Cisplatin-induced ototoxicity and pharmacokinetics: Preliminary findings in a dog model

The early effects of clinical dose of cisplatin (100 mg/m(2)) on distort ion-product otoacoustic emissions (DPOAE) thresholds and the relationship between DPOAE threshold shifts and changes in plasma concentrations of filterable and total platinum (Pt) following infusion of cisplatin in a dog model were investigated. The DPOAE thresholds (based on input-output function) were measured 2 days before a single high dose of cisplatin administration, and compared with measurements recorded 2 and 4 days after infusion. The results revealed DPOAE thresholds to be elevated by 4 days after the administration of cisplatin. However, this elevation could not be correlated with plasma concentrations of filterable and total Pt, which showed little variation over the 48-hour postinfusion period between animals. The present study demonstrated that DPOAE thresholds have the potential to be used as an indicator of cisplatin-induced ototoxicity, and cisplatin-induced ototoxicity could not be explained by plasma Pt kinetics in individual animals.

Stress correlation function evolution in lattice solid elasto-dynamic models of shear and fracture zones and earthquake prediction

It has been argued that power-law time-to-failure fits for cumulative Benioff strain and an evolution in size-frequency statistics in the lead-up to large earthquakes are evidence that the crust behaves as a Critical Point (CP) system. If so, intermediate-term earthquake prediction is possible. However, this hypothesis has not been proven. If the crust does behave as a CP system, stress correlation lengths should grow in the lead-up to large events through the action of small to moderate ruptures and drop sharply once a large event occurs. However this evolution in stress correlation lengths cannot be observed directly. Here we show, using the lattice solid model to describe discontinuous elasto-dynamic systems subjected to shear and compression, that it is for possible correlation lengths to exhibit CP-type evolution. In the case of a granular system subjected to shear, this evolution occurs in the lead-up to the largest event and is accompanied by an increasing rate of moderate-sized events and power-law acceleration of Benioff strain release. In the case of an intact sample system subjected to compression, the evolution occurs only after a mature fracture system has developed. The results support the existence of a physical mechanism for intermediate-term earthquake forecasting and suggest this mechanism is fault-system dependent. This offers an explanation of why accelerating Benioff strain release is not observed prior to all large earthquakes. The results prove the existence of an underlying evolution in discontinuous elasto-dynamic, systems which is capable of providing a basis for forecasting catastrophic failure and earthquakes.

The Three-dimensional Solution Structure of NaD1, a New Floral Defensin from Nicotiana alata and its Application to a Homology Model of the Crop Defense Protein alfAFP

NMR spectroscopy and simulated annealing calculations have been used to determine the three-dimensional structure of NaD1, a novel antifungal and insecticidal protein isolated from the flowers of Nicotiana alata. NaD1 is a basic, cysteine-rich protein of 47 residues and is the first example of a plant defensin from flowers to be characterized structurally. Its three-dimensional structure consists of an a-helix and a triple-stranded anti-parallel beta-sheet that are stabilized by four intramolecular disulfide bonds. NaD1 features all the characteristics of the cysteine-stabilized up motif that has been described for a variety of proteins of differing functions ranging from antibacterial insect defensins and ion channel-perturbing scorpion toxins to an elicitor of the sweet taste response. The protein is biologically active against insect pests, which makes it a potential candidate for use in crop protection. NaD1 shares 31% sequence identity with alfAFP, an antifungal protein from alfalfa that confers resistance to a fungal pathogen in transgenic potatoes. The structure of NaD1 was used to obtain a homology model of alfAFP, since NaD1 has the highest level of sequence identity with alfAFP of any structurally characterized antifungal defensin. The structures of NaD1 and alfAFP were used in conjunction with structure - activity data for the radish defensin Rs-AFP2 to provide an insight into structure-function relationships. In particular, a putative effector site was identified in the structure of NaD1 and in the corresponding homology model of alfAFP. (C) 2002 Elsevier Science Ltd. All rights reserved.

