Bcl-xL (S49) and (S62) sequential phosphorylation/dephosphorylation during mitosis prevents chromosome instability and aneuploidy

Une caractéristique intéressante de la protéine Bcl-xL est la présence d'un domaine en boucle non-structurée entre les hélices α1 and α2 de la protéine. Ce domaine protéique n'est pas essentiel pour sa fonction anti-apoptotique et absent chez CED-9, la protéine orthologue chez Caenorhabditis elegans. A l'intérieur de ce domaine, Bcl-xL subit une phosphorylation et déphosphorylation dynamique sur les résidus Ser49 et Ser62 en phase G2 du cycle cellulaire et lors de la mitose. Lorsque ces résidus sont mutés et les protéines exprimées dans des cellules cancéreuses, les cellules démontrent plusieurs défauts mitotiques liés à l'instabilité chromosomique. Pour analyser les effets de Bcl-xL Ser49 et Ser62 dans les cellules normales, les présentes études ont été réalisées dans des cellules diploïdes humaines normales, et in vivo chez Caenorhabditis elegans. Dans une première étude, nous avons utilisé la lignée cellulaire de cellules fibroblastiques diploïdes humaines normales BJ, exprimant Bcl-xL (type sauvage), (S49A), (S49D), (S62A), (S62D) et les double (S49/62A) et (S49/62D) mutants. Les cellules exprimant les mutants de phosphorylation ont montré des cinétiques de doublement de la population cellulaire réduites. Ces effets sur la cinétique de doublement de la population cellulaire corrèle avec l'apparition de la sénescence cellulaire, sans impact sur les taux de mort cellulaire. Ces cellules sénescentes affichent des phénotypes typiques de sénescence associés notamment à haut niveau de l'activité β-galactosidase associée à la sénescence, la sécrétion d' interleukine-6, l'activation de p53 et de p21WAF1/ Cip1, un inhibiteur des complexes kinase cycline-dépendant, ainsi que la formation de foyers de chromatine nucléaire associés à γH2A.X. Les analyses de fluorescence par hybridation in situ et des caryotypes par coloration au Giemsa ont révélé que l'expression des mutants de phosphorylation de Bcl-xL provoquent de l'instabilité chromosomique et l'aneuploïdie. Ces résultats suggèrent que les cycles de phosphorylation et déphosphorylation dynamiques de Bcl-xL Ser49 et Ser62 sont importants dans le maintien de l'intégrité des chromosomes lors de la mitose dans les cellules normales. Dans une deuxième étude, nous avons entrepris des expériences chez Caenorhabditis elegans pour comprendre l'importance des résidus Ser49 et Ser62 de Bcl-xL in vivo. Les vers transgéniques portant les mutations de Bcl-xL (S49A, S62A, S49D, S62D et S49/62A) ont été générés et leurs effets ont été analysés sur les cellules germinales des jeunes vers adultes. Les vers portant les mutations de Bcl-xL ont montré une diminution de ponte et d'éclosion des oeufs, des variations de la longueur de leurs régions mitotiques et des zones de transition, des anomalies chromosomiques à leur stade de diplotène, et une augmentation de l'apoptose des cellules germinales. Certaines de ces souches transgéniques, en particulier les variants Ser/Ala, ont également montré des variations de durée de vie par rapport aux vers témoins. Ces observations in vivo ont confirmé l'importance de Ser49 et Ser62 à l'intérieur du domaine à boucle de Bcl-xL pour le maintien de la stabilité chromosomique. Ces études auront une incidence sur les futures stratégies visant à développer et à identifier des composés qui pourraient cibler non seulement le domaine anti-apoptotique de la protéine Bcl-xL, mais aussi son domaine mitotique pour la thérapie du cancer.

