Development and analysis of formulations to the delivery of caffeine for the treatment of gynoid lipodystrophy

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Sustainable Wastewater Management: Is it Possible to Regulate Micropollution in the Future by Learning from the Past? A Policy Analysis

This paper applies a policy analysis approach to the question of how to effectively regulate micropollution in a sustainable manner. Micropollution is a complex policy problem characterized by a huge number and diversity of chemical substances, as well as various entry paths into the aquatic environment. It challenges traditional water quality management by calling for new technologies in wastewater treatment and behavioral changes in industry, agriculture and civil society. In light of such challenges, the question arises as to how to regulate such a complex phenomenon to ensure water quality is maintained in the future? What can we learn from past experiences in water quality regulation? To answer these questions, policy analysis strongly focuses on the design and choice of policy instruments and the mix of such measures. In this paper, we review instruments commonly used in past water quality regulation. We evaluate their ability to respond to the characteristics of a more recent water quality problem, i.e., micropollution, in a sustainable way. This way, we develop a new framework that integrates both the problem dimension (i.e., causes and effects of a problem) as well as the sustainability dimension (e.g., long-term, cross-sectoral and multi-level) to assess which policy instruments are best suited to regulate micropollution. We thus conclude that sustainability criteria help to identify an appropriate instrument mix of end-of-pipe and source-directed measures to reduce aquatic micropollution.

DEVELOPMENT OF NOVEL METHODS TO MINIMIZE THE IMPACT OF SEQUENCING ERRORS IN THE NEXT-GENERATION SEQUENCING DATA ANALYSIS

Next-generation sequencing (NGS) technology has become a prominent tool in biological and biomedical research. However, NGS data analysis, such as de novo assembly, mapping and variants detection is far from maturity, and the high sequencing error-rate is one of the major problems. . To minimize the impact of sequencing errors, we developed a highly robust and efficient method, MTM, to correct the errors in NGS reads. We demonstrated the effectiveness of MTM on both single-cell data with highly non-uniform coverage and normal data with uniformly high coverage, reflecting that MTM’s performance does not rely on the coverage of the sequencing reads. MTM was also compared with Hammer and Quake, the best methods for correcting non-uniform and uniform data respectively. For non-uniform data, MTM outperformed both Hammer and Quake. For uniform data, MTM showed better performance than Quake and comparable results to Hammer. By making better error correction with MTM, the quality of downstream analysis, such as mapping and SNP detection, was improved. SNP calling is a major application of NGS technologies. However, the existence of sequencing errors complicates this process, especially for the low coverage (

Computational methods to create and analyze a digital gene expression atlas of embryo development from microscopy images

