Lack of tissue glucocorticoid reactivation in 11β-hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) intracellularly regenerates active corticosterone from circulating inert 11-dehydrocorticosterone (11-DHC) in specific tissues. The hippocampus is a brain structure particularly vulnerable to glucocorticoid neurotoxicity with aging. In intact hippocampal cells in culture, 11β-HSD-1 acts as a functional 11β-reductase reactivating inert 11-DHC to corticosterone, thereby potentiating kainate neurotoxicity. We examined the functional significance of 11β-HSD-1 in the central nervous system by using knockout mice. Aged wild-type mice developed elevated plasma corticosterone levels that correlated with learning deficits in the watermaze. In contrast, despite elevated plasma corticosterone levels throughout life, this glucocorticoid-associated learning deficit was ameliorated in aged 11β-HSD-1 knockout mice, implicating lower intraneuronal corticosterone levels through lack of 11-DHC reactivation. Indeed, aged knockout mice showed significantly lower hippocampal tissue corticosterone levels than wild-type controls. These findings demonstrate that tissue corticosterone levels do not merely reflect plasma levels and appear to play a more important role in hippocampal functions than circulating blood levels. The data emphasize the crucial importance of local enzymes in determining intracellular glucocorticoid activity. Selective 11β-HSD-1 inhibitors may protect against hippocampal function decline with age.

Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.

Mutations in the genes encoding two proteins of the retinal rod phototransduction cascade, opsin and the beta subunit of rod cGMP phosphodiesterase, cause retinitis pigmentosa (RP) in some families. Here we report defects in a third member of this biochemical pathway in still other patients with this disease. We screened 94 unrelated patients with autosomal dominant RP and 173 unrelated patients with autosomal recessive RP for mutations in the gene encoding the alpha subunit of the rod cGMP-gated cation channel. Five mutant sequences cosegregated with disease among four unrelated families with autosomal recessive RP. Two of these were nonsense mutations early in the reading frame (Glu76End and Lys139End) and one was a deletion encompassing most if not all of the transcriptional unit; these three alleles would not be expected to encode a functional channel. The remaining two mutations were a missense mutation (Ser316Phe) and a frameshift [Arg654(1-bp del)] mutation truncating the last 32 aa in the C terminus. The latter two mutations were expressed in vitro and found to encode proteins that were predominantly retained inside the cell instead of being targeted to the plasma membrane. We conclude that the absence or paucity of functional cGMP-gated cation channels in the plasma membrane is deleterious to rod photoreceptors and is an uncommon cause of RP.

On formality of Sasakian manifolds

We investigate some topological properties, in particular formality, of compact Sasakian manifolds. Answering some questions raised by Boyer and Galicki, we prove that all higher (than three) Massey products on any compact Sasakian manifold vanish. Hence, higher Massey products do obstruct Sasakian structures. Using this, we produce a method of constructing simply connected K-contact non-Sasakian manifolds. On the other hand, for every n > 3, we exhibit the first examples of simply connected compact Sasakian manifolds of dimension 2n + 1 that are non-formal. They are non-formal because they have a non-zero triple Massey product. We also prove that arithmetic lattices in some simple Lie groups cannot be the fundamental group of a compact Sasakian manifold.

Sentidos de solidariedade

A solidariedade ressurge, na contemporaneidade, como valor ético e princípio jurídico, envolvendo o desafio da responsabilidade para com o outro. Torna-se fundamental, assim, investigar os diversos sentidos de solidariedade, a qual se mostra relevante para a construção de um espaço comum, marcado pelo respeito à pluralidade e destinado a uma eficaz proteção aos necessitados. Um dos princípios norteadores deste trabalho é a indagação acerca de até onde estamos dispostos a financiar um sistema fundado no princípio da solidariedade. Outro questionamento também se revela essencial: seria preciso buscar, em alguma esfera de transcendência, motivações possíveis para a solidariedade num mundo pós-moderno que parece primar pelo individualismo exacerbado? Na busca por respostas, delineia-se um sentido específico do humano, voltado à responsabilidade para com o outro, sobretudo para com aquele que é estranho, estrangeiro, diferente. A solidariedade, para além da mera noção de tolerância que incorpora a diferença, exige um compromisso coletivo. Alcançar a plenitude polissêmica da solidariedade passa pelo esforço de valorizar a diversidade humana, de modo a viabilizar o agir conjunto, pressuposto basilar da atitude política.

