DNA-binding preferences of bisantrene analogues: relevance to the sequence specificity of drug-mediated topoisomerase II poisoning

To elucidate structure-activity relationships for drugs that are able to poison or inhibit topoisomerase II, we investigated the thermodynamics and stereochemistry of the DNA binding of a number of anthracene derivatives bearing one or two 4, 5-dihydro-1H-imidazol-2-yl-hydrazone side chains (characteristic of bisantrene) at different positions of the planar aromatic system. An aza-bioisostere, which can be considered a bisantrene-amsacrine hybrid, was also tested. The affinity for nucleic acids in different sequence contexts was evaluated by spectroscopic techniques, using various experimental conditions. DNA-melting and DNase I footprinting experiments were also performed. The location and number of the otherwise identical side chains dramatically affected the affinity of the test compounds for the nucleic acid. In addition, the new compounds exhibited different DNA sequence preferences, depending on the locations of the dihydroimidazolyl-hydrazone groups, which indicates a major role for the side-chain position in generating specific contacts with the nucleic acid. Molecular modeling studies of the intercalative binding of the 1- or 9-substituted isomers to DNA fully supported the experimental data, because a substantially more favorable recognition of A-T steps, compared with G-C steps, was found for the 9-substituted derivative, whereas a much closer energy balance was found for the 1-substituted isomer. These results compare well with the alteration of base specificity found for the topoisomerase II-mediated DNA cleavage stimulated by the isomeric drugs. Therefore, DNA-binding specificity appears to represent an important determinant for the recognition of the topoisomerase-DNA cleavable complex by the drug, at least for poisons belonging to the amsacrine-bisantrene family.     

Conjugated effects of the compatibilization and the dynamic vulcanization on the phase inversion behavior in poly(butylene terephthalate)/epoxide-containing rubber reactive polymer blends

The conjugated effects of both reactive compatibilization and dynamic vulcanization on the phase inversion behavior of poly(butylene terephthalate) (PBT)/epoxide-containing rubber blends have been studied in detail. Pure ethylene-methyl acrylate random copolymer (E-MA) and ethylene-methyl acrylate-glycidyl methacrylate random terpolymer (E-MA-GMA) were used as non reactive or reactive rubber phase, respectively. Location of the phase inversion region was studied using several techniques, including transmission electron microscopy (TEM) and dynamical mechanical thermal analysis (DMTA). To evaluate the relative influence of the blend compatibilization and the dynamic vulcanization on the phase inversion behavior, the relative kinetics of the two reactions were modified using different PBT and E-MA-GMA grades. The obtained results show unambiguously that the position and the width of the phase inversion region is essentially governed by the kinetic of the dynamic vulcanization process. The effect of the blend compatibilization remains quite limited even in the case of fast interfacial reaction. The crosslinking of the rubber phase induces an important shift of the phase inversion composition to higher rubber content. For blends containing low molecular weight PBT, up to 60 wt% of rubber can be homogeneously dispersed in the PBT matrix at long mixing time. In this case, development of high performance PBT based thermoplastic vulcanisates can be envisioned.     

Mechanical characterization and modeling of the deformation and failure of the highly crosslinked RTM6 epoxy resin

The nonlinear deformation and fracture of RTM6 epoxy resin is characterized as a function of strain rate and temperature under various loading conditions involving uniaxial tension, notched tension, uniaxial compression, torsion, and shear. The parameters of the hardening law depend on the strain-rate and temperature. The pressure-dependency and hardening law, as well as four different phenomenological failure criteria, are identified using a subset of the experimental results. Detailed fractography analysis provides insight into the competition between shear yielding and maximum principal stress driven brittle failure. The constitutive model and a stress-triaxiality dependent effective plastic strain based failure criterion are readily introduced in the standard version of Abaqus, without the need for coding user subroutines, and can thus be directly used as an input in multi-scale modeling of fibre-reinforced composite material. The model is successfully validated against data not used for the identification and through the full simulation of the crack propagation process in the V-notched beam shear test.     