Abstract The creation of atlases, or digital models where information from different subjects can be combined, is a field of increasing interest in biomedical imaging. When a single image does not contain enough information to appropriately describe the organism under study, it is then necessary to acquire images of several individuals, each of them containing complementary data with respect to the rest of the components in the cohort. This approach allows creating digital prototypes, ranging from anatomical atlases of human patients and organs, obtained for instance from Magnetic Resonance Imaging, to gene expression cartographies of embryo development, typically achieved from Light Microscopy. Within such context, in this PhD Thesis we propose, develop and validate new dedicated image processing methodologies that, based on image registration techniques, bring information from multiple individuals into alignment within a single digital atlas model. We also elaborate a dedicated software visualization platform to explore the resulting wealth of multi-dimensional data and novel analysis algo-rithms to automatically mine the generated resource in search of bio¬logical insights. In particular, this work focuses on gene expression data from developing zebrafish embryos imaged at the cellular resolution level with Two-Photon Laser Scanning Microscopy. Disposing of quantitative measurements relating multiple gene expressions to cell position and their evolution in time is a fundamental prerequisite to understand embryogenesis multi-scale processes. However, the number of gene expressions that can be simultaneously stained in one acquisition is limited due to optical and labeling constraints. These limitations motivate the implementation of atlasing strategies that can recreate a virtual gene expression multiplex. The developed computational tools have been tested in two different scenarios. The first one is the early zebrafish embryogenesis where the resulting atlas constitutes a link between the phenotype and the genotype at the cellular level. The second one is the late zebrafish brain where the resulting atlas allows studies relating gene expression to brain regionalization and neurogenesis. The proposed computational frameworks have been adapted to the requirements of both scenarios, such as the integration of partial views of the embryo into a whole embryo model with cellular resolution or the registration of anatom¬ical traits with deformable transformation models non-dependent on any specific labeling. The software implementation of the atlas generation tool (Match-IT) and the visualization platform (Atlas-IT) together with the gene expression atlas resources developed in this Thesis are to be made freely available to the scientific community. Lastly, a novel proof-of-concept experiment integrates for the first time 3D gene expression atlas resources with cell lineages extracted from live embryos, opening up the door to correlate genetic and cellular spatio-temporal dynamics. La creación de atlas, o modelos digitales, donde la información de distintos sujetos puede ser combinada, es un campo de creciente interés en imagen biomédica. Cuando una sola imagen no contiene suficientes datos como para describir apropiadamente el organismo objeto de estudio, se hace necesario adquirir imágenes de varios individuos, cada una de las cuales contiene información complementaria respecto al resto de componentes del grupo. De este modo, es posible crear prototipos digitales, que pueden ir desde atlas anatómicos de órganos y pacientes humanos, adquiridos por ejemplo mediante Resonancia Magnética, hasta cartografías de la expresión genética del desarrollo de embrionario, típicamente adquiridas mediante Microscopía Optica. Dentro de este contexto, en esta Tesis Doctoral se introducen, desarrollan y validan nuevos métodos de procesado de imagen que, basándose en técnicas de registro de imagen, son capaces de alinear imágenes y datos provenientes de múltiples individuos en un solo atlas digital. Además, se ha elaborado una plataforma de visualization específicamente diseñada para explorar la gran cantidad de datos, caracterizados por su multi-dimensionalidad, que resulta de estos métodos. Asimismo, se han propuesto novedosos algoritmos de análisis y minería de datos que permiten inspeccionar automáticamente los atlas generados en busca de conclusiones biológicas significativas. En particular, este trabajo se centra en datos de expresión genética del desarrollo embrionario del pez cebra, adquiridos mediante Microscopía dos fotones con resolución celular. Disponer de medidas cuantitativas que relacionen estas expresiones genéticas con las posiciones celulares y su evolución en el tiempo es un prerrequisito fundamental para comprender los procesos multi-escala característicos de la morfogénesis. Sin embargo, el número de expresiones genéticos que pueden ser simultáneamente etiquetados en una sola adquisición es reducido debido a limitaciones tanto ópticas como del etiquetado. Estas limitaciones requieren la implementación de estrategias de creación de atlas que puedan recrear un multiplexado virtual de expresiones genéticas. Las herramientas computacionales desarrolladas han sido validadas en dos escenarios distintos. El primer escenario es el desarrollo embrionario temprano del pez cebra, donde el atlas resultante permite constituir un vínculo, a nivel celular, entre el fenotipo y el genotipo de este organismo modelo. El segundo escenario corresponde a estadios tardíos del desarrollo del cerebro del pez cebra, donde el atlas resultante permite relacionar expresiones genéticas con la regionalización del cerebro y la formación de neuronas. La plataforma computacional desarrollada ha sido adaptada a los requisitos y retos planteados en ambos escenarios, como la integración, a resolución celular, de vistas parciales dentro de un modelo consistente en un embrión completo, o el alineamiento entre estructuras de referencia anatómica equivalentes, logrado mediante el uso de modelos de transformación deformables que no requieren ningún marcador específico. Está previsto poner a disposición de la comunidad científica tanto la herramienta de generación de atlas (Match-IT), como su plataforma de visualización (Atlas-IT), así como las bases de datos de expresión genética creadas a partir de estas herramientas. Por último, dentro de la presente Tesis Doctoral, se ha incluido una prueba conceptual innovadora que permite integrar los mencionados atlas de expresión genética tridimensionales dentro del linaje celular extraído de una adquisición in vivo de un embrión. Esta prueba conceptual abre la puerta a la posibilidad de correlar, por primera vez, las dinámicas espacio-temporales de genes y células.

Contributions to uncertainty reduction in the estimation of PV plants performance

