Open Access Theses - Health Science - 2011-2020
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PublicationA bi-objective home care scheduling problem: Analyzing the trade-off between costs and client inconvenience( 2016)" Braekers, Kris, Hartl, Richard F., Parragh, Sophie, Tricoire, Fabien""Organizations providing home care services are inclined to optimize their activities in order to meet the constantly increasing demand for home care. In this context, home care providers are confronted with multiple, often conflicting, objectives such as minimizing their operating costs while maximizing the service level offered to their clients by taking into account their preferences. This paper is the first to shed some light on the trade-off relationship between these two objectives by modeling the home care routing and scheduling problem as a bi-objective problem. The proposed model accounts for qualifications, working regulations and overtime costs of the nurses, travel costs depending on the mode of transportation, hard time windows, and client preferences on visit times and nurses. A distinguishing characteristic of the problem is that the scheduling problem for a single route is a biobjective problem in itself, thereby complicating the problem considerably. A metaheuristic algorithm, embedding a large neighborhood search heuristic in a multi-directional local search framework, is proposed to solve the problem. Computational experiments on a set of benchmark instances based on reallife data are presented. A comparison with exact solutions on small instances shows that the algorithm performs well. An analysis of the results reveals that service providers face a considerable trade-off between costs and client convenience. However, starting from a minimum cost solution, the average service level offered to the clients may already be improved drastically with limited additional costs. (authors' abstract)"
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PublicationComputational Modelling of Cardiac Electrophysiology: from Cell to Bedside / Modellistica Computazionale dell'Elettrofisiologia Cardiaca: dalla Cellula al Paziente( 2015)Passini, Elisa"Heart diseases are the leading cause of death worldwide, both for men and women. However, the ionic mechanisms underlying many cardiac arrhythmias and genetic disorders are not completely understood, thus leading to a limited efficacy of the current available therapies and leaving many open questions for cardiac electrophysiologists. On the other hand, experimental data availability is still a great issue in this field: most of the experiments are performed in vitro and/or using animal models (e.g. rabbit, dog and mouse), even when the final aim is to better understand the electrical behaviour of in vivo human heart either in physiological or pathological conditions. Computational modelling constitutes a primary tool in cardiac electrophysiology: in silico simulations, based on the available experimental data, may help to understand the electrical properties of the heart and the ionic mechanisms underlying a specific phenomenon. Once validated, mathematical models can be used for making predictions and testing hypotheses, thus suggesting potential therapeutic targets. This PhD thesis aims to apply computational cardiac modelling of human single cell action potential (AP) to three clinical scenarios, in order to gain new insights into the ionic mechanisms involved in the electrophysiological changes observed in vitro and/or in vivo. The first context is blood electrolyte variations, which may occur in patients due to different pathologies and/or therapies. In particular, we focused on extracellular Ca2+ and its effect on the AP duration (APD). The second context is haemodialysis (HD) therapy: in addition to blood electrolyte variations, patients undergo a lot of other different changes during HD, e.g. heart rate, cell volume, pH, and sympatho-vagal balance. The third context is human hypertrophic cardiomyopathy (HCM), a genetic disorder characterised by an increased arrhythmic risk, and still lacking a specific pharmacological treatment. / Le malattie cardiache e cardiovascolari sono ad oggi la causa principale di morte nel mondo. Tuttavia, i meccanismi ionici responsabili di aritmie o di altre malattie cardiache non sono ancora del tutto conosciuti: questo spesso porta a una minore o mancata efficacia delle terapie attualmente disponibili, e lascia numerose domande aperte per gli elettrofisiologi. Inoltre, la difficoltà di acquisizione dei dati sperimentali rimane ancora uno dei problemi più grandi in questo campo. Infatti la maggior parte dei dati vengono raccolti in vitro e/o utilizzando modelli animali come coniglio, ratto o cane, sebbene l’obiettivo ultimo sia quello di una più completa comprensione del comportamento elettrico del cuore in vivo e nell’uomo, in condizioni sia fisiologiche sia patologiche. In questo contesto, la modellistica computazionale costituisceuno strumento indispensabile: infatti, le simulazioni in silico permettono di superare, almeno in parte, i limiti sperimentali, e di investigare i meccanismi ionici alla base di specifici fenomeni a diversi livelli (singola cellula, tessuto, intero cuore). Una volta validati sui dati sperimentali, i modelli matematici possono essere dunque utilizzati per fare predizioni, testare ipotesi e valutare l’efficacia di eventuali interventi farmacologici. Lo scopo di questa tesi di dottorato è stato quello di applicare tecniche di modellistica matematica a problemi di elettrofisiologia cardiaca, in particolare utilizzando modelli di potenziale d’azione (PA) umano in tre diversi contesti: variazioni elettrolitiche nel sangue, effetti della terapia dialitica sul cuore e cardiomiopatia ipertrofica."
