De novo development of novel DM1 toxic ncRNA targeting small molecules and its biological evaluation

La distròfia miotònica de tipus 1 (DM1) és un trastorn neuromuscular incurable causat per les transcripcions tòxiques del gen DMPK. Aquests transcrits porten expansions de repeticions CUG a les regions no traduïdes 3′ (3′UTR). La complexitat intrínseca i la falta de dades cristal·logràfiques fan que les regions d'ARN no codificant siguin objectius difícils d'estudiar en el camp del desenvolupament de nous fàrmacs. En el cas de la DM1, els transcrits tòxics tendeixen a estancar-se a l'interior dels nuclis formant complexos cossos d'inclusió anomenats foci i segrestant molts factors de splicing alternatiu essencials com el Muscleblind-like 1 (MBNL1). La majoria de les característiques fenotípiques de la DM1 es deriven de la reduïda disponibilitat de MBNL1 lliure, per la qual cosa molts esforços terapèutics es centren en recuperar la seva activitat regular. Per a això, en la present tesi, decidim utilitzar com a diana terapèutica l'ARN CUG, amb la finalitat d'alliberar MBNL1. Pel que respecta al disseny de noves estructures, es descriu el cribratge in-silico mitjançant tècniques de disseny de fàrmacs basades en estructura usant dues premisses diferents d'abordar CUG. A més, es desenvolupen vies sintètiques per als candidats seleccionats basades en química clic. Finalment, per a avaluar la seva activitat biològica, es posa a punt un assaig bioquímic ja descrit, i s'utilitzen models cel·lulars i cèl·lules musculars derivades de pacients per a avaluar els candidats més prometedors. Els resultats obtinguts poden conduir a posteriors generacions de lligands, posant de manifest un nou tractament assequible contra la DM1.La distrofia miotónica de tipo 1 (DM1) es un trastorno neuromuscular incurable causado por las transcripciones tóxicas del gen DMPK. Estos transcritos llevan expansiones de repeticiones CUG en las regiones no traducidas 3′ (3′UTR). La complejidad intrínseca y la falta de datos cristalográficos hacen que las regiones de ARN no codificante sean objetivos difíciles de estudiar en el campo del desarrollo de nuevos fármacos. En la DM1, los transcritos tóxicos tienden a estancarse en el interior de los núcleos formando complejos cuerpos de inclusión llamados foci y secuestrando muchos factores de splicing alternativo esenciales como el Muscleblind-like 1 (MBNL1). La mayoría de las características fenotípicas de la DM1 se derivan de la reducida disponibilidad de MBNL1 libre, por lo que muchos esfuerzos terapéuticos se centran en recuperar su actividad regular. Para ello, en la presente tesis, decidimos utilizar como diana terapéutica el ARN CUG, con el fin de liberar MBNL1. Por lo que respecta al diseño de nuevas estructuras, se describe el cribado in-silico mediante técnicas de diseño de fármacos basadas en estructura usando dos premisas diferentes de abordar CUG. Además, se desarrollan vías sintéticas para los candidatos seleccionados basadas en química click. Por último, para evaluar su actividad biológica, se pone a punto un ensayo bioquímico ya descrito, y se utilizan modelos celulares y células musculares derivadas de pacientes para evaluar los candidatos más prometedores. Los resultados obtenidos pueden conducir a posteriores generaciones de ligandos, poniendo de manifiesto un nuevo tratamiento asequible contra la DM1.Myotonic Dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by toxic DMPK transcripts that carry CUG repeat expansions in the 3′ untranslated regions (3′UTR). The intrinsic complexity and lack of crystallographic data make noncoding RNA regions challenging targets to study in the field of drug discovery. In DM1, toxic transcripts tend to stall in the nuclei forming complex inclusion bodies called foci and sequestering many essential alternative splicing factors such as Muscleblind-like 1 (MBNL1). Most DM1 phenotypic features stem from the reduced availability of free MBNL1, and therefore many therapeutic efforts are focused on recovering its regular activity. For that purpose, in the present thesis, we decide to target CUG RNA to free MBNL1. The in-silico screening using structure-based drug design techniques of novel candidates based on two different approaches is described. Furthermore, synthetic pathways are developed for the selected candidates based on the click chemistry approach. Finally, to assess their biological activity, an already described biochemical test is tuned, and cellular models and patient-derived muscular cells are used to evaluate the most promising candidates. The obtained results may lead to subsequent generations of ligands, highlighting a new affordable treatment against DM1

Spatial Data Infrastructure of the Plurinational State of Bolivia - A free and democratic SDI

