A dynamic model of the hypoxia-inducible factor 1α (HIF-1α) network

Activation of the hypoxia-inducible factor (HIF) pathway is a critical step in the transcriptional response to hypoxia. Although many of the key proteins involved have been characterised, the dynamics of their interactions in generating this response remain unclear. In the present study, we have generated a comprehensive mathematical model of the HIF-1a pathway based on core validated components and dynamic experimental data, and confirm the previously described connections within the predicted network topology. Our model confirms previous work demonstrating that the steps leading to optimal HIF-1a transcriptional activity require sequential inhibition of both prolyl- and asparaginyl-hydroxylases. We predict from our model (and confirm experimentally) that there is residual activity of the asparaginyl-hydroxylase FIH (factor inhibiting HIF) at low oxygen tension. Furthermore, silencing FIH under conditions where prolyl-hydroxylases are inhibited results in increased HIF-1a transcriptional activity, but paradoxically decreases HIF-1a stability. Using a core module of the HIF network and mathematical proof supported by experimental data, we propose that asparaginyl hydroxylation confers a degree of resistance upon HIF-1a to proteosomal degradation. Thus, through in vitro experimental data and in silico predictions, we provide a comprehensive model of the dynamic regulation of HIF-1a transcriptional activity by hydroxylases and use its predictive and adaptive properties to explain counter-intuitive biological observations.

Institutional contradiction and management control innovation:a field study of total quality management practices in a privatised telecommunications company

The purpose of this paper is to theorise the changes surrounding the introduction of a management control innovation, total quality management (TQM) techniques, within Telecom Fiji Limited. Using institutional theory and drawing on empirical evidence from multiple sources including interviews, discussions and documents, the paper explicates the institutionalization of these TQM practices. The focus of the paper is the micro-processes and practice changes around TQM implementation, rather than the influence of the macro-level structures that are often linked with institutional theory. The change agents used Quality Action Teams and the National Quality Council to introduce new TQM routines. The present study extends the scope of institutional analysis by explaining how institutional contradictions impact to create and make space for institutional entrepreneurs, who in turn, modify existing routines or introduce new routines in fluid organizational environments which also exhibit evidence of resistance.

Decreased efficiency of trypsinization of cells following photodynamic therapy:evaluation of a role for tissue transglutaminase

Identifying the cellular responses to photodynamic therapy (PDT) is important if the mechanisms of cellular damage are to be fully understood. The relationship between sensitizer, fluence rate and the removal of cells by trypsinization was studied using the RIF-1 cell line. Following treatment of RIF-1 cells with pyridinium zinc (II) phthalocyanine (PPC), or polyhaematoporphyrin at 10 mW cm−2 (3 J cm−2), there was a significant number of cells that were not removed by trypsin incubation compared to controls. Decreasing the fluence rate from 10 to 2.5 mW cm−2 resulted in a two-fold increase in the number of cells attached to the substratum when PPC used as sensitizer; however, with 5,10,15,20 meso-tetra(hydroxyphenyl) chlorin (m-THPC) there was no resistance to trypsinization following treatment at either fluence rate. The results indicate that resistance of cells to trypsinization following PDT is likely to be both sensitizer and fluence rate dependent. Increased activity of the enzyme tissue-transglutaminase (tTGase) was observed following PPC-PDT, but not following m-THPC-PDT. Similar results were obtained using HT29 human colonic carcinoma and ECV304 human umbilical vein endothelial cell lines. Hamster fibrosarcoma cell (Met B) clones transfected with human tTGase also exhibited resistance to trypsinization following PPC-mediated photosensitization; however, a similar degree of resistance was observed in PDT-treated control Met B cells suggesting that tTGase activity alone was not involved in this process.

