Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport

Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML), where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES). To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs), and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations.

Contributions to High-Throughput Computing Based on the Peer-to-Peer Paradigm

XII, 116 p.

Plan de Marketing Fisioterapia BE GOOD

El objetivo del presente documento es definir y presentar el Plan de Marketing asociado a una empresa basada en una propuesta empresarial. La empresa a la que se va a hacer referencia en dicho Plan es un centro fisioterapéutico que se denominará “Be Good”. La clínica fisioterapia “Be Good”, se situará en la calle “Villa de Plencia” localizada en el municipio de Getxo y nacerá con el objetivo de ofrecer un servicio de calidad dirigido a la cura y prevención de lesiones músculo-esqueléticas, afecciones respiratorias, patologías neurológicas y, en general, a la satisfacción de cualquier tipo de persona que solicite sus servicios. Aunque existan diferentes metodologías, para llevar a cabo el Plan de Marketing se ha decidido seguir el procedimiento propuesto por José María Sainz de Vicuña (2013). Por medio de la metodología seleccionada, el Plan de Marketing descrito en el presente documento tratará de mejorar la eficacia en la toma de decisiones que influyan en la empresa. Adicionalmente, se actuará de medio para el logro de los objetivos planteados a continuación. Por último, facilitará y optimizará la comunicación interna de la empresa de cara a disponer de procesos de evaluación y control más eficientes responsabilizando al área de marketing de los resultados obtenidos.

Contributions to time series data mining departing from the problem of road travel time modeling

194 p.

Paleobotánica del epipaleolítico y mesolítico vascos

Homenaje a Ignacio Barandiarán Maestu / coord. por Javier Fernández Eraso, Juan Santos Yanguas

Optimizing the Curie temperature of pseudo-binary RxR2-x ' Fe-17 (R, R ' = rare earth) for magnetic refrigeration

Several pseudo-binary RxR2-x'Fe-17 alloys (with R = Y, Ce, Pr, Gd and Dy) were synthesized with rhombohedral Th2Zn17-type crystal structure determined from x-ray and neutron powder diffraction. The choice of compositions was done with the aim of tuning the Curie temperature (T-C) in the 270 +/- 20 K temperature range, in order to obtain the maximum magneto-caloric effect around room temperature. The investigated compounds exhibit broad isothermal magnetic entropy changes, Delta S-M(T), with moderate values of the refrigerant capacity, even though the values of Delta S-M(Peak) are relatively low compared with those of the R2Fe17 compounds with R = Pr or Nd. The reduction on the Delta S-M(Peak) is explained in terms of the diminution in the saturation magnetization value. Furthermore, the Delta S-M(T) curves exhibit a similar caret-like behavior, suggesting that the magneto-caloric effect is mainly governed by the Fe-sublattice. A single master curve for Delta S-M/Delta S-M(Peak)(T) under different values of the magnetic field change are obtained for each compound by rescaling of the temperature axis.

Inflammatory Markers and Obstructive Sleep Apnea in Obese Children: The NANOS Study

Introduction. Obesity and obstructive sleep apnea syndrome (OSA) are common coexisting conditions associated with a chronic low-grade inflammatory state underlying some of the cognitive, metabolic, and cardiovascular morbidities. Aim. To examine the levels of inflammatory markers in obese community-dwelling children with OSA, as compared to no-OSA, and their association with clinical and polysomnographic (PSG) variables. Methods. In this cross-sectional, prospective multicenter study, healthy obese Spanish children (ages 4-15 years) were randomly selected and underwent nocturnal PSG followed by a morning fasting blood draw. Plasma samples were assayed for multiple inflammatory markers. Results. 204 children were enrolled in the study; 75 had OSA, defined by an obstructive respiratory disturbance index (RDI) of 3 events/hour total sleep time (TST). BMI, gender, and age were similar in OSA and no-OSA children. Monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in OSA children, with interleukin-6 concentrations being higher in moderate-severe OSA (i.e., AHI > 5/hrTST; P < 0.01), while MCP-1 levels were associated with more prolonged nocturnal hypercapnia (P < 0.001). Conclusion. IL-6, MCP-1, and PAI-1 are altered in the context of OSA among community-based obese children further reinforcing the proinflammatory effects of sleep disorders such as OSA. This trial is registered with ClinicalTrials.gov NCT01322763.

Etymological notes on Aleut (III). With methodological notes on (Eskimo-Aleut) historical linguistics

