A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo

The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.     

From ELF to Compressibility in Solids

Understanding the electronic nature of materials’ compressibility has always been a major issue behind tabulation and rationalization of bulk moduli. This is especially because this understanding is one of the main approaches to the design and proposal of new materials with a desired (e.g., ultralow) compressibility. It is well recognized that the softest part of the solid will be the one responsible for its compression at the first place. In chemical terms, this means that the valence will suffer the main consequences of pressurization. It is desirable to understand this response to pressure in terms of the valence properties (charge, volume, etc.). One of the possible approaches is to consider models of electronic separability, such as the bond charge model (BCM), which provides insight into the cohesion of covalent crystals in analogy with the classical ionic model. However, this model relies on empirical parametrization of bond and lone pair properties. In this contribution, we have coupled electron localization function (ELF) ab initio data with the bond charge model developed by Parr in order to analyze solid state compressibility from first principles and moreover, to derive general trends and shed light upon superhard behavior.     

Design,Synthesis, and Characterization of Macrocyclic Inhibitors of the Proprotein Convertase Furin

The activation of viral glycoproteins by the host protease furin is an essential step in the replication of numerous pathogenic viruses. Thus, effective inhibitors of furin could serve as broad-spectrum antiviral drugs. A crystal structure of an inhibitory hexapeptide derivative in complex with furin served as template for the rational design of various types of new cyclic inhibitors. Most of the prepared derivatives are relatively potent furin inhibitors with inhibition constants in the low nanomolar or even sub-nanomolar range. For seven derivatives the crystal structures in complex with furin could be determined. In three complexes, electron density was found for the entire inhibitor. In the other cases the structures could be determined only for the P6/P5-P1 segments, which directly interact with furin. The cyclic derivatives together with two non-cyclic reference compounds were tested as inhibitors of the proteolytic activation and replication of respiratory syncytial virus in cells. Significant antiviral activity was found for both linear reference inhibitors, whereas a negligible efficacy was determined for the cyclic derivatives.     

Beyond “Big Eaters”: The Versatile Role of Alveolar Macrophages in Health and Disease

Macrophages act as immune scavengers and are important cell types in the homeostasis of various tissues. Given the multiple roles of macrophages, these cells can also be found as tissue resident macrophages tightly integrated into a variety of tissues in which they fulfill crucial and organ-specific functions. The lung harbors at least two macrophage populations: interstitial and alveolar macrophages, which occupy different niches and functions. In this review, we provide the latest insights into the multiple roles of alveolar macrophages while unraveling the distinct factors which can influence the ontogeny and function of these cells. Furthermore, we will highlight pulmonary diseases, which are associated with dysfunctional macrophages, concentrating on congenital diseases as well as pulmonary infections and impairment of immunological pathways. Moreover, we will provide an overview about different treatment approaches targeting macrophage dysfunction. Improved knowledge of the role of macrophages in the onset of pulmonary diseases may provide the basis for new pharmacological and/or cell-based immunotherapies and will extend our understanding to other macrophage-related disorders.     

Zinc bioleaching from an iron concentrate using Acidithiobacillusferrooxidans strain from Hercules Mine of Coahuila, Mexico

The iron concentrate from Hercules Mine of Coahuila,Mexico,which mainly contained pyrite and pyrrhotite,was treated by the bioleaching process using native strain Acidithiobacillus ferrooxidans(A.ferrooxidans)to determime the ability of these bacteria on the leaching of zinc.The native bacteria were isolated from the iron concentrate of the mine.The bioleaching experiments were carried out in shake flasks to analyze the effects of pH values,pulp density,and the ferrous sulfate concentration on the bioleaching process.The results obtained by microbial kinetic analyses for the evaluation of some aspects of zinc leaching show that the native bacteria A.ferrooxidans,which is enriched with a 9K Silverman medium under the optimum conditions ofpH 2.0,20 g/L pulp density,and 40 g/L FeSO4,increases the zinc extraction considerably observed by monitoring duringl 5 d,i.e.,the zinc concentration has a decrease of about 95％ in the iron concentrate.     

