The close structural similarity between the two cyclooxygenase (COXs) isoforms and the absence of selective inhibitors without side effects continues to stimulate the development of novel approaches towards selective anti-inflammatory drugs. In the present study a small library of new indolic compounds involving two different substitutions patterns at the indole scaffold was synthesized. In order to establish a relation between the spatial distribution of known functional groups related with inhibitory activity, two substitution patterns were explored: one with substituents at N-1, C-3, C-5 positions and another at C-2, C-3 and C5 positions. Accordingly, indole positions C-5, C-3 and N-1 were substituted with: sulfonamide or methylsulfone at C-5, p-halo-benzyl group at C-3, and an alkyl chain with a trifluoromethyl group at N-1. Alternatively, a p-halo-benzyl group was introduced at C-2, leaving the indolic nitrogen free. Inhibitory studies were performed and the activity results obtained against both COXs isoforms were rationalized based on docking and NMR studies. Docking studies show that dialkyation at C-2 and C-3 favors a binding with an orientation similar to that of the known selective inhibitor SC-558. From the tested compounds, this substitution pattern is correlated with the highest inhibitory activity and selectivity: 70% COX-2 inhibition at 50 M, and low COX-1 inhibition (18±9%). Additionally, Saturation Transfer Difference NMR experiments reveal different interaction patterns with both COXs isoforms that may be related with different orientations of the sulfonamide group in the binding pocket. Despite the moderated inhibitory activities found, this study represents an innovative approach towards COXs inhibitory activity rationalization and to the design of anti-inflammatory drugs.

n this paper, we present MDSHEET, a framework for the embedding, evolution and inference of spreadsheet models. This framework offers a model-driven software development mechanism for spreadsheet users.

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This paper introduces a variability-aware methodology for the design of LC-VCOs in Nano-CMOS technologies. The complexity of the design as well as the necessity for having an environment offering the possibility for exploring design trade-offs has led to the development of design methodologies based multi-objective optimization procedures yielding the generation of Pareto-optimal surfaces. The efficiency of the process is granted by using analytical models for both passive and active devices. Although physics-based analytical expressions have been proposed for the evaluation of the lumped elements, the variability of the process parameters is usually ignored due to the difficulty to formalize it into an optimization performance index. The usually adopted methodology of considering only optimum solutions for the Pareto surface, may lead to pruning quasi-optimal solutions that may prove to be better, should their sensitivity to process parameter variation be accounted for. In this work we propose starting by generating an extended Pareto surface where both optimum and quasi-optimum solutions are considered. Finally information on the sensitivity to process parameter variations, is used for electing the best design solution.

The design and planning of efficient supply chains (SC) is a major challenge that increases when the return of products has to be accounted for, the so-called closed-loop supply chains (CLSC). In the present work the effect of disruptions and modifications in the operating conditions of CLSCs are investigated on the basis of a 2-stage scenario based model previously developed by the authors. Metrics derived from graph theory are used, along with more conventional economic and operational indices. A discussion on the results obtained is presented to assess how the design and planning of the CLSC respond to these challenges and how these metrics may contribute to this objective.

To focus on processes of scientific and technological design and on how newly designed objects are used in different ways than initially intended (“displaced”), the organizers (the Society for Social Studies on Science-4S and the European Association of Studies on Science and Technology-EASST) chose the conference theme “Design and Displacement”. The concept of design here referred to innovative processes in forming new ideas and material objects. This general idea was reflected in a multitude of sub-topics.

The present work aims to perform a multistep upgrading of chars obtained in the co-pyrolysis of PE, PP and PS plastic wastes, pine biomass and used tires. The quality of the upgraded chars was evaluated by measuring some of their physico-chemical properties in order to assess their valorisation as adsorbents’ precursors. The crude chars were submitted to a sequential solvent extraction with organic solvents of increasing polarity (hexane, mixture 1:1 v/v hexane:acetone and acetone) followed by an acidic demineralization procedure with 1 M HCl solution. The results obtained showed that the upgrading treatment allow the recovery of 63–81% of the pyrolysis oils trapped in the crude chars and a reduction in the char's ash content in the range of 64–86%. The textural and adsorption properties of the upgraded chars were evaluated and the results indicate that the chars are mainly mesoporous and macroporous materials, with adsorption capacities in the range of 3.59–22.2 mg/g for the methylene blue dye. The upgrading treatment allowed to obtain carbonaceous materials with quality to be reused as adsorbents or as precursors for activated carbon.