Equações de onda generalizadas e quantização funtorial para teorias de campo escalar livre

Nesta dissertação apresentamos um método de quantização matemática e conceitualmente rigoroso para o campo escalar livre de interações. Trazemos de início alguns aspéctos importantes da Teoria de Distribuições e colocamos alguns pontos de geometria Lorentziana. O restante do trabalho é dividido em duas partes: na primeira, estudamos equações de onda em variedades Lorentzianas globalmente hiperbólicas e apresentamos o conceito de soluções fundamentais no contexto de equações locais. Em seguida, progressivamente construímos soluções fundamentais para o operador de onda a partir da distribuição de Riesz. Uma vez estabelecida uma solução para a equação de onda em uma vizinhança de um ponto da variedade, tratamos de construir uma solução global a partir da extensão do problema de Cauchy a toda a variedade, donde as soluções fundamentais dão lugar aos operadores de Green a partir da introdução de uma condição de contorno. Na última parte do trabalho, apresentamos um mínimo da Teoria de Categorias e Funtores para utilizar esse formalismo na contrução de um funtor de segunda quantização entre a categoria de variedades Lorentzianas globalmente hiperbólicas e a categoria de redes de álgebras C* satisfazendo os axiomas de Haag-Kastler. Ao fim, retomamos o caso particular do campo escalar quântico livre.

Numerical modeling of electromagnetic coupling phenomena in the vicinities of overhead power transmission lines.

Electromagnetic coupling phenomena between overhead power transmission lines and other nearby structures are inevitable, especially in densely populated areas. The undesired effects resulting from this proximity are manifold and range from the establishment of hazardous potentials to the outbreak of alternate current corrosion phenomena. The study of this class of problems is necessary for ensuring security in the vicinities of the interaction zone and also to preserve the integrity of the equipment and of the devices there present. However, the complete modeling of this type of application requires the three- -dimensional representation of the region of interest and needs specific numerical methods for field computation. In this work, the modeling of problems arising from the flow of electrical currents in the ground (the so-called conductive coupling) will be addressed with the finite element method. Those resulting from the time variation of the electromagnetic fields (the so-called inductive coupling) will be considered as well, and they will be treated with the generalized PEEC (Partial Element Equivalent Circuit) method. More specifically, a special boundary condition on the electric potential is proposed for truncating the computational domain in the finite element analysis of conductive coupling problems, and a complete PEEC formulation for modeling inductive coupling problems is presented. Test configurations of increasing complexities are considered for validating the foregoing approaches. These works aim to provide a contribution to the modeling of this class of problems, which tend to become common with the expansion of power grids.

Análise de incerteza de um sistema automatizado para ensaios de aspersores de irrigação

Ensaios de distribuição de água de aspersores são convencionalmente realizados manualmente, requerendo tempo e mão de obra treinada. A automação desses ensaios proporciona redução da demanda por esses recursos e apresenta potencial para minimizar falhas e/ou desvios de procedimento. Atualmente, laboratórios de ensaio e calibração acreditados junto a organismos legais devem apresentar em seus relatórios a incerteza de medição de seus instrumentos e sistemas de medição. Além disso, normas de ensaio e calibração apresentam especificação de incerteza aceitável, como a norma de ensaios de distribuição de água por aspersores, ISO 15886-3 (2012), a qual exige uma incerteza expandida de até 3% em 80% dos coletores. Os objetivos deste trabalho foram desenvolver um sistema automatizado para os ensaios de aspersores em laboratório e realizar a análise de incerteza de medição, para sua quantificação nos resultados de ensaio e para dar suporte ao dimensionamento dos tubos de coleta. O sistema automático foi constituído por um subsistema de gerenciamento, por meio de um aplicativo supervisório, um de pressurização e um de coleta, por meio de módulos eletrônicos microprocessados desenvolvidos. De acordo com instruções do sistema de gerenciamento o sistema de pressurização ajustava a pressão no aspersor por meio do controle da rotação da motobomba, e o sistema de coleta realizava a medição da intensidade de precipitação de água ao longo do raio de alcance do aspersor. A água captada por cada coletor drenava para um tubo de coleta, que estava conectado a uma das válvulas solenoides de um conjunto, onde havia um transmissor de pressão. Cada válvula era acionada individualmente numa sequência para a medição do nível de água em cada tubo de coleta, por meio do transmissor. Por meio das análises realizadas, as menores incertezas foram obtidas para os menores diâmetros de tubo de coleta, sendo que se deve utilizar o menor diâmetro possível. Quanto ao tempo de coleta, houve redução da incerteza de medição ao se aumentar a duração, devendo haver um tempo mínimo para se atingir a incerteza-alvo. Apesar de cada intensidade requer um tempo mínimo para garantir a incerteza, a diferença mínima de nível a ser medida foi a mesma. Portanto, para os ensaios visando atender a incerteza, realizou-se o monitoramento da diferença de nível nos tubos, ou diferença de nível, facilitando a realização do ensaio. Outra condição de ensaio considerou um tempo de coleta para 30 voltas do aspersor, também exigido pela norma ISO 15886-3 (2012). A terceira condição considerou 1 h de coleta, como tradicionalmente realizado. As curvas de distribuição de água obtidas por meio do sistema desenvolvido foram semelhantes às obtidas em ensaios convencionais, para as três situações avaliadas. Para tempos de coleta de 1 h ou 30 voltas do aspersor o sistema automático requereu menos tempo total de ensaio que o ensaio convencional. Entretanto, o sistema desenvolvido demandou mais tempo para atingir a incerteza-alvo, o que é uma limitação, mesmo sendo automatizado. De qualquer forma, o sistema necessitava apenas que um técnico informasse os parâmetros de ensaio e o acionasse, possibilitando que o mesmo alocasse seu tempo em outras atividades.

