Computational and mathematical approaches to understand glioma cells metabolism: characterization from transcriptomic data and focus on HIF pathways

This Thesis questions the effect of hypoxia on cell metabolism, how different oxygen levels within the tumour lead to heterogeneity, and what is the impact on tumour growth. The study focuses on the main protein orchestrating the cellular adaptation to hypoxia: the Hypoxia Inducible Factor (HIF). Despite being the topic of many studies, HIF seems to be only characterized through its effect on genes observed during biological experiments. Mathematical modelling of HIF does not integrate the protein in models simulating large population of cells. This work will try to unravel some of the mechanisms by which HIF impact the tumour growth with a focus on the metabolim and the cell invasion. In this regard, an agent-based model (ABM) has been developed and the investigation paths for the model have been determined from a statistical analysis.The mathematical model developed describes a network of genes regulated by HIF which includes the two important metabolic genes lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) with a focus on the appearance of the Warburg Effect, a mechanism often considered as a tumour cell characteristic. An individual-based approach has been chosen to better represent cellular heterogeneity as each cell has its own set of parameters and experiences a different local environment. With that model, we could test different environmental conditions and genetic regulation. We saw that both rapid variations of extracellular oxygen and increased levels of HIF are enough to induce a Warburg phenotype, which therefore appears as influenced by both a contextual effect and a genetic effect.A statistical analysis of glioblastoma transcriptomic data has been performed to unravel the deregulated mechanisms into two datasets: one available on the The Cancer Genome Atlas (TCGA) platform and a Patient Derived Cell Lines (PDCL) dataset provided by the ICM (Paris). The workflow of analysis begins with a Differential Expression (DE) analysis of the transcriptomic data to find the deregulated genes, which are submitted to pathway enrichment tools to determine what are the corresponding pathways. Among the results, collagen biosynthesis was often deregulated in both datasets and cholesterol metabolism was often deregulated in PDCL data. Owing to its link to the current thematic, collagen biosynthesis has been selected as the new candidate for mathematical description in the current model.Thus, following the results of the statistical analysis, the collagen biosynthesis have been implemeted in the model of metabolism. Collagen and matrix remodelling have a noticeable impact on cellular migration and thus the invasion of distant tissues by cancer cells. The three genes P4HA1, MT1-MMP and LOX have been documented to be upregulated by HIF in the literature and to impact the secretion, degradation and cross-linking of collagen. Genetic parameters were fitted to transcriptomic data to define the genetic parameters of these new genes as well as for the ones already included. The results obtained with the new version of the model indicated that collagen density has a substantial effect on the proliferation of the tumour and its shape. Like collagen, oxygen alone could impact the tumour growth. Moreover, results showed that the oxygen and collagen seems to have a dual effect on tumour proliferation. Increased P4HA1 and MT1-MMP quantities, respectively decreased and increased cellular migration speed while LOX seemed to have little effect. Here, no cells adopted a Warburg phenotype in any of the simulations. The similarity of the production of H+ in this model observed when PDH sensitivity to HIF was reduced in the previous model indicates that this may be due to the new parameters values. Consequently, even if the microenvironment favours a Warburg phenotype, genetic regulation may dictate the cell ability to induce it.This model made it possible to show how HIF can impact the tumour growth and cellular invasion through few regulations. It suggests that both fast changes of oxygen levels and increased HIF stabilization in normoxia can induce a Warburg Effect. However, the ability of the cell to reduce the oxygen consumption through adaptation to hypoxia seemed to be a limiting factor preventing the adoption of a Warburg phenotype

Modelling and Validating a multiple-configuration railway signalling system using SDL

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Zika Virus: a Review from the Virus Basics to Proposed Management Strategies

This review aims to summarize the body of knowledge available on Zika virus to date. A comprehensive review of the scientific literature on Zika virus was performed with the aim to stress relevant aspects for healthcare professionals in the non-endemic areas. For several years, the Zika virus infection was considered an extremely rare exotic disease with poor clinical relevance. However, Zika virus has recently gained the attention of the scientific community and public opinion since the virus spread to the Pacific islands and the South America in an unprecedented epidemic, and additionally due to the definitive evidence that the infection could be complicated by Guillain-Barré syndrome, passed through vertical transmission, and result in central nervous system abnormalities (including microcephaly) of the fetus. Studies and scientific evidence on the complications associated with Zika virus infection are growing day by day. It is advisable that the healthcare professionals working in non-endemic areas maintain full awareness on this issue in order to practice proper management of the imported cases of Zika virus infection

ERMHAN: A Context-Aware Service Platform to Support Continuous Care Networks for Home-Based Assistance

