Prediction error and overt attention to relevant and irrelevant cues: Evidence for an interaction of two associability mechanisms

Humans and other animals use cues in the environment to make predictions about important outcomes, thus preparing themselves to respond to those events. Prediction error refers to the extent to which an outcome is surprising in the presence of one or more cues. Within the research area of associative learning, some theories suggest that prediction error changes the amount of attention paid to cues. It was initially proposed that the attentional changes were driven by either relative or overall prediction error. In the first case, attention increases for cues generating less prediction error than other concurrent cues, otherwise attention decreases (Mackintosh, 1975). In the second case, the amount of attention paid to each cue is directly related to overall prediction error, i.e. how surprising the outcome is considering all the present cues (Pearce & Hall, 1980). Evidence for the role of relative prediction error comes from studies with pairs of cues including a component relevant to outcome prediction, together with an irrelevant component. Evidence for a role of overall prediction error comes from studies in which cues generating different amounts of prediction error are trained separately. Given that considering both relative and overall prediction error may account for a wider range of attentional changes, the two mechanisms were incorporated into hybrid models (e.g., Le Pelley, 2004). However, evidence for those models in humans is still scarce. The aim of the present thesis was to study the effect of a sudden rise in overall prediction error on overt attention to cues that were either relevant or irrelevant to outcome prediction, i.e. differing in terms of relative prediction error. Rather than considering sustained levels of prediction error, we focused primarily on sudden changes, because they are involved in important behavioral phenomena, such as the return of pathological anxiety. Each of the two studies included in the thesis started with a discrimination training, in which participants had to predict the occurrence of two possible outcomes. Participants’ eye gaze showed that the relevant cues received more attention than the irrelevant cues. In a second stage, contingency reversal (Study I) or partial reinforcement (Study II) led to a rise in prediction error, as indicated by a drop in the accuracy of outcome predictions. The attentional preference for the relevant cues was temporarily weakened by contingency reversal, and it was completely lost following the introduction of partial reinforcement. In addition, both manipulations increased the amount of attention paid to both types of cues. The data were consistent with a combined effect of relative and overall prediction error, thus providing evidence for the hybrid models. In addition, the results have implications for understanding changes in attention to contextual cues

La acción exterior de las Comunidades Autónomas: ¿hacia una nueva interpretación de la competencia exclusiva del Estado en materia de relaciones internacionales?

A la luz de las previsiones estatutarias y de consolidada jurisprudencia constitucional, las Comunidades Autónomas han ido desarrollando, con distinta intensidad, actuaciones que han supuesto una proyección exterior de su actividad política. Recientemente, el marco regulador de la acción exterior de las CCAA se ha visto complementado con la entradaen vigor de la Ley 2/2014, de la Acción Exterior y del Servicio Exterior del Estado, y de la Ley 25/2014, de Tratados y otros Acuerdos Internacionales, así como con la adopción de la STC 85/2016, de 28 de abril, y de la STC 228/2016, de 22 de diciembre. Las dos leyes prevéncambios importantes en distintos ámbitos de la acción exterior autonómica, mientras que las dos sentencias dictadas por el TC han supuesto la introducción de una serie de matices a la jurisprudencia constitucional relativa a la competencia exclusiva del Estado en materia derelaciones internacionales. El objetivo de este estudio es, por una parte, analizar el impacto que las dos leyes pueden tener en la acción exterior de las CCAA y, por otra, valorar si ambas sentencias han supuesto una reinterpretación del artículo 149.1.3º de la CE otorgando al Estado unas nuevas facultades que implican condicionar y menoscabar la acción exterior de las Comunidades Autónomas

PAL2NAL: robust conversion of protein sequence alignments into the corresponding codon alignments

PAL2NAL is a web server that constructs a multiple codon alignment from the corresponding aligned protein sequences. Such codon alignments can be used to evaluate the type and rate of nucleotide substitutions in coding DNA for a wide range of evolutionary analyses, such as the identification of levels of selective constraint acting on genes, or to perform DNA-based phylogenetic studies. The server takes a protein sequence alignment and the corresponding DNA sequences as input. In contrast to other existing applications, this server is able to construct codon alignments even if the input DNA sequence has mismatches with the input protein sequence, or contains untranslated regions and polyA tails. The server can also deal with frame shifts and inframe stop codons in the input models, and is thus suitable for the analysis of pseudogenes. Another distinct feature is that the user can specify a subregion of the input alignment in order to specifically analyze functional domains or exons of interest. The PAL2NAL server is available at