Adaptive resistance to biocides in Salmonella enterica and Escherichia coli O157 and cross-resistance to antimicrobial agents

The mechanisms by which bacteria resist killing by antibiotics and biocides are still poorly defined, although repeated exposure to sublethal concentrations of antibacterial agents undoubtedly contributes to their development. This study aimed both to investigate the potential of Salmonella enterica and Escherichia coli O157 for adaptive resistance to commonly used biocides and to determine any cross-resistance to antibiotics. Strains were repeatedly passaged in media containing increasing concentrations of a biocide or antibiotic until adaptive resistance was obtained. A wide panel of antimicrobial agents was then screened by using the adapted strain to determine cross-resistance, if any. Adaptive resistance was readily achieved for both S. enterica and E. coli O157. Cross-resistance in adaptively resistant S. enterica varied with the serotype; Salmonella enterica serovar Enteritidis expressed cross-resistance to chloramphenicol, whereas Salmonella enterica serovar Typhimurium expressed cross-resistance to chlorhexidine. Benzalkonium chloride-resistant Salmonella enterica serovar Virchow showed elevated resistance to chlorhexidine; however, chlorhexidine-resistant Salmonella serovar Virchow did not demonstrate reciprocal cross-resistance to benzalkonium chloride, suggesting specific rather than generic resistance mechanisms. E. coli O157 strains acquired high levels of resistance to triclosan after only two sublethal exposures and, when adapted, repeatedly demonstrated decreased susceptibilities to various antimicrobial agents, including chloramphenicol, erythromycin, imipenem, tetracycline, and trimethoprim, as well as to a number of biocides. These observations raise concern over the indiscriminate and often inappropriate use of biocides, especially triclosan, in situations where they are unnecessary, whereby they may contribute to the development of microbial resistance mechanisms.

The political discourse and material practice of technology enhanced learning

Technology discloses man’s mode of dealing with Nature, the process of production by which he sustains his life, and thereby also lays bare the mode of formation of his social relations, and of the mental conceptions that flow from them (Marx, 1990: 372) My thesis is a Sociological analysis of UK policy discourse for educational technology during the last 15 years. My framework is a dialogue between the Marxist-based critical social theory of Lieras and a corpus-based Critical Discourse Analysis (CDA) of UK policy for Technology Enhanced Learning (TEL) in higher education. Embedded in TEL is a presupposition: a deterministic assumption that technology has enhanced learning. This conceals a necessary debate that reminds us it is humans that design learning, not technology. By omitting people, TEL provides a vehicle for strong hierarchical or neoliberal, agendas to make simplified claims politically, in the name of technology. My research has two main aims: firstly, I share a replicable, mixed methodological approach for linguistic analysis of the political discourse of TEL. Quantitatively, I examine patterns in my corpus to question forms of ‘use’ around technology that structure a rigid basic argument which ‘enframes’ educational technology (Heidegger, 1977: 38). In a qualitative analysis of findings, I ask to what extent policy discourse evaluates technology in one way, to support a Knowledge Based Economy (KBE) in a political economy of neoliberalism (Jessop 2004, Fairclough 2006). If technology is commodified as an external enhancement, it is expected to provide an ‘exchange value’ for learners (Marx, 1867). I therefore examine more closely what is prioritised and devalued in these texts. Secondly, I disclose a form of austerity in the discourse where technology, as an abstract force, undertakes tasks usually ascribed to humans (Lieras, 1996, Brey, 2003:2). This risks desubjectivisation, loss of power and limits people’s relationships with technology and with each other. A view of technology in political discourse as complete without people closes possibilities for broader dialectical (Fairclough, 2001, 2007) and ‘convivial’ (Illich, 1973) understandings of the intimate, material practice of engaging with technology in education. In opening the ‘black box’ of TEL via CDA I reveal talking points that are otherwise concealed. This allows me as to be reflexive and self-critical through praxis, to confront my own assumptions about what the discourse conceals and what forms of resistance might be required. In so doing, I contribute to ongoing debates about networked learning, providing a context to explore educational technology as a technology, language and learning nexus.