This paper describes for the first time the intimate molecular details of the association between a platinated oligonucleotide and a zinc-finger peptide. Site-specific platination of the guanine in a ss hexanucleotide gave {[Pt(dien)d(5’-TACGCC-3’)], Pt(dien)(6-mer)}, II, characterized by mass spectrometry and 1H-NMR spectroscopy. The work extends the study of platinum-nucleobase complex-zinc finger interactions using small molecules such as [Pt(dien)(9-EtGua)]2+, I . The structure of the (34-52) C-terminal finger of the HIV nucleocapsid protein HIVNCp7 (ZF1) was characterized by 1H-NMR spectroscopy and compared with that of the N-terminal single finger and the 2-finger “intact” NCp7. Interaction of II with ZF1 results in significant changes in comparison to the “free” uncomplexed hexanucleotide – the major shifts occur for Trp37 resonances are broadened and shifted upfield and other major shifts are for Gln45 (H21, H3, Q), Met46 (NH, H2), Lys47 (NH, Q) and Glu50 (H2, H3). The Zn-Cys/His chemical shifts show only marginal deviations. The solution structure of ZF1, the 6-mer/ZF1 and II/ZF1 adducts were calculated from the NOESY-derived distance constraints. The DNA position in II/ZF1 is completely different than in the absence of platinum. Major differences are the appearance of new Met46-Cyt6H5 and Trp37-Cyt5H5 contacts but severe weakening of the Trp37-Gua4 contact, attributed to the steric effects caused by Gua4 platination, accompanied by a change in the position of the aromatic ring. The results demonstrate the feasibility of targetting specific ZF motifs with DNA-tethered coordination compounds, such as Pt compounds and Co-macrocycles – with implications for drug targetting and indeed the intimate mechansims of DNA repair of platinated DNA.

The basal part of the Triassic-Jurassic (Rhaetian-Sinemurian) Kap Stewart Formation, exposed at Jameson Land, East Greenland, yields an extensive coprolite collection from black, parallel-laminated mudstone (“paper shale”), representing an open lacustrine system. Preliminary investigations show three different types of coprolites: elongated cylindrical masses, composed of irregularly wrapped layers; elongated cylindrical masses with constriction marks; and spirally-coiled specimens.

The function of prion-like protein Doppel was suggested to be related to male fertility. In this study, the importance of ovine Doppel polypeptide on spermatozoa capacitation and fertilization was evaluated. After refolding, recombinant Doppel (rDpl) was supplemented with different concentrations (40, 80 or 190 ng/ml) to ovine spermatozoa during the capacitation process. In experiment 1, post-thawed ovine spermatozoa were incubated with different concentrations of rDpl during 1 h for swim-up, and changes in sperm motility, concentration, vigour, viability and capacitation were monitored (10 replicates). In experiment 2, the fertilization ability of post-swim-up spermatozoa incubated as above was tested through heterologous fertilization of bovine in vitro matured oocytes (n = 423, three replicates). Regardless of dosage, rDpl improved (p = 0.03) spermatozoa viability. Sperm individual motility and vigour were the highest (p = 0.04) for the group receiving 190 ng/ml rDpl. Sperm supplemented with the highest doses of rDpl achieved higher (p = 0.02) fertilization rates (56.0 +/- 3.0%) than control (39.1 +/- 2.2%) and 40 ng/ml rDpl (39.8 +/- 2.7%). Preliminary data suggest that Doppel protein may enhance in vitro spermatozoa fertilizing ability.

This paper addresses an optimization-based approach for the design of RF integrated inductors. The methodology presented deals with the complexity of the design problem by formulating it as a multi-objective optimization. The multi-modal nature of the underlying functions combined with the need to be able to explore design trade-offs leads to the use of niching methods. This allows exploring not only the best trade-off solutions lying on the Pareto-optimum surface but also the quasi-optimum solutions that would be otherwise discarded. In this paper we take advantage of the niching properties of lbest PSO algorithm using ring topology to devise a simple optimizer able to find the local-optima. For the efficiency of the process analytical models are used for the passive/active devices. In spite the use of physics-based analytical expressions for the evaluation of the lumped elements, the variability of the process parameters is ignored in the optimization stage due to the significant computational burden it involves. Thus in the final stage both the Pareto-optimum solutions and the quasi-optimum solutions are evaluated with respect to the sensitivity to process parameter variations.

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In this paper we present a quality model for spreadsheets, based on the ISO/IEC 9126 standard that defines a generic quality model for software. To each of the software characteristics defined in the ISO/IEC 9126, we associate an equivalent spreadsheet characteristic. Then, we propose a set of spreadsheet specific metrics to assess the quality of a spreadsheet in each of the defined characteristics. In order to obtain the normal distribution of expected values for a spreadsheet in each of the metrics that we propose, we have executed them against all spreadsheets in the large and widely used EUSES spreadsheet corpus. Then, we quantify each characteristic of our quality model after computing the values of our metrics, and we define quality scores for the different ranges of values. Finally, to automate the atribution of a quality score to a given spreadsheet, according to our quality model, we have integrated the computation of the metrics it includes in both a batch and a web-based tool.

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This tool demo paper presents SmellSheet Detective: a tool for automatically detecting bad smells in spreadsheets. We have defined a catalog of bad smells in spreadsheet data which was fully implemented in a reusable library for the manipulation of spreadsheets. This library is the building block of the SmellSheet Detective tool, that has been used to detect smells in large, real-world spreadsheet within the EUSES corpus, in order to validate and evolve our bad smells catalog.

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