The Vice Presidency of the State, with the help of the GeoBolivia project, is building the Spatial Data Infrastructure of the Plurinational State of Bolivia (IDEEPB by its Spanish initials). The first phase of the project has already been completed. It consisted in implementing an infrastructure and a geoportal that nowadays gives access to the reference geographic information of Bolivia, through WMS, WFS, WCS and CSW services. The project is currently in its second phase dedicated to decentralizing the structure of IDE-EPB and promoting its use throughout the Bolivian State. The whole platform uses free software and open standards. As a complement, an on-line training module was developed to undertake the transfer of the knowledge the project generated. The main software components used in the SDI are: gvSIG, QGis, uDig as GIS desktop clients; Post-GreSQL and PostGIS as geographic database management system; geOrchestra as a framework containing the GeoServer map server, the GeoNetwork catalog server and the OpenLayers and Mapfish GIS webclient; MapServer as a map server for generating OpenStreetMap tiles; Debian as operating system; Apache and Tomcat as web servers

Enhancement of the advanced Fenton process (Fe0/H2O2) by ultrasound for the mineralization of phenol

In this study, a successful mineralization of phenol was achieved by means of coupling zero-valent iron (ZVI) particles, hydrogen peroxide and a short input of ultrasonic irradiation. This short sono-advanced Fenton process (AFP) provided a better performance of ZVI in a subsequent silent degradation stage, which involves neither extra cost of energy nor additional oxidant. The short input of ultrasound (US) irradiation enhanced the activity of the Fe0/H2O2 system in terms of the total organic carbon (TOC) removal. Then, the TOC mineralization continued during the silent stage, even after the total consumption of hydrogen peroxide, reaching values of ca. 90% TOC conversions over 24 h. This remarkable activity is attributed to the capacity of the ZVI/iron oxide composite formed during the degradation for the generation of oxidizing radical species and to the formation of another reactive oxidant species, such as the ferryl ion. The modification of the initial conditions of the sono-AFP system such as the ultrasonic irradiation time and the hydrogen peroxide dosage, showed significant variations in terms of TOC mineralization for the ongoing silent degradation stage. An appropriate selection of operation conditions will lead to an economical and highly efficient technology with eventual large-scale commercial applications for the degradation organic pollutants in aqueous effluents

Intensification of oxidation capacity using chloroalkanes as additives in hydrodynamic and acoustic cavitation reactors

The effect of the presence and absence of the chloroalkanes, dichloromethane (CH2Cl2), chloroform (CHCl3) and carbon tetrachloride (CCl4) on the extent of oxidation of aqueous I- to I3- has been investigated in (a) a liquid whistle reactor (LWR) generating hydrodynamic cavitation and (b) an ultrasonic probe, which produces acoustic cavitation. The aim has been to examine the intensification achieved in the extent of oxidation due to the generation of additional free radicals/oxidants in the reactor as a result of the presence of chloroalkanes. It has been observed that the extent of increase in the oxidation reaction is strongly dependent on the applied pressure in the case of the LWR. Also, higher volumes of the chloroalkanes favour the intensification and the order of effectiveness is CCl4> CHCl3 > CH2Cl2. However, the results with the ultrasonic probe suggest that an optimum concentration of CH2Cl2 or CHCl3 exists beyond which there is little increase in the extent of observed intensification. For CCl4, however, no such optimum concentration was observed and the extent of increase in the rates of oxidation reaction rose with the amount of CCl4 added. Stage wise addition of the chloroalkanes was found to give marginally better results in the case of the ultrasonic probe as compared to bulk addition at the start of the run. Although CCl4 is the most effective, its toxicity and carcinogenicity may mean that CH2Cl2 and CHCl3 offer a safer viable alternative and the present work should be useful in establishing the amount of chloroalkanes required for obtaining a suitable degree of intensification

Improving the prefetching performance through code region profiling

In this work, we propose a new technique to improve the performance of hardware data prefetching. This technique is based on detecting periods of time and regions of code where the prefetcher is not working properly, thus not providing any speedup or even producing slowdown. Once these periods of time and regions of code are detected, the prefetcher may be switched off and later on, switched on. To efficiently implement such mechanism, we identify three orthogonal issues that must be addressed: the granularity of the code region, when the prefetcher is switched on, and when the prefetcher is switched off

Análisis de viabilidad de una turbina de eje vertical en un domicilio particular

Disseny d'una turbina vertical per recaptar energia de l'aire i del circuit per poder emmagatzemar-la per al seu ús

Estrategia de solución de problemas y capacidades de matemática en los estudiantes de la Escuela Técnica del Ejército del Perú, 2019

