Thyroid hormone can increase estrogen-mediated transcription from a consensus estrogen response element in neuroblastoma cells

Thyroid hormones (T) and estrogens (E) are nuclear receptor ligands with at least two molecular mechanisms of action: (i) relatively slow genomic effects, such as the regulation of transcription by cognate T receptors (TR) and E receptors (ER); and (ii) relatively rapid nongenomic effects, such as kinase activation and calcium release initiated at the membrane by putative membrane receptors. Genomic and nongenomic effects were thought to be disparate and independent. However, in a previous study using a two-pulse paradigm in neuroblastoma cells, we showed that E acting at the membrane could potentiate transcription from an E-driven reporter gene in the nucleus. Because both T and E can have important effects on mood and cognition, it is possible that the two hormones can act synergistically. In this study, we demonstrate that early actions of T via TRalpha1 and TRbeta1 can potentiate E-mediated transcription (genomic effects) from a consensus E response element (ERE)-driven reporter gene in transiently transfected neuroblastoma cells. Such potentiation was reduced by inhibition of mitogen-activated protein kinase. Using phosphomutants of ERalpha, we also show that probable mitogen-activated protein kinase phosphorylation sites on the ERalpha, the serines at position 167 and 118, are important in TRbeta1-mediated potentiation of ERalpha-induced transactivation. We suggest that crosstalk between T and E includes potential interactions through both nuclear and membrane-initiated molecular mechanisms of hormone signaling.

Calcium Flux in Neuroblastoma Cells Is a Coupling Mechanism between Non-Genomic and Genomic Modes of Estrogens

Estrogens have been demonstrated to rapidly modulate calcium levels in a variety of cell types. However, the significance of estrogen-mediated calcium flux in neuronal cells is largely unknown. The relative importance of intra- and extracellular sources of calcium in estrogenic effects on neurons is also not well understood. Previously, we have demonstrated that membrane-limited estrogens, such as E-BSA given before an administration of a 2-hour pulse of 17beta-estradiol (E(2)), can potentiate the transcription mediated by E(2) from a consensus estrogen response element (ERE)-driven reporter gene. Inhibitors to signal transduction cascades given along with E-BSA or E(2) demonstrated that calcium flux is important for E-BSA-mediated potentiation of transcription in a transiently transfected neuroblastoma cell line. In this report, we have used inhibitors to different voltage-gated calcium channels (VGCCs) and to intracellular store receptors along with E-BSA in the first pulse or with E(2) in the second pulse to investigate the relative importance of these channels to estrogen-mediated transcription. Neither L- nor P-type VGCCs seem to play a role in estrogen action in these cells; while N-type VGCCs are important in both the non-genomic and genomic modes of estrogen action. Specific inhibitors also showed that the ryanodine receptor and the inositol trisphosphate receptor are important to E-BSA-mediated transcriptional potentiation. This report provides evidence that while intracellular stores of calcium are required to couple non-genomic actions of estrogen initiated at the membrane to transcription in the nucleus, extracellular sources of calcium are also important in both non-genomic and genomic actions of estrogens. Copyright (c) 2005 S. Karger AG, Basel.

Membrane-initiated actions of estrogens in neuroendocrinology: emerging principles

Hormonal ligands for the nuclear receptor superfamily have at least two interacting mechanisms of action: 1) classical transcriptional regulation of target genes (genomic mechanisms); and 2) nongenomic actions that are initiated at the cell membrane, which could impact transcription. Although transcriptional mechanisms are increasingly well understood, membrane-initiated actions of these ligands are incompletely understood. Historically, this has led to a considerable divergence of thought in the molecular endocrine field. We have attempted to uncover principles of hormone action that are relevant to membrane-initiated actions of estrogens. There is evidence that the membrane-limited actions of hormones, particularly estrogens, involve the rapid activation of kinases and the release of calcium. Membrane actions of estrogens, which activate these rapid signaling cascades, can also potentiate nuclear transcription. These signaling cascades may occur in parallel or in series but subsequently converge at the level of modification of transcriptionally relevant molecules such as nuclear receptors and/or coactivators. In addition, other hormones or neurotransmitters may also activate cascades to crosstalk with estrogen receptor-mediated transcription. The idea of synergistic coupling between membrane-initiated and genomic actions of hormones fundamentally revises the paradigms of cell signaling in neuroendocrinology.

