Huntington's disease: new aspects on phenotype and genotype

Huntington's disease typically presents with involuntary movements, cognitive decline and behavioural abnormalities; however, new data show a greater spectrum and more complexity in the mode of presentation than previously appreciated. On one hand efforts are under way to better assess all aspects of the evolving phenotype over the course of the disease, on the other hand large cohorts have been prospectively followed-up and similar efforts are now being started in China. In this communication, we briefly review the most salient findings from the last couple of years. The recently established large cohorts allow the performance of accurate studies examining correlation of genetic polymorphisms with specific aspects of the phenotype thus allowing for some mechanistic insight into the causes of phenotypic variation. While Huntington's disease is the most frequent hereditary cause of chorea, other disorders with similar clinical phenotypes, including neuroacanthocytosis, are now better known, including a better understanding of the primary cause as well as the pathophysiology at the molecular level. Studies on the mechanisms of disease in these different disorders may shed light on the respective pathomechanisms and may open new approaches to a better understanding and additional treatment options for choreatiform neurodegenerative disorders.

Landscapes of Education and the New Role of Social Work International Models of How to Combine Formal, Non-formal and Informal Education

Landscapes of education are a new topic within the debate about adequate and just education and human development for everybody. In particular, children and youths from social classes affected by poverty, a lack of prospects or minimal schooling are a focal group that should be offered new approaches and opportunities of cognitive and social development by way of these landscapes of education. It has become apparent that the traditional school alone does not suffice to meet this need. There is no doubt that competency-based orientation and employability are core areas with the help of which the generation now growing up will manage the start of its professional career. In addition and by no means less important, the development involves individual, social, cultural and societal perspectives that can be combined under the term of human development. In this context, the Capability Approach elaborated by Amartya Sen and Martha Nussbaum has developed a more extensive concept of human development and related it to empirical instruments. Using the analytic concept of individual capabilities and societal opportunities they shaped a socio-political formula that should be adapted in particular to modern social work. Moreover, the Capability Approach offers a critical foil with regard to further development and revision of institutionalised approaches in education and human development.

THE NEW ROLE OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9: A CONNECTION OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9, APOLIPOPROTEIN B, and AUTOPHAGY

Plasma low-density lipoprotein (LDL) levels are positively correlated with the incidence of coronary artery disease. In the circulation, the plasma LDL clearance is mainly achieved by the uptake via LDL receptor (LDLR). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a newly discovered gene, playing an important role in LDL metabolism. Gain-of-function mutations of PCSK9 lead to hypercholesterolemia and loss-of-function mutations of PCSK9 are associated with decrease of LDL cholesterol. The effects of PCSK9 on cholesterol levels are the consequence of a strong interaction between the catalytic domain of PCSK9 and epidermal growth factor-like repeat A (EGF-A) domain of LDLR on the cell surface of hepatocytes. This PCSK9/LDLR complex enters the cell via endocytosis, where both PCSK9 and LDLR are removed via the lysosome pathway, resulting in decreased levels of LDLR and accumulation of LDL in the plasma. However, whether this is the exclusive function of PCSK9 on LDL metabolism was challenged by us; we observed PCSK9 interacted with apolipoprotein B (apoB) and increased apoB production, irrespective of the LDLR. ApoB is the primary structure protein of LDL particle and it also serves as the ligand for the LDL receptor. There is ample evidence showing that the levels of apoB are a better indicator for heart disease than either total cholesterol or LDL cholesterol levels. We used a second-generation adenoviral vector to overexpress PCSK9 (Ad-PCSK9) in wild-type C57BL/6 and LDLR deficient mice (Ldlr-/- and Ldlr-/-Apobec1-/-). Our study revealed that overexpression of PCSK9 promoted the production and secretion of apoB in the form of very-low density lipoprotein (VLDL), which is the precursor of LDL, in the 3 mouse models studied (C57BL/6J, Ldlr-/-, and Ldlr-/-Apobec1-/-). The increased apoB production in mice was regulated at post-transcriptional levels, since there was no difference in apoB mRNA levels between mice treated with Ad-PCSK9 and control vector Ad-Null. By using pulse-chase experiment on primary hepatocytes, we showed that overexpression of PCSK9 increased the secretion of apoB, independent of LDLR. In the circulation, we showed that PCSK9 was associated with LDL particles. By using 3 different protein–protein interaction assays of co-immunoprecipitation, mammalian two-hybrid system, and in situ proximity ligation assay, we demonstrated a direct protein–protein interaction between PCSK9 and apoB. The impact of this interaction inhibited the physiological removal process of apoB via autophagosome/lysosome pathway in an LDLR-independent fashion, resulting in increased production and secretion of apoB-containing lipoproteins. The significance of this process was shown in the Pcsk9 knockout mice in the background of Ldlr-/-Apobec1-/- mice (triple knockout mice); in the absence of Pcsk9 (triple knockout mice) the levels of cholesterol, triacylglycerol, and apoB decreased significantly in comparison to that of Ldlr-/-Apobec1-/- mice. Taken together, our study demonstrated a direct intracellular interaction of PCSK9 with apoB, resulting in the inhibition of apoB degradation via the autophagosome/lysosome pathway independent of LDLR. This discovery provides a new concept of the importance of PCSK9 and suggests new approaches for the therapeutic intervention of hyperlipidemia.