La investigación tuvo como objetivo determinar la relación entre la aplicación Estrategia solución de problemas y las Capacidades matemáticas en los estudiantes de la Escuela Técnica del Ejército del Perú, 2019. La investigación es básica, el diseño fue no experimental, transversal correlacional, se trató de una muestra censal dado que se trabajó con toda la población de estudiantes del I año de estudios en la facultad de Educación en la especialidad de educación primaria, se aplicó dos instrumentos una escala de percepción respecto a la forma de uso de la estrategia de solución de problemas y una prueba objetiva basado en los contenidos de matemática básica del Plan curricular en la Escuela Técnica del Ejército del Perú, 2019. Finalmente, la técnica de procesamiento de datos, y su instrumento las tablas de procesamiento de datos para tabular, y procesar los resultados de la evaluación a través del software SPSS 19. Los resultados obtenidos permiten concluir que existe relación directa y significativa entre la estrategia de solución de problemas y las capacidades matemáticas en el curso de matemática básica con un valor rho Spearman de ,678 y un valor p= ,000 confirmando la hipótesis alterna dado que se infiere a mayor uso de estrategias de solución de problemas mejor nivel de aprendizaje en las capacidades matemáticas.The objective of the research was to determine the relationship between the Strategy Solution and Mathematics Capabilities application in the students of the Technical School of the Army of Peru, 2019. The research is basic, the design was non-experimental, cross- correlated, it was a census sample given that the entire population of students of the first year of studies was worked on in the Faculty of Education in the specialty of primary education, two instruments were applied a perception scale with respect to the use of the solution strategy of problems and an objective test based on the basic mathematics contents of the curricular plan at the Technical School of the Army of Peru, 2019. Finally, the data processing technique, and its instrument the data processing tables to tabulate, and process the results of the evaluation through the SPSS software 19. The results obtained allow us to conclude that there is a direct and significant relationship between the problem solving strategy and the mathematical abilities in the basic mathematics course with a rho Spearman value of, 678 and a value p =, 000 confirming the alternative hypothesis given that it is inferred from greater use of Problem solving strategies better level of learning in mathematical abilities

A Multistage Change detection methodology applying statistical multisource

Assessment and detection of environmental changes is one the most frequent applications in remote sensing. As a result, there has been a great proliferation of research on this particular topic, leading to different methodologies for detecting changes (Radke 2005, Foody 2009, Kennedy 2009) from data supplied by multitemporal images acquired from spaceborne sensors. The basic objective in a change detection process is to detect groups of pixels that are "significantly different" within a set of registered images of the same geographic area. Moreover it must be taken into account that in the recent decades, advances in space technologies made possible to collect a large amount of information about the Earth Surface and its environment. Since these data have been acquired from multiple sources, their quantitative exploitation requires optimal strategies to benefit from their interactions, so that information of high quality and great applicability for the proposed objectives can be extracted. (Petit 2001

Distribution of Chlamydia trachomatis genotypes in infertile patients of Cordoba, Argentina

To detect and characterize Chlamydia trachomatis (C. trachomatis) genotypes in infertile patients of Córdoba, Argentina; 660 endocervical and urethral swabs and semen samples were collected from infertile patients for detection of C. trachomatis by omp A gene with Hemi Nested-PCR and cryptic plasmid-PCR. Sequencing methods of omp A gene were used to identify C. trachomatis genotypes. The sequences obtained were aligned with chlamydial sequences currently available in the GenBank, for the design of the phylogenetic tree. The prevalence of C. trachomatis was 7.27% (48/660). We did not detect C. trachomatis cryptic plasmid free strains. According to the results of nucleotide sequences, the distribution of genotypes was L1 (50 %) followed by G (25 %), E (12.5%) and D (12.5%). Patients who tested positive to genotype L1 had no symptoms of lymphogranuloma venereum (LGV). This is the first study that provides information about the distribution of C. trachomatis genotypes and the circulation of cryptic plasmid negative strains of C. trachomatis among patients with infertility in Córdoba, Argentina.Fil: Monetti, Marina Soledad. Universidad Nacional de Cordoba. Facultad de Medicina. Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Molina, Rosa Alejandra. Laboratorio de Andrología y Reproducción; ArgentinaFil: Estofan, Patricia. Centro Integral de Ginecología, Obstericia y Reproducción; ArgentinaFil: Frutos, Maria Celia. Universidad Nacional de Cordoba. Facultad de Medicina. Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kiguen, Ana Ximena. Universidad Nacional de Cordoba. Facultad de Medicina. Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Venezuela, Raul Fernando. Universidad Nacional de Cordoba. Facultad de Medicina. Instituto de Virología; ArgentinaFil: Paglini, Maria Gabriela. Universidad Nacional de Cordoba. Facultad de Medicina. Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cuffini, Cecilia Gabriela. Universidad Nacional de Cordoba. Facultad de Medicina. Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin