Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype

BACKGROUND: Pulmonary fibrosis is a debilitating and lethal disease with no effective treatment options. Understanding the pathological processes at play will direct the application of novel therapeutic avenues. Hypoxia has been implicated in the pathogenesis of pulmonary fibrosis yet the precise mechanism by which it contributes to disease progression remains to be fully elucidated. It has been shown that chronic hypoxia can alter DNA methylation patterns in tumour-derived cell lines. This epigenetic alteration can induce changes in cellular phenotype with promoter methylation being associated with gene silencing. Of particular relevance to idiopathic pulmonary fibrosis (IPF) is the observation that Thy-1 promoter methylation is associated with a myofibroblast phenotype where loss of Thy-1 occurs alongside increased alpha smooth muscle actin (α-SMA) expression. The initial aim of this study was to determine whether hypoxia regulates DNA methylation in normal human lung fibroblasts (CCD19Lu). As it has been reported that hypoxia suppresses Thy-1 expression during lung development we also studied the effect of hypoxia on Thy-1 promoter methylation and gene expression.

METHODS: CCD19Lu were grown for up to 8 days in hypoxia and assessed for global changes in DNA methylation using flow cytometry. Real-time PCR was used to quantify expression of Thy-1, α-SMA, collagen I and III. Genomic DNA was bisulphite treated and methylation specific PCR (MSPCR) was used to examine the methylation status of the Thy-1 promoter.

RESULTS: Significant global hypermethylation was detected in hypoxic fibroblasts relative to normoxic controls and was accompanied by increased expression of myofibroblast markers. Thy-1 mRNA expression was suppressed in hypoxic cells, which was restored with the demethylating agent 5-aza-2'-deoxycytidine. MSPCR revealed that Thy-1 became methylated following fibroblast exposure to 1% O2.

CONCLUSION: These data suggest that global and gene-specific changes in DNA methylation may play an important role in fibroblast function in hypoxia.

Organisational and systems factors impacting on patient safety in acute care organisations: lessons from four multi-site research studies

Background Patient safety is concerned with preventable harm in healthcare, a subject that became a focus for study in the UK in the late 1990s. How to improve patient safety, presented both a practical and a research challenge in the early 2000s, leading to the eleven publications presented in this thesis. Research question The overarching research question was: What are the key organisational and systems factors that impact on patient safety, and how can these best be researched? Methods Research was conducted in over 40 acute care organisations in the UK and Europe between 2006 and 2013. The approaches included surveys, interviews, documentary analysis and non-participant observation. Two studies were longitudinal. Results The findings reveal the nature and extent of poor systems reliability and its effect on patient safety; the factors underpinning cases of patient harm; the cultural issues impacting on safety and quality; and the importance of a common language for quality and safety across an organisation. Across the publications, nine key organisational and systems factors emerged as important for patient safety improvement. These include leadership stability; data infrastructure; measurement capability; standardisation of clinical systems; and creating an open and fair collective culture where poor safety is challenged. Conclusions and contribution to knowledge The research presented in the publications has provided a more complete understanding of the organisation and systems factors underpinning safer healthcare. Lessons are drawn to inform methods for future research, including: how to define success in patient safety improvement studies; how to take into account external influences during longitudinal studies; and how to confirm meaning in multi-language research. Finally, recommendations for future research include assessing the support required to maintain a patient safety focus during periods of major change or austerity; the skills needed by healthcare leaders; and the implications of poor data infrastructure.

A Systematic Review of Entrepreneurship Education Literature in Nigeria: Where is the Focus of Research?

Purpose- Entrepreneurship education (EEd) plays a crucial role in the development of entrepreneurs and the enhancement of entrepreneurial activities in every economy. This paper examined what Higher education Institutions (HEIs) do in learning and teaching of entrepreneurship in general and how entrepreneurship development takes place in Nigerian HEIs. The outcome from this study will enable a deeper understanding on what HEIs do EEd, with more exposure as to what the areas and focus of research is in the Nigerian context. Design/methodology/approach- The study adopted a systematic literature review approach- drawing from a computerized search of five selected data bases, using predetermined key words by the researchers. Findings: The main finding of this paper is that, related concepts like skills, intention, drive and attitude have been use in expounding discussions on the outcome of EEd, but very little has been written on entrepreneurial mind-set (EMS), of which other studies have suggested that it’s a crucial point in the journey of an entrepreneurs (Reed & Stoltz, 2011; Quality Assurance Agency for Higher Education (QAA), 2012; Neneh, 2012). Furthermore, learning and teaching of entrepreneurship in Nigerian HEIs seems to be more on creating awareness (about entrepreneurship) than actual preparation for entrepreneurship (For entrepreneurship). Research limitations/implications- The paper is limited since it is based on a review of literature from a selected databases- covering a specific time span. This potentially excludes other studies outside this time span. A more comprehensive overview of these contributions would benefit from employing tools such as Google Scholar, for an overview of the sub–domains online. Originality/value – There are limited studies that focus on the issue of entrepreneurial mind-set in entrepreneurship education in Africa, specifically Nigeria. This paper and its focus in particular, have laid down pioneering ground work for research on entrepreneurial mind-set development in Nigerian entrepreneurship education.

