Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia

Growing evidence is showing that acetylation plays an essential role in cancer, but studies on the impact of KDAC inhibition (KDACi) on the metabolic profile are still in their infancy. Here, we analyzed, by using an iTRAQ-based quantitative proteomics approach, the changes in the proteome of KRAS-mutated non-small cell lung cancer (NSCLC) A549 cells in response to trichostatin-A (TSA) and nicotinamide (NAM) under normoxia and hypoxia. Part of this response was further validated by molecular and biochemical analyses and correlated with the proliferation rates, apoptotic cell death, and activation of ROS scavenging mechanisms in opposition to the ROS production. Despite the differences among the KDAC inhibitors, up-regulation of glycolysis, TCA cycle, oxidative phosphorylation and fatty acid synthesis emerged as a common metabolic response underlying KDACi. We also observed that some of the KDACi effects at metabolic levels are enhanced under hypoxia. Furthermore, we used a drug repositioning machine learning approach to list candidate metabolic therapeutic agents for KRAS mutated NSCLC. Together, these results allow us to better understand the metabolic regulations underlying KDACi in NSCLC, taking into account the microenvironment of tumors related to hypoxia, and bring new insights for the future rational design of new therapies.     

Local residence time,residence revolution,and residence volume distributions in twin‐screw extruders

This work was aimed at studying the overall, partial, and local residence time distributions (RTD); overall, partial and local residence revolution distributions (RRD) and overall, partial and local residence volume distributions (RVD) in a co‐rotating twin screw extruder, on the one hand; and establishing the relationships among them, on the other hand. Emphasis was placed on the effects of the type and geometry of mixing elements (a gear block and various types of kneading elements differing in staggering angle) and process parameters on the RTD, RRD and RVD. The overall and partial RTD were directly measured in‐line during the extrusion process and the local ones were calculated by deconvolution based on a statistical theory. The local RTD allowed comparing the mixing performance of mixing elements. Also it was confirmed both experimentally and theoretically that specific throughput, defined as a ratio of throughput (Q) over screw speed (N), controlled all the above three types of residence distributions, be they local, partial or overall. The RRD and RVD do not provide more information on an extrusion process than the corresponding RTD. Rather they are different ways of representing the same phenomena. POLYM. ENG. SCI., 48:19–28, 2008. © 2007 Society of Plastics Engineers     

JaTS: a fully portable seismic tomography software based on Fresnel wavepaths and a probabilistic reconstruction approach

JaTS, a Java 2D seismic tomography software, is presented. It implements original algorithms achieving optimal accuracy with reasonable computing costs. A second-order Fast Marching Method (FMM) is used for solving the eikonal equation, therefore enabling a fast and robust computation of seismic traveltimes between sources and receivers. The wavepaths are materialized by Fresnel volumes rather than by conventional rays. This approach accounts for complex velocity models and has the advantage of considering the effects of the wave frequency in the velocity model resolution. The model is computed by a Simultaneous Iterative Reconstruction Technique (SIRT) which has been reformulated to integrate Fresnel wavepaths by using a probabilistic approach. In addition, various utilities are implemented, such as a tapering filter, used to decrease artifact effects occurring in the vicinity of the sources and receivers. The software also offers the possibility of reconstructing the velocity field on a grid larger than the one used for the wave propagation computation. This contributes to stabilize the estimated values. All of the seismic processing tools have been integrated with a user-friendly graphical interface. JaTS represents a tightly integrated tool suite that supports the entire process of importing the SG2 field records, first-break picking, forward modeling and velocity-field computing across multiple platforms.     

Site-directed mutagenesis of a calcium binding site modifies specifically the different biochemical properties of annexin I

All the functions of annexins in vitro as well as in vivo aremediated and probably regulated by calcium. We have used recombinantannexin I, synthesized by Escherichia coli, and we have performedsite-directed mutagenesis. We have mutated the endonexin foldof domain 2 that binds calcium. Mutations were performed inthis domain of the molecule because it perfectly matches thecalcium binding consensus sequence. The two glycines of thisfold were mutated into glutamic acid. The helix content andthe stability of the mutants are identical to those of the wild-type,suggesting that the mutations did not drastically affect thestructure of the protein. The two mutants showed modified calciumbinding affinities. However, the calcium binding affinity ofthe G131E mutant was far more altered than that of the G129Emutant. Furthermore, other biochemical properties of these mutantswere modified to different extents. The binding to phospholipidwas not seriously affected, whereas the selfassociation waslost by the G131E mutant. In the same way, liposome aggregationis conserved, but modified, while the calcium affinity measuredby equilibrium dialysis is dramatically altered.     