In search of complex disease risk through genome wide association studies

The identification and characterisation of genomic changes (variants) that can lead to human diseases is one of the central aims of biomedical research. The generation of catalogues of genetic variants that have an impact on specific diseases is the basis of Personalised Medicine, where diagnoses and treatment protocols are selected according to each patient’s profile. In this context, the study of complex diseases, such as Type 2 diabetes or cardiovascular alterations, is fundamental. However, these diseases result from the combination of multiple genetic and environmental factors, which makes the discovery of causal variants particularly challenging at a statistical and computational level. Genome-Wide Association Studies (GWAS), which are based on the statistical analysis of genetic variant frequencies across non-diseased and diseased individuals, have been successful in finding genetic variants that are associated to specific diseases or phenotypic traits. But GWAS methodology is limited when considering important genetic aspects of the disease and has not yet resulted in meaningful translation to clinical practice. This review presents an outlook on the study of the link between genetics and complex phenotypes. We first present an overview of the past and current statistical methods used in the field. Next, we discuss current practices and their main limitations. Finally, we describe the open challenges that remain and that might benefit greatly from further mathematical developments.L.A. was supported by grant BES-2017-081635. This publication is part of R&D and Innovation grant BES-2017-081635 funded by MCIN and by “FSE Investing in your future”I.M. was supported by grant FJCI-2017-31878. This publication is part of R&D and Innovation grant FJCI-2017-31878 funded by MCIN. C.S. received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement H2020-MSCA-COFUND-2016-754433.Peer ReviewedPostprint (published version

Determining promoter location based on DNA structure first-principles calculations

A new method is presented which predicts promoter regions based on atomistic molecular dynamics simulations of small oligonucleotides, without requiring information on sequence conservation or features

Subunit and small-molecule interaction of ribonucleotide reductases via surface plasmon resonance biosensor analyses

Ribonucleotide reductase (RNR) synthesizes deoxyribonucleotides for DNA replication and repair and is controlled by sophisticated allosteric regulation involving differential affinity of nucleotides for regulatory sites. We have developed a robust and sensitive method for coupling biotinylated RNRs to surface plasmon resonance streptavidin biosensor chips via a 30.5 Å linker. In comprehensive studies on three RNRs effector nucleotides strengthened holoenzyme interactions, whereas substrate had no effect on subunit interactions. The RNRs differed in their response to the negative allosteric effector dATP that binds to an ATP-cone domain. A tight RNR complex was formed in Escherichia coli class Ia RNR with a functional ATP cone. No strengthening of subunit interactions was observed in the class Ib RNR from the human pathogen Bacillus anthracis that lacks the ATP cone. A moderate strengthening was seen in the atypical Aeromonas hydrophila phage 1 class Ia RNR that has a split catalytic subunit and a non-functional ATP cone with remnant dATP-mediated regulatory features. We also successfully immobilized a functional catalytic NrdA subunit of the E.coli enzyme, facilitating study of nucleotide interactions. Our surface plasmon resonance methodology has the potential to provide biological insight into nucleotide-mediated regulation of any RNR, and can be used for high-throughput screening of potential RNR inhibitor

Protein coding potential of retroviruses and other transposable elements in vertebrate genomes

We suggest an annotation strategy for genes encoded by retroviruses and transposable elements (RETRA genes) based on a set of marker protein domains. Usually RETRA genes are masked in vertebrate genomes prior to the application of automated gene prediction pipelines under the assumption that they provide no selective advantage to the host. Yet, we show that about 1000 genes in four vertebrate gene sets analyzed contain at least one RETRA gene marker domain. Using the conservation of genomic neighborhood (synteny), we were able to discriminate between RETRA genes with putative functionality in the vertebrates and those that probably function only in the context of mobile elements. We identified 35 such genes in human, along with their corresponding mouse and rat orthologs; which included almost all known human genes with similarity to mobile elements. The results also imply that the vast majority of the remaining RETRA genes in current gene sets are unlikely to encode vertebrate functions. To automatically annotate RETRA genes in other vertebrate genomes, we provide as a tool a set of marker protein domains and a manually refined list of domesticated or ancestral RETRA genes for rescuing genes with vertebrate functions