Pivoting the player: a framework for player character research in offline computer role-playing games

This article introduces a theoretical framework for the analysis of the player character (PC) in offline computer role-playing games (cRPGs). It derives from the assumption that the character constitutes the focal point of the game, around which all the other elements revolve. This underlying observation became the foundation of the Player Character Grid and its constituent Pivot Player Character Model, a conceptual framework illustrating the experience of gameplay as perceived through the PC’s eyes. Although video game characters have been scrutinised from many different perspectives, a systematic framework has not been introduced yet. This study aims to fill that void by proposing a model replicable across the cRPG genre. It has been largely inspired by Anne Ubersfeld’s semiological dramatic character research implemented in Reading Theatre I (1999) and is demonstrated with reference to The Witcher (CD Projekt RED 2007).

Small scale turbulence and mixing in semi-enclosed seas (Persian Gulf)

Turbulence and internal waves are probably important in generating layered structures in frontal region of marine environments (e.g. near river plumes outflow into the sea). Here we investigate the role of normal modes of internal waves in generation of layered structure in a part of Persian Gulf where river plume inters and in some laboratory experiments. The model prediction and observations show that layers so formed have a thickness of about 2m based on salinity variations with depth, but layers (about 5m) based on horizontal velocity profiles. Laboratory experiments with a plume outflow in a Filling Box profile also generate normal mode layered structure with 21H=0.5 (where A is layer thickness and H is the plume depth). In these experiments as Re of the flow is smaller than the Re of field flow. The normal modes are substantially dissipated with depth. Typical values of dissipation factor is about 0(100). This factor for field observation is 0(10) which is still substantial. Qualitative comparison between layered structure in field and laboratory is good. It should be emphasized that field observation is for semi-enclosed seas but the laboratory experiments are for enclosed region. Hence some of the discrepancies in the results of two cases are inevitable. Layered structures in marine environments are also produced by double diffusive convection. In this region this should be studied separately.

The impact of the MARINET initiative on the development of Marine Renewable Energy

Marine Renewable Energy Conversion systems comprise wave energy and tidal stream converters as well as offshore-wind turbines for electrical generation. These technologies are currently at different stages of development but are mostly at the pre-commercial stage and require research to be undertaken at a series of scales along the path to commercialization. However each of these technologies also needs specific research infrastructures in order to conduct this research. The aim of the MARINET initiative is to coordinate research and development at all scales (small models through to prototype scales, from laboratories through to open sea tests) and to allow access for researchers and developers to infrastructures which are not available universally in Europe, including test facilities for components such as power take-off systems, grid integration, moorings and environmental monitoring so as to ensure a focusing of activities in this area. The initiative offers researchers and developers access to 45 research facilities as well as to the associated network of expertise at all scales in Offshore Marine Renewable Energy technology research and development. The aim of this paper is to present this MARINET initiative that was started in 2011, bringing together a network of 29 partners spread across twelve countries. Details of the MARINET Transnational Access (TA) program are presented, for which over 260 applications were received throughout the 5 official calls for proposals. In particular, statistics on applications and completed projects are presented which provide an overview of the global development progress of the different offshore renewable energy conversion technologies at a European level. It also provides a good overview of the current research activity, as well as evidence of the requirement for specialised research facilities, in this burgeoning field.

