Alchemical Design of Pharmacological Chaperones with Higher Affinity for Phenylalanine Hydroxylase

Phenylketonuria (PKU) is a rare metabolic disease caused by variations in a human gene, PAH, encoding phenylalanine hydroxylase (PAH), and the enzyme converting the essential amino acid phenylalanine into tyrosine. Many PKU-causing variations compromise the conformational stability of the encoded enzyme, decreasing or abolishing its catalytic activity, and leading to an elevated concentration of phenylalanine in the blood, which is neurotoxic. Several therapeutic approaches have been developed to treat the more severe manifestations of the disorder, but they are either not entirely effective or difficult to adhere to throughout life. In a search for novel pharmacological chaperones to treat PKU, a lead compound was discovered (compound IV) that exhibited promising in vitro and in vivo chaperoning activity on PAH. The structure of the PAH-IV complex has been reported. Here, using alchemical free energy calculations (AFEC) on the structure of the PAH-IV complex, we design a new generation of compound IV-analogues with a higher affinity for the enzyme. Seventeen novel analogues were synthesized, and thermal shift and isothermal titration calorimetry (ITC) assays were performed to experimentally evaluate their stabilizing effect and their affinity for the enzyme. Most of the new derivatives bind to PAH tighter than lead compound IV and induce a greater thermostabilization of the enzyme upon binding. Importantly, the correspondence between the calculated alchemical binding free energies and the experimentally determined ΔΔG_b values is excellent, which supports the use of AFEC to design pharmacological chaperones to treat PKU using the X-ray structure of their complexes with the target PAH enzyme.     

A viral system algorithm to optimize the car dispatching in elevator group control systems of tall buildings

Nowadays is very common the presence of tall buildings in the business centres of the main cities of the world. Such buildings require the installation of numerous lifts that are coordinated and managed under a unique control system. Population working in the buildings follows a similar traffic pattern generating situations of traffic congestion. The problem arises when a passenger makes a hall call wishing to travel to another floor of the building. The dispatching of the most suitable car is the optimization problem we are tackling in this paper. We develop a viral system algorithm which is based on a bio-inspired virus infection analogy to deal with it. The viral system algorithm is compared to genetic algorithms, and tabu search approaches that have proven efficiency in the vertical transportation literature. The experiments undertaken in tall buildings from 10 to 24 floors, and several car configurations from 2 to 6 cars, provide valuable results and show how viral system outperforms such soft computing algorithms.     

‘Long autonomy or long delay?’ The importance of domain in opinion mining

Nowadays, people do not only navigate the web, but they also contribute contents to the Internet. Among other things, they write their thoughts and opinions in review sites, forums, social networks, blogs and other websites. These opinions constitute a valuable resource for businesses, governments and consumers. In the last years, some researchers have proposed opinion extraction systems, mostly domain-independent ones, to automatically extract structured representations of opinions contained in those texts. In this work, we tackle this task in a domain-oriented approach, defining a set of domain-specific resources which capture valuable knowledge about how people express opinions on a given domain. These resources are automatically induced from a set of annotated documents. Some experiments were carried out on three different domains (user-generated reviews of headphones, hotels and cars), comparing our approach to other state-of-the-art, domain-independent techniques. The results confirm the importance of the domain in order to build accurate opinion extraction systems. Some experiments on the influence of the dataset size and an example of aggregation and visualization of the extracted opinions are also shown.     

A semantic role labelling-based framework for learning ontologies from Spanish documents

Currently, most of the information available in the Web is adapted primarily for human consumption, but there is so much information that can no longer be processed by a person in a reasonable time, either in digital or physical formats. To solve this problem, the idea of the Semantic Web arose. The Semantic Web deals with adding machine-readable information to Web pages. Ontologies represent a very important element of this web, as they provide a valid and robust structure to represent knowledge based on concepts, relations, axioms, etc. The need for overcoming the bottleneck provoked by the manual construction of ontologies has generated several studies and research on obtaining semiautomatic methods to learn ontologies. In this sense, this paper proposes a new ontology learning methodology based on semantic role labeling from digital Spanish documents. The method makes it possible to represent multiple semantic relations specially taxonomic and partonomic ones in the standardized OWL 2.0. A set of experiments has been performed with the approach implemented in educational domain that show promising results.     

Analysis of the gate current as a suitable indicator for FET degradation under nonlinear dynamic regime

Electron device degradation, although not directly accounted for, represents a key issue in microwave circuit design. This is especially true when the particular applications involved (e.g., satellite, military, consumer) do not allow or strongly discourage any kind of maintenance. As a matter of fact, in order to account for device degradation in circuit design, a suitable electron device model is needed which is able to predict the performance degradation as a function of the actual electrical regime involved in the device operation. Such a kind of model is not available in literature. In this paper, quantitative results are provided for device degradation indicators which correlate DC and RF stress experiments. These results can be considered an important step toward the definition of a nonlinear model accounting for device degradation.     

Optimal haulage routing of off-road dump trucks in construction and mining sites using Google Earth and a modified least-cost path algorithm

This study presents new software, called Google Earth-based Optimal HAulage RouTing System (GEOHARTS), to improve the functionality of Google Earth for optimal haulage routing of off-road dump trucks in construction and mining sites. A modified least-cost path algorithm, which is applicable to working areas with both paved and unpaved temporary roads and can consider the effects of terrain relief and curves along a route on the route planning, was proposed and utilized for the software development. GEOHARTS can determine optimal haulage routes between loaders and dumps that ensure the least travel time or fuel consumption of off-road dump trucks and can visualize the results using an embedded 3D render window of Google Earth. The application to the Pasir open-pit coal mine in Indonesia demonstrates that GEOHARTS could provide a rational solution to support the truck haulage operations.     

Making a mesh router/gateway from a smartphone: Is that a practical solution?

This paper aims at answering the question whether it is practical to build a mesh-phone or not. A mesh-phone is a smartphone acting as a mesh router, i.e. either actively participating in the process of packet forwarding towards a mesh gateway, or acting itself as a gateway toward the Internet. Technical aspects of the mesh-phone implementation, such as design constraints and implementation details, are addressed. The technical feasibility is validated by describing the implementation of a prototype of the mesh-enabled phone over the Openmoko^TM open platform. Besides technical feasibility also convenience of the addressed solution is analyzed in terms of the consumed power, and some “energy-saving” related enhancements are suggested to be applied to future user’s devices.     

Salt Concentration Effects in Planar Light‐Emitting Electrochemical Cells

Incorporation of ions in the active layer of organic semiconductor devices may lead to attractive device properties like enhanced injection and improved carrier transport. In this paper, we investigate the effect of the salt concentration on the operation of light‐emitting electrochemical cells, using experiments and numerical calculations. The current density and light emission are shown to increase linearly with increasing ion concentration over a wide range of concentrations. The increasing current is accompanied by an ion redistribution, leading to a narrowing of the recombination zone. Hence, in absence of detrimental side reactions and doping‐related luminescence quenching, the ion concentration should be as high as possible.