Non-genomic actions of estrogens and their interaction with genomic actions in the brain

Ligands for the nuclear receptor superfamily have at least two mechanisms of action: (a) classical transcriptional regulation of target genes (genomic mechanisms); and (b) non-genomic actions, which are initiated at the cell membrane, which could also impact transcription. Though transcriptional mechanisms are increasingly well understood, membrane-initiated actions of these ligands are incompletely understood. This has led to considerable debate over the physiological relevance of membrane-initiated actions of hormones versus genomic actions of hormones, with genomic actions predominating in the endocrine field. There is good evidence that the membrane-limited actions of hormones, particularly estrogens, involve the rapid activation of kinases and the release of calcium and that these are linked to physiologically relevant scenarios in the brain. We show evidence in this review, that membrane actions of estrogens, which activate these rapid signaling cascades, can also potentiate nuclear transcription in both the central nervous system and in non-neuronal cell lines. We present a theoretical scenario which can be used to understand this phenomenon. These signaling cascades may occur in parallel or in series but subsequently, converge at the modification of transcriptionally relevant molecules such as nuclear receptors and/or coactivators. In addition, other non-cognate hormones or neurotransmitters may also activate cascades to crosstalk with estrogen receptor-mediated transcription, though the relevance of this is less clear. The idea that coupling between membrane-initiated and genomic actions of hormones is a novel idea in neuroendocrinology and provides us with a unified view of hormone action in the central nervous system.

Order and disorder in fiction labyrinths: the librarians` representations in some contemporary cultural productions

This paper, first result of a larger research, proposes a query about some aspects of social representation of libraries and librarians, as they appear in literary and cinematographic productions. Little by little, this query, which arose from purposes of organizing catalogues, revealed elements that established different series, in which the narrative genre (literary or cinematographic) has no relevance to either libraries or librarians` representations. The presence of these elements seems to show some expectations and utopias in relation to the common knowledge, independently from narratives being located in the past, in the present or in the future, stimulating reflection on some medieval and baroque traditions about the library universe and its main characters, the librarians. The cinematographic material selected for research was The time machine, Farenheit 451, The day after tomorrow, Star Wars - episode II and the novels Martin Eden, The man without qualities, The time machine and La sombra del viento.

Slicing the metric space to provide quick indexing of complex data in the main memory

Searching in a dataset for elements that are similar to a given query element is a core problem in applications that manage complex data, and has been aided by metric access methods (MAMs). A growing number of applications require indices that must be built faster and repeatedly, also providing faster response for similarity queries. The increase in the main memory capacity and its lowering costs also motivate using memory-based MAMs. In this paper. we propose the Onion-tree, a new and robust dynamic memory-based MAM that slices the metric space into disjoint subspaces to provide quick indexing of complex data. It introduces three major characteristics: (i) a partitioning method that controls the number of disjoint subspaces generated at each node; (ii) a replacement technique that can change the leaf node pivots in insertion operations; and (iii) range and k-NN extended query algorithms to support the new partitioning method, including a new visit order of the subspaces in k-NN queries. Performance tests with both real-world and synthetic datasets showed that the Onion-tree is very compact. Comparisons of the Onion-tree with the MM-tree and a memory-based version of the Slim-tree showed that the Onion-tree was always faster to build the index. The experiments also showed that the Onion-tree significantly improved range and k-NN query processing performance and was the most efficient MAM, followed by the MM-tree, which in turn outperformed the Slim-tree in almost all the tests. (C) 2010 Elsevier B.V. All rights reserved.

Paged similarity queries

An important feature of a database management systems (DBMS) is its client/server architecture, where managing shared memory among the clients and the server is always an tough issue. However, similarity queries are specially sensitive to this kind of architecture, since the answer sizes vary widely. Usually, the answers of similarity query are fully processed to be sent in full to the user, who often is interested in just parts of the answer, e.g. just few elements closer or farther to the query reference. Compelling the DBMS to retrieve the full answer, further ignoring its majority is at least a waste of server processing power. Paging the answer is a technique that splits the answer onto several pages, following client requests. Despite the success of paging on traditional queries, little work has been done to support it in similarity queries. In this work, we present a technique that not only provides paging in similarity range or k-nearest neighbor queries, but also supports them in two variations: the forward similarity query and the backward similarity query. They return elements either increasingly farther of increasingly closer to the query reference. The reported experiments show that, depending on the proportion of the interesting part over the full answer, both techniques allow answering queries much faster than it is obtained in the non-paged way. (C) 2010 Elsevier Inc. All rights reserved.

Seamlessly integrating similarity queries in SQL

Modern database applications are increasingly employing database management systems (DBMS) to store multimedia and other complex data. To adequately support the queries required to retrieve these kinds of data, the DBMS need to answer similarity queries. However, the standard structured query language (SQL) does not provide effective support for such queries. This paper proposes an extension to SQL that seamlessly integrates syntactical constructions to express similarity predicates to the existing SQL syntax and describes the implementation of a similarity retrieval engine that allows posing similarity queries using the language extension in a relational DBM. The engine allows the evaluation of every aspect of the proposed extension, including the data definition language and data manipulation language statements, and employs metric access methods to accelerate the queries. Copyright (c) 2008 John Wiley & Sons, Ltd.