The MOOC Dashboard: Visualising MOOC data for everyone

Abstract Massive Open Online Courses (MOOCs) generate enormous amounts of data. The University of Southampton has run and is running dozens of MOOC instances. The vast amount of data resulting from our MOOCs can provide highly valuable information to all parties involved in the creation and delivery of these courses. However, analysing and visualising such data is a task that not all educators have the time or skills to undertake. The recently developed MOOC Dashboard is a tool aimed at bridging such a gap: it provides reports and visualisations based on the data generated by learners in MOOCs. Speakers Manuel Leon is currently a Lecturer in Online Teaching and Learning in the Institute for Learning Innovation and Development (ILIaD). Adriana Wilde is a Teaching Fellow in Electronics and Computer Science, with research interests in MOOCs and Learning Analytics. Darron Tang (4th Year BEng Computer Science) and Jasmine Cheng (BSc Mathematics & Actuarial Science and starting MSc Data Science shortly) have been working as interns over this Summer (2016) as have been developing the MOOC Dashboard.

A DST-based Approach for Construction Project Risk Analysis

Despite its huge potential in risk analysis, the Dempster–Shafer Theory of Evidence (DST) has not received enough attention in construction management. This paper presents a DST-based approach for structuring personal experience and professional judgment when assessing construction project risk. DST was innovatively used to tackle the problem of lacking sufficient information through enabling analysts to provide incomplete assessments. Risk cost is used as a common scale for measuring risk impact on the various project objectives, and the Evidential Reasoning algorithm is suggested as a novel alternative for aggregating individual assessments. A spreadsheet-based decision support system (DSS) was devised to facilitate the proposed approach. Four case studies were conducted to examine the approach's viability. Senior managers in four British construction companies tried the DSS and gave very promising feedback. The paper concludes that the proposed methodology may contribute to bridging the gap between theory and practice of construction risk assessment.

Microcrédito emancipatório no nordeste do Brasil? : estudo de caso do Crediamigo Comunidade nos municípios de Caucaia-Ce e Maranguape-Ce

This piece of work consists in a study case of Crediamigo Comunidade, a product from the portfolio of Crediamigo Program of Banco do Nordeste, that uses the methodology of the Comunitary Banks in the concession of low amount loan to poor communities. The main question consists to understand how the Crediamigo Comunidade is characterized faced to the conflict of emancipatory versus liberal paradigms, that exists in the microcredit area. The main objective will analyze how the mechanisms: social capital, empowerment, formation to credit education and better conditions for economic and social issues promoted in the specific objectives of this product, before the dipute between these paradigms. The method adopted analyzed, in a longitudinal perspective, the three years of the product s existence (jun/2005 to jul 2008). Primary and secondary data made possible to identify qualitatively, emancipatory and non emancipatory attributes in the actions and results of Crediamigo Comunidade. It is concluded that the Crediamigo Comunidade works in a liberal logic of the Crediamigo Program, consequently, his focus is not in the emancipation of the poorest clients. The empowerment is individual and not communitary or Freiriano ; the social capital relations enlarges itself in its bounding and bridging ties, but not in its linkage ties, to have access to politic actors and consequently communitary strengthen. All the formation in the Crediamigo is strictly commercial. These characteristics happen by the liberal paradigm in the Crediamigo management and of all of its products, including the Crediamigo Comunidade

“It’s the People That Drive It”: Motivating and Supporting Collaborative Data Use Practices in Three Teacher Education Programs

Thesis (Ph.D.)--University of Washington, 2016-08

Resilience and development: mobilizing for transformation

In 2014, the Third International Conference on the resilience of social-ecological systems chose the theme “resilience and development: mobilizing for transformation.” The conference aimed specifically at fostering an encounter between the experiences and thinking focused on the issue of resilience through a social and ecological system perspective, and the experiences focused on the issue of resilience through a development perspective. In this perspectives piece, we reflect on the outcomes of the meeting and document the differences and similarities between the two perspectives as discussed during the conference, and identify bridging questions designed to guide future interactions. After the conference, we read the documents (abstracts, PowerPoints) that were prepared and left in the conference database by the participants (about 600 contributions), and searched the web for associated items, such as videos, blogs, and tweets from the conference participants. All of these documents were assessed through one lens: what do they say about resilience and development? Once the perspectives were established, we examined different themes that were significantly addressed during the conference. Our analysis paves the way for new collective developments on a set of issues: (1) Who declares/assign/cares for the resilience of what, of whom? (2) What are the models of transformations and how do they combine the respective role of agency and structure? (3) What are the combinations of measurement and assessment processes? (4) At what scale should resilience be studied? Social transformations and scientific approaches are coconstructed. For the last decades, development has been conceived as a modernization process supported by scientific rationality and technical expertise. The definition of a new perspective on development goes with a negotiation on a new scientific approach. Resilience is presently at the center of this negotiation on a new science for development.