[EN] The goal of this contribution is twofold: on the one hand, to review two relatively recent contributions in the field of Eskimo-Aleut historical linguistics in which it is proposed that Eskimo-Aleut languages are related genealogically to Wakashan (Holst 2004) and?/or Nostratic (Krougly-Enke 2008). These contributions can be characterized by saying that their authors have taken little care to be diligent and responsible in the application of the comparative method, and that their familiarity with the languages involved is insufficient. Eskimo-Aleut languages belong to a very exclusive group of language families that have been (and still are) used, sometimes compulsively, in the business of so-called “long-range comparisons”. Those carrying out such studies are very often unaware of the most basic facts regarding the philological and linguistic traditions of those languages, as a result of what mountains of very low quality works with almost no-relevancy for the specialist grow every year to the desperation of the scientific community, whose attitude toward them ranges from the most profound indifference to the toughest (and most explicit) critical tone. Since Basque also belongs to this group of “compare-with-everything-you-come- across” languages, it is my intention to provide the Basque readership with a sort of “pedagogical case” to show that little known languages, far from underrepresented in the field, already have a very long tradition in historical and comparative linguistics, i.e. nobody can approach them without previous acquaintance with the materials. Studies dealing with the methodological inappropriateness of the Moscow School’s Nostratic hypothesis or the incorrectness of many of the proposed new taxonomic Amerindian subfamilies (several of them involving the aforementioned Wakashan languages), that is to say, the frameworks on which Krougly-Enke and Holst work, respectively, are plenty (i.a. Campbell 1997: 260-329, Campbell & Poser 2008: 234-96), therefore there is no reason to insist once more on the very same point. This is the reason why I will not discuss per se Eskimo-Aleut–Wakashan or Eskimo-Aleut–Nostratic. On the contrary, I will focus attention upon very concrete aspects of Krougly-Enke and Holst´s proposals, i.e. when they work on “less ambitious” problems, for example, dealing with the minutiae of internal facts or analyzing certain words from the sole perspective of Eskimo-Aleut materials (in other words, those cases in which even they do not invoke the ad hoc help of Nostratic stuff). I will try to explain why some of their proposals are wrong, demonstrate where the problem lies, and fix it if possible. In doing so, I will propose new etymologies in an attempt at showing how we may proceed. The main difference between this and handbook examples lies in the reality of what we are doing: this is a pure etymological exercise from beginning to end. I will try to throw a bit of light on a couple of problematic questions regarding Aleut historical phonology, demonstrating how much work should be done at the lowest level of the Eskimo-Aleut pyramid; it is technically impossible to reach the peak of the pyramid without having completed the base. As far as Aleut is regarded, I will mainly profit not only from the use of the traditional philological analysis of Aleut (and, eventually, of Eskimo) materials, but also of diachronic typology, bringing into discussion what in my opinion seems useful, and in some cases I think decisive, parallels. It is worth noting that this paper makes up yet another part of a series of exploratory works dealing with etymological aspects of the reconstruction of Proto-Eskimo-Aleut, with special emphasis on Aleut (vid. i.a. Alonso de la Fuente 2006/2007, 2008a, 2008b, 2010a), whose main goal is to become the solid basis for an etymological dictionary of the Aleut language, currently in progress.

Neurolinguistic measure of typological effects in multilingual transfer: introducing an ERP methodology

This article has two main objectives. First, we offer an introduction to the subfield of generative third language (L3) acquisition. Concerned primarily with modeling initial stages transfer of morphosyntax, one goal of this program is to show how initial stages L3 data make significant contributions toward a better understanding of how the mind represents language and how (cognitive) economy constrains acquisition processes more generally. Our second objective is to argue for and demonstrate how this subfield will benefit from a neuro/psycholinguistic methodological approach, such as event-related potential experiments, to complement the claims currently made on the basis of exclusively behavioral experiments. Palabras clave

Effect of Neonatal Asphyxia on the Impairment of the Auditory Pathway by Recording Auditory Brainstem Responses in Newborn Piglets: A New Experimentation Model to Study the Perinatal Hypoxic-Ischemic Damage on the Auditory Syste

Introduction Hypoxia-ischemia (HI) is a major perinatal problem that results in severe damage to the brain impairing the normal development of the auditory system. The purpose of the present study is to study the effect of perinatal asphyxia on the auditory pathway by recording auditory brain responses in a novel animal experimentation model in newborn piglets. Method Hypoxia-ischemia was induced to 1.3 day-old piglets by clamping 30 minutes both carotid arteries by vascular occluders and lowering the fraction of inspired oxygen. We compared the Auditory Brain Responses (ABRs) of newborn piglets exposed to acute hypoxia/ischemia (n = 6) and a control group with no such exposure (n = 10). ABRs were recorded for both ears before the start of the experiment (baseline), after 30 minutes of HI injury, and every 30 minutes during 6 h after the HI injury. Results Auditory brain responses were altered during the hypoxic-ischemic insult but recovered 30-60 minutes later. Hypoxia/ischemia seemed to induce auditory functional damage by increasing I-V latencies and decreasing wave I, III and V amplitudes, although differences were not significant. Conclusion The described experimental model of hypoxia-ischemia in newborn piglets may be useful for studying the effect of perinatal asphyxia on the impairment of the auditory pathway.

Efficient Synthesis of Single-Chain Polymer Nanoparticles via Amide Formation

Single-chain technology (SCT) allows the transformation of individual polymer chains to folded/collapsed unimolecular soft nanoparticles. In this work we contribute to the enlargement of the SCT toolbox by demonstrating the efficient synthesis of single-chain polymer nanoparticles (SCNPs) via intrachain amide formation. In particular, we exploit cross-linking between active methylene groups and isocyanate moieties as powerful "click" chemistry driving force for SCNP construction. By employing poly(methyl methacrylate)- (PMMA-) based copolymers bearing beta-ketoester units distributed randomly along the copolymer chains and bifunctional isocyanate cross-linkers, SCNPs were successfully synthesized at r.t. under appropriate reaction conditions. Characterization of the resulting SCNPs was carried out by means of a combination of techniques including size exclusion chromatography (SEC), infrared (IR) spectroscopy, proton nuclear magnetic resonance (H-1 NMR) spectroscopy, dynamic light scattering (DLS), and elemental analysis (EA).

Long-Term Epidemiology of Streptococcus pneumoniae Serogroup 6 in a Region of Southern Europe with Special Reference to Serotype 6E

Streptococcus pneumoniae serotype 6E has recently been described, but its long-term epidemiology is not well known. From 1981-2013, 704 serogroup 6 clinical isolates were obtained in Gipuzkoa, Basque Country, Spain. All invasive and one in four non-invasive isolates were included. Overall, 75, 97, 51 and 45 serotypes 6A, 6B, 6C and 6E isolates, respectively, were detected. No serotype 6D isolates were identified. The prevalence of serotypes 6E and 6B, but not that of serotypes 6A and 6C, declined after the introduction of pneumococcal conjugate vaccines. Serotype 6E isolates showed the highest resistance rate. Most serotype 6E isolates were ST90.