2D QSAR and similarity studies on cruzain inhibitors aimed at improving selectivity over cathepsin L

Hologram quantitative structure-activity relationships (HQSAR) were applied to a data set of 41 cruzain inhibitors. The best HQSAR model (Q(2) = 0.77; R-2 = 0.90) employing Surflex-Sim, as training and test sets generator, was obtained using atoms, bonds, and connections as fragment distinctions and 4-7 as fragment size. This model was then used to predict the potencies of 12 test set compounds, giving satisfactory predictive R-2 value of 0,88. The contribution maps obtained from the best HQSAR model are in agreement with the biological activities of the study compounds. The Trypanosoma cruzi cruzain shares high similarity with the mammalian homolog cathepsin L. The selectivity toward cruzam was checked by a database of 123 compounds, which corresponds to the 41 cruzain inhibitors used in the HQSAR model development plus 82 cathepsin L inhibitors. We screened these compounds by ROCS (Rapid Overlay of Chemical Structures), a Gaussian-shape volume overlap filter that can rapidly identify shapes that match the query molecule. Remarkably, ROCS was able to rank the first 37 hits as being only cruzain inhibitors. In addition, the area under the curve (AUC) obtained with ROCS was 0.96, indicating that the method was very efficient to distinguishing between cruzain and cathepsin L inhibitors. (c) 2007 Elsevier Ltd. All rights reserved.

Friskfaktorer på en enhet : Identifiera & fortsatt bevara

Detta är en kvalitativ studie med syftet att inom en enhet på Stockholms Stad identifiera friskfaktorer och undersöka vad som krävs för att fortsatt bevara dessa. Vidare är syftet att undersöka vilket stöd som är nödvändigt för bevarandet samt HR-funktionens roll i detta avseende. Enheten är, sett till sjukfrånvaro, en välmående grupp som står inför förändringar inom marknaden och målsättning då de påverkas av det nyligen genomförda regeringsskiftet. Ett frågeverktyg användes för att framställa de åtta viktigaste dimensionerna av det attraktiva arbetet och en fördjupad diskussion kring dessa fördes sedan under en fokusgruppsintervju tillsammans med enhetens medarbetare. Resultatet visade att de viktigaste dimensionerna var bland annat arbetstid och relationer. Vidare påvisades att en balans mellan arbetsliv och privatliv är av stor vikt för medarbetarnas hälsa och välmående. För att fortsatt bevara det attraktiva i arbetet visade empirin att gruppens relationer och ledaren var nyckelfaktorer och att HR-funktionen, den personalstrategiska avdelningen, enbart bidrar med en administrativ och vägledande roll i frågan om stöd. Arbetets slutsatser innefattar att bevarandet av friskfaktorer kräver att tillvaron måste vara begriplig, hanterlig och meningsfull men även att medarbetarna behöver rimliga krav i relation till deras handlingsutrymme. En vidare slutsats är behovet av en förändring i ledarskapsbeteendet i kommande stadier då gruppen eventuellt kommer att hamna i en ny mognadsfas på grund förändrade omständigheter. Författarna drar även slutsatsen att friskfaktorer är till viss del individuellt beroende på livssituation men att balansen mellan arbetsliv och privatliv är betydande för de flesta. HR-funktionen, den personalstrategiska avdelningen, har en informativ och administrativ roll i frågan om stöd och författarna anser att det ligger en logik i denna roll. Sett till organisationens storlek är det lättare att vända psykosociala frågor till företagshälsovård eller en psykologgrupp och få det arbetsrättsliga stödet eller information från HR-funktionen.

Electronically Querying for the Provenance of Entities

The provenance of entities, whether electronic data or physical artefacts, is crucial information in practically all domains, including science, business and art. The increased use of software in automating activities provides the opportunity to add greatly to the amount we can know about an entityâ??s history and the process by which it came to be as it is. However, it also presents difficulties: querying for the provenance of an entity could potentially return detailed information stretching back to the beginning of time, and most of it possibly irrelevant to the querier. In this paper, we define the concept of provenance query and describe techniques that allow us to perform scoped provenance queries.

Personalised Grid Service Discovery

The authors take a broad view that ultimately Grid- or Web-services must be located via personalised, semantic-rich discovery processes. They argue that such processes must rely on the storage of arbitrary metadata about services that originates from both service providers and service users. Examples of such metadata are reliability metrics, quality of service data, or semantic service description markup. This paper presents UDDI-MT, an extension to the standard UDDI service directory approach that supports the storage of such metadata via a tunnelling technique that ties the metadata store to the original UDDI directory. They also discuss the use of a rich, graph-based RDF query language for syntactic queries on this data. Finally, they analyse the performance of each of these contributions in our implementation.

Personalised Grid Service Discovery

We take a broad view that ultimately Grid- or Web-services must be located via personalised, semantic-rich discovery processes. We argue that such processes must rely on the storage of arbitrary metadata about services that originates from both service providers and service users. Examples of such metadata are reliability metrics, quality of service data, or semantic service description markup. This paper presents UDDI-MT, an extension to the standard UDDI service directory approach that supports the storage of such metadata via a tunnelling technique that ties the metadata store to the original UDDI directory. We also discuss the use of a rich, graph-based RDF query language for syntactic queries on this data. Finally, we analyse the performance of each of these contributions in our implementation.