Mixing of a self-assembled supramolecular polymer and a covalent polymer in organic solutions

We report on a neutron scattering study of the molecular structure of a self-assembled supramolecular polymer composed of a bicopper complex within a solution of a covalent polymer (atactic polystyrene/trans-decalin). The study is achieved by putting two binary phases in contact and allowing for diffusion of both components in either phase. It is shown that the one-dimensional bicopper filaments are compatible to a high extent with the atactic polymer. These results are discussed in the light of a recently devised encapsulation process of the bicopper filaments within the fibrils of a physical network of isotactic polystyrene.     

Reactive Robust Routing: Anomaly Localization and Routing Reconfiguration for Dynamic Networks

This paper presents a novel approach to deal with dynamic and highly uncertain traffic in dynamic network scenarios. The Reactive Robust Routing (RRR) approach is introduced, a combination of proactive and reactive techniques to improve network efficiency and robustness, simplifying network operation. RRR optimizes routing for normal-operation traffic, using a time-varying extension of the already established Robust Routing technique that outperforms the stable approach. To deal with anomalous and unexpected traffic variations, RRR uses a fast anomaly detection and localization algorithm that rapidly detects and localizes abrupt changes in traffic flows, permitting an accurate routing adaptation. This algorithm presents well-established optimality properties in terms of detection/localization rates and localization delay, which allows for generalization of results, independently of particular evaluations. The algorithm is based on a novel parsimonious model for traffic demands which allows for detection of anomalies using easily available aggregated-traffic measurements, reducing the overheads of data collection.     

Students’ performance and satisfaction with Web vs. paper-based practice quizzes and lecture notes

The use of computers to deliver course-related materials is rapidly expanding in most universities. Yet the effects of computer vs. printed delivery modes on students’ performance and motivation are not yet fully known. We compared the impacts of Web vs. paper to deliver practice quizzes that require information search in lecture notes. Hundred and twenty two undergraduate students used either a web site or printed documents to answer 18 mathematics questions during a tutored session. A revised Web site was designed based on ergonomic criteria, to test the hypothesis that improved usability would decrease time spent on the task, the number of pages consulted, and students’ perceived cognitive load. The group working with printed documents had the highest performance. Furthermore, students perceived the paper materials as less effortful to read, and expressed preference for printing lecture notes and questions. However, students appreciated having a Web site available. No differences were found between the two sites. We conclude that Web delivery imposed higher perceived cognitive load due to the need to read lengthy documents. We suggest possible ways to improve Web-based practice materials, such as simultaneous display of questions and lecture notes.     

Organic‐polymer thin‐film transistors for active‐matrix flat‐panel displays?

Abstract— Organic‐polymer‐based thin‐film transistors (OP‐TFTs) look very promising for flexible, large‐area, and low‐cost organic electronics. In this paper, we describe devices based on spin‐coated organic polymer that reproducibly exhibit field‐effect mobility values around 5 × 10^?3 cm²/V‐sec. We also address fabrication, performance, and stability issues that are critical for the use of such devices in active‐matrix flat‐panel displays.     

Revisiting the Roles of Filaggrin in Atopic Dermatitis

The discovery in 2006 that loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and can predispose to atopic dermatitis (AD) galvanized the dermatology research community and shed new light on a skin protein that was first identified in 1981. However, although outstanding work has uncovered several key functions of filaggrin in epidermal homeostasis, a comprehensive understanding of how filaggrin deficiency contributes to AD is still incomplete, including details of the upstream factors that lead to the reduced amounts of filaggrin, regardless of genotype. In this review, we re-evaluate data focusing on the roles of filaggrin in the epidermis, as well as in AD. Filaggrin is important for alignment of keratin intermediate filaments, control of keratinocyte shape, and maintenance of epidermal texture via production of water-retaining molecules. Moreover, filaggrin deficiency leads to cellular abnormalities in keratinocytes and induces subtle epidermal barrier impairment that is sufficient enough to facilitate the ingress of certain exogenous molecules into the epidermis. However, although FLG null mutations regulate skin moisture in non-lesional AD skin, filaggrin deficiency per se does not lead to the neutralization of skin surface pH or to excessive transepidermal water loss in atopic skin. Separating facts from chaff regarding the functions of filaggrin in the epidermis is necessary for the design efficacious therapies to treat dry and atopic skin.