Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease

Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-I, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 mu M. Their activities against HIV-1 protease (K-i 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC50 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC50 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 Angstrom (1) and 1.85 Angstrom (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.

Knowledge-based system on optimum design of liquid retaining structures with genetic algorithms

This paper delineates the development of a prototype hybrid knowledge-based system for the optimum design of liquid retaining structures by coupling the blackboard architecture, an expert system shell VISUAL RULE STUDIO and genetic algorithm (GA). Through custom-built interactive graphical user interfaces under a user-friendly environment, the user is directed throughout the design process, which includes preliminary design, load specification, model generation, finite element analysis, code compliance checking, and member sizing optimization. For structural optimization, GA is applied to the minimum cost design of structural systems with discrete reinforced concrete sections. The design of a typical example of the liquid retaining structure is illustrated. The results demonstrate extraordinarily converging speed as near-optimal solutions are acquired after merely exploration of a small portion of the search space. This system can act as a consultant to assist novice designers in the design of liquid retaining structures.

A coupled knowledge-based expert system for design of liquid-retaining structures

This paper describes a coupled knowledge-based system (KBS) for the design of liquid-retaining structures, which can handle both the symbolic knowledge processing based on engineering heuristics in the preliminary synthesis stage and the extensive numerical crunching involved in the detailed analysis stage. The prototype system is developed by employing blackboard architecture and a commercial shell VISUAL RULE STUDIO. Its present scope covers design of three types of liquid-retaining structures, namely, a rectangular shape with one compartment, a rectangular shape with two compartments and a circular shape. Through custom-built interactive graphical user interfaces, the user is directed throughout the design process, which includes preliminary design, load specification, model generation, finite element analysis, code compliance checking and member sizing optimization. It is also integrated with various relational databases that provide the system with sectional properties, moment and shear coefficients and final member details. This system can act as a consultant to assist novice designers in the design of liquid-retaining structures with increase in efficiency and optimization of design output and automated record keeping. The design of a typical example of the liquid-retaining structure is also illustrated. (C) 2003 Elsevier B.V All rights reserved.

Synthesis and characterization of mono- and bis-ligand zinc(II) and cadmium(II) complexes of the di-2-pyridylketone Schiff base of S-benzyl dithiocarbazate (Hdpksbz) and the X-ray crystal structures of the [Zn(dpksbz)2] and [Cd(dpksbz)NCS]2 complexes

New mono- and bis-chelated zinc(II) and cadmium(II) complexes of formula, [M(dpksbz)NCS] (dpksbz = anionic form of the di-2-pyridylketone Schiff base of S-benzyldithiocarbazate) and [M(dpksbz)(2)] (M = Zn-II, Cd-II) have been prepared and characterized. The structure of the bis-ligand complex, [Zn(dpksbZ)(2)] has been determined by X-ray diffraction. The complex has a distorted octahedral geometry in which the ligands are coordinated to the zinc(II) ion as uninegatively charged tridentate chelates via the thiolate sulfur atoms, the azomethine nitrogen atoms and the pyridine nitrogen atoms. The distortion from a regular octahedral geometry is attributed to the restricted bite angles of the Schiff base ligands. X-ray structural analysis shows that the [Cd(dpksbz)NCS](2) complex is a centrosymmetric dimer in which each of the cadmium(II) ions adopts a five-coordinate, approximately square-pyramidal configuration with the Schiff base acting as a tetradentate chelating agent coordinating a cadmium(II) ion via one of the pyridine nitrogen atoms, the azomethine nitrogen atom and the thiolate sulfur atom; the second pyridine nitrogen atom is coordinated to the other cadmium(II) ion of the dimer. The fifth coordination position around each cadmium(II) is occupied by an N-bonded thiocyanate ligand. (C) 2003 Elsevier Science Ltd. All rights reserved.

Geometric nonlinear analysis of thin plates by a refined nonlinear non-conforming triangular plate element

Based on the refined non-conforming element method for geometric nonlinear analysis, a refined nonlinear non-conforming triangular plate element is constructed using the Total Lagrangian (T.L.) and the Updated Lagrangian (U.L.) approach. The refined nonlinear non-conforming triangular plate element is based on the Allman's triangular plane element with drilling degrees of freedom [1] and the refined non-conforming triangular plate element RT9 [2]. The element is used to analyze the geometric nonlinear behavior of plates and the numerical examples show that the refined non-conforming triangular plate element by the T.L. and U.L. approach can give satisfactory results. The computed results obtained from the T.L. and U.L. approach for the same numerical examples are somewhat different and the reasons for the difference of the computed results are given in detail in this paper. © 2003 Elsevier Science Ltd. All rights reserved.

