Automatic filtering and substantiation of drug safety signals

Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions

The origins and impact of primate segmental duplications

Duplicated sequences are substrates for the emergence of new genes and are an important source of genetic instability associated with rare and common diseases. Analyses of primate genomes have shown an increase in the proportion of interspersed segmental duplications (SDs) within the genomes of humans and great apes. This contrasts with other mammalian genomes that seem to have their recently duplicated sequences organized in a tandem configuration. In this review, we focus on the mechanistic origin and impact of this difference with respect to evolution, genetic diversity and primate phenotype. Although many genomes will be sequenced in the future, resolution of this aspect of genomic architecture still requires high quality sequences and detailed analyses.

Dietary n-6- or n-3-rich vegetable fats and antioxidants: effects on fatty acid composition and stability of rabbit plasma, liver and meat

We supplemented diets with a-tocopheryl acetate (100 mg/kg) and replaced beef tallow (BT) in feeds with increasing doses of n-6- or n-3-rich vegetable fat sources (linseed and sunflower oil), and studied the effects on the fatty acid (FA) composition, the a-tocopherol (aT) content and the oxidative stability of rabbit plasma and liver. These effects were compared with those observed in a previous study in rabbit meat. As in meat, the content of saturated, monounsaturated and trans FA in plasma and liver mainly reflected feed FA profile, except stearic acid in liver, which increased as feeds contained higher doses of vegetable fat, which could be related to an inhibition of the activity of the stearoyl-CoA-desaturase. As linseed oil increased in feeds, the n-6/n-3 FA ratio was decreased in plasma and liver as a result of the incorporation of FA from diets and also, due to the different performance and selectivity of desaturase enzymes. However, an increase in the dose of vegetable fat in feeds led to a significant reduction in the aT content of plasma and liver, which was greater when the fat source was linseed oil. Increasing the dose of vegetable fat in feeds also led to an increase in the susceptibility to oxidation (lipid hydroperoxide (LHP) value) of rabbit plasma, liver and meat and on the thiobarbituric acid (TBA) values of meat. Although the dietary supplementation with a-tocopheryl acetate increased the aT content in plasma and liver, it did not modify significantly their TBA or LHP values. In meat however, both TBA and LHP values were reduced by the dietary supplementation with a-tocopheryl acetate. The plasma aT content reflected the aT content in tissues, and correlated negatively with tissue oxidability. From the studied diets, those containing 1.5% linseed oil plus 1.5% BT and 100 mg of a-tocopheryl acetate/kg most improved the FA composition and the oxidative stability of rabbit tissues.

N-myc controls proliferation, morphogenesis, and patterning of the inner ear

Myc family members play crucial roles in regulating cell proliferation, size, and differentiation during organogenesis. Both N-myc and c-myc are expressed throughout inner ear development. To address their function in the mouse inner ear, we generated mice with conditional deletions in either N-myc or c-myc. Loss of c-myc in the inner ear causes no apparent defects, whereas inactivation of N-myc results in reduced growth caused by a lack of proliferation. Reciprocally, the misexpression of N-myc in the inner ear increases proliferation. Morphogenesis of the inner ear in N-myc mouse mutants is severely disturbed, including loss of the lateral canal, fusion of the cochlea with the sacculus and utriculus, and stunted outgrowth of the cochlea. Mutant cochleas are characterized by an increased number of cells exiting the cell cycle that express the cyclin-dependent kinase inhibitor p27Kip1 and lack cyclin D1, both of which control the postmitotic state of hair cells. Analysis of different molecular markers in N-myc mutant ears reveals the development of a rudimentary organ of Corti containing hair cells and the underlying supporting cells. Differentiated cells, however, fail to form the highly ordered structure characteristic for the organ of Corti but appear as rows or clusters with an excess number of hair cells. The Kölliker's organ, a transient structure neighboring the organ of Corti and a potential source of ectopic hair cells, is absent in the mutant ears. Collectively, our data suggest that N-myc regulates growth, morphogenesis, and pattern formation during the development of the inner ear.

Promoting the Creation, Share and Use of OERs through Open Repositories and Social Networks

In this paper we discuss and analyze the process of using a learning object repository and building a social network on the top of it, including aspects related to open source technologies, promoting the use of the repository by means of social networks and helping learners to develop their own learning paths.

Concentrations of resveratrol and derivatives in foods and estimation of dietary intake in a Spanish population: European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort

Resveratrol has been shown to have beneficial effects on diseases related to oxidant and/or inflammatory processes and extends the lifespan of simple organisms including rodents. The objective of the present study was to estimate the dietary intake of resveratrol and piceid (R&P) present in foods, and to identify the principal dietary sources of these compounds in the Spanish adult population. For this purpose, a food composition database (FCDB) of R&P in Spanish foods was compiled. The study included 40 685 subjects aged 3564 years from northern and southern regions of Spain who were included in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort. Usual food intake was assessed by personal interviews using a computerised version of a validated diet history method. An FCDB with 160 items was compiled. The estimated median and mean of R&P intake were 100 and 933 mg/d respectively. Approximately, 32% of the population did not consume RΠ The most abundant of the four stilbenes studied was trans-piceid (53·6 %), followed by trans-resveratrol (20·9 %), cis-piceid (19·3 %) and cis-resveratrol (6·2 %). The most important source of R&P was wines (98·4 %) and grape and grape juices (1·6 %), whereas peanuts, pistachios and berries contributed to less than 0·01 %. For this reason the pattern of intake of R&P was similar to the wine pattern. This is the first time that R&P intake has been estimated in a Mediterranean country.