An energy-based model for swing hammer mills

An energy-based swing hammer mill model has been developed for coke oven feed preparation. it comprises a mechanistic power model to determine the dynamic internal recirculation and a perfect mixing mill model with a dual-classification function to mimic the operations of crusher and screen. The model parameters were calibrated using a pilot-scale swing hammer mill at various operating conditions. The effects of the underscreen configurations and the feed sizes on hammer mill operations were demonstrated through the fitted model parameters. Relationships between the model parameters and the machine configurations were established. The model was validated using the independent experimental data of single lithotype coal tests with the same BJD pilot-scale hammer mill and full operation audit data of an industrial hammer mill. The outcome of the energy-based swing hammer mill model is the capability to simulate the impact of changing blends of coal or mill configurations and operating conditions on product size distribution. Alternatively, the model can be used to select the machine settings required to achieve a desired product. (C) 2003 Elsevier Science B.V. All rights reserved.

Study of n-fold Weibull competing risk model

This paper deals with an n-fold Weibull competing risk model. A characterisation of the WPP plot is given along with estimation of model parameters when modelling a given data set. These are illustrated through two examples. A study of the different possible shapes for the density and failure rate functions is also presented. (C) 2003 Elsevier Ltd. All rights reserved.

Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down syndrome: Effects of environmental enrichment

Mental retardation in individuals with Down syndrome (DS) is thought to result from anomalous development and function of the brain; however, the underlying neuropathological processes have yet to be determined. Early implementation of special care programs result in limited, and temporary, cognitive improvements in DS individuals. In the present study, we investigated the possible neural correlates of these limited improvements. More specifically, we studied cortical pyramidal cells in the frontal cortex of Ts65Dn mice, a partial trisomy of murine chromosome 16 (MMU16) model characterized by cognitive deficits, hyperactivity, behavioral disruption and reduced attention levels similar to those observed in DS, and their control littermates. Animals were raised either in a standard or in an enriched environment. Environmental enrichment had a marked effect on pyramidal cell structure in control animals. Pyramidal cells in environmentally enriched control animals were significantly more branched and more spinous than non-enriched controls. However, environmental enrichment had little effect on pyramidal cell structure in Ts65Dn mice. As each dendritic spine receives at least one excitatory input, differences in the number of spines found in the dendritic arbors of pyramidal cells in the two groups reflect differences in the number of excitatory inputs they receive and, consequently, complexity in cortical circuitry. The present results suggest that behavioral deficits demonstrated in the Ts65Dn model could be attributed to abnormal circuit development.

Structural characterization of respiratory syncytial virus fusion inhibitor escape mutants: homology model of the F protein and a syncytium formation assay

Respiratory syncytial virus (RSV) is a ubiquitous human pathogen and the leading cause of lower respiratory tract infections in infants. Infection of cells and subsequent formation of syncytia occur through membrane fusion mediated by the RSV fusion protein (RSV-F). A novel in vitro assay of recombinant RSV-F function has been devised and used to characterize a number of escape mutants for three known inhibitors of RSV-F that have been isolated. Homology modeling of the RSV-F structure has been carried out on the basis of a chimera derived from the crystal structures of the RSV-F core and a fragment from the orthologous fusion protein from Newcastle disease virus (NDV). The structure correlates well with the appearance of RSV-F in electron micrographs, and the residues identified as contributing to specific binding sites for several monoclonal antibodies are arranged in appropriate solvent-accessible clusters. The positions of the characterized resistance mutants in the model structure identify two promising regions for the design of fusion inhibitors. (C) 2003 Elsevier Science (USA). All rights reserved.

A theoretical model of the evolution of virulence in sexually transmitted HIV/AIDS

INTRODUCTION: The evolution of virulence in host-parasite relationships has been the subject of several publications. In the case of HIV virulence, some authors suggest that the evolution of HIV virulence correlates with the rate of acquisition of new sexual partners. In contrast some other authors argue that the level of HIV virulence is independent of the sexual activity of the host population. METHODS: Provide a mathematical model for the study of the potential influence of human sexual behaviour on the evolution of virulence of HIV is provided. RESULTS: The results indicated that, when the probability of acquisition of infection is a function both of the sexual activity and of the virulence level of HIV strains, the evolution of HIV virulence correlates positively with the rate of acquisition of new sexual partners. CONCLUSION: It is concluded that in the case of a host population with a low (high) rate of exchange of sexual partners the evolution of HIV virulence is such that the less (more) virulent strain prevails.