New methods for the estimation of Takagi-Sugeno model based extended Kalman filter and its applications to optimal control for nonlinear systems

This paper describes new approaches to improve the local and global approximation (matching) and modeling capability of Takagi–Sugeno (T-S) fuzzy model. The main aim is obtaining high function approximation accuracy and fast convergence. The main problem encountered is that T-S identification method cannot be applied when the membership functions are overlapped by pairs. This restricts the application of the T-S method because this type of membership function has been widely used during the last 2 decades in the stability, controller design of fuzzy systems and is popular in industrial control applications. The approach developed here can be considered as a generalized version of T-S identification method with optimized performance in approximating nonlinear functions. We propose a noniterative method through weighting of parameters approach and an iterative algorithm by applying the extended Kalman filter, based on the same idea of parameters’ weighting. We show that the Kalman filter is an effective tool in the identification of T-S fuzzy model. A fuzzy controller based linear quadratic regulator is proposed in order to show the effectiveness of the estimation method developed here in control applications. An illustrative example of an inverted pendulum is chosen to evaluate the robustness and remarkable performance of the proposed method locally and globally in comparison with the original T-S model. Simulation results indicate the potential, simplicity, and generality of the algorithm. An illustrative example is chosen to evaluate the robustness. In this paper, we prove that these algorithms converge very fast, thereby making them very practical to use.

Nanoinformatics: developing new computing applications for nanomedicine

Nanoinformatics has recently emerged to address the need of computing applications at the nano level. In this regard, the authors have participated in various initiatives to identify its concepts, foundations and challenges. While nanomaterials open up the possibility for developing new devices in many industrial and scientific areas, they also offer breakthrough perspectives for the prevention, diagnosis and treatment of diseases. In this paper, we analyze the different aspects of nanoinformatics and suggest five research topics to help catalyze new research and development in the area, particularly focused on nanomedicine. We also encompass the use of informatics to further the biological and clinical applications of basic research in nanoscience and nanotechnology, and the related concept of an extended ?nanotype? to coalesce information related to nanoparticles. We suggest how nanoinformatics could accelerate developments in nanomedicine, similarly to what happened with the Human Genome and other -omics projects, on issues like exchanging modeling and simulation methods and tools, linking toxicity information to clinical and personal databases or developing new approaches for scientific ontologies, among many others.

VR BioViewer - A new interactive-visual model to represent medical information

Virtual reality (VR) techniques to understand and obtain conclusions of data in an easy way are being used by the scientific community. However, these techniques are not used frequently for analyzing large amounts of data in life sciences, particularly in genomics, due to the high complexity of data (curse of dimensionality). Nevertheless, new approaches that allow to bring out the real important data characteristics, arise the possibility of constructing VR spaces to visually understand the intrinsic nature of data. It is well known the benefits of representing high dimensional data in tridimensional spaces by means of dimensionality reduction and transformation techniques, complemented with a strong component of interaction methods. Thus, a novel framework, designed for helping to visualize and interact with data about diseases, is presented. In this paper, the framework is applied to the Van't Veer breast cancer dataset is used, while oncologists from La Paz Hospital (Madrid) are interacting with the obtained results. That is to say a first attempt to generate a visually tangible model of breast cancer disease in order to support the experience of oncologists is presented.

Social inclusion, new regionalism and associational governance: The Queensland experience

In recent years there has been a resurgence of decentralized social governance concerned with the spatial dimensions of disadvantage. This article examines aspects of this resurgence in the Australian state of Queensland where, after the hasty birth of 'place management' in response to the rise of 'Hansonism', a plethora of 'joined-up' policy initiatives were undertaken in relation to the regional dimensions of poverty. We propose that these trends reflect in part new ways of thinking about the spatial aspects of disadvantage which have emerged in recent years and which have the potential to take regional policy beyond the narrow confines imposed by neoliberal economic orthodoxy. These new ways of thinking have arisen in social policy through the refraining of disadvantage in terms of social exclusion and in regional economic policy through the influence of the so-called 'new regionalism'. The article shows how together these bodies of theory point us towards a new model of 'associational governance'. The article reviews recent Queensland experience and indicates those features of 'associational governance' which have become characteristic of locality-based social policy ideas in Queensland. 'Joined-up' and regional policy aspirations of the Queensland State government have shown the influence of these new approaches. The political and policy sustainability of these trends, however, is uncertain. The lingering shadow of managerialism and neoliberal policy frameworks remains a significant barrier to the innovation and viability of these approaches. More directly, the inherent limits of the 'local' or 'regional' initiatives in the face of broader national and global factors will significantly constrain the capacity of associational governance systems to deliver positive democratic, social and economic outcomes. The article examines recent Queensland policy refors in light of this complex set of factors and concludes by offering directions for future research and policy development.

