Rescue of gene expression by modified REST decoy oligonucleotides in a cellular model of Huntington's disease

Transcriptional dysfunction is a prominent hallmark of Huntington's disease (HD). Several transcription factors have been implicated in the aetiology of HD progression and one of the most prominent is repressor element 1 (RE1) silencing transcription factor (REST). REST is a global repressor of neuronal gene expression and in the presence of mutant Huntingtin increased nuclear REST levels lead to elevated RE1 occupancy and a concomitant increase in target gene repression, including brain-derived neurotrophic factor. It is of great interest to devise strategies to reverse transcriptional dysregulation caused by increased nuclear REST and determine the consequences in HD. Thus far, such strategies have involved RNAi or mutant REST constructs. Decoys are double-stranded oligodeoxynucleotides corresponding to the DNA-binding element of a transcription factor and act to sequester it, thereby abrogating its transcriptional activity. Here, we report the use of a novel decoy strategy to rescue REST target gene expression in a cellular model of HD. We show that delivery of the decoy in cells expressing mutant Huntingtin leads to its specific interaction with REST, a reduction in REST occupancy of RE1s and rescue of target gene expression, including Bdnf. These data point to an alternative strategy for rebalancing the transcriptional dysregulation in HD.

The outsourcing strategy of local and multinational firms: A supply base perspective

Firms outsource through connecting to local and global supply bases and making such connections produces costs of search and evaluation, which are a function of transaction characteristics and firm capabilities. We argue that firms outsource more when those costs are low. Hence, domestic subsidiaries of multinational firms, with low cost access to both local and global supply bases, outsource more than either domestic firms or foreign subsidiaries, as confirmed by evidence from a large data panel. We also propose that among foreign subsidiaries, distance from the home country co-determines search and evaluation costs such that subsidiaries from more distant countries outsource less. This is confirmed for geographic distance, but a positive effect is found for political distance and a mixed effect for cultural distance.

Capturing and sharing our collective expertise on climate data: the CHARMe project

For users of climate services, the ability to quickly determine the datasets that best fit one's needs would be invaluable. The volume, variety and complexity of climate data makes this judgment difficult. The ambition of CHARMe ("Characterization of metadata to enable high-quality climate services") is to give a wider interdisciplinary community access to a range of supporting information, such as journal articles, technical reports or feedback on previous applications of the data. The capture and discovery of this "commentary" information, often created by data users rather than data providers, and currently not linked to the data themselves, has not been significantly addressed previously. CHARMe applies the principles of Linked Data and open web standards to associate, record, search and publish user-derived annotations in a way that can be read both by users and automated systems. Tools have been developed within the CHARMe project that enable annotation capability for data delivery systems already in wide use for discovering climate data. In addition, the project has developed advanced tools for exploring data and commentary in innovative ways, including an interactive data explorer and comparator ("CHARMe Maps") and a tool for correlating climate time series with external "significant events" (e.g. instrument failures or large volcanic eruptions) that affect the data quality. Although the project focuses on climate science, the concepts are general and could be applied to other fields. All CHARMe system software is open-source, released under a liberal licence, permitting future projects to re-use the source code as they wish.

Auriculo-condylar syndrome: mapping of a first locus and evidence for genetic heterogeneity

Auriculo-condylar syndrome (ACS), an autosomal dominant disorder of first and second pharyngeal arches, is characterized by malformed ears (`question mark ears`), prominent cheeks, microstomia, abnormal temporomandibular joint, and mandibular condyle hypoplasia. Penetrance seems to be complete, but there is high inter-and intra-familial phenotypic variation, with no evidence of genetic heterogeneity. We herein describe a new multigeneration family with 11 affected individuals (F1), in whom we confirm intra-familial clinical variability. Facial asymmetry, a clinical feature not highlighted in other ACS reports, was highly prevalent among the patients reported here. The gene responsible for ACS is still unknown and its identification will certainly contribute to the understanding of human craniofacial development. No chromosomal rearrangements have been associated with ACS, thus mapping and positional cloning is the best approach to identify this disease gene. To map the ACS gene, we conducted linkage analysis in two large ACS families, F1 and F2 (F2; reported elsewhere). Through segregation analysis, we first excluded three known loci associated with disorders of first and second pharyngeal arches (Treacher Collins syndrome, oculo-auriculo-vertebral spectrum, and Townes-Brocks syndrome). Next, we performed a wide genome search and we observed evidence of linkage to 1p21.1-q23.3 in F2 (LOD max 3.01 at theta = 0). Interestingly, this locus was not linked to the phenotype segregating in F1. Therefore, our results led to the mapping of a first locus of ACS (ACS1) and also showed evidence for genetic heterogeneity, suggesting that there are at least two loci responsible for this phenotype.

