Instance-driven TBox revision in DL-Lite

The development and maintenance of large and complex ontologies are often time-consuming and error-prone. Thus, automated ontology learning and revision have attracted intensive research interest. In data-centric applications where ontologies are designed or automatically learnt from the data, when new data instances are added that contradict to the ontology, it is often desirable to incrementally revise the ontology according to the added data. This problem can be intuitively formulated as the problem of revising a TBox by an ABox. In this paper we introduce a model-theoretic approach to such an ontology revision problem by using a novel alternative semantic characterisation of DL-Lite ontologies. We show some desired properties for our ontology revision. We have also developed an algorithm for reasoning with the ontology revision without computing the revision result. The algorithm is efficient as its computational complexity is in coNP in the worst case and in PTIME when the size of the new data is bounded.

Stereochemical and steric control of enzymatic glucuronidation : A rational approach for the design of novel Inhibitors for the human UDP-glucuronosyltransferase 2B7

The UDP-glucuronosyltransferases (UGTs) are enzymes of the phase II metabolic system. These enzymes catalyze the transfer of α-D-glucuronic acid from UDP-glucuronic acid to aglycones bearing nucleophilic groups affording exclusively their corresponding β-D-glucuronides to render lipophilic endobiotics and xenobiotics more water soluble. This detoxification pathway aids in the urinary and biliary excretion of lipophilic compounds thus preventing their accumulation to harmful levels. The aim of this study was to investigate the effect of stereochemical and steric features of substrates on the glucuronidation catalyzed by UGTs 2B7 and 2B17. Furthermore, this study relates to the design and synthesis of novel, selective inhibitors that display high affinity for the key enzyme involved in drug glucuronidation, UGT2B7. The starting point for the development of inhibitors was to assess the influence of the stereochemistry of substrates on the UGT-catalyzed glucuronidation reaction. A set of 28 enantiomerically pure alcohols was subjected to glucuronidation assays employing the human UGT isoforms 2B7 and 2B17. Both UGT enzymes displayed high stereoselectivity, favoring the glucuronidation of the (R)-enantiomers over their respective mirror-image compounds. The spatial arrangement of the hydroxy group of the substrate determined the rate of the UGT-catalyzed reaction. However, the affinity of the enantiomeric substrates to the enzymes was not significantly influenced by the spatial orientation of the nucleophilic hydroxy group. Based on these results, a rational approach for the design of inhibitors was developed by addressing the stereochemical features of substrate molecules. Further studies showed that the rate of the enzymatic glucuronidation of substrates was also highly dependent on the steric demand in vicinity of the nucleophilic hydroxy group. These findings provided a rational approach to turn high-affinity substrates into true UGT inhibitors by addressing stereochemical and steric features of substrate molecules. The tricyclic sesquiterpenols longifolol and isolongifolol were identified as high-affinity substrates which displayed high selectivity for the UGT isoform 2B7. These compounds served therefore as lead structures for the design of potent and selective inhibitors for UGT2B7. Selective and potent inhibitors were prepared by synthetically modifying the lead compounds longifolol and isolongifolol taking stereochemical and steric features into account. The best inhibitor of UGT2B7, β-phenyllongifolol, displayed an inhibition constant of 0.91 nM.

The Human UDP-Glucuronosyltransferases: Studies on Substrate Binding and Catalytic Mechanism

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The key enzyme in galactose metabolism, UDP-galactose-4-epimerase, affects cell-wall integrity and morphology in Candida albicans even in the absence of galactose

The enzyme UDP-galactose-4-epimerase (GAL10) catalyzes a key step in galactose metabolism converting UDP-galactose to UDPglucose which then can get metabolized through glycolysis and TCA cycle thus allowing the cell to use galactose as a carbon and energy source. As in many fungi, a functional homolog of GAL10 exists in Candida albicans. The domainal organization of the homologs from Saccharomyces cerevisiae and C albicans show high degree of homology having both mutarotase and an epimerase domain. The former is responsible for the conversion of beta-D-galactose to alpha-D-galactose and the hitter for epimerization of UDP-galactose to UDP-glucose. Absence of C albicans GAL10 (CaGAL10) affects cell-wall organization, oxidative stress response, biofilm formation and filamentation. Cagal10 mutant cells tend to flocculate extensively as compared to the wild-type cells. The excessive filamentation in this mutant is reflected in its irregular and wrinkled colony morphology. Cagal10 strain is more susceptible to oxidative stress when tested in presence of H2O2. While the S. cerevsiae GAL10 (ScGAL10), essential for survival in the presence of galactose, has not been reported to have defects in the absence of galactose, the C albicans homolog shows these phenotypes during growth in the absence of galactose. Thus a functional CaGal10 is required not only for galactose metabolism but also for normal hyphal morphogenesis, colony morphology, maintenance of cell-wall integrity and for resistance to oxidative stress even in the absence of galactose. (c) 2006 Elsevier Inc. All rights reserved.