Reexposure and advection of C-14-depleted organic carbon from old deposits at the upper continental slope

Outcrops of old strata at the shelf edge resulting from erosive gravity-driven flows have been globally described on continental margins. The reexposure of old strata allows for the reintroduction of aged organic carbon (OC), sequestered in marine sediments for thousands of years, into the modern carbon cycle. This pool of reworked material represents an additional source of C-14-depleted organic carbon supplied to the ocean, in parallel with the weathering of fossil organic carbon delivered by rivers from land. To understand the dynamics and implications of this reexposure at the shelf edge, a biogeochemical study was carried out in the Gulf of Lions (Mediterranean Sea) where erosive processes, driven by shelf dense water cascading, are currently shaping the seafloor at the canyon heads. Mooring lines equipped with sediment traps and current meters were deployed during the cascading season in the southwestern canyon heads, whereas sediment cores were collected along the sediment dispersal system from the prodelta regions down to the canyon heads. Evidence from grain-size, X-radiographs and Pb-210 activity indicate the presence in the upper slope of a shelly-coarse surface stratum overlying a consolidated deposit. This erosive discontinuity was interpreted as being a result of dense water cascading that is able to generate sufficient shear stress at the canyon heads to mobilize the coarse surface layer, eroding the basal strata. As a result, a pool of aged organic carbon (Delta C-14 = -944.5 +/- 24.7%; mean age 23,650 +/- 3,321 ybp) outcrops at the modern seafloor and is reexposed to the contemporary carbon cycle. This basal deposit was found to have relatively high terrigenous organic carbon (lignin = 1.48 +/- 0.14 mg/100 mg OC), suggesting that this material was deposited during the last low sea-level stand. A few sediment trap samples showed anomalously depleted radiocarbon concentrations (Delta C-14 = -704.4 +/- 62.5%) relative to inner shelf (Delta C-14 = -293.4 +/- 134.0%), mid-shelf (Delta C-14 = -366.6 +/- 51.1%), and outer shelf (Delta C-14 = -384 +/- 47.8%) surface sediments. Therefore, although the major source of particulate material during the cascading season is resuspended shelf deposits, there is evidence that this aged pool of organic carbon can be eroded and laterally advected downslope.

Use and availability of scholarly journals in Catalan academic libraries

This paper presents the results of a survey of academics affiliated to the universities that are members of the Consortium of Academic Libraries of Catalonia (CBUC) and an analysis of the availability in the libraries of these universities of the references cited in a sample of articles published by these academics. The results reflect the major importance that researchers assign to scholarly journals as the main source of scientific information. Most state that they use electronic journals either exclusively or in any case more than print journals, a preference that is higher among younger scholars. With regard to frequency of reading, four out of ten researchers state that they read journals virtually every day, while nine out of ten report that they do so at least once a week. Scholars claim that the obstacles they face when trying to download an article are related to the lack of subscriptions. However, the availability study showed that most of the articles cited in their publications are available at least at one of the CBUC libraries. Though most researchers keep a copy of the articles they consult, just over a third of them use some kind of reference management software.

In situ spectroellipsometric study of the nucleation and growth of amorphous silicon

A detailed in situ spectroellipsometric analysis of the nucleation and growth of hydrogenated amorphous silicon (a:Si:H) is presented. Photoelectronic quality a‐Si:H films are deposited by plasma‐enhanced chemical vapor deposition on smooth metal (NiCr alloy) and crystalline silicon (c‐Si) substrates. The deposition of a‐Si:H is analyzed from the first monolayer up to a final thickness of 1.2 μm. In order to perform an improved analysis, real time ellipsometric trajectories are recorded, using fixed preparation conditions, at various photon energies ranging from 2.2 to 3.6 eV. The advantage of using such a spectroscopic experimental procedure is underlined. New insights into the nucleation and growth mechanisms of a‐Si:H are obtained. The nucleation mechanism on metal and c‐Si substrates is very accurately described assuming a columnar microstructural development during the early stage of the growth. Then, as a consequence of the incomplete coalescence of the initial nuclei, a surface roughness at the 10-15 Å scale is identified during the further growth of a‐Si:H on both substrates. The bulk a‐Si:H grows homogeneously beneath the surface roughness. Finally, an increase of the surface roughness is evidenced during the long term growth of a‐Si:H. However, the nature of the substrate influenced the film growth. In particular, the film thickness involved in the nucleation‐coalescence phase is found lower in the case of c‐Si (67±8 Å) as compared to NiCr (118±22 Å). Likewise films deposited on c‐Si present a smaller surface roughness even if thick samples are considered (>1 μm). More generally, the present study illustrates the capability of in situ spectroellipsometry to precisely analyze fundamental processes in thin‐film growth, but also to monitor the preparation of complex structures on a few monolayers scale.

