Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: A platform for antiviral drug design

HIV integrase, the enzyme that inserts the viral DNA into the host chromosome, has no mammalian counterpart, making it an attractive target for antiviral drug design. As one of the three enzymes produced by HIV, it can be expected that inhibitors of this enzyme will complement the therapeutic use of HIV protease and reverse transcriptase inhibitors. We have determined the structure of a complex of the HIV-1 integrase core domain with a novel inhibitor, 5ClTEP, 1-(5-chloroindol-3-yl)-3-hydroxy-3-(2H-tetrazol-5-yl)-propenone, to 2.1-Å resolution. The inhibitor binds centrally in the active site of the integrase and makes a number of close contacts with the protein. Only minor changes in the protein accompany inhibitor binding. This inhibitor complex will provide a platform for structure-based design of an additional class of inhibitors for antiviral therapy.

Specific molecular recognition of mixed nucleic acid sequences: An aromatic dication that binds in the DNA minor groove as a dimer

Phenylamidine cationic groups linked by a furan ring (furamidine) and related compounds bind as monomers to AT sequences of DNA. An unsymmetric derivative (DB293) with one of the phenyl rings of furamidine replaced with a benzimidazole has been found by quantitative footprinting analyses to bind to GC-containing sites on DNA more strongly than to pure AT sequences. NMR structural analysis and surface plasmon resonance binding results clearly demonstrate that DB293 binds in the minor groove at specific GC-containing sequences of DNA in a highly cooperative manner as a stacked dimer. Neither the symmetric bisphenyl nor bisbenzimidazole analogs of DB293 bind significantly to the GC containing sequences. DB293 provides a paradigm for design of compounds for specific recognition of mixed DNA sequences and extends the boundaries for small molecule-DNA recognition.

The design of an agent to bend DNA.

An artificial DNA bending agent has been designed to assess helix flexibility over regions as small as a protein binding site. Bending was obtained by linking a pair of 15-base-long triple helix forming oligonucleotides (TFOs) by an adjustable polymeric linker. By design, DNA bending was introduced into the double helix within a 10-bp spacer region positioned between the two sites of 15-base triple helix formation. The existence of this bend has been confirmed by circular permutation and phase-sensitive electrophoresis, and the directionality of the bend has been determined as a compression of the minor helix groove. The magnitude of the resulting duplex bend was found to be dependent on the length of the polymeric linker in a fashion consistent with a simple geometric model. Data suggested that a 50-70 degrees bend was achieved by binding of the TFO chimera with the shortest linker span (18 rotatable bonds). Equilibrium analysis showed that, relative to a chimera which did not bend the duplex, the stability of the triple helix possessing a 50-70 degrees bend was reduced by less than 1 kcal/mol of that of the unbent complex. Based upon this similarity, it is proposed that duplex DNA may be much more flexible with respect to minor groove compression than previously assumed. It is shown that this unusual flexibility is consistent with recent quantitation of protein-induced minor groove bending.

Design of artificial sequence-specific DNA bending ligands.

Proteins that bend DNA are important regulators of biological processes. Sequence-specific DNA bending ligands have been designed that bind two noncontiguous sites in the major groove and induce a bend in the DNA. An oligonucleotide containing pyrimidine segments separated by a central variable linker domain simultaneously binds by triple helix formation two 15-bp purine tracts separated by 10 bp. Bend angles of 61 degrees, 50 degrees, and 38 degrees directed towards the minor groove were quantitated by phasing analysis for linkers of four, five, and six T residues, respectively. The design and synthesis of nonnatural architectural factors may provide a new class of reagents for use in biology and human medicine.

Igualdades e diferenças nas políticas educacionais: a agenda das diversidades nos governos Lula e Dilma

Esta pesquisa aborda as chamadas políticas de diversidade na educação e sua contribuição para o reconhecimento e a promoção dos direitos humanos e a superação do racismo, do sexismo, da homofobia e das demais desigualdades e discriminações que marcam profundamente a sociedade e a educação brasileiras. Com base nas vozes de gestores/as públicos/as e ativistas da sociedade civil, na análise documental e da execução orçamentária e na experiência política da pesquisadora, é apresentado um balanço sobre os dez anos de existência da Secretaria de Educação Continuada, Alfabetização e Diversidade (Secad), órgão do Ministério da Educação criado no primeiro governo do Presidente Luiz Inácio Lula da Silva. Em especial, buscou-se identificar as provocações e os tensionamentos gerados pelas agendas das diversidades para o atual desenho, funcionamento e institucionalidade das políticas educacionais e sua influência nas concepções de qualidade educacional em disputa nas políticas federais. Essas disputas estiveram presentes nas Conferências Nacionais de Educação e no processo conflitivo de tramitação do novo Plano Nacional de Educação (Lei Federal n. 13.005/2014), analisados neste trabalho. Respaldado por convenções e pelas resoluções internacionais das Conferências da ONU e por normativas nacionais, o debate sobre diferenças ganhou espaço na agenda das políticas educacionais brasileiras. Essa discussão foi impulsionada por movimentos sociais negros, indígenas, LGBTs, feministas, de trabalhadores do campo, de pessoas com deficiências, de quilombolas, ambientalistas e por agendas de fronteira na efetividade do direito humano à educação, como a educação de jovens e adultos, a educação em territórios de alta vulnerabilidade social e a educação de pessoas privadas de liberdade, entre outras. Apresenta-se, neste trabalho, uma contribuição teórica ao debate sobre a relação entre qualidade educacional, diferenças e igualdades, com base nas teorias críticas de justiça social. Discutem-se as possibilidades de a noção da diversidade constituir uma resposta interseccional às múltiplas discriminações e desigualdades que atingem os sujeitos concretos no cotidiano da vida e, especificamente, nas instituições educacionais. Ao final da tese, embasadas na definição do contexto de estratégia política de Stephen Ball e nas contribuições para o aperfeiçoamento das políticas 14 previstas na metodologia de análise das políticas públicas, são apresentadas reflexões comprometidas com a ampliação da capacidade das políticas educacionais no sentido de dar respostas a essas agendas, em uma perspectiva de promoção da justiça na educação no marco dos direitos humanos.