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PublicationConveying expressivity and vocal effort transformation in synthetic speech with Harmonic plus Noise Models( 2016)Calzada Defez, Àngel"Aquesta tesi s'ha dut a terme dins del Grup en de Tecnologies Mèdia (GTM) de l'Escola d'Enginyeria i Arquitectura la Salle. El grup te una llarga trajectòria dins del cap de la síntesi de veu i fins i tot disposa d'un sistema propi de síntesi per concatenació d'unitats (US-TTS) que permet sintetitzar diferents estils expressius usant múltiples corpus. De forma que per a realitzar una síntesi agressiva, el sistema usa el corpus de l'estil agressiu, i per a realitzar una síntesi sensual, usa el corpus de l'estil corresponent. Aquesta tesi pretén proposar modificacions del esquema del US-TTS que permetin millorar la flexibilitat del sistema per sintetitzar múltiples expressivitats usant només un únic corpus d'estil neutre. L'enfoc seguit en aquesta tesi es basa en l'ús de tècniques de processament digital del senyal (DSP) per aplicar modificacions de senyal a la veu sintetitzada per tal que aquesta expressi l'estil de parla desitjat. Per tal de dur a terme aquestes modificacions de senyal s'han usat els models harmònic més soroll per la seva flexibilitat a l'hora de realitzar modificacions de senyal. La qualitat de la veu (VoQ) juga un paper important en els diferents estils expressius. És per això que es va estudiar la síntesi de diferents emocions mitjançant la modificació de paràmetres de VoQ de baix nivell. D'aquest estudi es van identificar un conjunt de limitacions que van donar lloc als objectius d'aquesta tesi, entre ells el trobar un paràmetre amb gran impacte sobre els estils expressius. Per aquest fet l'esforç vocal (VE) es va escollir per el seu paper important en la parla expressiva. Primer es va estudiar la possibilitat de transferir l'VE entre dues realitzacions amb diferent VE de la mateixa paraula basant-se en la tècnica de predicció lineal adaptativa del filtre de pre-èmfasi (APLP). La proposta va permetre transferir l'VE correctament però presentava limitacions per a poder generar nivells intermitjos d'VE. Amb la finalitat de millorar la flexibilitat i control de l'VE expressat a la veu sintetitzada, es va proposar un nou model d'VE basat en polinomis lineals. Aquesta proposta va permetre transferir l'VE entre dues paraules qualsevols i sintetitzar nous nivells d'VE diferents dels disponibles al corpus. Aquesta flexibilitat esta alineada amb l'objectiu general d'aquesta tesi, permetre als sistemes US-TTS sintetitzar diferents estils expressius a partir d'un únic corpus d'estil neutre. La proposta realitzada també inclou un paràmetre que permet controlar fàcilment el nivell d'VE sintetitzat. Això obre moltes possibilitats per controlar fàcilment el procés de síntesi tal i com es va fer al projecte CreaVeu usant interfícies gràfiques simples i intuïtives, també realitzat dins del grup GTM. Aquesta memòria conclou presentant el treball realitzat en aquesta tesi i amb una proposta de modificació de l'esquema d'un sistema US-TTS per incloure els blocs de DSP desenvolupats en aquesta tesi que permetin al sistema sintetitzar múltiple nivells d'VE a partir d'un corpus d'estil neutre. Això obre moltes possibilitats per generar interfícies d'usuari que permetin controlar fàcilment el procés de síntesi, tal i com es va fer al projecte CreaVeu, també realitzat dins del grup GTM. Aquesta memòria conclou presentant el treball realitzat en aquesta tesi i amb una proposta de modificació de l'esquema del sistema US-TTS per incloure els blocs de DSP desenvolupats en aquesta tesi que permetin al sistema sintetitzar múltiple nivells d'VE a partir d'un corpus d'estil neutre. / Esta tesis se llevó a cabo en el Grup en Tecnologies Mèdia de la Escuela de Ingeniería y Arquitectura la Salle. El grupo lleva una larga trayectoria dentro del campo de la síntesis de voz y cuenta con su propio sistema de síntesis por concatenación de unidades (US-TTS). El sistema permite sintetizar múltiples estilos expresivos mediante el uso de corpus específicos para cada estilo expresivo. De este modo, para realizar una síntesis agresiva, el sistema usa el corpus de este estilo, y para un estilo sensual, usa otro corpus específico para ese estilo. La presente tesis aborda el problema con un enfoque distinto proponiendo cambios en el esquema del sistema con el fin de mejorar la flexibilidad para sintetizar múltiples estilos expresivos a partir de un único corpus de estilo de habla neutro. El planteamiento seguido en esta tesis esta basado en el uso de técnicas de procesamiento de señales (DSP) para llevar a cabo modificaciones del señal de voz para que este exprese el estilo de habla deseado. Para llevar acabo las modificaciones de la señal de voz se han usado los modelos harmónico más ruido (HNM) por su flexibilidad para efectuar