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.     

Collective intelligence as mechanism of medical diagnosis: The iPixel approach

Collective intelligence (CI) is an active field of research, which capitalizes the knowledge of human collectives in order to create, to innovate and to invent. There are two important mechanisms to implement CI: recommender and reputation systems. Recommender systems are used to provide filtered information from a large amount of elements. The recommendations are intended to provide interesting elements to users. Recommendation systems can be developed using different techniques and algorithms where the selection of these techniques depends on the area in which they will be applied. This work presents iPixel Recommender Engine, which is focused on the medical field. iPixel Recommendation Engine supports the process of differential diagnosis by recommending mammographic evaluations. Each mammogram is collectively tagged by the users’ community with a semantic sense; this feature allows iPixel acquires collective knowledge. iPixel can associate more than one feature with each mammogram. This work also presents a qualitative evaluation, where the basic features that a recommendation system should have in the medical field were obtained. Finally, a comparison was carried out with other similar recommender systems in order to know the Pixel advantages.     

Optimization of the material flow in a manufacturing plant by use of artificial bee colony algorithm

To survive in today’s competitive global market, companies must perform strategic changes in order to increase productivity, eliminating wasted materials, time, and effort. This study will examine how to optimize the time and effort required to supply raw material to different production lines in a manufacturing plant in Juarez, Mexico by minimizing the distance an operator must travel to distribute material from a warehouse to a set of different production lines with corresponding demand. The core focus of this study is similar to that of the Vehicle Routing Problem in that it is treated as a combinatorial optimization problem. The artificial bee colony algorithm is applied in order to find the optimal distribution of material with the aim of establishing a standard time for this duty by examining how this is applied in a local manufacturing plant. Results show that using this approach may be convenient to set standard times in the selected company.     

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.     

Phase stability and transformations in NiTi from density functional theory calculations

We used density functional theory to characterize various crystalline phases of NiTi alloys: (i) high-temperature austenite phase B2; (ii) orthorhombic B19; (iii) the monoclinic martensite phase B19′; and (iv) a body-centered orthorhombic phase (BCO), theoretically predicted to be the ground state. We also investigated possible transition pathways between the various phases and the energetics involved. We found B19 to be metastable with a 1 meV energy barrier separating it from B19′. Interestingly, we predicted a new phase of NiTi, denoted B19′′, that is involved in the transition between B19′ and BCO. B19′′ is monoclinic and can exhibit shape memory; furthermore, its presence reduces the internal stress required to stabilize the experimentally observed B19′ structure, and it consequently plays a key role in NiTi’s properties.     

Nanoscale Ferroelectricity in Crystalline γ‐Glycine

Ferroelectrics are multifunctional materials that reversibly change their polarization under an electric field. Recently, the search for new ferroelectrics has focused on organic and bio‐organic materials, where polarization switching is used to record/retrieve information in the form of ferroelectric domains. This progress has opened a new avenue for data storage, molecular recognition, and new self‐assembly routes. Crystalline glycine is the simplest amino acid and is widely used by living organisms to build proteins. Here, it is reported for the first time that γ‐glycine, which has been known to be piezoelectric since 1954, is also a ferroelectric, as evidenced by local electromechanical measurements and by the existence of as‐grown and switchable ferroelectric domains in microcrystals grown from the solution. The experimental results are rationalized by molecular simulations that establish that the polarization vector in γ‐glycine can be switched on the nanoscale level, opening a pathway to novel classes of bioelectronic logic and memory devices.     

Enhancing Planar Inverted Perovskite Solar Cells with Innovative Dumbbell-Shaped HTMs: A Study of Hexabenzocoronene and Pyrene-BODIPY-Triarylamine Derivatives

Dumbbell-shaped systems based on PAHs-BODIPY-triarylamine hybrids TM-(01-04) are designed as novel and highly efficient hole-transporting materials for usage in planar inverted perovskite solar cells. BODIPY is employed as a bridge between the PAH units, and the effects of the conjugated π-system's covalent attachment and size are investigated. Fluorescence quenching, 3D fluorescence heat maps, and theoretical studies support energy transfer within the moieties. The systems are extremely resistant to UVC 254 nm germicidal light sources and present remarkable thermal stability at degradation temperatures exceeding 350 °C. Integrating these systems into perovskite solar cells results in outstanding power conversion efficiency (PCE), with TM-02-based devices exhibiting a PCE of 20.26%. The devices base on TM-01, TM-03, and TM-04 achieve PCE values of 16.98%, 17.58%, and 18.80%, respectively. The long-term stability of these devices is measured for 600 h, with initial efficiency retention between 94% and 86%. The TM-04-based device presents noticeable stability of 94%, better than the reference polymer PTAA with 91%. These findings highlight the exciting potential of dumbbell-shaped systems based on PAHs-BODIPY-triarylamine derivatives for next-generation photovoltaics.     

Average block error probability in the reverse link of a packetDS/CDMA system under Rayleigh fading channel conditions

Analytic expressions have been derived for the probability density functions of the total signal-to-interference ratio when considering mixed-type interference sources in the reverse link of a DS/CDMA packet radio system with Rayleigh fading. Four different scenarios were studied, and the corresponding expressions are presented for each situation. The users are divided into two groups: those that apply a closed-loop power control and those that only use an open-loop power control. By making use of these expressions, the mean block error probability is derived as a function of the number of total interfering users in each group     

Ultrasound image segmentation with shape priors: application to automatic cattle rib-eye area estimation.

Automatic ultrasound (US) image segmentation is a difficult task due to the quantity of noise present in the images and the lack of information in several zones produced by the acquisition conditions. In this paper, we propose a method that combines shape priors and image information to achieve this task. In particular, we introduce knowledge about the rib-eye shape using a set of images manually segmented by experts. A method is proposed for the automatic segmentation of new samples in which a closed curve is fitted taking into account both the US image information and the geodesic distance between the evolving curve and the estimated mean rib-eye shape in a shape space. This method can be used to solve similar problems that arise when dealing with US images in other fields. The method was successfully tested over a database composed of 610 US images, for which we have the manual segmentations of two experts.