Continuous care models for chronic diseases pose several technology-oriented challenges for home-based continuous care, where assistance services rely on a close collaboration among different stakeholders such as health operators, patient relatives, and social community members. Here we describe Emilia Romagna Mobile Health Assistance Network (ERMHAN) a multichannel context-aware service platform designed to support care networks in cooperating and sharing information with the goal of improving patient quality of life. In order to meet extensibility and flexibility requirements, this platform has been developed through ontology-based context-aware computing and a service oriented approach. We also provide some preliminary results of performance analysis and user survey activity

The History of Science, Art and Technology: an innovative teaching proposal

El Informe Rocard (2007) evidenció que la enseñanza de las ciencias y las matemáticas dista mucho de atraer multitudes. El Informe y las sucesivas Recomendaciones (2017) animaban, por ello, a la introducción de enfoques educativos centrados en la investigación y la tecnología, la adquisición de competencias científicas y su puesta en relación con las artes, la creatividad y la innovación. Desde estas consideraciones, el objetivo principal de este proyecto es investigar si la historia de la ciencia puede ser un instrumento adecuado para poner en práctica las líneas sugeridas por aquel informe. Con este fin se diseñó una propuesta didáctica, de enfoque histórico, para una intervención-acción en un instituto de Florencia (un curso de física con alumnos de 4º de ESO). Como tema central se eligió los descubrimientos astronómicos de Galileo y sus consecuencias astronómicas, religiosas, filosóficas y físicas. La intervención-acción incluyó el uso de múltiples estrategias de enseñanza: lectura de textos originales, construcción de instrumentos y el uso de Thinglink. Thinglink es una plataforma digital que permite construir recorridos de forma interactiva con imágenes y vídeos, también en forma de realidad virtual inmersiva. Con fotos tomadas con una cámara 360 grados por la investigadora, los estudiantes, usando una cardboard, pudieron moverse por los pasillos de museos, palacios e iglesias de Roma, Florencia, Madrid y Mónaco en busca de obras de arte relacionadas con el tema que estaban tratando. Para evaluar el proceso se diseñaron pruebas pre-test y post-test, además de un cuestionario sobre las emociones experimentadas por los alumnos. El análisis de los resultados muestra que la historia de la ciencia es un instrumento muy eficaz cuando se quiere motivar a los estudiantes y desarrollar competencias básicas para el aprendizaje.The Rocard Report (2007) showed that teaching science and mathematics is far from attracting crowds. The Report and the subsequent Recommendations (2017) encouraged, therefore, the introduction of educational approaches focused on research and technology, the acquisition of scientific competences and their relationship with the arts, creativity and innovation. From these considerations, the main objective of this project is to investigate whether the history of science can be an adequate instrument to put into practice the lines suggested by that report. To this end, a didactic proposal, with a historical approach, was designed for an intervention-action in an Italian Institute in Florence (a physics course with 4th ESO students). Galileo's astronomical discoveries and their astronomical, religious, philosophical and physical consequences were chosen as the central theme. The intervention-action included the use of multiple teaching strategies: reading original texts, building instruments, and the use of Thinglink. Thinglink is a digital platform that allows building interactive tours with images and videos, also in the form of immersive virtual reality. With photos taken with a 360-degree camera by the researcher, the students, using a cardboard, were able to move through the corridors of museums, palaces and churches in Rome, Florence, Madrid and Monaco in search of works of art related to the subject they were studying. To evaluate the process, pre-test and post-test checkpoints were designed, in addition to a questionnaire about the emotions experienced by the students. The analysis of the results shows that the history of science is a very effective instrument when a teacher aims at motivating students and developing basic skills for learning.Fac. de EducaciónTRUEpu

Due domande sulla natura dell'immaginazione

The aim of this paper is to focus on a particular subject \u2013 imagination \u2013 in order to set limits and to underscore the validity of a phenomenological understanding of our experience. Imagination is, first of all, a general heading under which we comprehend a range of psychological faculties, whose adaptive meaning (still poorly understood) deserve to be analyzed from a naturalistic point of view. Under the same heading we are used to understand a variety of social and individual activities, of playful gestures and utterances, which belong to the realm of meaning and which deserve to be analyzed and clarified from a descriptive point of view. Phenomenology, as a description of the meaning of our personal experience, has here its possible field of application

Il mare color del vino: Riflessioni fenomenologiche su un’immagine omerica

The article offers a phenomenological reflection on Homer’s image of the sea being the colour of wine. Indeed, this image refers to its deep imaginative connection with blood and life, with the earth and death