Web designers, social e-value creation and e-business planning:understanding resistance from conflicting demands

This chapter investigates the conflicting demands faced by web designers in the development of social e-atmospherics that aim to encourage e-value creation, thus strengthening and prolonging market planning strategies. While recent studies have shown that significant shifts are occurring concerning the importance of users’ generated content by way of social e-communication tools (e.g. blogs), these trends are also creating expectations that social and cultural cues ought to become a greater part of e-atmospherics and e-business strategies. Yet, there is growing evidence that organizations are resisting such efforts, fearing that they will lose control of their e-marketing strategy. This chapter contributes to the theory and literature on online cross-cultural understanding and the impact website designers (meso-level) can have on improving the sustainability of e-business planning, departing from recent studies that focus mainly on firms’ e-business plans (macro-level) or final consumers (micro-level). A second contribution is made with respect to online behavior regarding the advancement of technologies that facilitate the development and shaping of new social e-atmospherics that affect users’ behavior and long term e-business strategies through the avoidance of traditional, formal decision making processes and marketing strategy mechanisms implemented by firms. These issues have been highlighted in the literature on the co-production and co-creation of value, which few organizations have thus far integrated in their strategic and pragmatic e-business plans. Drawing upon fifteen online interviews with web designers in the USA, as key non-institutional actors at the meso-level who are developing what future websites will be like, this chapter analyzes ways in which identifying points of resistance and conflicting demands can lead to engagement with the debate over the online co-creation of value and more sustainable future e-business planning. A number of points of resistance to the inclusion of more e-social atmospherics are identified, and the implications for web designers’ roles and web design planning are discussed along with the limitations of the study and potential future research for e-business studies.

Online grocery provision resistance:understanding urban (non-)collaboration and ambiguous supply chain environments

This chapter investigates the resistance by institutional actors in ambiguous supply chain environments for online grocery provision. Recent studies have shown that significant shifts in urban geographies are increasing consumers' expectations of online retail provision. However, at the same time there is also growing evidence that the collaborative practice in online grocery provision within the urban supply chains is resisted. That these trends are found despite growing demand of online provision highlights both the difficulty of bringing geographically dispersed supply partners together and the problems associated with operating within and across ambiguous environments. Drawing upon twenty-nine in-depth interviews with a range of institutional actors, including retail, logistics, and urban planning experts within an urban metropolis in an emerging market, we detail the different ways that collaboration is resisted in online retail provision. Several different patterns of resistance were identified in (non-) collaboration notably, ideological, functional, regulatory and spatial. © 2011, IGI Global. C.

Stabilization of catalyst particles against sintering on oxide supports with high oxygen ion lability exemplified by Ir-catalyzed decomposition of N2O

Iridium nanoparticles deposited on a variety of surfaces exhibited thermal sintering characteristics that were very strongly correlated with the lability of lattice oxygen in the supporting oxide materials. Specifically, the higher the lability of oxygen ions in the support, the greater the resistance of the nanoparticles to sintering in an oxidative environment. Thus with γ-Al2O3 as the support, rapid and extensive sintering occurred. In striking contrast, when supported on gadolinia-ceria and alumina-ceria-zirconia composite, the Ir nanoparticles underwent negligible sintering. In keeping with this trend, the behavior found with yttria-stabilized zirconia was an intermediate between the two extremes. This resistance, or lack of resistance, to sintering is considered in terms of oxygen spillover from support to nanoparticles and discussed with respect to the alternative mechanisms of Ostwald ripening versus nanoparticle diffusion. Activity towards the decomposition of N2O, a reaction that displays pronounced sensitivity to catalyst particle size (large particles more active than small particles), was used to confirm that catalytic behavior was consistent with the independently measured sintering characteristics. It was found that the nanoparticle active phase was Ir oxide, which is metallic, possibly present as a capping layer. Moreover, observed turnover frequencies indicated that catalyst-support interactions were important in the cases of the sinter-resistant systems, an effect that may itself be linked to the phenomena that gave rise to materials with a strong resistance to nanoparticle sintering.

