Can metal complexes serve as hypoxia activated prodrugs? Investigations of a Co(III) complex of the MMP inhibitor marimastat

For many years proof that the hypoxic nature of malignant tumours can be used to selectively target anticancer drugs has been sought. Several classes of potential redox activated anticancer drugs have been developed to take advantage of the reducing environment resulting from the hypoxia. Drug complexes with redox active metal centres as carriers have been investigated, but have largely been employed with cytotoxic drugs that require release of the drug intracellularly, complicating the design of such complexes. MMP inhibitors, a new class of anticancer drug, conversely act in the extracellular environment and we have investigated inhibitor complexes with several redox active transition metals. Marimastat is an MMP inhibitor with potent in-vitro antimetastatic activity and was recently in Phase III clinical trials for a variety of cancer types. We have synthesised a Co(II1) complex of marimastat incorporating the tetradentate ligand tpa (tris(2-methylpyridyl)amine) as a carrier ligand. The complex was structurally characterised in the solid state by single crystal X-ray diffraction, the first example of a crystal structure containing marimastat. 2D COSY and NOESY NMR spectra showed that the complex exists in two isomeric forms in solution, corresponding to the cis and trans isomers yet only crystallises in one of these forms. Biological testing of the complex in mice with 4T1.2 tumours showed interesting and unexpected outcomes. Initial results of the tumour growth inhibition study showed that a significant inhibition of growth was exhibited by the complex over the free inhibitor and the control. However, the metastatic potential of both free marimastat and the complex were higher than the control indicating likely problems with the experimental protocol. Further experiments are needed to determine the potential of such complexes as hypoxia activated prodrugs but there appears at least to be some promise.

Hierarchical determinants of capital structure

We analyze the influence of time-, firm-, industry- and country-level determinants of capital structure. First, we apply hierarchical linear modeling in order to assess the relative importance of those levels. We find that time and firm levels explain 78% of firm leverage. Second, we include random intercepts and random coefficients in order to analyze the direct and indirect influences of firm/industry/country characteristics on firm leverage. We document several important indirect influences of variables at industry and country-levels on firm determinants of leverage, as well as several structural differences in the financial behavior between firms of developed and emerging countries. (C) 2010 Elsevier B.V. All rights reserved.

Activation of visual areas during the attentional blink

When two targets are presented in rapid succession, identification of the first target is nearly perfect while identification of the second is severely impaired at shorter inter-target lags, and then gradually improves as lag increases. This second-target deficit is known as the attentional blink (AB). Numerous studies have implicated competition for access to higher-order processing mechanisms as the primary cause of the AB. However, relatively few studies have directly examined how the AB modulates activity in specific brain areas. To this end, we used fMRI to measure activation in the occipital and parietal cortices (including V1, V2, and area MT) during an AB task. Participants were presented with an initial target of oriented line segments embedded in a central stream of letter distractors. This central target was followed 100 - 700 ms later by a peripheral ‘X’ presented at one of four locations along with three ‘+’ distractors. All peripheral items were presented in the centre of a small field of moving dots. Participants made non-speeded judgments about line-segment orientation and the location of the second target at the end of a trial and to ignore all other stimuli. The results showed a robust AB characterised by a linear improvement in second-target accuracy as lag increased. This pattern of behavioural results was mirrored by changes in activation patterns across a number of visual areas indicating robust modulation of brain activity by the AB.

A synergistic relationship of elevated low-density lipoprotein cholesterol levels and systolic blood pressure with coronary artery calcification

We sought to evaluate this ""response-to-injury"" hypothesis of atherosclerosis by studying the interaction between systolic blood pressure (SBP) and LDL-cholesterol (LDL-C) in predicting the presence of coronary artery calcification (CAC) in asymptomatic men. We Studied 526 men (46 +/- 7 years of age) referred for electron-beam tomography (EBT) exam. The prevalence of CAC was determined across LDL-C tertiles (low: <115 mg/dl; middle: 115-139 mg/dl high: >= 140 mg/dl) within tertiles of SBP (low: <121 mmHg; middle: 121-130 mmHg; high: >= 131 mmHg). CAC was found in 220 (42%) men. There was no linear trend in the presence of CAC across LDL-C tertiles in the low (p = 0.6 for trend) and middle (p = 0.3 for trend) SBP tertile groups, respectively. In contrast, there was a significant trend for increasing CAC with increasing LDL-C (1st: 44%; 2nd: 49%; 3rd: 83%; p < 0.0001 for trend) in the high SBP tertile group. In multivariate logistic analyses (adjusting for age, smoking, triglyceride levels, HDL-cholesterol levels, body mass index, and fasting glucose levels), the odds ratio for any CAC associated with increasing LDL-C was significantly higher in those with highest SBP levels, whereas no such relationship was observed among men with SBP in the lower two tertiles. An interaction term (LDL-C x SBP) incorporated in the multivariate analyses was statistically significant (p = 0.038). The finding of an interaction between SBP and LDL-C relation to CAC in asymptomatic men support the response-to-injury model of atherogenesis. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