Concentrations of resveratrol and derivatives in foods and estimation of dietary intake in a Spanish population: European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort

Resveratrol has been shown to have beneficial effects on diseases related to oxidant and/or inflammatory processes and extends the lifespan of simple organisms including rodents. The objective of the present study was to estimate the dietary intake of resveratrol and piceid (R&P) present in foods, and to identify the principal dietary sources of these compounds in the Spanish adult population. For this purpose, a food composition database (FCDB) of R&P in Spanish foods was compiled. The study included 40 685 subjects aged 35-64 years from northern and southern regions of Spain who were included in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort. Usual food intake was assessed by personal interviews using a computerised version of a validated diet history method. An FCDB with 160 items was compiled. The estimated median and mean of R&P intake were 100 and 933 mg/d respectively. Approximately, 32% of the population did not consume RΠ The most abundant of the four stilbenes studied was trans-piceid (53·6 %), followed by trans-resveratrol (20·9 %), cis-piceid (19·3 %) and cis-resveratrol (6·2 %). The most important source of R&P was wines (98·4 %) and grape and grape juices (1·6 %), whereas peanuts, pistachios and berries contributed to less than 0·01 %. For this reason the pattern of intake of R&P was similar to the wine pattern. This is the first time that R&P intake has been estimated in a Mediterranean country.

Radial dose function of a 90Sr 90Y seed in water and A150: Comment on Calibration and characterization of beta-particle sources for intravascular brachytherapy

Intravascular brachytherapy with beta sources has become a useful technique to prevent restenosis after cardiovascular intervention. In particular, the Beta-Cath high-dose-rate system, manufactured by Novoste Corporation, is a commercially available 90Sr 90Y source for intravascular brachytherapy that is achieving widespread use. Its dosimetric characterization has attracted considerable attention in recent years. Unfortunately, the short ranges of the emitted beta particles and the associated large dose gradients make experimental measurements particularly difficult. This circumstance has motivated the appearance of a number of papers addressing the characterization of this source by means of Monte Carlo simulation techniques.

Design and evaluation of learning algorithms for dynamic resource management in virtual networks

Network virtualisation is considerably gaining attentionas a solution to ossification of the Internet. However, thesuccess of network virtualisation will depend in part on how efficientlythe virtual networks utilise substrate network resources.In this paper, we propose a machine learning-based approachto virtual network resource management. We propose to modelthe substrate network as a decentralised system and introducea learning algorithm in each substrate node and substrate link,providing self-organization capabilities. We propose a multiagentlearning algorithm that carries out the substrate network resourcemanagement in a coordinated and decentralised way. The taskof these agents is to use evaluative feedback to learn an optimalpolicy so as to dynamically allocate network resources to virtualnodes and links. The agents ensure that while the virtual networkshave the resources they need at any given time, only the requiredresources are reserved for this purpose. Simulations show thatour dynamic approach significantly improves the virtual networkacceptance ratio and the maximum number of accepted virtualnetwork requests at any time while ensuring that virtual networkquality of service requirements such as packet drop rate andvirtual link delay are not affected.

Spiders on a Hot Volcanic Roof: Colonisation Pathways and Phylogeography of the Canary Islands Endemic Trap-Door Spider Titanidiops canariensis (Araneae, Idiopidae)

Studies conducted on volcanic islands have greatly contributed to our current understanding of how organisms diversify. The Canary Islands archipelago, located northwest of the coast of northern Africa, harbours a large number of endemic taxa. Because of their low vagility, mygalomorph spiders are usually absent from oceanic islands. The spider Titanidiops canariensis, which inhabits the easternmost islands of the archipelago, constitutes an exception to this rule. Here, we use a multi-locus approach that combines three mitochondrial and four nuclear genes to investigate the origins and phylogeography of this remarkable trap-door spider. We provide a timeframe for the colonisation of the Canary Islands using two alternative approaches: concatenation and species tree inference in a Bayesian relaxed clock framework. Additionally, we investigate the existence of cryptic species on the islands by means of a Bayesian multi-locus species delimitation method. Our results indicate that T. canariensis colonised the Canary Islands once, most likely during the Miocene, although discrepancies between the timeframes from different approaches make the exact timing uncertain. A complex evolutionary history for the species in the archipelago is revealed, which involves two independent colonisations of Fuerteventura from the ancestral range of T. canariensis in northern Lanzarote and a possible back colonisation of southern Lanzarote. The data further corroborate a previously proposed volcanic refugium, highlighting the impact of the dynamic volcanic history of the island on the phylogeographic patterns of the endemic taxa. T. canariensis includes at least two different species, one inhabiting the Jandia peninsula and central Fuerteventura and one spanning from central Fuerteventura to Lanzarote. Our data suggest that the extant northern African Titanidiops lineages may have expanded to the region after the islands were colonised and, hence, are not the source of colonisation. In addition, T. maroccanus may harbour several cryptic species.