Marketing practices and their effectiveness in Taiwan's colleges of technology

The main purpose of this study was to investigate marketing practices in Taiwan's institutions of higher education and their relationship with students' college choice behaviors and attitudes. The study was conducted in 11 Taiwan's colleges of technology. It employed a multistrand conversion mixed model design, consisting of a qualitative and a quantitative strand. Funnel-sequenced interviews were conducted with 19 college administrators and the results were content analyzed using a constant-comparative method. The administrator interview data were also quantitized and used in cluster analysis of the institutions. Questionnaire data were collected from 1474 freshmen students, and analyzed using several univariate and multivariate statistical techniques including factor analysis, MANOVA, and correspondence analysis. ^ Analyses indicated that a weak relationship existed between institutions' marketing intensity and students' college choice. Students did not consider institutions' recruitment activities useful in their college searching process. They also reported little knowledge of their current school when they were deciding to enroll. Data analysis also revealed that students were practically oriented in their college selection. Academic resources, employability after graduation, and tuition were the most important attributes in students' college selection. Parents and students' social network such as friends and high school teachers were significant personal sources in enrollment decisions while institutions' representatives (i.e., recruiters) were considered the least influential. ^ Using cluster analysis, institutions were divided into three groups based on intensity of marketing efforts. Multivariate analysis of variance did not reveal significant differences between the college choice behaviors and attitudes of students who entered these three types of institutions. ^ Content analysis of the administrators' interviews indicated that the majority of them practiced passive marketing. This was primarily as a result of resistance to active marketing, lack of leadership commitment, insufficient financial and human resources, little faculty involvement, and inexperience in marketing. In comparison to public institutions, private institutions showed a more favorable attitude towards marketing concepts. They were well advanced in their recruitment activities while public schools were relatively hesitant to use marketing. Curriculum issues were not well represented in marketing activities and did not seem to be impacted by marketing needs. Based on the analysis of qualitative and quantitative data, it can be concluded that in these colleges, curriculum was more driven by commercial and industrial interest than by students' demands. ^ Theoretical, policy, and methodological implementation of the results were discussed. ^

Boundary maintenance in Qatar: Interpretation of domination, segregation and subordination

This study explores the interaction of expatriates in Qatar and their perception of their subordination. The study design included participant observation in an all female University and University housing as well as interviews with Qatari government agencies and ministries, expatriate embassies and expatriates. Semi-structured interviews were conducted across seven expatriate groups: domestic workers, unskilled laborers, semiskilled, professionals, housewives, second-generation expatriates with host country other than Qatar, second-generation expatriates with host country Qatar, and Gulf Cooperation Council citizens. Forty-two subjects completed the interview schedule while 87 interviews were incomplete. ^ Physical control of expatriates occurs through the Gulf practice of sponsorship (The Kafeel System), and local cultural and Islamic related controls intertwined with the Arab Code of honor. Interviews and observations revealed rankings of Arabs and foreigners which emphasize Qatari superiority such as tribal identity, moral ranking of female groups by dress, legal protection and power, sexual consideration and desexualization and salaries and job opportunities based on nationality and ethnicity. Individuals who desire to transcend boundaries into the Qatari realm through citizenship or marriage view Qataris as possessing the “image of the unlimited good” and have acquired Qatari social and cultural capital. Members from all expatriate groups engaged in various forms of resistance to labor and gender domination which ranged from forms of “exit,” expressing a hidden transcript in the privacy of their own group, disguised resistance in public, and occasionally, direct confrontation with the Qatari. Although the legal arena created the appearance that worker's needs were being addressed, laborers engaged in forms of “exit” to escape their oppression. Omani students in the hostel disguised their resistance by spreading gossip, nick-naming homosexual Qatari students at the University, acting out a skit depicting their exclusion from Qatari privilege, spreading rumors of impending freedom, and singing songs of despair in the courtyard. Other sites of resistance were expatriate embassies, the road, the newspaper and technology. This study emphasizes that blaming oppression of the expatriate worker on globalization is a simplistic view of oppression in the Gulf, and ignores complex issues within Qatari society and other Gulf States. Sponsorship, servitude, and gender segregation intersect in Qatar to create a system of segregation and domination of expatriates. ^

Electrical Transport Properties of Multilayered Single-Walled Carbon Nanotube Films

An improved layer-by-layer vacuum filtration method was adopted for the fabrication of single-walled carbon nanotube (SWCNT) films aiming at a series of SWCNT films with controllable thickness and density. The electrical transport properties of the multilayered SWCNT films have been investigated. With the constant film density, the decrease of the layer number of the SWCNT film results in an increase of the temperature coefficient of resistance (TCR). SWCNT film with 95% metallic nanotubes has shown a lower TCR than that of the SWCNT films with a low percentage of metallic nanotubes. The effect of thermal annealing and subsequent acid (HNO3) treatment on the electrical properties of the SWCNT films has also been investigated.