A new joint coding and modulation scheme for channels with clipping

A major limitation in any high-performance digital communication system is the linearity region of the transmitting amplifier. Nonlinearities typically lead to signal clipping. Efficient communication in such conditions requires maintaining a low peak-to-average power ratio (PAR) in the transmitted signal while achieving a high throughput of data. Excessive PAR leads either to frequent clipping or to inadequate resolution in the analog-to-digital or digital-to-analog converters. Currently proposed signaling schemes for future generation wireless communications suffer from a high PAR. This paper presents a new signaling scheme for channels with clipping which achieves a PAR as low as 3. For a given linear range in the transmitter's digital-to-analog converter, this scheme achieves a lower bit-error rate than existing multicarrier schemes, owing to increased separation between constellation points. We present the theoretical basis for this new scheme, approximations for the expected bit-error rate, and simulation results. (C) 2002 Elsevier Science (USA).

As formas simbólicas espaciais e a dinâmica da centralidade em Vitória : um esforço de análise

O presente trabalho aborda, sob a perspectiva da geografia cultural renovada, a temática das formas simbólicas no espaço urbano, tento como problematização o estudo de caso das formas simbólicas espaciais mais representativas da centralidade na Área Central de Vitória (ES). O interesse sobre o tema está associado o quadro relativamente recente no qual a Área Central de Vitória, sobretudo nas últimas duas décadas do século XX, passa a sofrer com um intenso processo de descentralização apresentando como alguns efeitos dessa dinâmica não só aparecimento de núcleos secundários de comércio e serviços afastados da Área Central, quanto também exerce um papel fundamental no que se ficou consagrado como “crise da área central”. Entretanto, se o quadro acima descrito é muito recente, por outro lado, durante o amplo período da produção do espaço urbano da capital capixaba em que a organização interna da cidade foi tributária, fundamentalmente, do processo de centralização, o Centro de Vitória foi o lócus privilegiado de materialização de formas simbólicas espaciais tipicamente associadas à centralidade intra-urbana tais como edificações que são símbolos dos poderes político, jurídico e econômico; igrejas; os monumentos, dentre outras formas simbólicas espaciais. Deste modo, a dissertação pretende investigar o advento da descentralização sobre as formas simbólicas espaciais tipicamente associadas à Área Central da capital capixaba, questionando em que medida essas formas permanecem enquanto signos de resistência simbólica a importância da área, bem como a natureza da eventual requalificação de significado ao qual foram, eventualmente, submetidas.

Effect of plant-biostimulant on cassava initial growth

ABSTRACT Biostimulants are complex substances that promote hormonal balance in plants, favor the genetic potential expression, and enhance growth of shoots and root system. The use of these plant growth promoters in crops can increase quantitatively and qualitatively crop production. Therefore, the aim of this study was to evaluate the effect of a commercial biostimulant on the initial growth of cassava. The experiment was arranged in a 2 x 5 factorial design, corresponding to two cassava cultivars (Cacau-UFV and Coimbra) and five biostimulant concentrations (0, 4, 8, 12 and 16 mL L-1). At 90 days after planting, the characteristics leaf area, plant height, stem diameter, leaf number, total dry matter and dry matter of roots, stems and leaves were evaluated. The biostimulant promoted linear increases in plant height, leaf number, leaf area, total dry matter, dry matter of stems, leaves and roots. The cultivar Cacau-UFV had a higher growth rate than the cultivar Coimbra. The growth promoter stimulated the early growth of the cassava crop.