3D-based reconstruction using growing neural gas landmark: application to rapid prototyping in shoe last manufacturing

Customizing shoe manufacturing is one of the great challenges in the footwear industry. It is a production model change where design adopts not only the main role, but also the main bottleneck. It is therefore necessary to accelerate this process by improving the accuracy of current methods. Rapid prototyping techniques are based on the reuse of manufactured footwear lasts so that they can be modified with CAD systems leading rapidly to new shoe models. In this work, we present a shoe last fast reconstruction method that fits current design and manufacturing processes. The method is based on the scanning of shoe last obtaining sections and establishing a fixed number of landmarks onto those sections to reconstruct the shoe last 3D surface. Automated landmark extraction is accomplished through the use of the self-organizing network, the growing neural gas (GNG), which is able to topographically map the low dimensionality of the network to the high dimensionality of the contour manifold without requiring a priori knowledge of the input space structure. Moreover, our GNG landmark method is tolerant to noise and eliminates outliers. Our method accelerates up to 12 times the surface reconstruction and filtering processes used by the current shoe last design software. The proposed method offers higher accuracy compared with methods with similar efficiency as voxel grid.

3D reconstruction of medical images from slices automatically landmarked with growing neural models

In this study, we utilise a novel approach to segment out the ventricular system in a series of high resolution T1-weighted MR images. We present a brain ventricles fast reconstruction method. The method is based on the processing of brain sections and establishing a fixed number of landmarks onto those sections to reconstruct the ventricles 3D surface. Automated landmark extraction is accomplished through the use of the self-organising network, the growing neural gas (GNG), which is able to topographically map the low dimensionality of the network to the high dimensionality of the contour manifold without requiring a priori knowledge of the input space structure. Moreover, our GNG landmark method is tolerant to noise and eliminates outliers. Our method accelerates the classical surface reconstruction and filtering processes. The proposed method offers higher accuracy compared to methods with similar efficiency as Voxel Grid.

Geometry of Dirac Operators

Thesis (Master, Mathematics & Statistics) -- Queen's University, 2016-07-04 20:27:20.386

The need for a New Pact. CHALLENGE EUROPE Issue 22 - Challenges and new beginnings: Priorities for the EU’s new leadership, September 2014.

During the last political cycle (2009-2014), the European Union (EU) went through the worst crisis of its history. In the months and years to come, the new EU leadership and Member States will have to take major decisions if Europeans want to sustainably overcome the crisis, prepare themselves for the manifold internal and external tests ahead, and provide the grounds for Europe to exploit more of its potential and meet the needs and expectations of citizens. The outcome of this venture is unclear considering the 'state of the Union' and the current mood in Brussels and national capitals. But one thing seems rather certain: to generate active support from citizens and elites, future developments at European and national level need to be driven by confidence and renewed ambition and not, as in the past years, by fear first – fear of a euro implosion; or of an involuntary exit from the common currency with unforeseeable consequences. In order to take strategic decisions about the Union's future, there is a need to identify and address the key challenge(s) and provide a coherent and holistic response on the grounds of an ambitious but at the same time pragmatic 'package deal', taking into account the diverging interests of Member States and their citizens. But what is the state of affairs, what is the key strategic challenge and how can the new EU leadership cope with it in the next political cycle (2014-2019)?

Mutual recognition in goods and services: an economic perspective. Bruges European Economic Policy (BEEP) Briefing 2/2002

Mutual recognition is a remarkable innovation facilitating economic intercourse across borders. In the EU's internal goods market it has been helpful in tackling or avoiding the remaining obstacles, namely, regulatory barriers between Member States. However, there is a curious paradox. Despite the almost universal acclaim of the great merits of mutual recognition the principle has, in and by itself, contributed only modestly to the actual realisation of free movement in the single market. It is also surprising that economists have not or hardly underpinned their widespread appreciation for the principle by providing rigorous analysis which could substantiate the case for mutual recognition for policy makers. Business in Europe has shown a sense of disenc hantment with the principle because of the many costs and uncertainties in its application in actual practice. The purpose of the present paper is to provide the economic and strategic arguments for employing mutual recognition much more systematically in the single market for goods and services. The strategic and the "welfare" gains are analysed and adetailed exposition of the fairly high information , transaction and compliance costs is provided. The information costs derive from the fact that mutual recognition remains a distant abstraction for day-to-day business life. Understandably, verifying the "equivalence" of objectives of health and safety between Member States is perceived as difficult and uncertain. This sentiment is exacerbated by the complications of interpreting the equivalence of "effects". In actual practice, these abstractions are expected to override clear and specific national product or services rules, which local inspectors or traders may find problematic without guidance. The paper enumerates several other costs including, inter alia, the absence of sectoral rule books and the next-to-prohibitive costs of monitoring of the application of the principle. The basic problems in applying mutual recognition in the entire array of services are inspected, showing why the principle can only be used in a limited number of services markets and even there it may contribute only modestly to genuine free movement and competitive exposure. A special section is devoted to a range of practical illustrations of the difficulties business experiences when relying on mutual recognition. Finally, the corollary of mutual recognition - regulatory competition - is discussed in terms of a cost/benefits analysis compared to what is often said to be the alternative , that is "harmonisation" , in EU parlance the "new approach" to approximation. The conclusion is that the manifold benefits of mutual recognition for Europe are too great to allow the present ambiguities to continue. The Union needs much more pro-active approaches to reduce the costs of mutual recognition as well as permanent monitoring structures for its application to services (analogous to those already successfully functioning in goods markets). Above all, what is required is a "mutual recognition culture" so that the EU can better enjoy the fruits of its own regulatory ingenuity.

The Legal Status and Influence of Decisions of International Organizations and other Bodies in the European Union. College of Europe Research Paper in Law 01/2014

Introduction. The European Union’s external action is not only defined by its influence on international developments, but also by its ability and the need to respond to those developments. While traditionally many have stressed the EU’s ‘autonomy’, over the years its ‘dependence’ on global developments has become more clear.2 International law has continued to play a key role in, not only in the EU’s external relations, but also in the Union’s own legal order.3 The purpose of this paper is not to assess the role or performance of the EU in international institutions.4 Rather it purports to reverse the picture and focus on a somewhat under-researched topic: the legal status of decisions of international organizations in the EU’s legal order.5 While parts of the status of these decisions relate to the status of international agreements and international customary law, it can be argued that decisions of international organizations and other international bodies form a distinct category. In fact, it has been observed that “this phenomenon has added a new layer of complexity to the already complex law of external relations of the European Union”.6 Emerging questions relate to the possible difference between decisions of international organizations of which the EU is a member (such as the FAO) and decisions of organizations where it is not (irrespective of existing competences in that area – such as in the ILO). Questions also relate to the hierarchical status of these decisions in the EU’s legal order and to the possibility of them being invoked in direct or indirect actions before the Court of Justice. This contribution takes a broad perspective on decisions of international organizations by including decisions taken in other international institutions which do not necessarily comply with the standard definition of international organizations,7 be it bodies set-up by multilateral conventions or informal (transnational / regulatory) bodies. Some of these bodies are relatively close to the EU (such as the Councils established by Association Agreements – see further Section 5 below); others operate at a certain distance. Limiting the analysis to formal international organizations will not do justice to the manifold relationships between the European Union and various international bodies and to the effects of the norms produced by these bodies. The term ‘international decisions’ is therefore used to refer to any normative output of international institutional arrangements.

The refugee crisis: Schengen’s slippery slope. EPC Commentary, 22 September 2015

While the European Union (EU) is facing one of the most divisive crises in its history, the pressure to take immediate action is enormous. Yet, negotiations in the Council have shown that the prospect of a common European response to the manifold effects and underlying reasons of the refugee crisis still belongs to the distant future. Only a few days after Commission President Jean-Claude Juncker delivered his State of the Union address – avowing that Schengen will not be abolished under his term – national decisions to reintroduce temporary border controls are multiplying. Germany, one of the most ardent defenders of a borderless Union, decided to temporarily reinstate border checks. Austria and Slovenia came next. Slovakia, the Czech Republic, Poland, the Netherlands and France might follow.