OntoMap: an ontology-based architecture to perform the semantic mapping between an interlingua and software components

This paper is about the use of natural language to communicate with computers. Most researches that have pursued this goal consider only requests expressed in English. A way to facilitate the use of several languages in natural language systems is by using an interlingua. An interlingua is an intermediary representation for natural language information that can be processed by machines. We propose to convert natural language requests into an interlingua [universal networking language (UNL)] and to execute these requests using software components. In order to achieve this goal, we propose OntoMap, an ontology-based architecture to perform the semantic mapping between UNL sentences and software components. OntoMap also performs component search and retrieval based on semantic information formalized in ontologies and rules.

Russian Arctic Ports : Problems with the development and management of tourist flows

The potential changes to the territory of the Russian Arctic open up unique possibilities for the development of tourism. More favourable transport opportunities along the Northern Sea Route (NSR) create opportunities for tourism development based on the utilisation of the extensive areas of sea shores and river basins. A major challenge for the Russian Arctic sea and river ports is their strong cargo transport orientation originated by natural resource extraction industries. A careful assessment of the prospects of current and future tourism development is presented here based on the development of regions located along the shores of the Arctic ocean (including Murmansk and Arkhangelsk oblast, Nenets Autonomous okrug (AO), Yamal-Nenets AO, Taymyr AO, Republic of Sakha, Chykotsky AO). An evaluation of the present development of tourism in maritime cities suggests that a considerable qualitative and quantitative increase of tourism activities organised by domestic tourism firms is made virtually impossible. There are several factors contributing to this. The previously established Soviet system of state support for the investments into the port facilities as well as the sea fleet were not effectively replaced by creation of new structures. The necessary investments for reconstruction could be contributed by the federal government but the priorities are not set towards the increased passenger transportation. Having in mind, increased environmental pressures in this highly sensitive area it is especially vital to establish a well-functioning monitoring and rescue system in the situation of ever increasing risks which come not only from the increased transports along the NSR, but also from the exploitation of the offshore oil and gas reserves in the Arctic seas. The capacity and knowledge established in Nordic countries (Norway, Finland) concerning cruise tourism should not be underestimated and the already functioning cooperation in Barents Region should expand towards this particular segment of the tourism industry. The current stage of economic development in Russia makes it clear that tourism development is not able to compete with the well-needed increase in the cargo transportation, which means that Russia’s fleet is going to be utilised by other industries. However, opening up this area to both local and international visitors could contribute to the economic prosperity of these remote areas and if carefully managed could sustain already existing maritime cities along the shores of the Arctic Ocean.

Financial regulation and international criminal policy: the anti-money laundering system in Brazil and Argentina

The objective of this paper is to present and compare the process and the results of the implementation of the anti-money laundering system in Brazil and Argentina. Considering that the internal transformations cannot be discussed without a clear understanding of the international apparatus, attention will be given to the description of the “international policy” designed and conducted by FATF. Therefore, its incorporation into two different national realities, the Brazilian and the Argentinean ones, will shed light not only on the transnational transformations both States underwent but also on the anti-money laundering regime itself. The paper is divided into five parts. The first one presents a brief introduction on the emergence and development of the relationship between financial regulation and criminal policy. The two following sections are designed to present an overview of the anti money laundering system in Brazil and Argentina and of the role of FATF in their implementation process. The fourth section presents two Brazilian examples of situations in which full advantage of the FATF regime was taken: the National Strategy to Combat Corruption and Money Laundering and the BacenJud, a communication channel between the financial system and the judicial power. To conclude, final comments will be presented in connection with the central questions of the project this paper is part of .

Sustainable silvopastoral systems: theory and a practical case

Muitas transformações são esperadas por causa das mudanças do clima, especialmente das atividades agrícolas realizadas nos trópicos. Esta tese centra-se em dois aspectos. O primeiro deles é o de reunir o conhecimento de sistemas silvipastoris; este ponto de vista estabelece a importância de solos tropicais e sua gestão adequada de acordo com as normas ambientais e sustentáveis. A segunda parte da tese é a aplicação desses princípios em um caso específico: a fazenda "El Paraíso". O objetivo central ou problema a resolver da segunda parte é propor um projeto para melhorar as atividades de produção de carne e, ao mesmo tempo, ajudar a preservar e melhorar o meio ambiente e especialmente os ecossistemas tropicais. A metodologia utilizada na tese foi buscar e analisar informações sobre o assunto. Depois disso, a investigação experimental e de campo foi realizada para levantar o projeto que combinaria as duas partes da obra. No final, com a informação recolhida uma proposta de projeto foi feita. O objetivo era propor a transformação dos processos de produção na fazenda selecionada. Logo de desenvolver e apresentar o projeto, foram analisadas as possibilidades de implementação do projeto. A conclusão do estudo foi o de apresentar e discutir três cenários possíveis após a implementação. Finalmente, a conclusão geral apresenta as realizações, as oportunidades e possíveis expansões futuras do projeto.