Multiple sulfur isotope fractionations in inorganic aqueous systems

New constraints on isotope fractionation factors in inorganic aqueous sulfur systems based on theoretical and experimental techniques relevant to studies of the sulfur cycle in modern environments and the geologic rock record are presented in this dissertation. These include theoretical estimations of equilibrium isotope fractionation factors utilizing quantum mechanical software and a water cluster model approach for aqueous sulfur compounds that span the entire range of oxidation state for sulfur. These theoretical calculations generally reproduce the available experimental determinations from the literature and provide new constraints where no others are available. These theoretical calculations illustrate in detail the relationship between sulfur bonding environment and the mass dependence associated with equilibrium isotope exchange reactions involving all four isotopes of sulfur. I additionally highlight the effect of isomers of protonated compounds (compounds with the same chemical formula but different structure, where protons are bound to either sulfur or oxygen atoms) on isotope partitioning in the sulfite (S4+) and sulfoxylate (S2+) systems, both of which are key intermediates in oxidation-reduction processes in the sulfur cycle. I demonstrate that isomers containing the highest degree of coordination around sulfur (where protonation occurs on the sulfur atom) have a strong influence on isotopic fractionation factors, and argue that isomerization phenomenon should be considered in models of the sulfur cycle. Additionally, experimental results of the reaction rates and isotope fractionations associated with the chemical oxidation of aqueous sulfide are presented. Sulfide oxidation is a major process in the global sulfur cycle due largely to the sulfide-producing activity of anaerobic microorganisms in organic-rich marine sediments. These experiments reveal relationships between isotope fractionations and reaction rate as a function of both temperature and trace metal (ferrous iron) catalysis that I interpret in the context of the complex mechanism of sulfide oxidation. I also demonstrate that sulfide oxidation is a process associated with a mass dependence that can be described as not conforming to the mass dependence typically associated with equilibrium isotope exchange. This observation has implications for the inclusion of oxidative processes in environmental- and global-scale models of the sulfur cycle based on the mass balance of all four isotopes of sulfur. The contents of this dissertation provide key reference information on isotopic fractionation factors in aqueous sulfur systems that will have far-reaching applicability to studies of the sulfur cycle in a wide variety of natural settings.

Foreign direct investment determinants revisited in the context of global value chains

In this paper, we aim at contributing to the new field of research that intends to bring up-to-date the tools and statistics currently used to look to the current reality given by Global Value Chains (GVC) in international trade and Foreign Direct Investment (FDI). Namely, we make use of the most recent data published by the World Input-Output Database to suggest indicators to measure the participation and net gains of countries by being a part of GVC; and use those indicators in a pooled-regression model to estimate determinants of FDI stocks in Organization for Economic Co-operation and Development (OECD)-member countries. We conclude that one of the measures proposed proves to be statistically significant in explaining the bilateral stock of FDI in OECD countries, meaning that the higher the transnational income generated between two given countries by GVC, taken as a proxy to the participation of those countries in GVC, the higher one could expect the FDI entering those countries to be. The regression also shows the negative impact of the global financial crisis that started in 2009 in the world’s bilateral FDI stocks and, additionally, the particular and significant role played by the People’s Republic of China in determining these stocks.

A NATURALISTIC COMPUTATIONAL MODEL OF HUMAN BEHAVIOR IN NAVIGATION AND SEARCH TASKS

Planning, navigation, and search are fundamental human cognitive abilities central to spatial problem solving in search and rescue, law enforcement, and military operations. Despite a wealth of literature concerning naturalistic spatial problem solving in animals, literature on naturalistic spatial problem solving in humans is comparatively lacking and generally conducted by separate camps among which there is little crosstalk. Addressing this deficiency will allow us to predict spatial decision making in operational environments, and understand the factors leading to those decisions. The present dissertation is comprised of two related efforts, (1) a set of empirical research studies intended to identify characteristics of planning, execution, and memory in naturalistic spatial problem solving tasks, and (2) a computational modeling effort to develop a model of naturalistic spatial problem solving. The results of the behavioral studies indicate that problem space hierarchical representations are linear in shape, and that human solutions are produced according to multiple optimization criteria. The Mixed Criteria Model presented in this dissertation accounts for global and local human performance in a traditional and naturalistic Traveling Salesman Problem. The results of the empirical and modeling efforts hold implications for basic and applied science in domains such as problem solving, operations research, human-computer interaction, and artificial intelligence.

The use of digital educational resources : the contribution of research in the supervised teaching practice in basic education

This article aims to reflect on the impact of Information and Communication Technologies (ICT) in the educational context, focusing on the potential contributions of the use of Digital Educational Resources (RED) in the process of teaching and learning. For this purpose, the results of the use of the RED will be presented:. Digital Classroom - The World's 1st Year Carochinha The study was accomplished in a class of the 1st grade of the 1st CEB, composed of 27 students, aged 6-7 years in Castelo Branco City Schools Group within the Supervised Teaching Practice. The results obtained after the analysis and processing of the data showed that when using this RED students show they have acquired the content covered by the fact that they enhanced levels of greater interest, commitment, motivation, commitment and initiative in the course of activities proposals. But, perhaps because they are students of 1st year of the 1st CEB, do not neglect the presence and monitoring of the teacher and the use of paper-based resources. This means that there should be a complementarity that reconciles the human factor (teacher), with the use of digital media resources and paper support resources (Manual).

