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.     

From latex specifications to parallel codes

The advent of multicore systems, joined to the potential acceleration of the graphics processing units, has given us a low cost computation capability unprecedented. The new systems alleviate some well-known important architectural problems at the expense of a considerable increment of the programmability wall. Heterogeneity, at both the architectural and programming levels, poses a great challenge to programmers. As a contribution, we propose a development methodology for the automatic source-to-source transformation on specific domains. This methodology is successfully instantiated as a framework to solve Dynamic Programming problems. As a result of applying our framework, the end user (a physicist, a mathematician or a biologist) can express her problem through a latex equation and automatically derive efficient parallel codes for current homogeneous or heterogeneous architectures. The approach allows an easy portability to new emergent architectures.     

Analyzing probabilistic pushdown automata

The paper gives a summary of the existing results about algorithmic analysis of probabilistic pushdown automata and their subclasses.     

‘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.     

Efficient implementation of the implicit error correction nVoD schema

Implicit Error Correction is a near Video-on-Demand (nVoD) schema that trades bandwidth utilization for initial playback delay while potentially allowing an infinite number of users. Additionally, it provides error protection without further bandwidth increase by exploiting the implicit redundancy of nVoD protocols, using linear combinations of the segments transmitted in a given time slot. This paper introduces a new implementation that outperforms the original schema by adding two new mechanisms: redundancy channels and feedback error correction.     

Experimental tile with phase change materials (PCM) for building use

The use of phase change materials (PCM) and their possible architectural integration is a path in the search for optimizing energy efficiency in construction. As part of this path, a pavement has been designed which, in combination with the PCM, serves as a passive thermal conditioning system (new patent n°. ES2333092 A1) [1]. The prototype has been tested experimentally and the results proved that it is a viable constructive solution improving the energy performance of sunny locals.     

Influence of oxides on the stability of zinc foam

The influence of oxides on the stabilisation of zinc foam made by foaming-compacted powder mixtures has been investigated by varying the oxide content in the zinc powder used by oxidation and reduction. Optical, scanning electron and transmission electron microscopy as well as energy dispersive X-ray mapping were used to determine the oxide distribution, morphology and structure in the foams. The study revealed that with increase in the oxide content of the foam, the maximum expansion and expansion rate increased. Small amount of nano-sized oxide particles and their cluster, which are randomly distributed, were observed within the bulk of foam. But the major fraction of oxides is observed on the surface of pores in the form of clusters. These clusters are distributed uniformly all over the surface. Effect of these oxides on the stability of foam is discussed. The formation of satellite pores, which is characteristic signature of zinc foams, and their stability, is investigated.