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.

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Green and lean paradigms have been adopted by companies in order to manage their relationships with suppliers in a supply chain management context, but nearly always separately and with little understanding of their influence on company performance. This paper proposes a theoretical framework for the analysis of the influence of green and lean upstream supply chain management practices on the sustainable development of businesses. To attend this objective, a set of performance measures covering economic (operational cost, environmental cost, and inventory cost), environmental (business wastage, green image, and CO2 emission), and social (corruption risk, supplier screening and local supplier) perspectives is proposed. An explanatory case study was conducted at a Portuguese automaker to test qualitatively the validity of the proposed theoretical framework. From the case study, a model is suggested, which encompasses the relationships between green and lean upstream supply chain practices and sustainable business development.

A clutch of several crushed eggs and embryos from the Late Jurassic (near the Kimmeridgian-Tithonian
boundary), Lourinhã Formation, Portugal contains a complete maxilla, erupted and scattered teeth,
and presacral vertebrae. The maxilla bears four teeth separated by individualized interdental plates,
the dorsal process of the maxilla is confluent with the maxillary body, the ventral rim of the antorbital
fossa is parallel to the tooth row, and the anterior border of the maxilla forms a right angle with the
ventral margin. The teeth are conical and recurved distally with carinae on mesial and distal sides. The
vertebrae are amphiplatyan, with a ventral pair of neurovascular foramina and heavily pitted articular
facets. These fossils allow unambiguous association of basal theropod osteology (Megalosauroidea) with
a new eggshell morphotype. Synchrotron micro-computed tomographic scanning (SRμCT), scanning
electron microscopy, and thin-sections under polarized and normal light revealed that the outer
ornamentation of the eggshell is composed of anastomosing ridges and islets, the pores communicate
near the outer region of the eggshells, and in radial section they are irregular canals that ramify towards
the surface. Micro-proto induced x-ray emission (micro-PIXE) analysis of the eggshell (excluding pores)
revealed the presence of Mg, Fe, Mn (0.33%, 0.27% and 0.18%, respectively) and several trace elements,
with a corresponding loss of Ca (39.4% detected but 40.0% expected for calcite), which suggests minimal
eggshell diagenesis. The eggshells do not luminesce, which could imply that no diagenetic alteration
took effect. However, the quenching effect of Fe2+ has to be taken into consideration. Conversely,
luminescence is observed in the pores since they are filled with sediment, composed of phyllosilicates,
as revealed by SRμCT, micro-PIXE and x-ray diffraction analyses.

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Supply chains (SCs) may experience instability induced by disturbances such as extreme climate conditions or accidents. These events can cause severe negative effects on SCs, jeopardising the on-time delivery of products and services to customers. This paper proposes a mapping framework to improve SC resilience to such events, avoiding possible failure modes. The proposed mapping framework allows identification of the current SC operation and possible transition states, together with points of vulnerability. An illustrative example of the framework applied to a real-life wine SC is presented.

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.

Although spreadsheets can be seen as a flexible programming environment, they lack some of the concepts of regular programming languages, such as structured data types. This can lead the user to edit the spreadsheet in a wrong way and perhaps cause corrupt or redundant data. We devised a method for extraction of a relational model from a spreadsheet and the subsequent embedding of the model back into the spreadsheet to create a model-based spreadsheet programming environment. The extraction algorithm is specific for spreadsheets since it considers particularities such as layout and column arrangement. The extracted model is used to generate formulas and visual elements that are then embedded in the spreadsheet helping the user to edit data in a correct way. We present preliminary experimental results from applying our approach to a sample of spreadsheets from the EUSES Spreadsheet Corpus.

Spreadsheets can be viewed as programming languages for non-professional programmers. These so-called ``end-user'' programmers vastly outnumber professional programmers creating millions of new spreadsheets every year. As a programming language, spreadsheets lack support for abstraction, testing, encapsulation, or structured programming. As a result, and as numerous studies have shown, the high rate of production is accompanied by an alarming high rate of errors. Some studies report that up to 90% of real-world spreadsheets contain errors. After their initial creation, many spreadsheets turn out to be used for storing and processing increasing amounts of data and supporting increasing numbers of users over long periods of time, making them complicated systems. An emerging solution to handle the complex and evolving software systems is Model-driven Engineering (MDE). To consider models as first class entities and any software artifact as a model or a model element is one of the basic principles of MDE. We adopted some techniques from MDE to solve spreadsheet problems. Most spreadsheets (if not all) lack a proper specification or a model. Using reverse engineering techniques we are able to derive various models from legacy spreadsheets. We use functional dependencies (a formalism that allow us to define how some column values depend on other column values) as building blocks for these models. Models can be used for several spreadsheet improvements, namely refactoring, safe evolution, migration or even generation of edit assistance. The techniques presented in this work are available under the framework HAEXCEL that we developed. It is composed of online and batch tools, reusable HASKELL libraries and OpenOffice.org extensions. A study with several end-users was organized to survey the impact of the techniques we designed. The results of this study indicate that the models can bring great benefits to spreadsheet engineering helping users to commit fewer errors and to work faster.