Close Shadowing Natural Versus Synthetic Speech

Close shadowing experiments involving natural and synthetic stimuli are described. Preliminary results show that speakers are able to follow natural stimuli with an average delay of 70 ms whereas this delay typically exceeds 100 ms for stimuli produced by text-to-speech systems. A complementary experiment shows that this contrast is mainly due to the inappropriate or impoverished prosody generated by actual text-to-speech systems.     

Causal fault detection and isolation based on a set-membership approach

This paper presents a diagnostic methodology relying on a set-membership approach for fault detection and on a causal model for fault isolation. Set-membership methods are a promising approach to fault detection because they take into account a priori knowledge of model uncertainties and measurement errors. Every uncertain model parameter and/or measurement is represented by a bounded variable. In this paper, detection consists of verifying the membership of measurements to an interval. First order discrete time models are used and their output is explicitly computed with interval arithmetic. Fault isolation relies on a causal analysis and the exoneration principle, which allows focusing the consistency tests on simple local models. The isolation strategy consists of two steps: performing minimal tests found with the causal graph and determining on line additional relevant tests that reduce the final diagnosis. An application for a nuclear process is used in order to illustrate the method's efficiency.     

Combining FDI and AI approaches within causal-model-based diagnosis.

This paper presents a model-based diagnostic method designed in the context of process supervision. It has been inspired by both artificial intelligence and control theory. AI contributes tools for qualitative modeling, including causal modeling, whose aim is to split a complex process into elementary submodels. Control theory, within the framework of fault detection and isolation (FDI), provides numerical models for generating and testing residuals, and for taking into account inaccuracies in the model, unknown disturbances and noise. Consistency-based reasoning provides a logical foundation for diagnostic reasoning and clarifies fundamental assumptions, such as single fault and exoneration. The diagnostic method presented in the paper benefits from the advantages of all these approaches. Causal modeling enables the method to focus on sufficient relations for fault isolation, which avoids combinatorial explosion. Moreover, it allows the model to be modified easily without changing any aspect of the diagnostic algorithm. The numerical submodels that are used to detect inconsistency benefit from the precise quantitative analysis of the FDI approach. The FDI models are studied in order to link this method with DX component-oriented reasoning. The recursive on-line use of this algorithm is explained and the concept of local exoneration is introduced.     

Investigation of Functional Hemispheric Asymmetry of Language in Tinnitus Sufferers.

The authors tested functional hemispheric asymmetry through word dichotic listening and lateralized lexical decision tasks in tinnitus patients and controls stimulated by a continuous tinnitus-like noise to test the influence of a tinnitus-like external stimulation. A classic right-ear advantage was shown in the auditory task for all but right-ear tinnitus patients, who performed as equally badly when the stimuli were presented to the right and left ears. Concerning the visual task, all participants demonstrated the expected right visual field advantage for word stimuli. Moreover, those who submitted to external stimulation demonstrated normal asymmetric patterns. These data suggest a specific effect of tinnitus on central processing and provide evidence for a functional reorganization induced by this auditory phantom perception. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

MINIATURE PULSE TUBE FOR THE COOLING OF ELECTRONIC DEVICES: FUNCTIONING PRINCIPLES AND PRACTICAL MODELING

The miniaturization of refrigerating systems represents a very current scientific and technical challenge to improve the performances of numerous electronic components. This work presents a global approach to the problem and suggests studying the cooling by means of small channels filled with an oscillating gas: the double inlet pulse tube refrigerator (DIPTR). A great level of miniaturization based on the technology of carving silicon is exposed. This study proposes to apply an electric analogy for modeling both hydrodynamic and thermal phenomena. Considering the complexity of the theoretical problem including mechanical, thermal, thermodynamical, and acoustic considerations, the authors take care to summarize the main governing equations in a particular form so any scientific engineer could understand the DIPTR principle.