Investigating and Understanding Student Learning Outcomes in an Online and Face-to-Face Graduate Level Legal Administration Course: An Embedded Mixed Methods Design

Online education is a new teaching and learning medium with few current guidelines for faculty, administrators or students. Its rapid growth over the last decade has challenged academic institutions to keep up with the demand, while also providing a quality education. Our understanding of the factors that determine quality and effective online learning experiences that lead to student learning outcomes is still evolving. There is a lack of consensus on the effectiveness of online versus face-to-face education in the current research. The U.S. Department of Education conducted a meta-analysis in 2009 and concluded that student-learning outcomes in online courses were equal to and, often times, better than face-to-face traditional courses. Subsequent research has found contradictory findings, and further inquiry is necessary. The purpose of this embedded mixed methods design research study is to further our understanding of the factors that create quality and successful educational outcomes in an online course. To achieve this, the first phase of this study measured and compared learning outcomes in an online and in class graduate-level legal administration course. The second phase of the study entailed interviews with those students in both the online and face-to-face sections to understand their perspectives on the factors contributing to learning outcomes. Six themes emerged from the qualitative findings: convenience, higher order thinking, discussions, professor engagement, professor and student interaction, and face-to-face interaction. Findings from this study indicate the factors students perceive as contributing to learning outcomes in an online course are consistent among all students and are supported in the existing literature. Higher order thinking, however, emerged as a stronger theme than indicated in the current research, and the face-to-face nature of the traditional classroom may be more an issue of familiarity than a factor contributing to learning outcomes. As education continues to reach new heights and developments in technology advance, the factors found to contribute to student learning outcomes will be refined and enhanced. These developments will continue to transform the ways in which we deliver and receive knowledge in both traditional and online classrooms. While there is a growing body of research on online education, the field’s evolution has unsettled earlier findings and posed new areas to investigate.

Delphi study for the design and validation of a questionnaire about digital competences in higher education

The study of digital competence remains an issue of interest for both the scientific community and the supranational political agenda. This study uses the Delphi method to validate the design of a questionnaire to determine the perceived importance of digital competence in higher education. The questionnaire was constructed from different framework documents in digital competence standards (NETS, ACLR, UNESCO). The triangulation of non-parametric techniques made it possible to consolidate the results obtained through the Delphi panel, the suitability of which was highlighted through the expert competence index (K). The resulting questionnaire emerges as a good tool for undertaking future national and international studies on digital competence in higher education.

Co-design: setting relational domains for deep sustainability

This paper draws mainly on the work of Elizabeth Sanders who has being practising, thinking and mapping participatory design research for over 25 years, connecting it to insights from Maturana (1984), Capra (2002), Jovchelovitch (1995, 2000, 2007) and Preece (2011), to propose that the process of design per se is a relational domain of cocreativity that is essential to construct a way toward deeper sustainability.

A Minor Change?: A Case Study of Carleton Place's Integration of Minor Variance Procedures into Ontario's Development Permit System

The Development Permit System has been introduce with minimal directives for establishing a decision making process. This is in opposition to the long established process for minor variances and suggests that the Development Permit System does not necessarily incorporate all of Ontario’s fundamental planning principles. From this concept, the study aimed to identify how minor variances are incorporated into the Development Permit System. In order to examine this topic, the research was based around the following research questions: • How are ‘minor variance’ applications processed within the DPS? • To what extent do the four tests of a minor variance influence the outcomes of lower level applications in the DPS approval process? A case study approach was used for this research. The single-case design employed both qualitative and quantitative research methods including a review of academic literature, court cases, and official documents, as well as a content analysis of Class 1, 1A, and 2 Development Permit application files from the Town of Carleton Place that were decided between 2011 and 2015. Upon the completion of the content analysis, it was found that minor variance issues were most commonly assigned to Class 1 applications. Planning staff generally met approval timelines and embraced their delegated approval authority, readily attaching conditions to applications in order to mitigate off-site impacts. While staff met the regulatory requirements of the DPS, ‘minor variance’ applications were largely decided on impact alone, demonstrating that the principles established by the four tests, the defining quality of the minor variance approval process, had not transferred to the Development Permit System. Alternatively, there was some evidence that the development community has not fully adjusted to the requirements of the new approvals process, as some applications were supported using a rationale containing the four tests. Subsequently, a set of four recommendations were offered which reflect the main themes established by the findings. The first two recommendations are directed towards the Province, the third to municipalities and the fourth to developers and planning consultants: 1) Amend Ontario Regulation 608/06 so that provisions under Section 4(3)(e) fall under Section 4(2). 2) Change the rhetoric from “combining elements of minor variances” to “replacing minor variances”. 3) Establish clear evaluation criteria. 4) Understand the evaluative criteria of the municipality in which you are working.