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Building stones, particularly sandstone and granite, are very important in the building elements of Portugal’s historical and cultural heritage. Experimental research, based on uniaxial compressive tests, was carried out on selected representative samples of lithotypes of rocks used in historic built heritage, with a view to evaluating the compressive mechanical behaviour of different building stones. The results showed that porosity plays a central role in the compressive behaviour of granites and sandstones. As porosity can be evaluated in field conditions with non-destructive tests it was decided to derive an analytical model to predict compressive behaviour based on the knowledge of porosity of the building stones. A cubic polynomial function was adopted to describe the pre-peak regime under compression to implement the model. Furthermore, a statistical correlation between mechanical and porosity data had to be defined. Good agreement between experimental and analytical compressive stress–strain diagrams, from which the mechanical properties like compressive strength and modulus of elasticity can be derived, was achieved.

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 use of FRP composites for the confinement of concrete has become an important aspect to consider on strengthening of concrete columns. It is important therefore that accurate modelling tools are available for the design of this system considering, not only the peak values of load and strain, but also the complete stress–strain behaviour. A wide group of authors have proposed several models specific for FRP-confined concrete based either on theoretical assumptions (analysis-oriented-models – AOMs) or on mathematical calibration from testing results (design-oriented-models – DOMs). This article carries out the implementation and analysis of nine existing models for circular concrete columns in view of axially tested reinforced concrete columns confined with CFRP with three different diameters: 150; 250 and 400 mm. The global shape of curves, peak compressive load, stress–strain relation, axial-to-lateral relation and dilation response were studied to conclude which models’ curves were closer to tests. Quantification of errors in face of the testing results was carried out for the most important parameters – ultimate load, strain and lateral stress – as well as for other curve parameters. Some models are accurate in predicting the peak load, though only few can accurately predict the load–strain and dilation behaviour.

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.

Service orientation is a main trend in the development of support infrastructures for collaborative networks, namely in the manufacturing sector. Nevertheless, a literature review still shows the lack of a common understanding of the service concept, namely when we compare the software and business perspectives. As a contribution towards the integration of these two perspectives, this article introduces a conceptual framework based on the notion of representation of services in an ambassador-like manner through the introduction of a proactiveness mechanism. An example scenario and results with a prototype implementation are also discussed.

Collaborative-Networks (CN) have experienced a fast evolution in the last two decades. The
collaboration among independent entities or professionals supported by Information and
Communication Technology (ICT) has attracted the research community to establish the
conceptual basis for this scientific discipline. Service Orientation has been one of the key selected
paradigms for that conceptual basis. Nevertheless, the service concept itself does not have a
common understanding in the Business and ICT worlds. In the former, client satisfaction,
resources management and business process models are some example concerns, whilst the later
deals with interoperability, remote function calling or communication protocols.
If for example an enterprise provides some service, it may hire specialists to wrap such
service into web-services, expecting to reach worldwide potential new clients. In fact, nowadays
Web Services and Service Oriented Architectures (SOA) are the technological elements most
commonly used. However, these are passive elements in the sense they do not perform any action
towards pursuing business interests, which constitute a limiting factor from a business
perspective. Another approach for the above mentioned enterprise is to follow the Multi-Agent
Systems (MAS) approach, as the pro-activity is a keyword in such contexts. Nevertheless, as
MAS approaches are not so commonly used and not so robust yet, the worldwide potential set of
new clients is reduced; which also constitutes an inhibitor factor from the business perspective.
This dissertation proposes a Pro-Active Services Ecosystem Framework, gathering
inspiration from both the SOA and MAS research areas, trying to bridge the business and ICT
worlds through the base concepts for the creation of a Services’ Ecosystem where business
services are represented in a pro-active manner towards pursuing business interests, like finding
collaboration opportunities or improving the chances each CN member has to see its services
selected among competitors, for example. This work also includes a prototype system applied /
validated in the area of a Professional Virtual Community of Senior Professionals.

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