Genotoxic and mutagenic effects of permethrin in mice: Micronuclei analysis in peripheral blood erythrocytes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases: a review

The modern approach to the development of new chemical entities against complex diseases, especially the neglected endemic diseases such as tuberculosis and malaria, is based on the use of defined molecular targets. Among the advantages, this approach allows (i) the search and identification of lead compounds with defined molecular mechanisms against a defined target (e.g. enzymes from defined pathways), (ii) the analysis of a great number of compounds with a favorable cost/benefit ratio, (iii) the development even in the initial stages of compounds with selective toxicity (the fundamental principle of chemotherapy), (iv) the evaluation of plant extracts as well as of pure substances. The current use of such technology, unfortunately, is concentrated in developed countries, especially in the big pharma. This fact contributes in a significant way to hamper the development of innovative new compounds to treat neglected diseases. The large biodiversity within the territory of Brazil puts the country in a strategic position to develop the rational and sustained exploration of new metabolites of therapeutic value. The extension of the country covers a wide range of climates, soil types, and altitudes, providing a unique set of selective pressures for the adaptation of plant life in these scenarios. Chemical diversity is also driven by these forces, in an attempt to best fit the plant communities to the particular abiotic stresses, fauna, and microbes that co-exist with them. Certain areas of vegetation (Amazonian Forest, Atlantic Forest, Araucaria Forest, Cerrado-Brazilian Savanna, and Caatinga) are rich in species and types of environments to be used to search for natural compounds active against tuberculosis, malaria, and chronic-degenerative diseases. The present review describes some strategies to search for natural compounds, whose choice can be based on ethnobotanical and chemotaxonomical studies, and screen for their ability to bind to immobilized drug targets and to inhibit their activities. Molecular cloning, gene knockout, protein expression and purification, N-terminal sequencing, and mass spectrometry are the methods of choice to provide homogeneous drug targets for immobilization by optimized chemical reactions. Plant extract preparations, fractionation of promising plant extracts, propagation protocols and definition of in planta studies to maximize product yield of plant species producing active compounds have to be performed to provide a continuing supply of bioactive materials. Chemical characterization of natural compounds, determination of mode of action by kinetics and other spectroscopic methods (MS, X-ray, NMR), as well as in vitro and in vivo biological assays, chemical derivatization, and structure-activity relationships have to be carried out to provide a thorough knowledge on which to base the search for natural compounds or their derivatives with biological activity.

Esterase patterns and phylogenetic relationships of Drosophila species in the saltans subgroup (saltans group)

The esterase patterns of sixteen strains from four species in the saltans subgroup were analyzed using polyacrylamide gel electrophoresis. Thirty-four esterase bands were detected. By using alpha and beta naphthyl acetates as substrates, they were classified in 18 alpha-esterases (they hydrolyse the alpha-naphtyl substrate), 15 beta-esterases (they hydrolyse the beta-naphtyl substrate) and 1 alpha/beta-esterase (it hydrolyses the alpha and beta-naphtyl substrates). Among the alpha-esterases, three were detected exclusively in males. Malathion, Eserine and pCMB were used as inhibitors in order to characterize biochemically the esterases. The results indicated the presence of cholinesterases, carboxylesterases and acetylesterases. The degree of mobility of the bands in the gels, their specificity to alpha and beta naphthyl acetates and the results of the inhibition tests allowed us to recognize tentatively nine genetic loci. Phylogenetic relationships among species inferred on the basis of the esterase patterns by PAUP 4.0 b8, with neighbor-joining search and a bootstrap analysis showed that, although the four species are closely related, D. septentriosaltans, D. saltans and D. austrosaltans are closer to each other than to D. prosaltans. These results showed to be consistent with phylogenetic relationships previously inferred from inversion polymorphism.

Distributed generation impact evaluation using a multi-objective tabu search

Distribution networks paradigm is changing currently requiring improved methodologies and tools for network analysis and planning. A relevant issue is analyzing the impact of the Distributed Generation penetration in passive networks considering different operation scenarios. Studying DG optimal siting and sizing the planner can identify the network behavior in presence of DG. Many approaches for the optimal DG allocation problem successfully used multi-objective optimization techniques. So this paper contributes to the fundamental stage of multi-objective optimization of finding the Pareto optimal solutions set. It is proposed the application of a Multi-objective Tabu Search and it was verified a better performance comparing to the NSGA-II method. © 2009 IEEE.

The millennium development goals: a Latin American and Caribbean perspective

Includes bibliography

Contribution of energy services to the Millennium Development Goals and to poverty alleviation in Latin America and the Caribbean: executive summary

Includes bibliography

Contribution of energy services to the millennium development goals and to poverty alleviation in Latin America and the Caribbean

Includes bibliography