Strategic Diplomacies: Indigenous Governance, International Politics, and Natural Resources in Canada

International Relations theory would predict that central governments, with their considerable material resources, would be unlikely to face a challenge from a substate government. However, substate governments, and particularly Indigenous governments, are pushing back against central government control in both domestic and international spheres. Indigenous governments are leveraging their local mining sectors to realize their interests and express local identities—interests and identities that may not be congruent with those of the central government. Applying the case study of the resource extraction sector in Canada, this thesis asks: under what conditions are substate governments able to challenge the authority of central governments in the international arena? Canada’s reliance on the global extractive resource sector is a major driver of its international policy preferences, but the increased engagement of Indigenous governments in the sector challenges the control of the federal government. Focusing on the resource extraction sectors in British Columbia, Saskatchewan, and Ontario, this thesis argues that there is a mutually reinforcing relationship between Indigenous governments’ international engagement and their domestic autonomy; both challenge the parameters of state authority. Both force the state to respond to claims of control from multiple sites and to clarify convoluted policy environments. A confluence of factors—including increased Indigenous connections to the globalized economy, new Canadian regulatory frameworks, and recent Supreme Court of Canada cases regarding Indigenous lands—have all altered the space in which Indigenous governments in Canada participate in the resource extraction sector and produce overlapping or multilevel governance structures. This thesis demonstrates that Indigenous international engagement entrenches the authority and political legitimacy manifest in Indigenous governments’ insistence on equitable and horizontal negotiations in Canada’s lucrative resource extraction sector. A cumulative process occurs in which domestic and international expressions of political autonomy reinforce each other, produce further opportunities to express authority in both environments, and trouble the state’s capacity to fully realize its international policy preferences.

Niveles de actividad física en los periodos de recreo de niños y adolescentes en un colegio distrital de Bogotá

Objetivo: determinar los niveles de actividad física (AF) de niños y adolescentes entre 10 y 17 años durante los periodos de recreo escolar en un colegio distrital de Bogotá. Método: estudio de corte transversal en un colegio distrital de la localidad de Puente Aranda en Bogotá. Fueron observados a través del sistema de observación de juego y de actividad en el tiempo libre en jóvenes (SOPLAY) los niveles y tipos de AF de niños y adolescentes en los periodos de recreo durante tres semanas, utilizando una condición de observación diferente para cada semana. Adicionalmente, las condiciones del contexto de las áreas recreo deportivas fueron evaluadas. Resultados: las prevalencias de escolares sedentarios fueron de 52,4 %, 77,3 % y 64,9 % durante la 1ª, 2ª y 3ª semana respectivamente. El sexo femenino fue más sedentario con el masculino (57 %, 82 % y 73 % vs 45 %, 70 % y 54 %) para cada semana observada. Se obtuvieron diferencias significativas (p<0,05) en los niveles de AF de los escolares. Conclusión: niños y adolescentes presentan elevadas prevalencias de sedentarismo siendo las actividades más frecuentes estar sentado, de pie o acostado durante los periodos de recreo. El sexo masculino mostró porcentajes superiores de participación en AF moderadas vigorosas. Las áreas recreo deportivas no contaban con condiciones del contexto relacionadas con disponibilidad de equipamiento para realizar AF ni existencia de actividades organizadas. Son necesarios programas e intervenciones eficaces que promuevan la AF en niños y adolescentes durante el recreo de la jornada escolar.

The significant role of third-party logistics (3pl) operators as fosterers of organizational performance in colombian companies

La eliminación de barreras entre países es una consecuencia que llega con la globalización y con los acuerdos de TLC firmados en los últimos años. Esto implica un crecimiento significativo del comercio exterior, lo cual se ve reflejado en un aumento de la complejidad de la cadena de suministro de las empresas. Debido a lo anterior, se hace necesaria la búsqueda de alternativas para obtener altos niveles de productividad y competitividad dentro de las empresas en Colombia, ya que el entorno se ha vuelto cada vez más complejo, saturado de competencia no sólo nacional, sino también internacional. Para mantenerse en una posición competitiva favorable, las compañías deben enfocarse en las actividades que le agregan valor a su negocio, por lo cual una de las alternativas que se están adoptando hoy en día es la tercerización de funciones logísticas a empresas especializadas en el manejo de estos servicios. Tales empresas son los Proveedores de servicios logísticos (LSP), quienes actúan como agentes externos a la organización al gestionar, controlar y proporcionar actividades logísticas en nombre de un contratante. Las actividades realizadas pueden incluir todas o parte de las actividades logísticas, pero como mínimo la gestión y ejecución del transporte y almacenamiento deben estar incluidos (Berglund, 2000). El propósito del documento es analizar el papel de los Operadores Logísticos de Tercer nivel (3PL) como promotores del desempeño organizacional en las empresas colombianas, con el fin de informar a las MIPYMES acerca de los beneficios que se obtienen al trabajar con LSP como un medio para mejorar la posición competitiva del país.