The 2030 framework on climate and energy - Getting Europe on the right track? EPC Commentary, 30 January 2014

Climate vs competitiveness? The European Commission published its proposal on the 2030 climate and energy framework on 22 January. Reflective of the current economic climate, it was accompanied by a report on energy prices and the Commission decided not to propose regulation on shale gas but to issue recommendations on environmental standards. The same day also saw the publication of a communication “For a European Industrial Renaissance”. Climate considerations no longer drive the agenda. The enthusiasm of 2007, when the “20/20/20” climate and energy targets were set for 2020, has diminished. The new reality has brought competitiveness to the top of the EU’s priority agenda.

Will this time be different for Greece? How to assess its ability to deliver on the reform agenda. CEPS Commentary, 13 March 2015

Taking its inspiration from the ongoing debate on whether this time will be different for Greece and whether Syriza will deliver on its reform promises to the European partners, this Commentary expresses bemusement that the public debate on such an important issue as well as internal discussions among senior policy-makers frequently resort to ‘gut feelings’ or simple stereotypes. To counteract this tendency, the author presents a simple analytical framework that can be used to assess the likelihood that a government will deliver on its reform agenda. Its purpose is not to allow for a precise probabilistic calculation, but to enable better structuring of the knowledge we have. It emphasises that the change depends NOT only on the capacity of the state to design and deliver policies, but even more crucially on state autonomy from both illegitimate and legitimate interests and cognitive models used by policy-makers to make sense of the world.

Towards the social inclusion of youth: Tools for analysis and policy design

The integration of youth into development processes is crucial in order to advance towards more egalitarian societies. Over the past few years, the Economic Commission for Latin America and the Caribbean (ECLAC) has regarded equality as the horizon for development, structural change as the way to achieve it, and policy as the instrument to reach that horizon. Equality is viewed as going beyond the distribution of means, such as monetary income, to include equal opportunities and capacities. This implies understanding equality as the full exercise of citizenship, with dignity and the reciprocal recognition of actors. Progress in this direction requires policies that promote the autonomy of subjects and pay attention to their vulnerabilities.

The International Consortium on Mental Health Policy and Services: objectives, design and project implementation

The concept of the burden of disease, introduced and estimated for a broad range of diseases in the World Bank report of 1993 illustrated that mental and neurological disorders not only entail a higher burden than cancer, but are responsible, in developed and developing countries, for more than 15% of the total burden of all diseases. As a consequence, over the past decade, mental disorders have ranked increasingly highly on the international agenda for health. However, the fact that mental health and nervous system disorders are now high on the international health agenda is by no means a guarantee that the fate of patients suffering from these disorders in developing countries will improve. In most developing countries the treatment gap for mental and neurological disorders is still unacceptably high. To address this problem, an international network of collaborating institutions in low-income countries has been set up. The establishment and the achievements of this network-the International Consortium on Mental Health Policy and Services-are reported. Sixteen institutions in developing countries collaborate (supported by a small number of scientific resource centres in industrialized nations) in projects on applied mental health systems research. Over a two-year period, the network produced the key elements of a national mental health policy; provided tools and methods for assessing a country's current mental health status (context, needs and demands, programmes, services and care and outcomes); established a global network of expertise, i.e., institutions and experts, for use by countries wishing to reform their mental health policy, services and care; and generated guidelines and examples for upgrading mental health policy with due regard to the existing mental health delivery system and demographic, cultural and economic factors.

The role of software tools in influencing creative problem solving in engineering design and education

Creativity is increasingly recognised as an essential component of engineering design. This paper describes an exploratory study into the nature and importance of creativity in engineering design problem solving in relation to the possible impact of software design tools. The first stage of the study involved an empirical investigation in the form of a case study of the use of standard CAD tool sets and the development of a systems engineering software support tool. It was found that there were several ways in which CAD influenced the creative process, including enhancing visualisation and communication, premature fixation, circumscribed thinking and bounded ideation. The tool development experience uncovered the difficulty in supporting creative processes from the developer's perspective. The issues were the necessity of making assumptions, achieving a balance between structure and flexibility, and the pitfalls of satisfying user wants and needs. The second part of the study involved the development of a model of the creative problem solving process in engineering design. This provided a possible explanation for why purpose designed engineering software tools might encourage an analytical problem solving approach and discourage a more creative approach.