Fc-fusion mimetics

The Fc-fusion mimetic RpR 2 was prepared by disulfide bridging conjugation using a PEG in the place of the Fc. RpR 2 displayed higher affinity for VEGF than aflibercept caused primarily by a slower dissociation rate, which can prolong a drug at its site of action. RpRs have considerable potential for development as stable, organ specific therapeutics.

Desordens músculo-esqueléticas relacionadas com o exercício da Medicina Dentária

Os profissionais de Saúde Oral, nomeadamente os Médicos Dentistas, têm vindo a enfrentar variados riscos decorrentes da sua atividade profissional. Apesar de haver um esforço constante no sentido de melhorar os equipamentos e materiais dentários, através dos avanços tecnológicos, estes não conseguiram, ainda, colmatar significativamente os problemas Músculo-Esqueléticos dos Médicos Dentistas. Este tipo de problemas surge enquanto estudantes, durante a prática clínica, muitas vezes devido às condições de trabalho, à inexperiência inerente, mas, principalmente, devido às postura e aos hábitos de trabalho errados que adquirem e que, consequentemente, persistem ao longo da sua vida profissional. A presente dissertação, aliada a uma vasta literatura relacionada, pretende alertar os profissionais de Saúde Oral, com foco nos Médicos Dentistas, para as patologias decorrentes das posturas erradas no exercício da Medicina Dentária, denominadas de Desordens Músculo-Esqueléticas relacionadas com o Trabalho, identificando-as, assim como aos fatores de risco que influenciam o seu aparecimento. A elaboração desta dissertação, pretende, ainda, propor exercícios de Ginástica Laboral a realizar entre consultas, como estratégia de prevenção para o surgimento de Lesões MúsculoEsqueléticas Relacionadas com o Trabalho nos Médicos Dentistas e alertar para a importância da Ergonomia na conceção de um Consultório Dentário. Para a presente revisão bibliográfica, foi realizada uma pesquisa bibliográfica com recurso a livros e artigos publicados em revistas, e que foram consultados nas Bibliotecas da Faculdade de Medicina Dentária da Universidade do Porto e da Universidade Fernando Pessoa. Procedeu-se à pesquisa por recurso aos motores de busca na internet, tais como, PubMed, Scielo, B-On e Medline, utilizando as seguintes palavras-chave, em conjunto ou individualmente: “Lesões por esforços repetitivos”; “Lesões Músculo-Esqueléticas”; “Ergonomia”; “Prevenção”; “Fatores de Risco”; “Ginástica Laboral”; “Work related musculoskeletal disorders”; “Dentistry”; “Ergonomics”; “Pain”; “Prevention”; “Risk factors”. Foram selecionados artigos entre 1987 e 2015, com relevância para o presente trabalho de dissertação de Mestrado, escritos em Português e Inglês. Desta forma, a pesquisa bibliográfica permitiu verificar a prevalência de Lesões Músculo-Esqueléticas Relacionadas com o Trabalho, no âmbito da Medicina Dentária, assim como os fatores de risco associados ao seu aparecimento. Foram ainda tecidas algumas recomendações de forma a contribuir para o bem-estar dos Médicos Dentistas, elucidando-os para a necessidade de adotar posturas corretas e usando a Ergonomia como base para a organização e conceção de um Consultório Dentário. Recorreu-se, ainda, à ilustração de um programa de Ginástica Laboral, através de dois cartazes elucidativos, com o objetivo de prevenir, corrigir e compensar este tipo de patologias do Médico Dentista, desde a sua prática clínica. Após a elaboração desta dissertação, acredita-se ser de extrema importância a aplicação de diretrizes ergonómicas na conceção de um Consultório Dentário, na organização de tarefas, no procedimento clínico, na adoção de posturas, no posto de trabalho, na localização do equipamento e na escolha dos instrumentos. Este método, para além de minimizar o risco do aparecimento de doenças profissionais, também simplifica tarefas, proporciona a correta comunicação entre o Médico Dentista e o assistente e melhora a qualidade e produtividade laboral, através da redução da fadiga física e mental e do aumento da confiança e bem-estar dos Médicos Dentistas.