modificaciones de señales. La cualidad de la voz (VoQ) juega un papel importante en diferentes estilos expresivos. Por ello se exploró la síntesis expresiva basada en modificaciones de parámetros de bajo nivel de la VoQ. Durante este estudio se detectaron diferentes problemas que dieron pié a los objetivos planteados en esta tesis, entre ellos el encontrar un único parámetro con fuerte influencia en la expresividad. El parámetro seleccionado fue el esfuerzo vocal (VE) por su importante papel a la hora de expresar diferentes emociones. Las primeras pruebas se realizaron con el fin de transferir el VE entre dos realizaciones con diferente grado de VE de la misma palabra usando una metodología basada en un proceso filtrado de pre-émfasis adaptativo con coeficientes de predicción lineales (APLP). Esta primera aproximación logró transferir el nivel de VE entre dos realizaciones de la misma palabra, sin embargo el proceso presentaba limitaciones para generar niveles de esfuerzo vocal intermedios. A fin de mejorar la flexibilidad y el control del sistema para expresar diferentes niveles de VE, se planteó un nuevo modelo de VE basado en polinomios lineales. Este modelo permitió transferir el VE entre dos palabras diferentes e incluso generar nuevos niveles no presentes en el corpus usado para la síntesis. Esta flexibilidad está alineada con el objetivo general de esta tesis de permitir a un sistema US-TTS expresar múltiples estilos de habla expresivos a partir de un único corpus de estilo neutro. Además, la metodología propuesta incorpora un parámetro que permite de forma sencilla controlar el nivel de VE expresado en la voz sintetizada. Esto abre la posibilidad de controlar fácilmente el proceso de síntesis tal y como se hizo en el proyecto CreaVeu usando interfaces simples e intuitivas, también realizado dentro del grupo GTM. Esta memoria concluye con una revisión del trabajo realizado en esta tesis y con una propuesta de modificación de un esquema de US-TTS para expresar diferentes niveles de VE a partir de un único corpus neutro. / This thesis was conducted in the Grup en Tecnologies M`edia (GTM) from Escola d’Enginyeria i Arquitectura la Salle. The group has a long trajectory in the speech synthesis field and has developed their own Unit-Selection Text-To-Speech (US-TTS) which is able to convey multiple expressive styles using multiple expressive corpora, one for each expressive style. Thus, in order to convey aggressive speech, the US-TTS uses an aggressive corpus, whereas for a sensual speech style, the system uses a sensual corpus. Unlike that approach, this dissertation aims to present a new schema for enhancing the flexibility of the US-TTS system for performing multiple expressive styles using a single neutral corpus. The approach followed in this dissertation is based on applying Digital Signal Processing (DSP) techniques for carrying out speech modifications in order to synthesize the desired expressive style. For conducting the speech modifications the Harmonics plus Noise Model (HNM) was chosen for its flexibility in conducting signal modifications. Voice Quality (VoQ) has been proven to play an important role in different expressive styles. Thus, low-level VoQ acoustic parameters were explored for conveying multiple emotions. This raised several problems setting new objectives for the rest of the thesis, among them finding a single parameter with strong impact on the expressive style conveyed. Vocal Effort (VE) was selected for conducting expressive speech style modifications due to its salient role in expressive speech. The first approach working with VE was based on transferring VE between two parallel utterances based on the Adaptive Pre-emphasis Linear Prediction (APLP) technique. This approach allowed transferring VE but the model presented certain restrictions regarding its flexibility for generating new intermediate VE levels. Aiming to improve the flexibility and control of the conveyed VE, a new approach using polynomial model for modelling VE was presented. This model not only allowed transferring VE levels between two different utterances, but also allowed to generate other VE levels than those present in the speech corpus. This is aligned with the general goal of this thesis, allowing US-TTS systems to convey multiple expressive styles with a single neutral corpus. Moreover, the proposed methodology introduces a parameter for controlling the degree of VE in the synthesized speech signal. This opens new possibilities for controlling the synthesis process such as the one in the CreaVeu project using a simple and intuitive graphical interfaces, also conducted in the GTM group. The dissertation concludes with a review of the conducted work and a proposal for schema modifications within a US-TTS system for introducing the VE modification blocks designed in this dissertation."