Diversity of Vancomycin Genes in Sub-tropical Soils

With the increased antibiotic exposure from anthropogenic sources, soil microbes are an ever-increasing ecological pool of resistant bacteria. This is the case with bacterial resistance to vancomycin through transfer of van-resistance genes by transposons. Studies show that bacterial species other than enteroccoci harbor genetic-like elements such as the Tn1546 transposon containing vancomycin-resistant genes. Overuse and misuse of antibiotics in hospital settings and agricultural practices have led to an increase in transferability of vancomycin-resistant genes among microbes. The objective of this project is to analyze the diversity of these genes found in the soil microbes from Miami-Dade County. Bacterial isolates were Gram-stained and the Kirby-Bauer antibiotic disk diffusion test was performed to determine the degree of resistance. Results showed that all bacterial isolates were resistant to penicillin at the 10 µg concentration and most were susceptible to varying vancomycin concentrations (10 µg, 20 µg, and 30 µg). A 1465 bp fragment was amplified from the 16S rDNA gene using 27F and 1492R universal primers from the multi-antibiotic resistant bacteria and sequenced to identify the isolates. Three Gram-negative bacteria genera were identified with the closest phylogenetic match to: Pseudomonas sp., Stenotrophomonas sp., Xanthomonas sp., as well as two Gram-positive bacteria genera: Bacillus sp. and Brevibacillus sp. The isolates’ vanA and vanB genes were amplified using the respective primers. Ongoing work is underway to sequence and compare these known van resistant genes, with the goal of revealing intrinsic vancomycin resistance present in soil bacteria.

Connectivity of fragmented amphibian populations in a neotropical landscape

A high proportion of amphibian species are threatened with extinction globally, and habitat loss and degradation are the most frequently implicated causes. Rapid deforestation for the establishment of agricultural production is a primary driver of habitat loss in tropical zones where amphibian diversity is highest. Land-cover change affects native assemblages, in part, through the reduction of habitat area and the reduction of movement among remnant populations. Decreased gene flow contributes to loss of genetic diversity, which limits the ability of local populations to respond to further environmental changes. The focus of this dissertation is on the degree to which common land uses in Sarapiquí, Costa Rica impede the movement of two common amphibian species. First, I used field experiments, including displacement trials, and a behavioral landscape ecology framework to investigate the resistance of pastures to movement of Oophaga pumilio. Results from experiments demonstrate that pastures do impede movement of O. pumilio relative to forest. Microclimatic effects on movement performance as well as limited perceptual ranges likely contribute to reduced return rates through pastures. Next, I linked local processes to landscape scale estimates of resistance. I conducted experiments to measure habitat-specific costs to movement for O. pumilio and Craugastor bransfodrii, and then used experimental results to parameterize connectivity models. Model validation indicated highest support for resistance estimates generated from responses to land-use specific microclimates for both species and to predator encounters for O. pumilio. Finally, I used abundance and experiment-derived resistance estimates to analyze the effects of prevalent land uses on population genetic structure of the two focal species. While O. pumilio did not exhibit a strong response to landscape heterogeneity and was primarily structured by distances among sites, C. bransfordii genetic variation was explained by resistance estimates from abundance and experiment data. Collectivity, this work demonstrates that common land uses can offer different levels of resistance to amphibian movements in Sarapiquí and illustrates the value of investigating local scales processes to inform interpretation of landscape-scale patterns.^

Application of a new method in the study of pelvic floor muscle passive properties in continent women

