Differentiation of Cancer Stem Cells by Using Synthetic Small Molecules: Toward New Therapeutic Strategies against Therapy Resistance

Despite the existing arsenal of anti-cancer drugs, 10 million people die each year worldwide due to cancers; this highlights the need to discover new therapies based on innovative modes of action against these pathologies. Current chemotherapies are based on the use of cytotoxic agents, targeted drugs, monoclonal antibodies or immunotherapies that are able to reduce or stop the proliferation of cancer cells. However, tumor eradication is often hampered by the presence of resistant cells called cancer stem-like cells or cancer stem cells (CSCs). Several strategies have been proposed to specifically target CSCs such as the use of CSC-specific antibodies, small molecules able to target CSC signaling pathways or drugs able to induce CSC differentiation rendering them sensitive to classical chemotherapy. These latter compounds are the focus of the present review, which aims to report recent advances in anticancer-differentiation strategies. This therapeutic approach was shown to be particularly promising for eradicating tumors in which CSCs are the main reason for therapeutic failure. This general view of the chemistry and mechanism of action of compounds inducing the differentiation of CSCs could be particularly useful for a broad range of researchers working in the field of anticancer therapies as the combination of compounds that induce differentiation with classical chemotherapy could represent a successful approach for future therapeutic applications.     

Towards the generation of dialogue acts in socio-affective ECAs: a corpus-based prosodic analysis

We present a corpus-based prosodic analysis with the aim of uncovering the relationship between dialogue acts, personality and prosody in view to providing guidelines for the ECA Greta’s text-to-speech system. The corpus used is the SEMAINE corpus, featuring four different personalities, further annotated for dialogue acts and prosodic features. In order to show the importance of the choice of dialogue act taxonomy, two different taxonomies were used, the first corresponding to Searle’s taxonomy of speech acts and the second, inspired by Bunt’s DIT++, including a division of directive acts into finer categories. Our results show that finer-grained distinctions are important when choosing a taxonomy. We also show with some preliminary results that the prosodic correlates of dialogue acts are not always as cited in the literature and prove more complex and variable. By studying the realisation of different directive acts, we also observe differences in the communicative strategies of the ECA depending on personality, in view to providing input to a speech system.     

Review of the Year,Part II: 2001: A game of two halves

In Part 1 of this Review, we got as far as the middle of the year. The economic climate was driving a lot of discussion and technology usage seemed to take second place to what was economically viable. The major event of this year took place in September, but we still have a little way to go before we get there. And, don’t forget to check out our predictions for 2002 as well. But enough of the doom and gloom, let’s kick off Part II by revisiting some moments the world’s largest software firm would rather forget…     

Families of automata characterizing context-sensitive languages

In the hierarchy of infinite graph families, rational graphs are defined by rational transducers with labelled final states. This paper proves that their traces are precisely context-sensitive languages and that this result remains true for synchronized rational graphs.Received: 17 December 2003, Published online: 27 December 2004     

Exploration of GH94 Sequence Space for Enzyme Discovery Reveals a Novel Glucosylgalactose Phosphorylase Specificity

The substantial increase in DNA sequencing efforts has led to a rapid expansion of available sequences in glycoside hydrolase families. The ever-increasing sequence space presents considerable opportunities for the search for enzymes with novel functionalities. In this work, the sequence-function space of glycoside hydrolase family 94 (GH94) was explored in detail, using a combined approach of phylogenetic analysis and sequence similarity networks. The identification and experimental screening of unknown clusters led to the discovery of an enzyme from the soil bacterium Paenibacillus polymyxa that acts as a 4-O-β-d -glucosyl-d -galactose phosphorylase (GGalP), a specificity that has not been reported to date. Detailed characterization of GGalP revealed that its kinetic parameters were consistent with those of other known phosphorylases. Furthermore, the enzyme could be used for production of the rare disaccharides 4-O-β-d -glucosyl-d -galactose and 4-O-β-d -glucosyl-l -arabinose. Our current work highlights the power of rational sequence space exploration in the search for novel enzyme specificities, as well as the potential of phosphorylases for rare disaccharide synthesis.     

Impregnation of Composite Materials: a Numerical Study

Oxide ceramic matrix composites are currently being developed for aerospace applications such as the exhaust, where the parts are subject to moderately high temperatures (≈?700 ^°C) and oxidation. These composite materials are normally formed by, among other steps, impregnating a ceramic fabric with a slurry of ceramic particles. This impregnation process can be complex, with voids possibly forming in the fabric depending on the process parameters and material properties. Unwanted voids or macroporosity within the fabric can decrease the mechanical properties of the parts. In order to design an efficient manufacturing process able to impregnate the fabric well, numerical simulations may be used to design the process as well as the slurry. In this context, a tool is created for modeling different processes. Thétis, which solves the Navier-Stokes-Darcy-Brinkman equation using finite volumes, is expanded to take into account capillary pressures on the mesoscale. This formulation allows for more representativity than for Darcy’s law (homogeneous preform) simulations while avoiding the prohibitive simulation times of a full discretization for the composing fibers at the representative elementary volume scale. The resulting tool is first used to investigate the effect of varying the slurry parameters on impregnation evolution. Two different processes, open bath impregnation and wet lay-up, are then studied with emphasis on varying their input parameters (e.g. inlet velocity).     

Electroactive Ionic Soft Actuators with Monolithically Integrated Gold Nanocomposite Electrodes

Electroactive ionic gel/metal nanocomposites are produced by implanting supersonically accelerated neutral gold nanoparticles into a novel chemically crosslinked ion conductive soft polymer. The ionic gel consists of chemically crosslinked poly(acrylic acid) and polyacrylonitrile networks, blended with halloysite nanoclays and imidazolium‐based ionic liquid. The material exhibits mechanical properties similar to that of elastomers (Young's modulus ≈ 0.35 MPa) together with high ionic conductivity. The fabrication of thin (≈100 nm thick) nanostructured compliant electrodes by means of supersonic cluster beam implantation (SCBI) does not significantly alter the mechanical properties of the soft polymer and provides controlled electrical properties and large surface area for ions storage. SCBI is cost effective and suitable for the scaleup manufacturing of electroactive soft actuators. This study reports the high‐strain electromechanical actuation performance of the novel ionic gel/metal nanocomposites in a low‐voltage regime (from 0.1 to 5 V), with long‐term stability up to 76 000 cycles with no electrode delamination or deterioration. The observed behavior is due to both the intrinsic features of the ionic gel (elasticity and ionic transport capability) and the electrical and morphological features of the electrodes, providing low specific resistance (<100 Ω cm^?2), high electrochemical capacitance (≈mF g^?1), and minimal mechanical stress at the polymer/metal composite interface upon deformation.     

When,where, and for what industries does broadband foster establishment births?

We examine the effects of broadband on establishment births for five types of areas, six industries and two speed levels. Econometric results indicate that broadband has an overall positive effect in larger, medium and small urban centres and in periurban areas but has little or no impact in rural areas. However, industry-level analyses show that broadband can foster establishment births in rural areas in some industries, including selected knowledge-intensive industries. Finally, there are no great differences between the impacts of basic and fast broadband, except in larger urban centres with a higher skilled workforce able to use sophisticated applications.