Pharmacogenetics of MicroRNAs and MicroRNAs Biogenesis Machinery in Pediatric Acute Lymphoblastic Leukemia

Despite the clinical success of acute lymphoblastic leukemia (ALL) therapy, toxicity is frequent. Therefore, it would be useful to identify predictors of adverse effects. In the last years, several studies have investigated the relationship between genetic variation and treatment-related toxicity. However, most of these studies are focused in coding regions. Nowadays, it is known that regions that do not codify proteins, such as microRNAs (miRNAs), may have an important regulatory function. MiRNAs can regulate the expression of genes affecting drug response. In fact, the expression of some of those miRNAs has been associated with drug response. Genetic variations affecting miRNAs can modify their function, which may lead to drug sensitivity. The aim of this study was to detect new toxicity markers in pediatric B-ALL, studying miRNA-related polymorphisms, which can affect miRNA levels and function. We analyzed 118 SNPs in pre-miRNAs and miRNA processing genes in association with toxicity in 152 pediatric B-ALL patients all treated with the same protocol (LAL/SHOP). Among the results found, we detected for the first time an association between rs639174 in DROSHA and vomits that remained statistically significant after FDR correction. DROSHA had been associated with alterations in miRNAs expression, which could affect genes involved in drug transport. This suggests that miRNA-related SNPs could be a useful tool for toxicity prediction in pediatric B-ALL.

[B_Zalla_Bolunburu] Documentación Geométrica de la Ferrería Bolunburu (Zalla, Bizkaia)

[ES] El conjunto de dos edificios divididos en varias estancias, un canal de captación de aguas y un puente, todo ello arruinado. Los muros aún se mantienen en pie aunque ya no quedan restos de los tejados ni del mobiliario, maquinaria o decoración.

Informe técnico sobre posibles alternativas de valorización energética de residuos forestales

[ES]Mediante este proyecto, se trata de buscar diferentes alternativas de valorización energética de residuos forestales, analizar su proceso y los equipos involucrados, y al final elegir la más adecuada en base a ciertos criterios.

Influencia de la internacionalización en el desempeño social de las empresas

[ES] Recientemente estudios previos han comenzado a plantear la posible relación entre el fenómeno de la internacionalización y responsabilidad social corporativa de las organizaciones. En este trabajo analizamos en qué medida la internacionalización contribuye a una mejora sustancial del desempeño social de las empresas. Usando una muestra de 102 empresas estadounidenses de los sectores químico, energético y de maquinaria industrial, nuestros resultados muestran que no todas las dimensiones de la internacionalización permiten a las empresas adquirir conocimiento valioso que conduzca a una mejora de su desempeño social. Concretamente, comprobamos que, mientras el porcentaje de ventas en mercados extranjeros y la diversificación internacional cultural favorecen la puesta en marcha de prácticas de responsabilidad social corporativa avanzadas que redundan en un mejor desempeño social (cumpliendo con las demandas sociales de los grupos de interés de los distintos mercados donde operan), la diversificación internacional geográfica no tiene efecto directo en el desempeño social de las empresas. Por tanto, no es tan importante el número de mercados donde la empresa actúa, sino el grado de diferenciación cultural existente entre los mismos lo que hace que la propia empresa mejore su desempeño social. El presente trabajo incluye implicaciones relevantes para el mundo académico, directivos y reguladores públicos.

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.

Diseño de una tarjeta de drivers para un inversor de potencia.

[EN]The purpose of this project is to design a system which improves the e ciency of power inverters. The project is focused in the analysis of the di erent power semiconductors (based on silicon, silicon carbide and gallium nitride) and driver applications. This system can be implemented in di erent future versions of power inverters and in many kind of applications like electrical vehicles. Other than that, it can be also implemented on any machinery requiring an inverter obtaining more energy and reduce manufacturing costs.

Visibility recovery on images acquired in attenuating media. Application to underwater, fog, and mammographic imaging

136 p.

Development of nucleic acid vaccines: use of self-amplifying RNA in lipid nanoparticles

Self-amplifying RNA or RNA replicon is a form of nucleic acid-based vaccine derived from either positive-strand or negative-strand RNA viruses. The gene sequences encoding structural proteins in these RNA viruses are replaced by mRNA encoding antigens of interest as well as by RNA polymerase for replication and transcription. This kind of vaccine has been successfully assayed with many different antigens as vaccines candidates, and has been shown to be potent in several animal species, including mice, nonhuman primates, and humans. A key challenge to realizing the broad potential of self-amplifying vaccines is the need for safe and effective delivery methods. Ideally, an RNA nanocarrier should provide protection from blood nucleases and extended blood circulation, which ultimately would increase the possibility of reaching the target tissue. The delivery system must then be internalized by the target cell and, upon receptor-mediated endocytosis, must be able to escape from the endosomal compartment into the cell cytoplasm, where the RNA machinery is located, while avoiding degradation by lysosomal enzymes. Further, delivery systems for systemic administration ought to be well tolerated upon administration. They should be safe, enabling the multiadministration treatment modalities required for improved clinical outcomes and, from a developmental point of view, production of large batches with reproducible specifications is also desirable. In this review, the concept of self-amplifying RNA vaccines and the most promising lipid-based delivery systems are discussed.