Identificação de compostos que modulam a patogénese da doença de Machado-Joseph em C.elegans: autofagia como alvo terapêutico: identification of small compounds that modulate pathogenesis of Machado-Joseph disease in a C.elegans model: targeting autophagy

A doença de Machado-Joseph (DMJ) ou ataxia espinocerebelosa do tipo 3 (SCA3), conhecida por ser a mais comum das ataxias hereditárias dominantes em todo o mundo, é uma doença neurodegenerativa autossómica dominante que leva a uma grande incapacidade motora, embora sem alterar o intelecto, culminando com a morte do doente. Atualmente não existe nenhum tratamento eficaz para esta doença. A DMJ é resultado de uma alteração genética causada pela expansão de uma sequência poliglutamínica (poliQ), na região C-terminal do gene que codifica a proteína ataxina-3 (ATXN3). Os mecanismos celulares das doenças de poliglutaminas que provocam toxicidade, bem como a função da ATXN3, não são ainda totalmente conhecidos. Neste trabalho, usamos, pela sua simplicidade e potencial genético, um pequeno animal invertebrado, o nemátode C. elegans, com o objetivo de identificar fármacos eficazes para o combate contra a patogénese da DMJ, analisando simultaneamente o seu efeito na agregação da ATXN3 mutante nas células neuronais in vivo e o seu impacto no comportamento motor dos animais. Este pequeno invertebrado proporciona grandes vantagens no estudo dos efeitos tóxicos de proteínas poliQ nos neurónios, uma vez que a transparência das suas 959 células (das quais 302 são neurónios) facilita a deteção de proteínas fluorescentes in vivo. Para além disso, esta espécie tem um ciclo de vida curto, é económica e de fácil manutenção. Neste trabalho testámos no nosso modelo transgénico da DMJ com 130Qs em C.elegans dois compostos potencialmente moduladores da agregação da ATXN3 mutante e da resultante disfunção neurológica, atuando pela via da autofagia. De modo a validar a possível importância terapêutica da ativação da autofagia os compostos candidatos escolhidos foram o Litío e o análogo da Rapamicina CCI-779, testados independentemente e em combinação. A neuroproteção conferida pelo Litío e pelo CCI-779 independentemente sugere que o uso destes fármacos possa ser considerado uma boa estratégia como terapia para a DMJ, a testar em organismos evolutivamente mais próximos do humano. A manipulação da autofagia, segundo vários autores, parece ser benéfica e pode ser a chave para o desenvolvimento de novos tratamentos para várias doenças relacionadas com a agregação proteica e o envelhecimento.

Solving a signalized traffic intersection problem with an hyperbolic penalty function

Mathematical Program with Complementarity Constraints (MPCC) finds many applications in fields such as engineering design, economic equilibrium and mathematical programming theory itself. A queueing system model resulting from a single signalized intersection regulated by pre-timed control in traffic network is considered. The model is formulated as an MPCC problem. A MATLAB implementation based on an hyperbolic penalty function is used to solve this practical problem, computing the total average waiting time of the vehicles in all queues and the green split allocation. The problem was codified in AMPL.

A model for heterogeneous networks management and Performance evaluation

In general, modern networks are analysed by taking several Key Performance Indicators (KPIs) into account, their proper balance being required in order to guarantee a desired Quality of Service (QoS), particularly, cellular wireless heterogeneous networks. A model to integrate a set of KPIs into a single one is presented, by using a Cost Function that includes these KPIs, providing for each network node a single evaluation parameter as output, and reflecting network conditions and common radio resource management strategies performance. The proposed model enables the implementation of different network management policies, by manipulating KPIs according to users' or operators' perspectives, allowing for a better QoS. Results show that different policies can in fact be established, with a different impact on the network, e.g., with median values ranging by a factor higher than two.