Trends in physical activity participation and the impact of integrated campaigns among Australian adults, 1997-99

Objectives: To determine whether awareness of the moderate physical activity message and prevalence of participation changed among Australian adults between 1997 and 1999, and if changes differed across Australia. Methods: Data were compared on awareness of the moderate physical activity message and on physical activity participation from identical national physical activity surveys in 1997 and 1999. Results: In 1999, following integrated public health efforts, recognition of the Active Australia campaign was substantially higher in NSW/ACT (61.7%) than elsewhere (29.3%). Knowledge about benefits of moderate activity increased between 1997 and 1999, more so in States with public health campaigns. National participation in 'sufficient physical activity' declined between 1997 and 1999, from 63% to 57%, but the decline was smaller in NSW/ACT (4.4%) than in the other States (6.0%). Conclusions and implications: Declining trends in physical activity in Australia require increased public health investments, including strategic planning and public education, such as occurred in NSW (1997/98).

Representing organizational structures in enterprise architecture : an ontology-based approach

Arquitetura Corporativa promove o estabelecimento de uma visão holística da estrutura e forma de trabalho de uma organização. Um dos aspectos abordados em Arquitetura Corporativa está associada a "estrutura ativa" da organização, que diz respeito a “quem" realiza as atividades organizacionais. Várias abordagens têm sido propostas a fim de proporcionar um meio para a representação de Arquitetura Corporativa, entre as quais ARIS, RM-ODP, UPDM e ArchiMate. Apesar da aceitação por parte da comunidade, as abordagens existentes se concentram em propósitos diferentes, têm limitações de escopo e algumas não têm semântica de mundo real bem definida. Além das abordagens de modelagem, muitas abordagens de ontologias têm sido propostas, a fim de descrever o domínio de estrutura ativa, incluindo as ontologias de SUPER Project, TOVE, Enterprise Ontology e W3C Org Ontology. Embora especificadas para fundamentação semântica e negociação de significado, algumas das abordagens propostas têm fins específicos e cobertura limitada. Além disso, algumas das abordagens não são definidas usando linguagens formais e outras são especificadas usando linguagens sem semântica bem definida. Este trabalho apresenta uma ontologia de referência bem fundamentada para o domínio organizacional. A ontologia organizacional de referência apresentada abrange os aspectos básicos discutidos na literatura organizacional, tais como divisão do trabalho, relações sociais e classificação das unidades estruturais. Além disso, também abrange os aspectos organizacionais definidos em abordagens existentes, levando em consideração tanto abordagens de modelagem quanto abordagens ontológicas. A ontologia resultante é especificada em OntoUML e estende os conceitos sociais de UFO-C.

Mentoplastia para avanço do músculo genioglosso em pacientes com síndrome da apnéia-hipopnéia do sono obstrutiva e retrognatismo mandibular

A Síndrome da Apnéia-Hipopnéia do Sono Obstrutiva (SAHSO) é um doença de fisiopatologia complexa, e sua etiologia é multifatorial e não entendida completamente. Cirurgia com avanço do músculo genioglosso é indicado em obstrução na região de hipofaringe. OBJETIVO: Avaliar a eficácia e complicações da técnica de mentoplastia para avanço do músculo genioglosso em pacientes com síndrome da apnéia-hipopnéia do sono obstrutiva (SAHSO). MÉTODOS: Polissonografia, exame físico e análise cefalométrica foram realizados em 10 pacientes não-obesos, que apresentavam SAHSO leve ou moderada, índice de apnéia-hipopnéia (IAH) entre 5 e 30, obstrução de hipofaringe e retrognatismo mandibular. RESULTADOS: IAH pré-operatório médio foi de 12,4±4,6 diminuindo a média pós-operatória para 4,4±5,7 (p < 0,001). Quando 50% de redução do IAH pré-operatório foram escolhidos como parâmetro, o índice de sucesso foi de 70%. A análise cefalométrica revelou um aumento do espaço aéreo posterior (EAP) em todos os pacientes, a média pré-operatória foi de 7,9±2,3mm para uma média pós-operatória de 10,8±2,5mm (p < 0,001). CONCLUSÃO: Mentoplastia para avanço do músculo genioglosso parece reduzir os sinais da SAHSO, podendo ser considerada uma opção com tratamento cirúrgico em pacientes com obstrução na hipofaringe. Os dados coletados indicam esse procedimento como opção em pacientes com SAHSO e retrognatismo mandibular.