Coupling of magnetic, strain and electric polarization fields in the structure of multiferroic material

The comprehensive study on the coupling of magnetism, electrical polarization and the crystalline lattice with the off-stoichiometric effects in self-doped multiferroic hexagonal h-LuMnxO3±δ (0.92≤x≤1.12) ceramic oxides was carried out for the PhD work. There is a complex coupling of the three ferroic degrees. The cancelation of the magnetic moments of ions in the antiferromagnetic order, electric polarization with specific vortex/antivortex topology and lattice properties have pushed researchers to find out ways to disclose the underlying physics and chemistry of magneto-electric and magneto-elastic couplings of h-RMnO3 multiferroic materials. In this research work, self-doping of Lu-sites or Mn-sites of h-LuMnxO3±δ ceramics prepared via solid state route was done to pave a way for deeper understanding of the antiferromagnetic transition, the weak ferromagnetism often reported in the same crystalline lattices and the ferroelectric properties coupled to the imposed lattice changes. Accordingly to the aim of the PhD thesis, the objectives set for the sintering study in the first chapter on experimental results were two. First, study of sintering off-stoichiometric samples within conditions reported in the bibliography and also extracted from the phase diagrams of the LuMnxO3±δ, with a multiple firings ending with a last high temperature step at 1300ºC for 24 hours. Second, explore longer annealing times of up to 240 hours at the fixed temperature of 1300 ºC in a search for improving the properties of the solid solution under study. All series of LuMnxO3±δ ceramics for each annealing time were characterized to tentatively build a framework enabling comparison of measured properties with results of others available in literature. XRD and Rietveld refinement of data give the evolution the lattice parameters as a function to x. Shrinkage of the lattice parameters with increasing x values was observed, the stability limit of the solid solution being determined by analysis of lattice parameters. The evolution of grain size and presence of secondary phases have been investigated by means of TEM, SEM, EDS and EBSD techniques. The dependencies of grain growth and regression of secondary phases on composition x and time were further characterized. Magnetic susceptibility of samples and magnetic irreversibility were extensively examined in the present work. The dependency of magnetic susceptibility, Neel ordering transition and important magnetic parameters are determined and compared to observation in other multiferroics in the following chapter of the thesis. As a tool of high sensitivity to detect minor traces of the secondary phase hausmannite, magnetic measurements are suggested for cross-checking of phase diagrams. Difficulty of previous studies on interpreting the magnetic anomaly below 43 K in h-RMnO3 oxides was discussed and assigned to the Mn3O4 phase, with supported of the electron microscopy. Magneto-electric coupling where AFM ordering is coupled to dielectric polarization is investigated as a function of x and of sintering condition via frequency and temperature dependent complex dielectric constant measurements in the final chapter of the thesis. Within the limits of solid solubility, the crystalline lattice of off-stoichiometric ceramics was shown to preserve the magneto-electric coupling at TN. It represents the first research work on magneto-electric coupling modified by vacancy doping to author’s knowledge. Studied lattices would reveal distortions at the atomic scale imposed by local changes of x dependent on sintering conditions which were widely inspected by using TEM/STEM methods, complemented with EDS and EELS spectroscopy all together to provide comprehensive information on cross coupling of distortions, inhomogeneity and electronic structure assembled and discussed in a specific chapter. Internal interfaces inside crystalline grains were examined. Qualitative explanations of the measured magnetic and ferroelectric properties were established in relation to observed nanoscale features of h-LuMnxO3±δ ceramics. Ferroelectric domains and topological defects are displayed both in TEM and AFM/PFM images, the later technique being used to look at size, distribution and switching of ferroelectric domains influenced by vacancy doping at the micron scale bridging to complementary TEM studies on the atomic structure of ferroelectric domains. In support to experimental study, DFT simulations using Wien2K code have been carried out in order to interpret the results of EELS spectra of O K-edge and to obtain information on the cation hybridization to oxygen ions. The L3,2 edges of Mn is used to access the oxidation state of the Mn ions inside crystalline grains. In addition, rehybridization driven ferroelectricity is also evaluated by comparing the partial density of states of the orbitals of all ions of the samples, also the polarization was calculated and correlated to the off-stoichiometric effect.