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PublicationCumulative Effects on Human Health within the Hydroelectric Sector: A Case Study of Manitoba Hydro( 2015)Noble, Bram, Hackett, PaulThe construction and operation of hydroelectric projects consist of multiple activities in a single watershed, which can generate significant impacts on the surrounding biophysical environment and on the health and well-being of local communities. The impacts of those activities may be insignificant individually, yet together may have an important cumulative effect. The impacts of hydroelectric development on human health and well-being have been widely documented. Current practices of cumulative effects assessment (CEA), however, as conducted under project-based environmental assessment (EA), often fail to address the deeper issues of human health and social well-being. This thesis was developed to examine how health effects, including cumulative health effects, are considered within regulatory EA practices in the hydroelectric sector in Manitoba. This was achieved by reviewing the EAs of three recent hydroelectric projects –Wuskwatim Generating Station, Bipole III Transmission Project, and Keeyask Hydroelectric Generating Station – located in the Nelson River watershed in northern Manitoba. Results indicate that the consideration of human health issues in EA has gradually improved over time; however, the assessment of health impacts was invariably limited to physical health components and often lacked due consideration of broader social health issues. The inadequacy of the practice of health impact assessment (HIA) was also evident by the lack of health-related indicators and the poor consistency in the use of indicators across projects and over time for measuring and predicting changes in the health conditions of the communities due to project development. An in-depth analysis regarding the assessment of cumulative health effects was carried out in the CEA of the most recent hydroelectric development – the Keeyask project. The findings show that cumulative health effects were not adequately considered in each of the basic components of CEA – scoping, retrospective analysis, prospective analysis, and management measures. Improving the consideration of health in EA requires paying more attention to broader range of health determinants, including both biophysical and social determinants and their interconnectedness in EA. Moreover, there is a need to improve greater consistency in the use of health indicators across projects and over time. It can be assisted by developing standardized terms of reference (ToR) for project proponents to ensure the consideration and monitoring of those indicators used for development projects built within the same geographic region and affecting the same communities and environments. Approaching cumulative health effects in a more regional and strategic framework of CEA, beyond the scale of individual projects, is likely to provide the best mechanism to understand and monitor the cumulative impacts of project development on the health and well-being of the affected communities.
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PublicationData management and data analysis in the large European projects GEHA (GEnetics of Healthy Aging) and NU-AGE (NUtrition and AGEing): a bioinformatic approach( 2015)Vianello, DarioThe aging process is characterized by the progressive fitness decline experienced at all the levels of physiological organization, from single molecules up to the whole organism. Studies confirmed inflammaging, a chronic low-level inflammation, as a deeply intertwined partner of the aging process, which may provide the “common soil” upon which age-related diseases develop and flourish. Thus, albeit inflammation per se represents a physiological process, it can rapidly become detrimental if it goes out of control causing an excess of local and systemic inflammatory response, a striking risk factor for the elderly population. Developing interventions to counteract the establishment of this state is thus a top priority. Diet, among other factors, represents a good candidate to regulate inflammation. Building on top of this consideration, the EU project NU-AGE is now trying to assess if a Mediterranean diet, fortified for the elderly population needs, may help in modulating inflammaging. To do so, NU-AGE enrolled a total of 1250 subjects, half of which followed a 1-year long diet, and characterized them by mean of the most advanced –omics and non –omics analyses. The aim of this thesis was the development of a solid data management pipeline able to efficiently cope with the results of these assays, which are now flowing inside a centralized database, ready to be used to test the most disparate scientific hypotheses. At the same time, the work hereby described encompasses the data analysis of the GEHA project, which was focused on identifying the genetic determinants of longevity, with a particular focus on developing and applying a method for detecting epistatic interactions in human mtDNA. Eventually, in an effort to propel the adoption of NGS technologies in everyday pipeline, we developed a NGS variant calling pipeline devoted to solve all the sequencing-related issues of the mtDNA.