Emoções positivas e motivação na reabilitação biopsicossocial

RESUMO: O presente estudo tem como principal objectivo verificar o fluxo emocional e a motivação para a mudança num programa de reabilitação biopsicossocial de alcoolismo e toxicodependências, com a duração de quatro semanas. Para esse efeito, procedeu-se à recolha da amostra de 30 participantes dentro do programa, utilizando para avaliar o fluxo emocional os relatos de episódios emocionais, o Teste de Positividade (TP), a Analogical Emotional Scale (AES), o Subjective Well-being (SWB), o Controlo Percebido Subjectivo (CPS) em três momentos distintos do programa, pelo que para avaliar a motivação foi utilizada a escala SOCRATES 8D no inicio e no final do programa de reabilitação. A teoria argumenta a existência de um aumento na satisfação pessoal e nas emoções positivas durante o processo de mudança, ou seja, quando o processo terapêutico decorre de forma favorável. Os resultados confirmam a existência de uma evolução linear positiva no TP, como também no SWB e CPS. Contudo não foi totalmente confirmado um aumento positivo da motivação, pelo que os resultados apenas demonstraram diferenças significativas na subescala Ambivalência da escala SOCRATES 8D, verificando-se um decréscimo acentuado entre os dois momentos, o que se revela favorável para o processo de mudança desejado no programa. ABSTRACT: The main objective of this study is to verify the emotional flow and the motivation for change process in a bio-psychosocial rehabilitation program for alcoholism and drug addictions, with a duration of four weeks. To this end, we proceeded to collect the sample of 30 participants in the program, to evaluate the emotional flow we use the emotional reports, the Positivity Test (PT), the Analogical Emotional Scale (AES), the Subjective Well-Being (SWB), the Subjective Perceived Control (PSC) in three separate moments of the program, to assess the motivation scale was used the SOCRATES 8D scale at the beginning and in the end of the rehabilitation program. The theory argues that there is an increase in personal satisfaction and positive emotions during the change process, when the therapeutic process runs optimally. The results confirm the existence of a positive linear trend in the PT, in SWB and CPS. However it was not totally confirmed an positive increase in motivation, so the results only showed significant differences in ambivalence subscale of the SOCRATES 8D, and there is a sharp decrease between the two moments, which proves favorable for the desired process of change in the program.

Interest rate exposure of Spanish banks: A nonparametric analysis

Interest rate risk is one of the major financial risks faced by banks due to the very nature of the banking business. The most common approach in the literature has been to estimate the impact of interest rate risk on banks using a simple linear regression model. However, the relationship between interest rate changes and bank stock returns does not need to be exclusively linear. This article provides a comprehensive analysis of the interest rate exposure of the Spanish banking industry employing both parametric and non parametric estimation methods. Its main contribution is to use, for the first time in the context of banks’ interest rate risk, a nonparametric regression technique that avoids the assumption of a specific functional form. One the one hand, it is found that the Spanish banking sector exhibits a remarkable degree of interest rate exposure, although the impact of interest rate changes on bank stock returns has significantly declined following the introduction of the euro. Further, a pattern of positive exposure emerges during the post-euro period. On the other hand, the results corresponding to the nonparametric model support the expansion of the conventional linear model in an attempt to gain a greater insight into the actual degree of exposure.

Desenvolvimento de um plano de manutenção preventiva na rede de distribuição de água de Lisboa

O presente relatório de estágio enquadra-se no âmbito do trabalho final de Mestrado do curso de Engenharia Civil, área de especialização em Hidráulica, do Instituto Superior de Engenharia de Lisboa, e incide na temática dos sistemas de distribuição de água. O estágio decorreu na empresa EPAL – Empresa Portuguesa das Águas Livres, S.A., e teve como objecto o desenvolvimento de um plano de manutenção preventiva para a rede de distribuição de água de Lisboa. Devido à crescente complexidade dos sistemas de abastecimento de água e à grande dispersão territorial dos diversos órgãos integrados na rede, surge a necessidade de desenvolver um sistema que permita simplificar o planeamento e a gestão das intervenções de inspecção e manutenção preventiva dos órgãos. Para esse efeito, recorreu-se a um software SIG (Sistema de Informação Geográfica) para proceder à sectorização da rede de distribuição de água em pequenos grupos (Polígonos), constituídos por um número determinado de órgãos de manobra e segurança. Esta metodologia permite organizar as intervenções em pequenos grupos e optimizar as rotinas de Inspecção diárias. No decorrer do estágio efectuou-se ainda um levantamento dos procedimentos de inspecção e manutenção dos diversos órgãos integrados na rede de distribuição de água de Lisboa, quer por acompanhamento de actividades com as equipas de inspecção, quer por recolha de recomendações junto dos fabricantes dos órgãos. Este levantamento permitiu elaborar fichas de procedimento para as actividades de inspecção e manutenção preventiva dos diversos órgãos, afim de serem usadas como referência pelos trabalhadores.