Anquilose da articulação têmporo-mandibular

A anquilose pode ser definida como sendo a fusão das superfícies articulares e seu tratamento é um verdadeiro desafio devido à alta taxa de recorrência. OBJETIVO: Descrever seis casos clínicos tratados pela técnica da reconstrução articular, avaliar os resultados dessas cirurgias e fazer uma revisão da literatura. METODOLOGIA: A população estudada neste estudo retrospectivo foi obtida dos prontuários do hospital universitário e tinha que ter sido submetida a cirurgia para tratamento de anquilose por reconstrução aloplástica ou autógena entre os períodos de março de 2001 e outubro de 2005. Dados como a máxima abertura de boca (MAB), etiologia, tipo de anquilose e tratamento, e ocorrência de recidiva e lesão do nervo facial foram coletados no pré-operatório, através dos prontuários, e no pós-operatório, através de entrevista. RESULTADOS: A média da MAB no pré-operatório foi de 9,6mm (0 a 17mm) e no pós-operatório foi de 31,33mm (14mm a 41mm), não houve lesão do nervo facial e apenas em um caso houve recidiva da anquilose. CONCLUSÃO: A reconstrução da articulação com material autógeno ou alógeno, para o tratamento da anquilose da ATM se mostrou eficaz em relação à MAB pós-operatória, recidiva e função da articulação.

Ameloblastoma mandibular tratado por ressecção óssea e reconstrução imediata

O ameloblastoma multicístico acomete principalmente pacientes adultos, entre a terceira e a sétima década de vida, freqüentemente na região posterior de mandíbula. A ressecção de um segmento mandibular, sem reconstrução adequada, produz grave seqüela estética e funcional levando a uma perda da qualidade de vida. O objetivo desta apresentação é mostrar que o tratamento multidisciplinar do ameloblastoma possibilita radicalidade oncológica associada à completa reconstrução da área lesada. Apresentamos um paciente de 47 anos, acometido por um ameloblastoma em região posterior de mandíbula tratado com ressecção completa de um segmento mandibular. A reconstrução no mesmo tempo operatório utilizou enxerto ósseo de crista ilíaca fixado com placas e parafusos de titânio. Após oito meses completou-se a reabilitação com implantes de elementos dentários na área do enxerto. As vantagens deste procedimento incluem a diminuição do risco de recidivas pelo uso da ressecção segmentar, reconstrução mandibular confiável e diminuição do número de procedimentos cirúrgicos, permitindo completa reabilitação em um período mais curto de tempo.

Trends in South American weapons purchases at the beginning of the new millennium

In recent years, with some frequency it is heard that Latin America, especially South America, is witnessing the rise of an arms race. Frequent reports in the press and strong statements made by politicians in the region have fueled this fear. At the same time, scholars have also reached to this conclusion, as pointed out by Malamud and Garcia: "The famous arms race in Latin America, led by Venezuela, is no longer just talk."

Morphometry of testis and seminiferous tubules of the adult crab-eating fox (Cerdocyon thous, Linnaeus, 1766)

Body and testicular biometric parameters are very important for establishing reproductive patterns and, consequently, the development of protocols for assisted reproduction in different species. A direct correlation between the testis weight and the sperm population was observed in other studied species, because the testis size primarily reflects the total volume of the seminiferous tubule, its main component. The objective of this study was to determine the testicular volume parameters and correlate data from morphometry of testis and seminiferous tubules with body mass in six adult crab-eating foxes. The mean body weight of the crab-eating foxes in this study was 6.53 kg, with approximately 0.068% allocated to the testicular mass and 0.042% specifically to seminiferous tubules, which represented 87.5% of the testicular parenchyma. The albuginea comprised 12.5% of the testicular mass. The mean diameter of seminiferous tubules was 236 µm, and the mean thickness of the seminiferous epithelium was 62.9 µm. Values of tubular parameters indicate a sperm productivity close to those observed in previously studied carnivores.

Chronic stress disrupts neural coherence between cortico-limbic structures

Chronic stress impairs cognitive function, namely on tasks that rely on the integrity of cortico-limbic networks. To unravel the functional impact of progressive stress in cortico-limbic networks we measured neural activity and spectral coherences between the ventral hippocampus (vHIP) and the medial prefrontal cortex (mPFC) in rats subjected to short term stress (STS) and chronic unpredictable stress (CUS). CUS exposure consistently disrupted the spectral coherence between both areas for a wide range of frequencies, whereas STS exposure failed to trigger such effect. The chronic stress-induced coherence decrease correlated inversely with the vHIP power spectrum, but not with the mPFC power spectrum, which supports the view that hippocampal dysfunction is the primary event after stress exposure. Importantly, we additionally show that the variations in vHIP-to-mPFC coherence and power spectrum in the vHIP correlated with stress-induced behavioral deficits in a spatial reference memory task. Altogether, these findings result in an innovative readout to measure, and follow, the functional events that underlie the stress-induced reference memory impairments.