The aim of this study was to present a new methodology for evaluating the pelvic floor muscle (PFM) passive properties. The properties were assessed in 13 continent women using an intra-vaginal dynamometric speculum and EMG (to ensure the subjects were relaxed) in four different conditions: (1) forces recorded at minimal aperture (initial passive resistance); (2) passive resistance at maximal aperture; (3) forces and passive elastic stiffness (PES) evaluated during five lengthening and shortening cycles; and (4) percentage loss of resistance after 1 min of sustained stretch. The PFMs and surrounding tissues were stretched, at constant speed, by increasing the vaginal antero-posterior diameter; different apertures were considered. Hysteresis was also calculated. The procedure was deemed acceptable by all participants. The median passive forces recorded ranged from 0.54 N (interquartile range 1.52) for minimal aperture to 8.45 N (interquartile range 7.10) for maximal aperture while the corresponding median PES values were 0.17 N/mm (interquartile range 0.28) and 0.67 N/mm (interquartile range 0.60). Median hysteresis was 17.24 N∗mm (interquartile range 35.60) and the median percentage of force losses was 11.17% (interquartile range 13.33). This original approach to evaluating the PFM passive properties is very promising for providing better insight into the patho-physiology of stress urinary incontinence and pinpointing conservative treatment mechanisms.

Structural and Functional Analysis of the Caspase –dependent and –independent Domains of the X-linked Inhibitor of Apoptosis Protein in Inflammatory Breast Cancer Tumor Biology

Inflammatory breast cancer (IBC) is an extremely rare but highly aggressive form of breast cancer characterized by the rapid development of therapeutic resistance leading to particularly poor survival. Our previous work focused on the elucidation of factors that mediate therapeutic resistance in IBC and identified increased expression of the anti-apoptotic protein, X-linked inhibitor of apoptosis protein (XIAP), to correlate with the development of resistance to chemotherapeutics. Although XIAP is classically thought of as an inhibitor of caspase activation, multiple studies have revealed that XIAP can also function as a signaling intermediate in numerous pathways. Based on preliminary evidence revealing high expression of XIAP in pre-treatment IBC cells rather than only subsequent to the development of resistance, we hypothesized that XIAP could play an important signaling role in IBC pathobiology outside of its heavily published apoptotic inhibition function. Further, based on our discovery of inhibition of chemotherapeutic efficacy, we postulated that XIAP overexpression might also play a role in resistance to other forms of therapy, such as immunotherapy. Finally, we posited that targeting of specific redox adaptive mechanisms, which are observed to be a significant barrier to successful treatment of IBC, could overcome therapeutic resistance and enhance the efficacy of chemo-, radio-, and immuno- therapies. To address these hypotheses our objectives were: 1. to determine a role for XIAP in IBC pathobiology and to elucidate the upstream regulators and downstream effectors of XIAP; 2. to evaluate and describe a role for XIAP in the inhibition of immunotherapy; and 3. to develop and characterize novel redox modulatory strategies that target identified mechanisms to prevent or reverse therapeutic resistance.

Using various genomic and proteomic approaches, combined with analysis of cellular viability, proliferation, and growth parameters both in vitro and in vivo, we demonstrate that XIAP plays a central role in both IBC pathobiology in a manner mostly independent of its role as a caspase-binding protein. Modulation of XIAP expression in cells derived from patients prior to any therapeutic intervention significantly altered key aspects IBC biology including, but not limited to: IBC-specific gene signatures; the tumorigenic capacity of tumor cells; and the metastatic phenotype of IBC, all of which are revealed to functionally hinge on XIAP-mediated NFκB activation, a robust molecular determinant of IBC. Identification of the mechanism of XIAP-mediated NFκB activation led to the characterization of novel peptide-based antagonist which was further used to identify that increased NFκB activation was responsible for redox adaptation previously observed in therapy-resistant IBC cells. Lastly, we describe the targeting of this XIAP-NFκB-ROS axis using a novel redox modulatory strategy both in vitro and in vivo. Together, the data presented here characterize a novel and crucial role for XIAP both in therapeutic resistance and the pathobiology of IBC; these results confirm our previous work in acquired therapeutic resistance and establish the feasibility of targeting XIAP-NFκB and the redox adaptive phenotype of IBC as a means to enhance survival of patients.