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PublicationElectronic Media Use and Sleep Disturbance in German Adolescents Aged 11 to 17 Years: A Focus on Insomnia( 2016)Lange, Anna Karoline
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PublicationEnhancing human health and wellness through neighborhood development standards( 2015)Ruiz, Dominic"Master of Regional and Community Planning / Landscape Architecture/Regional and Community Planning / Katherine Nesse / Formally debuted in 2014, WELL Building Standard v1.0 is the world’s first building standard focusing solely on health and wellness. The WELL Building Standard is a performance-based standard that is designed to improve human health outcomes by integrating medical research into the design and construction of buildings. However, given the relatively young age of the building standard, it does not yet address health at the community level. Focusing on the wellness concepts established in WELL Standard v1.0, this research project re-imagines the standard as a metric to measure the health and wellness of master-planned communities. Through an analysis of the WELL Building Standard and other health-related literature, this research project identifies design strategies, protocols, and policies that can be used to improve health outcomes at the community level."
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PublicationEpigenetic signature in persons with Down Syndrome( 2015)Fontanesi, Elisa"Persons affected by Down Syndrome show a heterogeneous phenotype that includes developmental defects and cognitive and haematological disorders. Premature accelerated aging and the consequent development of age associated diseases like Alzheimer Disease (AD) seem to be the cause of higher mortality late in life of DS persons. Down Syndrome is caused by the complete or partial trisomy of chromosome 21, but it is not clear if the molecular alterations of the disease are triggered by the specific functions of a limited number of genes on chromosome 21 or by the disruption of genetic homeostasis due the presence of a trisomic chromosome. As epigenomic studies can help to shed light on this issue, here we used the Infinium HumanMethilation450 BeadChip to analyse blood DNA methylation patterns of 29 persons affected by Down syndrome (DSP), using their healthy siblings (DSS) and mothers (DSM) as controls. In this way we obtained a family-based model that allowed us to monitor possible confounding effects on DNA methylation patterns deriving from genetic and environmental factors. We showed that defects in DNA methylation map in genes involved in developmental, neurological and haematological pathways. These genes are enriched on chromosome 21 but localize also in the rest of the genome, suggesting that the trisomy of specific genes on chromosome 21 induces a cascade of events that engages many genes on other chromosomes and results in a global alteration of genomic function. We also analysed the methylation status of three target regions localized at the promoter (Ribo) and at the 5’ sequences of 18S and 28S regions of the rDNA, identifying differently methylated CpG sites. In conclusion, we identified an epigenetic signature of Down Syndrome in blood cells that sustains a link between developmental defects and disease phenotype, including segmental premature aging."