Memória de longo prazo nos retornos acionistas dos índices de referência da euronext, implicações para a hipótese de mercados eficientes e contributo fractal para aperfeiçoamento do capital asset pricing model

Não existe uma definição única de processo de memória de longo prazo. Esse processo é geralmente definido como uma série que possui um correlograma decaindo lentamente ou um espectro infinito de frequência zero. Também se refere que uma série com tal propriedade é caracterizada pela dependência a longo prazo e por não periódicos ciclos longos, ou que essa característica descreve a estrutura de correlação de uma série de longos desfasamentos ou que é convencionalmente expressa em termos do declínio da lei-potência da função auto-covariância. O interesse crescente da investigação internacional no aprofundamento do tema é justificado pela procura de um melhor entendimento da natureza dinâmica das séries temporais dos preços dos ativos financeiros. Em primeiro lugar, a falta de consistência entre os resultados reclama novos estudos e a utilização de várias metodologias complementares. Em segundo lugar, a confirmação de processos de memória longa tem implicações relevantes ao nível da (1) modelação teórica e econométrica (i.e., dos modelos martingale de preços e das regras técnicas de negociação), (2) dos testes estatísticos aos modelos de equilíbrio e avaliação, (3) das decisões ótimas de consumo / poupança e de portefólio e (4) da medição de eficiência e racionalidade. Em terceiro lugar, ainda permanecem questões científicas empíricas sobre a identificação do modelo geral teórico de mercado mais adequado para modelar a difusão das séries. Em quarto lugar, aos reguladores e gestores de risco importa saber se existem mercados persistentes e, por isso, ineficientes, que, portanto, possam produzir retornos anormais. O objetivo do trabalho de investigação da dissertação é duplo. Por um lado, pretende proporcionar conhecimento adicional para o debate da memória de longo prazo, debruçando-se sobre o comportamento das séries diárias de retornos dos principais índices acionistas da EURONEXT. Por outro lado, pretende contribuir para o aperfeiçoamento do capital asset pricing model CAPM, considerando uma medida de risco alternativa capaz de ultrapassar os constrangimentos da hipótese de mercado eficiente EMH na presença de séries financeiras com processos sem incrementos independentes e identicamente distribuídos (i.i.d.). O estudo empírico indica a possibilidade de utilização alternativa das obrigações do tesouro (OT’s) com maturidade de longo prazo no cálculo dos retornos do mercado, dado que o seu comportamento nos mercados de dívida soberana reflete a confiança dos investidores nas condições financeiras dos Estados e mede a forma como avaliam as respetiva economias com base no desempenho da generalidade dos seus ativos. Embora o modelo de difusão de preços definido pelo movimento Browniano geométrico gBm alegue proporcionar um bom ajustamento das séries temporais financeiras, os seus pressupostos de normalidade, estacionariedade e independência das inovações residuais são adulterados pelos dados empíricos analisados. Por isso, na procura de evidências sobre a propriedade de memória longa nos mercados recorre-se à rescaled-range analysis R/S e à detrended fluctuation analysis DFA, sob abordagem do movimento Browniano fracionário fBm, para estimar o expoente Hurst H em relação às séries de dados completas e para calcular o expoente Hurst “local” H t em janelas móveis. Complementarmente, são realizados testes estatísticos de hipóteses através do rescaled-range tests R/S , do modified rescaled-range test M - R/S e do fractional differencing test GPH. Em termos de uma conclusão única a partir de todos os métodos sobre a natureza da dependência para o mercado acionista em geral, os resultados empíricos são inconclusivos. Isso quer dizer que o grau de memória de longo prazo e, assim, qualquer classificação, depende de cada mercado particular. No entanto, os resultados gerais maioritariamente positivos suportam a presença de memória longa, sob a forma de persistência, nos retornos acionistas da Bélgica, Holanda e Portugal. Isto sugere que estes mercados estão mais sujeitos a maior previsibilidade (“efeito José”), mas também a tendências que podem ser inesperadamente interrompidas por descontinuidades (“efeito Noé”), e, por isso, tendem a ser mais arriscados para negociar. Apesar da evidência de dinâmica fractal ter suporte estatístico fraco, em sintonia com a maior parte dos estudos internacionais, refuta a hipótese de passeio aleatório com incrementos i.i.d., que é a base da EMH na sua forma fraca. Atendendo a isso, propõem-se contributos para aperfeiçoamento do CAPM, através da proposta de uma nova fractal capital market line FCML e de uma nova fractal security market line FSML. A nova proposta sugere que o elemento de risco (para o mercado e para um ativo) seja dado pelo expoente H de Hurst para desfasamentos de longo prazo dos retornos acionistas. O expoente H mede o grau de memória de longo prazo nos índices acionistas, quer quando as séries de retornos seguem um processo i.i.d. não correlacionado, descrito pelo gBm(em que H = 0,5 , confirmando- se a EMH e adequando-se o CAPM), quer quando seguem um processo com dependência estatística, descrito pelo fBm(em que H é diferente de 0,5, rejeitando-se a EMH e desadequando-se o CAPM). A vantagem da FCML e da FSML é que a medida de memória de longo prazo, definida por H, é a referência adequada para traduzir o risco em modelos que possam ser aplicados a séries de dados que sigam processos i.i.d. e processos com dependência não linear. Então, estas formulações contemplam a EMH como um caso particular possível.