Development of a biosensor for urea assay based on amidase inhibition, using an ion-selective electrode

A biosensor for urea has been developed based on the observation that urea is a powerful active-site inhibitor of amidase, which catalyzes the hydrolysis of amides such as acetamide to produce ammonia and the corresponding organic acid. Cell-free extract from Pseudomonas aeruginosa was the source of amidase (acylamide hydrolase, EC 3.5.1.4) which was immobilized on a polyethersulfone membrane in the presence of glutaraldehyde; anion-selective electrode for ammonium ions was used for biosensor development. Analysis of variance was used for optimization of the biosensorresponse and showed that 30 mu L of cell-free extract containing 7.47 mg protein mL(-1), 2 mu L of glutaraldehyde (5%, v/v) and 10 mu L of gelatin (15%, w/v) exhibited the highest response. Optimization of other parameters showed that pH 7.2 and 30 min incubation time were optimum for incubation ofmembranes in urea. The biosensor exhibited a linear response in the range of 4.0-10.0 mu M urea, a detection limit of 2.0 mu M for urea, a response timeof 20 s, a sensitivity of 58.245 % per mu M urea and a storage stability of over 4 months. It was successfully used for quantification of urea in samples such as wine and milk; recovery experiments were carried out which revealed an average substrate recovery of 94.9%. The urea analogs hydroxyurea, methylurea and thiourea inhibited amidase activity by about 90%, 10% and 0%, respectively, compared with urea inhibition.

Evaluation of solubility and partition properties of ampicillin-based ionic liquids

In order to overcome the problems associated with low water solubility, and consequently low bioavailability of active pharmaceutical ingredients (APIs), herein we explore a modular ionic liquid synthetic strategy for improved APIs. Ionic liquids containing l-ampicillin as active pharmaceutical ingredient anion were prepared using the methodology developed in our previous work, using organic cations selected from substituted ammonium, phosphonium, pyridinium and methylimidazolium salts, with the intent of enhancing the solubility and bioavailability of l-ampicillin forms. In order to evaluate important properties of the synthesized API-ILs, the water solubility at 25 °C and 37 °C (body temperature) as well as octanol–water partition coefficients (Kow's) and HDPC micelles partition at 25 °C were measured. Critical micelle concentrations (CMC's) in water at 25 °C and 37 °C of the pharmaceutical ionic liquids bearing cations with surfactant properties were also determined from ionic conductivity measurements.

Contribuição para a caracterização da emissão de nanopartículas em processos de soldadura e avaliação de riscos decorrentes do processo

Trabalho Final de Mestrado para obtenção do grau de Mestre em Engenharia Química e Biológica Ramo de processos químicos

Lendo e explorando histórias: a emergência do pensamento algébrico em crianças de 4 anos

Dissertação apresentada à Escola Superior de Educação de Lisboa para obtenção do grau de mestre em Educação Matemática na Educação Pré-escolar e nos 1º e 2º Ciclos do Ensino Básico

Endothelialization of chitosan porous conduits via immobilization of a recombinant fibronectin fragment (rhFNIII7–10)

The present study aimed to develop a pre-endothelialized chitosan (CH) porous hollowed scaffold for application in spinal cord regenerative therapies. CH conduits with different degrees of acetylation (DA; 4% and 15%) were prepared, characterized (microstructure, porosity and water uptake) and functionalized with a recombinant fragment of human fibronectin (rhFNIII7–10). Immobilized rhFNIII7–10 was characterized in terms of amount (125I-radiolabelling), exposure of cell-binding domains (immunofluorescence) and ability to mediate endothelial cell (EC) adhesion and cytoskeletal rearrangement. Functionalized conduits revealed a linear increase in immobilized rhFNIII7–10 with rhFNIII7–10 concentration, and, for the same concentration, higher amounts of rhFNIII7–10 on DA 4% compared with DA 15%. Moreover, rhFNIII7–10 concentrations as low as 5 and 20 lgml 1 in the coupling reaction were shown to provide DA 4% and 15% scaffolds, respectively, with levels of exposed cell-binding domains exceeding those observed on the control (DA 4% scaffolds incubated in a 20 lgml 1 human fibronectin solution). These grafting conditions proved to be effective in mediating EC adhesion/cytoskeletal organization on CH with DA 4% and 15%, without affecting the endothelial angiogenic potential. rhFNIII7–10 grafting to CH could be a strategy of particular interest in tissue engineering applications requiring the use of endothelialized porous matrices with tunable degradation rates.