Document analysis of PDF files: methods, results and implications

A strategy for document analysis is presented which uses Portable Document Format (PDF the underlying file structure for Adobe Acrobat software) as its starting point. This strategy examines the appearance and geometric position of text and image blocks distributed over an entire document. A blackboard system is used to tag the blocks as a first stage in deducing the fundamental relationships existing between them. PDF is shown to be a useful intermediate stage in the bottom-up analysis of document structure. Its information on line spacing and font usage gives important clues in bridging the semantic gap between the scanned bitmap page and its fully analysed, block-structured form. Analysis of PDF can yield not only accurate page decomposition but also sufficient document information for the later stages of structural analysis and document understanding.

If not the Virtual university then what? Co-producing e-learning and configuring its users

This paper reflects the changing notion of the Virtual University and its realization. We introduce an approach from the Sociology of Science and Technology (STS) which analyses the construction of the “student as a user” as seen through the “eyes of designers”. We ask how social relations are built into technological artefacts. In showing how socio-technical developments transcend sometimes contradict and various notions of “the student” we discuss difficulties and chances of bridging the gap between designers of e-learning-artefacts and its assumed addresses. (DIPF/Orig.)

Tourism Media Dynamics: Narratives of the Nation-State

With the premise that the tourism promotional video “China, Forever” provides a crucial access to understanding how tourism engages in a wider circle of socio-culture formation, this dissertation research approaches tourism by examining communicative practices initiated by “China, Forever”. In doing so, it seeks to reveal two dialogues – firstly, between the discursive construction of tourism representational language and China’s nation-state ideology; secondly, between interpretations from overseas Chinese audiences and nation-state narratives delivered via the tourism media. In analyzing the first dialogue, this dissertation reveals that the pursuit of collective and monolithic national imagery has caused a representational violence – one that is committed by the nation-state ideology operated through the organization of tourism language. The very representational coercion itself, however, signifies the nature of tourism media as a vehicle mediating the global gaze and China’s self-representation; illuminating the fact that China’s nation-state building is only to be understood as deeply-grounded in the complexity of postcolonial politics. Furthermore, in a dialectic view, such finding consolidates the nature of “China, Forever” as a cultural product that actively exists as a component in the overall social fabric, co-creating a wider circle of culture politics together with other genres of media products; thus, calling for a more comprehensive understanding of tourism media at large. In the second approach, this dissertation seeks to understand how the tourism video “China, Forever” mediates the relationship between tourism narratives of the nation-state and overseas Chinese individuals; thus bridging together tourism media and ongoing life experiences of the audiences chosen. The analysis reveals that audiences’ interpretations heavily concentrate on resisting and fragmenting the hegemonic nation-state language in “China, Forever”. While some interviewees seek to decentralize the nation-state perspective from aspects of aesthetics, representational style, and representational subjects in “China, Forever” by incorporating their individual memories and past experiences, to some others, the over-polished glorification of China in the mediated tourism discourse is only coercive to China’s social realities experienced by the individual interviewees - the disheartening contrasts of poverty and affluence as well as other social inequalities. From the perspective of the audience group, the Chinese scholars and students at the University of Illinois interviewed for this dissertation research constitute a cohort of exiled audiences for the tourism video “China, Forever”. The audiences subject themselves to voluntary interpellation, a process in which they find themselves defending, negotiating, and resisting the nation-state representation of China – even though they are not its intended audience and have had no input into its production. Nevertheless, such process is one of identification, in which viewers articulate a subject position from which to speak of their own experiences, dilemmas and desires. The usefulness of tourism media discourse in mediating the nation-state narratives and the individual experience is amplified.