Esta tesis doctoral presenta un procedimiento integral de control de calidad en centrales fotovoltaicas, que comprende desde la fase inicial de estimación de las expectativas de producción hasta la vigilancia del funcionamiento de la instalación una vez en operación, y que permite reducir la incertidumbre asociada su comportamiento y aumentar su fiabilidad a largo plazo, optimizando su funcionamiento. La coyuntura de la tecnología fotovoltaica ha evolucionado enormemente en los últimos años, haciendo que las centrales fotovoltaicas sean capaces de producir energía a unos precios totalmente competitivos en relación con otras fuentes de energía. Esto hace que aumente la exigencia sobre el funcionamiento y la fiabilidad de estas instalaciones. Para cumplir con dicha exigencia, es necesaria la adecuación de los procedimientos de control de calidad aplicados, así como el desarrollo de nuevos métodos que deriven en un conocimiento más completo del estado de las centrales, y que permitan mantener la vigilancia sobre las mismas a lo largo del tiempo. Además, los ajustados márgenes de explotación actuales requieren que durante la fase de diseño se disponga de métodos de estimación de la producción que comporten la menor incertidumbre posible. La propuesta de control de calidad presentada en este trabajo parte de protocolos anteriores orientados a la fase de puesta en marcha de una instalación fotovoltaica, y las complementa con métodos aplicables a la fase de operación, prestando especial atención a los principales problemas que aparecen en las centrales a lo largo de su vida útil (puntos calientes, impacto de la suciedad, envejecimiento…). Además, incorpora un protocolo de vigilancia y análisis del funcionamiento de las instalaciones a partir de sus datos de monitorización, que incluye desde la comprobación de la validez de los propios datos registrados hasta la detección y el diagnóstico de fallos, y que permite un conocimiento automatizado y detallado de las plantas. Dicho procedimiento está orientado a facilitar las tareas de operación y mantenimiento, de manera que se garantice una alta disponibilidad de funcionamiento de la instalación. De vuelta a la fase inicial de cálculo de las expectativas de producción, se utilizan los datos registrados en las centrales para llevar a cabo una mejora de los métodos de estimación de la radiación, que es la componente que más incertidumbre añade al proceso de modelado. El desarrollo y la aplicación de este procedimiento de control de calidad se han llevado a cabo en 39 grandes centrales fotovoltaicas, que totalizan una potencia de 250 MW, distribuidas por varios países de Europa y América Latina. ABSTRACT This thesis presents a comprehensive quality control procedure to be applied in photovoltaic plants, which covers from the initial phase of energy production estimation to the monitoring of the installation performance, once it is in operation. This protocol allows reducing the uncertainty associated to the photovoltaic plants behaviour and increases their long term reliability, therefore optimizing their performance. The situation of photovoltaic technology has drastically evolved in recent years, making photovoltaic plants capable of producing energy at fully competitive prices, in relation to other energy sources. This fact increases the requirements on the performance and reliability of these facilities. To meet this demand, it is necessary to adapt the quality control procedures and to develop new methods able to provide a more complete knowledge of the state of health of the plants, and able to maintain surveillance on them over time. In addition, the current meagre margins in which these installations operate require procedures capable of estimating energy production with the lower possible uncertainty during the design phase. The quality control procedure presented in this work starts from previous protocols oriented to the commissioning phase of a photovoltaic system, and complete them with procedures for the operation phase, paying particular attention to the major problems that arise in photovoltaic plants during their lifetime (hot spots, dust impact, ageing...). It also incorporates a protocol to control and analyse the installation performance directly from its monitoring data, which comprises from checking the validity of the recorded data itself to the detection and diagnosis of failures, and which allows an automated and detailed knowledge of the PV plant performance that can be oriented to facilitate the operation and maintenance of the installation, so as to ensure a high operation availability of the system. Back to the initial stage of calculating production expectations, the data recorded in the photovoltaic plants is used to improved methods for estimating the incident irradiation, which is the component that adds more uncertainty to the modelling process. The development and implementation of the presented quality control procedure has been carried out in 39 large photovoltaic plants, with a total power of 250 MW, located in different European and Latin-American countries.

Effectiveness and Content Analysis of Interventions to Enhance Oral Antidiabetic Drug Adherence in Adults with Type 2 Diabetes : Systematic Review and Meta-Analysis

Peer reviewed

Down syndrome-critical region contains a gene homologous to Drosophila sim expressed during rat and human central nervous system development.

Many features of Down syndrome might result from the overdosage of only a few genes located in a critical region of chromosome 21. To search for these genes, cosmids mapping in this region were isolated and used for trapping exons. One of the trapped exons obtained has a sequence very similar to part of the Drosophila single-minded (sim) gene, a master regulator of the early development of the fly central nervous system midline. Mapping data indicated that this exonic sequence is only present in the Down syndrome-critical region in the human genome. Hybridization of this exonic sequence with human fetal kidney poly(A)+ RNA revealed two transcripts of 6 and 4.3 kb. In situ hybridization of a probe derived from this exon with human and rat fetuses showed that the corresponding gene is expressed during early fetal life in the central nervous system and in other tissues, including the facial, skull, palate, and vertebra primordia. The expression pattern of this gene suggests that it might be involved in the pathogenesis of some of the morphological features and brain anomalies observed in Down syndrome.