Understanding Human Drug Conjugating Enzymes; Regio- and Stereoselectivity in Sulfotransferase 1A3 and the UDP-Glucuronosyltransferases

Sulfotransferases (SULTs) and UDP-glucuronosyltransferases (UGTs) are important detoxification enzymes and they contribute to bioavailability and elimination of many drugs. SULT1A3 is an extrahepatic enzyme responsible for the sulfonation of dopamine, which is often used as its probe substrate. A new method for analyzing dopamine-3-O-sulfate and dopamine-4-O-sulfate by high-performance liquid chromatography was developed and the enzyme kinetic parameters for their formation were determined using purified recombinant human SULT1A3. The results show that SULT1A3 strongly favors the 3-hydroxy group of dopamine, which indicates that it may be the major enzyme responsible for the difference between the circulating levels of dopamine sulfates in human blood. All 19 known human UGTs were expressed as recombinant enzymes in baculovirus infected insect cells and their activities toward dopamine and estradiol were studied. UGT1A10 was identified as the only UGT capable of dopamine glucuronidation at a substantial level. The results were supported by studies with human intestinal and liver microsomes. The affinity was low indicating that UGT1A10 is not an important enzyme in dopamine metabolism in vivo. Despite the low affinity, dopamine is a potential new probe substrate for UGT1A10 due to its selectivity. Dopamine was used to study the importance of phenylalanines 90 and 93 in UGT1A10. The results revealed distinct effects that are dependent on differences in the size of the side chain and on the differences in their position within the protein. Examination of twelve mutants revealed lower activity in all of them. However, the enzyme kinetic studies of four mutants showed that their affinities were similar to that of UGT1A10 suggesting that F90 and F93 are not directly involved in dopamine binding in the active site. The glucuronidation of β-estradiol and epiestradiol (α-estradiol) was studied to elucidate how the orientation of the 17-OH group affects conjugation at the 3-OH or the 17-OH of either diastereomer. The results show that there are clear differences in the regio- and stereoselectivities of UGTs. The most active isoforms were UGT1A10 and UGT2B7 demonstrating opposite regioselectivity. The stereoselectivities of UGT2Bs were more complex than those of UGT1As. The amino acid sequences of the human UGTs 1A9 and 1A10 are 93% identical, yet there are large differences in their activity and substrate selectivity. Several mutants were constructed to identify the residues responsible for the activity differences. The results revealed that the residues between Leu86 and Tyr176 of UGT1A9 determine the differences between UGT1A9 and UGT1A10. Phe117 of UGT1A9 participated in 1-naphthol binding and the residues at positions 152 and 169 contributed to the higher glucuronidation rates of UGT1A10. In summary, the results emphasize that the substrate selectivities, including regio- and stereoselectivities, of UGTs are complex and they are controlled by many amino acids rather than one critical residue.

UDP-glucose 4, 6-dehydratase Activity Plays an Important Role in Maintaining Cell Wall Integrity and Virulence of Candida albicans

Candida albicans, a human fungal pathogen, undergoes morphogenetic changes that are associated with virulence. We report here that GAL102 in C. albicans encodes a homolog of dTDP-glucose 4,6-dehydratase, an enzyme that affects cell wall properties as well as virulence of many pathogenic bacteria. We found that GAL102 deletion leads to greater sensitivity to antifungal drugs and cell wall destabilizing agents like Calcofluor white and Congo red. The mutant also formed biofilms consisting mainly of hyphal cells that show less turgor. The NMR analysis of cell wall mannans of gal102 deletion strain revealed that a major constituent of mannan is missing and the phosphomannan component known to affect virulence is greatly reduced. We also observed that there was a substantial reduction in the expression of genes involved in biofilm formation but increase in the expression of genes encoding glycosylphosphatidylinositol-anchored proteins in the mutant. These, along with altered mannosylation of cell wall proteins together might be responsible for multiple phenotypes displayed by the mutant. Finally, the mutant was unable to grow in the presence of resident peritoneal macrophages and elicited a weak pro-inflammatory cytokine response in vitro. Similarly, this mutant elicited a poor serum pro-inflammatory cytokine response as judged by IFN gamma and TNF alpha levels and showed reduced virulence in a mouse model of systemic candidiasis. Importantly, an Ala substitution for a conserved Lys residue in the active site motif YXXXK, that abrogates the enzyme activity also showed reduced virulence and increased filamentation similar to the gal102 deletion strain. Since inactivating the enzyme encoded by GAL102 makes the cells sensitive to antifungal drugs and reduces its virulence, it can serve as a potential drug target in combination therapies for C. albicans and related pathogens.

Performance analysis of UDP with energy efficient link layer on Markov fading channels

In this paper, we analyze the throughput and energy efficiency performance of user datagram protocol (UDP) using linear, binary exponential, and geometric backoff algorithms at the link layer (LL) on point-to-point wireless fading links. Using a first-order Markov chain representation of the packet success/failure process on fading channels, we derive analytical expressions for throughput and energy efficiency of UDP/LL with and without LL backoff. The analytical results are verified through simulations. We also evaluate the mean delay and delay variation of voice packets and energy efficiency performance over a wireless link that uses UDP for transport of voice packets and the proposed backoff algorithms at the LL. We show that the proposed LL backoff algorithms achieve energy efficiency improvement of the order of 2-3 dB compared to LL with no backoff, without compromising much on the throughput and delay performance at the UDP layer. Such energy savings through protocol means will improve the battery life in wireless mobile terminals.

SYNTHESIS OF CONCEPTUAL DESIGNS FOR SENSORS USING SAPPHIRE-LITE

The demand for variety of products and the shorter time to market is encouraging designers to adopt computer aided concept generation techniques. One such technique is being explored here. The present work makes an attempt towards synthesis of concepts for sensors using physical laws and effects as building blocks. A database of building blocks based upon the SAPPhIRE-lite model of causality is maintained. It uses composition to explore the solution space. The algorithm has been implemented in a web based tool. The tool generates two types of sensor designs: direct sensing designs and feedback sensing designs. According to the literature, synthesis using building blocks often lead to vague solutions principles. The current work tries to avoid uninteresting solutions by using some heuristics. A particularly novel outcome of the work described here is the generation of feedback based solutions, something not generated automatically before. A number of patent violations were observed with the set of generated concepts; thus emphasizing some amount of novelty in the designs.

Proposta de projeto de implementação de gerenciamento de serviços de TI baseado em ITIL V3, utilizando a abordagem ITIL Lite, para o Centro de Informática da Câmara dos Deputados

Com a retirada da ITIL V2 anunciada recentemente pela OGC, organizações do mundo todo que dependem dos serviços de TI começam a pensar em, pelo menos, dar início à implementação de gerenciamento de serviços de TI baseada em ITIL na sua versão 3. A partir de desdobramentos deste cenário mundial, o presente trabalho teve como objetivo apresentar uma proposta de plano de projeto para o Centro de Informática da Câmara dos Deputados do Brasil, identificando atividades baseadas na abordagem oficial ITIL Lite, que possibilita a implantação de um subconjunto de componentes ITIL V3 de acordo com a atual situação da organização, deixando o caminho aberto para uma eventual total implementação dos processos e funções.

Características antropométricas, condición física y velocidad de lanzamiento en balonmano de élite y amateur

166 p.

Cuantificación de la carga interna en jóvenes futbolistas de élite

Objetivo: El objetivo de este estudio es analizar los diferentes métodos existentes para la cuantificación de la carga interna (CI) en el fútbol y estudiar las diferencias existentes en la CI en jóvenes jugadores élite de fútbol dependiendo de las características de las sesiones, equipo y puestos. Métodos: Se obtuvo la carga percibida, y la frecuencia cardiaca de 36 jóvenes jugadores élite (18,87 ± 1,24 años, masa:70,81 ± 5,62 kg) de las sesiones de entrenamiento realizadas durante tres semanas. Resultados: Las correlación encontrada entre el método de Edwards-TL y Stagno-TL fue de r=0,921 ± 0,126 entre Edwards-TL y el método de Foster r=0,47 ± 0,343 y entre el método de Stagno-TL y el método de Foster fue de r=0,451 ± 0,386. Los distintos indicadores, sRPE, Edwards-TL y Stagno-TL describen una CI similar en los diferentes tipos de sesión analizadas (Recuperación, Simulación, Resistencia, Fuerza y Velocidad) aunque no siempre coincidían. Siendo la sesión denominada Resistencia la que acumulaba más CI (172,68 ± 47,87; 76,01 ± 28,62y 445,49 ± 115,02 AU; Edwards-TL, Stagno-TL y Foster respectivamente). No se encontraron diferencias significativas en la CI dependiendo de los puestos jugadores, y solo se encontraron diferencias significativas entre los jugadores más veteranos y jóvenes en la carga percibida. Conclusiones: Los diferentes tipos de sesión suponen una CI diferente para los jugadores. Las diferencias existentes entre los tipos de sesión varían dependiendo del método de cuantificación utilizado. Los indicadores de CI basados en la FC y en la carga percibida no siempre pueden ser intercambiables y pueden aportar información distinta a los técnicos.

Análisis de la mejora en el rendimiento en el test de 20 minutos en diez remeros de élite

En el siguiente estudio se analiza, mediante el test de 20 minutos, la mejora en el rendimiento de diez remeros pertenecientes a un club de elite. Estos sujetos, se sometieron a dos test en diferentes fechas de la temporada. Se hizo una comparación entre ambas pruebas. Las variables analizadas en esa comparación y que muestran la evolución de los deportistas son las siguientes: wattios, ritmo y frecuencia cardiaca. Analizando los wattios se calculó la potencia obtenida durante todo el test, con el ritmo nos referimos a las paladas por minuto y mirando la frecuencia cardiaca pudimos obtener dos indicadores: cuál es el porcentaje de la frecuencia cardiaca máxima con la que cada deportista realizó la prueba y en qué medida recuperaba cada sujeto.