ProxiMAX randomisation:a new technology for non-degenerate saturation mutagenesis of contiguous codons

Back in 2003, we published ‘MAX’ randomisation, a process of non-degenerate saturation mutagenesis using exactly 20 codons (one for each amino acid) or else any required subset of those 20 codons. ‘MAX’ randomisation saturates codons located in isolated positions within a protein, as might be required in enzyme engineering, or else on one face of an alpha-helix, as in zinc finger engineering. Since that time, we have been asked for an equivalent process that can saturate multiple, contiguous codons in a non-degenerate manner. We have now developed ‘ProxiMAX’ randomisation, which does just that: generating DNA cassettes for saturation mutagenesis without degeneracy or bias. Offering an alternative to trinucleotide phosphoramidite chemistry, ProxiMAX randomisation uses nothing more sophisticated than unmodified oligonucleotides and standard molecular biology reagents. Thus it requires no specialised chemistry, reagents nor equipment and simply relies on a process of saturation cycling comprising ligation, amplification and digestion for each cycle. The process can encode both unbiased representation of selected amino acids or else encode them in pre-defined ratios. Each saturated position can be defined independently of the others. We demonstrate accurate saturation of up to 11 contiguous codons. As such, ProxiMAX randomisation is particularly relevant to antibody engineering.

Charting new territory for organizational ethnography:insights from a team-based video ethnography of reinsurance trading in Lloyd’s of London

An increasing interest in “bringing actors back in” and gaining a nuanced understanding of their actions and interactions across a variety of strands in the management literature, has recently helped ethnography to unknown prominence in the field of organizational studies. Yet, calls remain that ethnography should “play a much more central role in the organization and management studies repertoire than it currently does” (Watson, 2011: 202). Ironically, those organizational realities that ethnographers are called to examine have at the same time become less and less amenable to ethnographic study. In this paper, we respond to these calls for innovative ethnographic methods in two ways. First, we report on the practices and ethnographic experiences of conducting a year-long team-based video ethnography of reinsurance trading in Lloyd’s of London. Second, drawing on these experiences, we propose an initial framework for systematizing new approaches to organizational ethnography and visualizing the ways in which they are ‘expanding’ ethnography as it was traditionally practiced.

Evaluation of approaches to estimate fish catches on Lake Victoria: a case study using CAS and frame data from Uganda

Since 2005, harmonized catch assessment surveys (CASs) have been implemented on Lake Victoria in the three riparian countries Uganda, Kenya, and Tanzania to monitor the commercial fish stocks and provide their management advice. The regionally harmonized standard operating procedures for CASs have not been wholly followed due to logistical difficulties. Yet the new approaches adopted have not been documented. This study investigated the alternative approaches used to estimate fish catches on the lake with the aim of determining the most reliable one for providing management advice and also the effect of current sampling routine on the precision of catch estimates provided. The study found the currently used lake-wide approach less reliable and more biased in providing catch estimates compared to the district based approach. Noticeable differences were detected in catch estimates between different months of the year. The study recommends future analyses of CAS data collected on the lake to follow the district based approach. Future CASs should also consider seasonal variations in the sampling design by providing for replication of sampling. The SOPs need updating to document the procedures that deviate from the original sampling design.

