclone disaster as a result of the lack of alternatives especially in terms of their livelihood patterns. The vulnerability of women, due to their lack of authority, domestic work, and fear of exposure within the society was also highlighted. The study revealed how vulnerability factors are interlinked with each other making them further difficult to manage. This calls for multi-faceted disaster risk reduction strategies that targets vulnerability factors deriving from different origins and root causes.

Evaluation of vulnerability factors for cyclones:the case of Patuakhali, Bangladesh

Tropical cyclones are considered as the most severe natural disasters in Bangladesh; they cause extensive damage, create losses in the country[U+05F3]s economy, and affect social settings. The impact of natural disasters has been further intensified due to various vulnerability factors within the Bangladeshi community such as low income; shortages of food; lack of assets such as land and permanent housing; dense population, illiteracy. This study evaluates the vulnerability factors for cyclones in the community based in the Patuakhali region of south western Bangladesh. The bottom-up research approach was adopted for the study, whereby the local community was consulted for their viewpoints by using focus group interviews and semi-structured interviews. Different community groups and social categories including both men and women, from different age groups and livelihoods, participated in the study. The study revealed how the community[U+05F3]s vulnerability to cyclones has been further aggravated by socio-economic factors such as social status, political influences and economic conditions. The majority of the community in Patuakhali has been "knowingly" vulnerable to cyclone disaster as a result of the lack of alternatives especially in terms of their livelihood patterns. The vulnerability of women, due to their lack of authority, domestic work, and fear of exposure within the society was also highlighted. The study revealed how vulnerability factors are interlinked with each other making them further difficult to manage. This calls for multi-faceted disaster risk reduction strategies that targets vulnerability factors deriving from different origins and root causes. © 2014 Elsevier Ltd.