Negative regulation of the hepatic fibrogenic response by suppressor of cytokine signaling 1 (SOCS1)

Abstract: Suppressor of cytokine signaling 1 (SOCS1) is an indispensable regulator of IFN-γ signaling and has been implicated in the regulation of liver fibrosis. However, it is not known whether SOCS1 mediates its anti-fibrotic functions in the liver directly, or via modulating IFN-γ, which has been implicated in attenuating hepatic fibrosis. Additionally, it is possible that SOCS1 controls liver fibrosis by regulating hepatic stellate cells (HSC), a key player in fibrogenic response. While the activation pathways of HSCs have been well characterized, the regulatory mechanisms are not yet clear. The goals of this study were to dissociate IFN-γ-dependent and SOCS1-mediated regulation of hepatic fibrogenic response, and to elucidate the regulatory functions of SOCS1 in H SC activation. Liver fibrosis was induced in Socs1[superscript -/-]Ifng[superscript -/-] mice with dimethylnitrosamine or carbon tetrachloride. Ifng[superscript -/-] and C57BL/6 mice served as controls. Following fibrogenic treatments, Socs1[superscript -/-]Ifng[superscript -/-] mice showed elevated serum ALT levels and increased liver fibrosis com-pared to mice Ifng[superscript -/-]. The latter group showed higher alanine aminotransferase (ALT) levels and fibrosis than C57BL/6 controls. The livers of Socs1-deficient mice showed bridging fibrosis, which was associated with increased accumulation of myofibroblasts and abundant collagen deposition. Socs1-deficient livers showed increased expression of genes coding for smooth muscle actin, collagen, and enzymes involved in remodeling the extracellular matrix, namely matrix metalloproteinases and tissue inhibitor of metalloproteinases. Primary HSCs from Socs1-deficient mice showed increased proliferation in response to growth factors such as HGF, EGF and PDGF, and the fibrotic livers of Socs1-deficient mice showed increased expression of the Pdgfb gene. Taken together, these data indicate that SOCS1 controls liver fibrosis independently of IFN-γ and that part of this regulation may occur via regulating HSC proliferation and limiting growth factor availability.

Training civic bridge builders: Outcomes of community leadership development programs

As rural communities experience rapid economic, demographic, and political change, program interventions that focus on the development of community leadership capacity could be valuable. Community leadership development programs have been deployed in rural U.S. communities for the past 30 years by university extension units, chambers of commerce, and other nonprofit foundations. Prior research on program outcomes has largely focused on trainees’ self-reported change in individual leadership knowledge, skills, and attitudes. However, postindustrial leadership theories suggest that leadership in the community relies not on individuals but on social relationships that develop across groups akin to social bridging. The purpose of this study is to extend and strengthen prior evaluative research on community leadership development programs by examining program effects on opportunities to develop bridging social capital using more rigorous methods. Data from a quasi-experimental study of rural community leaders (n = 768) in six states are used to isolate unique program effects on individual changes in both cognitive and behavioral community leadership outcomes. Regression modeling shows that participation in community leadership development programs is associated with increased leadership development in knowledge, skills, attitudes, and behaviors that are a catalyst for social bridging. The community capitals framework is used to show that program participants are significantly more likely to broaden their span of involvement across community capital asset areas over time compared to non-participants. Data on specific program structure elements show that skills training may be important for cognitive outcomes while community development learning and group projects are important for changes in organizational behavior. Suggestions for community leadership program practitioners are presented.