Climate Adaptation Finance Mechanisms: New Frontiers For Familiar Tools

Demands for mechanisms to pay for adaptation to climate risks have multiplied rapidly as concern has shifted from greenhouse gas mitigation alone to also coping with the now-inevitable impacts. A number of viable approaches to how to pay for those adjustments to roads, drainage systems, lifeline utilities and other basic infrastructure are emerging, though untested at the scale required across the nation, which already has a trillion-dollar deferred maintenance and replacement problem. There are growing efforts to find new ways to harness private financial resources via new market arrangements to meet needs that clearly outstrip public resources alone, as well as to utilize and combine public resources more effectively. To date, mechanisms are often seen through a specific lens of scale, time, and method, for example national versus local and public versus market-based means. The purpose here is to integrate a number of those perspectives and also to highlight the following in particular. Current experience with seemingly more pedestrian needs like stormwater management funding is in fact a learning step towards new approaches for broader adaptation needs, using re-purposed but existing fiscal tools. The resources raised from new large-scale market approaches for using catastrophe- and resiliency-bond-derived funds will have their use embodied and operationalized in many separate local and state projects. The invention and packaging of innovative projects—the pre-development phase—will be pivotal to better using fiscal resources of many types. Those efforts can be greatly aided or hindered by larger national and especially state government policy, regulatory and capital market arrangements. Understanding the path to integration of effort across these scales deserves much more attention. Examples are given of how federal, state and local roles are each dimensions of that frontier, how existing tools can apply in new ways and how smart project creation plays a role.

Escola Nacional de Educação Fisica e Desportos : uma possivel historia

Universidade Estadual de Campinas . Faculdade de Educação Física

Contribution Of Antepartum And Intrapartum Hemorrhage To The Burden Of Maternal Near Miss And Death In A National Surveillance Study

Objective To evaluate the occurrence of severe obstetric complications associated with antepartum and intrapartum hemorrhage among women from the Brazilian Network for Surveillance of Severe Maternal Morbidity.Design Multicenter cross-sectional study.Setting Twenty-seven obstetric referral units in Brazil between July 2009 and June 2010.Population A total of 9555 women categorized as having obstetric complications.Methods The occurrence of potentially life-threatening conditions, maternal near miss and maternal deaths associated with antepartum and intrapartum hemorrhage was evaluated. Sociodemographic and obstetric characteristics and the use of criteria for management of severe bleeding were also assessed in these women.Main outcome measures The prevalence ratios with their respective 95% confidence intervals adjusted for the cluster effect of the design, and multiple logistic regression analysis were performed to identify factors independently associated with the occurrence of severe maternal outcome.Results Antepartum and intrapartum hemorrhage occurred in only 8% (767) of women experiencing any type of obstetric complication. However, it was responsible for 18.2% (140) of maternal near miss and 10% (14) of maternal death cases. On multivariate analysis, maternal age and previous cesarean section were shown to be independently associated with an increased risk of severe maternal outcome (near miss or death).Conclusion Severe maternal outcome due to antepartum and intrapartum hemorrhage was highly prevalent among Brazilian women. Certain risk factors, maternal age and previous cesarean delivery in particular, were associated with the occurrence of bleeding.

Dopamina, óxido nítrico e suas interações em modelos para o estudo da esquizofrenia

Modelos experimentais baseados no aumento da neurotransmissão dopaminérgica mimetizam aspectos comportamentais e neuroquímicos característicos da esquizofrenia. Psicoestimulantes, como a anfetamina, são utilizados com esta finalidade, pois aumentam os níveis de dopamina extracelular nas vias mesocorticolímbica e mesoestriatal. As limitações da manipulação direta do sistema dopaminérgico nos modelos animais incentivam abordagens complementares. O óxido nítrico (NO), um neurotransmissor atípico que inibe a recaptação de dopamina e estimula sua liberação, parece modular comportamentos controlados pelo sistema dopaminérgico. O teste de inibição pré-pulso revela uma deficiência no filtro sensório-motor, verificada em esquizofrênicos ou após tratamentos com psicotomiméticos, podendo ser prevenida pela inibição do NO. Esta revisão apresenta evidências da interação do NO com o sistema dopaminérgico em modelos para o estudo da esquizofrenia como uma nova ferramenta de investigação desta patologia.

A frequency approach to identifying asteroid families II. Families interacting with nonlinear secular resonances and low-order mean-motion resonances

Aims. In an earlier paper we introduced a new method for determining asteroid families where families were identified in the proper frequency domain (n, g, g + s) ( where n is the mean-motion, and g and s are the secular frequencies of the longitude of pericenter and nodes, respectively), rather than in the proper element domain (a, e, sin(i)) (semi-major axis, eccentricity, and inclination). Here we improve our techniques for reliably identifying members of families that interact with nonlinear secular resonances of argument other than g or g + s and for asteroids near or in mean-motion resonant configurations. Methods. We introduce several new distance metrics in the frequency space optimal for determining the diffusion in secular resonances of argument 2g - s, 3g - s, g - s, s, and 2s. We also regularize the dependence of the g frequency as a function of the n frequency (Vesta family) or of the eccentricity e (Hansa family). Results. Our new approaches allow us to recognize as family members objects that were lost with previous methods, while keeping the advantages of the Carruba & Michtchenko (2007, A& A, 475, 1145) approach. More important, an analysis in the frequency domain permits a deeper understanding of the dynamical evolution of asteroid families not always obtainable with an analysis in the proper element domain.