Increased HDL Size and Enhanced Apo A-I Catabolic Rates Are Associated With Doxorubicin-Induced Proteinuria in New Zealand White Rabbits

The catabolism and structure of high‐density lipoproteins (HDL) may be the determining factor of their atheroprotective properties. To better understand the role of the kidney in HDL catabolism, here we characterized HDL subclasses and the catabolic rates of apo A‐I in a rabbit model of proteinuria. Proteinuria was induced by intravenous administration of doxorubicin in New Zealand white rabbits (n = 10). HDL size and HDL subclass lipids were assessed by electrophoresis of the isolated lipoproteins. The catabolic rate of HDL‐apo A‐I was evaluated by exogenous radiolabelling with iodine‐131. Doxorubicin induced significant proteinuria after 4 weeks (4.47 ± 0.55 vs. 0.30 ± 0.02 g/L of protein in urine, P < 0.001) associated with increased uremia, creatininemia, and cardiotoxicity. Large HDL2b augmented significantly during proteinuria, whereas small HDL3b and HDL3c decreased compared to basal conditions. HDL2b, HDL2a, and HDL3a subclasses were enriched with triacylglycerols in proteinuric animals as determined by the triacylglycerol‐to‐phospholipid ratio; the cholesterol content in HDL subclasses remained unchanged. The fractional catabolic rate (FCR) of [¹³¹I]‐apo A‐I in the proteinuric rabbits was faster (FCR = 0.036 h^?1) compared to control rabbits group (FCR = 0.026 h^?1, P < 0.05). Apo E increased and apo A‐I decreased in HDL, whereas PON‐1 activity increased in proteinuric rabbits. Proteinuria was associated with an increased number of large HDL2b particles and a decreased number of small HDL3b and 3c. Proteinuria was also connected to an alteration in HDL subclass lipids, apolipoprotein content of HDL, high paraoxonase‐1 activity, and a rise in the fractional catabolic rate of the [¹³¹I]‐apo A‐I.     

Thionine immobilized in crosslinked chitosan films

Redox and acid–base properties of thionine immobilized in crosslinked chitosan films are analyzed. The experimental conditions for the preparation of the films are described. Results obtained with cyclic voltammetry, spectroelectrochemistry and spectrophotometry indicate that the immobilized dye retains the redox and acid–base activity of free thionine. An acid dissociation constant (K_a) for the immobilized dye of K_a = 2.7 × 10⁻¹¹ was obtained.

Due to the stable and reversible pH dependent optical signal of the studied film, this membrane can be used as a building component of an optical pH sensor.     

Interactive structural learning of Bayesian networks

We propose an hybrid approach for structure learning of Bayesian networks, in which a computer system and a human expert cooperate to search for the best structure. The system builds an initial tree structure which is graphically presented to the expert, and then the expert can modify this structure according to his knowledge of the domain. The system has several tools for aiding the human in this task: it allows for graphical editing (adding, deleting, inverting arcs) of the network, it shows graphically the correlation between variables, and it gives a measure of the quality and complexity for each structure. A measure which combines both quality and complexity, that we call quality, is defined. We have tested the tool in two domains: atmospheric pollution and car insurance, with good results.     

Objective and subjective assessments of socioeconomic status and their relationship to self-rated health in an ethnically diverse sample of pregnant women.

A new measure of subjective socioeconomic status (SES) was examined in relation to self-rated physical health in pregnant women. Except among African Americans, subjective SES was significantly related to education, household income, and occupation. Subjective SES was significantly related to self-rated health among all groups. In multiple regression analyses, subjective SES was a significant predictor of self-rated health after the effects of objective indicators were accounted for among White and Chinese American women; among African American women and Latinas, household income was the only significant predictor of self-rated health. After accounting for the effects of subjective SES on health, objective indicators made no additional contribution to explaining health among White and Chinese American women; household income continued to predict health after accounting for subjective SES among Latinas and African American women. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intelligent security and access control framework for service-oriented architecture

One of the most significant difficulties with developing Service-Oriented Architecture (SOA) involves meeting its security challenges, since the responsibilities of SOA security are based on both the service providers and the consumers. In recent years, many solutions to these challenges have been implemented, such as the Web Services Security Standards, including WS-Security and WS-Policy. However, those standards are insufficient for the new generation of Web technologies, including Web 2.0 applications. In this research, we propose an intelligent SOA security framework by introducing its two most promising services: the Authentication and Security Service (NSS), and the Authorization Service (AS). The suggested autonomic and reusable services are constructed as an extension of WS-¹ security standards, with the addition of intelligent mining techniques, in order to improve performance and effectiveness. In this research, we apply three different mining techniques: the Association Rules, which helps to predict attacks, the Online Analytical Processing (OLAP) Cube, for authorization, and clustering mining algorithms, which facilitate access control rights representation and automation. Furthermore, a case study is explored to depict the behavior of the proposed services inside an SOA business environment. We believe that this work is a significant step towards achieving dynamic SOA security that automatically controls the access to new versions of Web applications, including analyzing and dropping suspicious SOAP messages and automatically managing authorization roles.