analytical model and measurements of the target erosion depth profile of balanced and unbalanced planar magnetron cathodes

The erosion depth profile of planar targets in balanced and unbalanced magnetron cathodes with cylindrical symmetry is measured along the target radius. The magnetic fields have rotational symmetry. The horizontal and vertical components of the magnetic field B are measured at points above the cathode target with z = 2 x 10(-3) m. The experimental data reveal that the target erosion depth profile is a function of the angle. made by B with a horizontal line defined by z = 2 x 10(-3) m. To explain this dependence a simplified model of the discharge is developed. In the scope of the model, the pathway lengths of the secondary electrons in the pre-sheath region are calculated by analytical integration of the Lorentz differential equations. Weighting these lengths by using the distribution law of the mean free path of the secondary electrons, we estimate the densities of the ionizing events over the cathode and the relative flux of the sputtered atoms. The expression so deduced correlates for the first time the erosion depth profile of the target with the angle theta. The model shows reasonably good fittings to the experimental target erosion depth profiles confirming that ionization occurs mainly in the pre-sheath zone.

Desirable role in an international duopoly model with tariffs

In this paper, we study an international market model in which the home government imposes a tariff on the imported goods. The model has two stages. In the first stage, the home government chooses an import tariff to maximize a function that cares about the home firm’s profit and the total revenue. Then, the firms engage in a Cournot or in a Stackelberg competition. We compare the results obtained in the three different ways of moving on the decision make of the firms.

Structure to function studies in UDP-glucose dehydrogenases and nitroreductases

The thesis is divided into two parts corresponding to structural studies on two different proteins. The first part concerns the study of two UDP-glucose dehydrogenases (UGDs) from Sphingomonas elodea ATCC 31461 and Burkholderia cepacia IST 408, both involved in exopolysaccharide production. Their relevance arises because some of these bacterial exopolysaccharides are valuable as established biotechnological products, the former case, whilst others are highly problematic, when used by pathogens in biofilm formation over biological surfaces, as the latter case, namely in the human lungs. The goal of these studies is to increase our knowledge regarding UGDs structural properties, which can potentiate either the design of activity enhancers to respond to the increased demand of useful biofilms, or the design of inhibitors of biofilm production, in order to fight invading pathogens present in several infections. The thesis reports the production and crystallisation of both proteins, the determination of initial phases by single-wavelength anomalous dispersion (SAD) in S. elodea crystals using a seleno-methionine isoform, and phasing of B. cepacia crystals by molecular replacement (MR) using the S. elodea model, as well as the refinement, structural analysis and comparison between the several UGDs structures available during this work.(...)