Adenylate Cyclase Toxin promotes bacterial internalisation into non phagocytic cells

Bordetella pertussis causes whooping cough, a respiratory infectious disease that is the fifth largest cause of vaccine-preventable death in infants. Though historically considered an extracellular pathogen, this bacterium has been detected both in vitro and in vivo inside phagocytic and non-phagocytic cells. However the precise mechanism used by B. pertussis for cell entry, or the putative bacterial factors involved, are not fully elucidated. Here we find that adenylate cyclase toxin (ACT), one of the important toxins of B. pertussis, is sufficient to promote bacterial internalisation into non-phagocytic cells. After characterization of the entry route we show that uptake of "toxin-coated bacteria" proceeds via a clathrin-independent, caveolae-dependent entry pathway, allowing the internalised bacteria to survive within the cells. Intracellular bacteria were found inside non-acidic endosomes with high sphingomyelin and cholesterol content, or "free" in the cytosol of the invaded cells, suggesting that the ACT-induced bacterial uptake may not proceed through formation of late endolysosomes. Activation of Tyr kinases and toxin-induced Ca2+-influx are essential for the entry process. We hypothesize that B. pertussis might use ACT to activate the endocytic machinery of non-phagocytic cells and gain entry into these cells, in this way evading the host immune system.

Study on the activation mechanism of BCL-2 related ovarian killer (BOK)

BCL-2 family proteins are key regulators of the mitochondrial apoptotic machinery, controlling the mitochondrial outer membrane (MOM) permeabilization (MOMP). BCL-2 related Ovarian Killer (BOK) is a poorly understood pro-apoptotic member of this protein family. It has been reported that BOK localizes predominantly (although not exclusively) at membranes of the endoplasmic reticulum and of the Golgi apparatus. However, it is unclear whether BOK also operates at the MOM to promote apoptosis, as other pro-apoptotic BCL-2 family members do. Basing on the fact that the other two BAX-like pro-apoptotic members have been reported to oligomerize in order to induce MOMP, site-directed mutagenesis was used to generate two point mutations that predictably eliminated BOK’s oligomerization capacity. Then, the effect of such mutations on BOK’s membrane activity was examined using fluorescence spectroscopy.

Innovación, capacidad productiva, formación en el puesto de trabajo y productividad

[ES] Este estudio analiza la relación entre productividad laboral, innovación radical, innovación incremental, tecnología incorporada en maquinaria y equipos, utilización de la capacidad productiva y formación. Los datos utilizados son de empresas españolas, manufactureras y de servicios, procedentes de la Business Environment and enterprise Performance Survey (BEEPS). La técnica empleada para estimar los coeficientes del modelo es la regresión mínimo cuadrática ordinaria, ya que la variable dependiente (productividad laboral) es continua. Los resultados indican que la innovación radical y la formación influyen positiva y significativamente sobre la productividad laboral. La influencia de la tecnología incorporada también es significativa, pero de signo negativo. Finalmente, señalar que las empresas que más exportan y las de mayor tamaño alcanzan mayores niveles de productividad. Los hallazgos encontrados en este estudio tienen implicaciones para los responsables de la política económica. Los decisores políticos españoles deben promover y subsidiar la adquisición de maquinaria y equipos más eficientes para las empresas que alcanzan menores niveles de productividad, así como subsidiar la formación de trabajadores cualificados en el manejo de estos nuevos equipos. Además, también deben promover y subsidiar el desarrollo de actividades de elevado contenido en I+D para las empresas que consiguen elevados niveles de productividad, a fin de que incrementen su desempeño en innovación radical. La promoción y subsidiación de programas de formación relacionados con la I+D también resulta esencial en este tipo de empresas, máxime en un escenario caracterizado por un cambio tecnológico intenso y que se produce con gran rapidez.

Analysis of multivariate stochastic signals sampled by on-line particle analyzers: Application to the quantitative assessment of occupational exposure to NOAA in multisource industrial scenarios (MSIS)

In multisource industrial scenarios (MSIS) coexist NOAA generating activities with other productive sources of airborne particles, such as parallel processes of manufacturing or electrical and diesel machinery. A distinctive characteristic of MSIS is the spatially complex distribution of aerosol sources, as well as their potential differences in dynamics, due to the feasibility of multi-task configuration at a given time. Thus, the background signal is expected to challenge the aerosol analyzers at a probably wide range of concentrations and size distributions, depending of the multisource configuration at a given time. Monitoring and prediction by using statistical analysis of time series captured by on-line particle analyzers in industrial scenarios, have been proven to be feasible in predicting PNC evolution provided a given quality of net signals (difference between signal at source and background). However the analysis and modelling of non-consistent time series, influenced by low levels of SNR (Signal-Noise Ratio) could build a misleading basis for decision making. In this context, this work explores the use of stochastic models based on ARIMA methodology to monitor and predict exposure values (PNC). The study was carried out in a MSIS where an case study focused on the manufacture of perforated tablets of nano-TiO2 by cold pressing was performed