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PublicationGenetic genealogy and epidemiology of Francisella( 2009)Svensson, KerstinThis thesis is about analyzing genetic differences among isolates of Francisella tularensis – the tularemia-causing bacterium. To elucidate how these bacterial isolates are related, and their geographical and genetic origins, I have developed typing assays for Francisella and used them to study the epidemiology of tularemia. Tularemia is an infectious disease of humans and other mammals found throughout the Northern Hemisphere. The severity of the disease depends on the type of F. tularensis causing the infection. In Sweden, as in other countries of Europe and Eurasia, tularemia is caused by F. tularensis subsp. holarctica, while other varieties of the bacterium occur in Middle Asia and North America. It is important to identify a tularemia infection promptly in order to initiate the correct antibiotic treatment. A rapid identification of the causative F. tularensis variety gives additional clinical information. In recent years, several genomes of various Francisella strains have been sequenced, and in this thesis, I have utilized these genomes to identify genetic markers. In studies reported in the first paper (I) appended to the thesis, we identified and analyzed insertion/deletion mutations (INDELs) inferred to have resulted from a sequence repeat-mediated excision mechanism. We found eight new Regions of Difference (RDs) among Francisella strains. Using RDs together with single nucleotide polymorphisms (SNPs), we were able to predict an evolutionary scenario for F. tularensis in which Francisella novicida was the oldest variety while F. tularensis subsp. holarctica was the youngest. We also found that all virulence-attenuated isolates analyzed had deletions at two specific genetic regions - denoted RD18 and RD19 – suggesting that repeat-mediated excision is a mechanism of attenuation in F. tularensis. In subsequent studies (presented in paper II), we developed a combined analysis of INDELs lacking flanking repeats and variable number of tandem repeats (VNTRs). Both markers could be assayed using the same analytical equipment. The inclusion of INDELs provided increased phylogenetic robustness compared with the use of VNTRs alone, while still maintaining a high level of genetic resolution. In analyses described in the next paper (III), we selected INDELs from paper (II) and discovered novel SNPs by DNA comparisons of multiple Francisella strains. Thirty-four phylogenetically informative genetic markers were included in a hierarchical real-time PCR array for rapid and robust characterization of Francisella. We successfully used the assay to genotype 14 F. tularensis isolates from tularemia patients and DNA in six clinical ulcer specimens. Finally, in paper (IV) we demonstrated a strategy to enhance epidemiological investigations of tularemia by combining GIS-mapping of disease-transmission place collected from patient interviews, with high-resolution genotyping of F. tularensis subsp. holarctica isolates recovered from tularemia patients. We found the geographic distributions of specific F. tularensis subsp. holarctica sub-populations to be highly localized during outbreaks (infections by some genotypes being restricted to areas as small as 2 km2), indicative of a landscape epidemiology of tularemia with distinct point sources of infection. In conclusion, the results acquired during the studies underlying this thesis contribute to our understanding of the genetic genealogy of tularemia at both global and local outbreak scales.
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PublicationHealth and safety management of lead in soil in U.S. Air Force bases( 2014)De Jesus, Ricardo"Master of Science / Department of Chemical Engineering / Larry Erickson / Urban soils contaminated with lead can pose a health risk if vegetables and fruits from the garden are consumed. In general, we don’t think our gardens as dangerous or toxic, but unfortunately some garden soils do contain toxic levels of lead. Chipping paint around older structures will raise the lead level in the soils directly adjacent to the building. Restrictions to lead paint started in the 1950’s. Today lead paint content has been reduced; however paint companies are allowed to mix up to 0.05% lead in paints. Lead use has been reduced significantly, but not entirely eliminated. Soil can be contaminated with lead from other sources such as industrial sites, industrial sludge with heavy metals, auto emissions, old lead plumbing pipes or even old orchard sites in production when lead arsenate was in use. The main concern with lead in firing ranges is the fate and transport of heavy metals from bullets fragments accumulating in soil. Of these metals, lead is the predominant contaminant. Lead is considered the top environmental threat to children’s health. The U.S. military alone has cleaned up more than 700 firing ranges across the country over the past several years. The U.S. Air Force conducted a study at Shaw Air Force base to determine the lead concentrations in ground water and soil collected from the Small Arms Firing Range in 1992. The purpose of this study was to determine the levels of contamination in the soil in order to develop a restoration plan. The goal of the restoration plan was to clean up the land for future use. The Defense Environmental Restoration Program (DERP) conducted a project at Beale Air Force Base to clean up contaminated lead soil and to prevent any future fine and environmental expenses for the base. The main goal was to protect the base population from the lead and other contaminants hazards. In 1992 the Air Force conducted an investigation that included environmental sampling of soil and lead of the Tyndall Elementary School grounds. The Air Force collected lead samples in areas where children play on the school ground. Because lead concentrations results were below the toxic levels for lead, the Air Force concluded that no further action was needed. Further investigation for soil removal took part in 1992 and 2009. Under the Critical Removal Action field activities included site preparation, waste characterization, investigative sample chemical analysis, contaminated soil excavation, dust control, disposal, backfill and grading, and site restoration. Over the years the Air Force has been able to educate the military community on health hazards in the base facilities especially lead exposure and have been able to implement programs dedicated to prevent any lead overexposure."
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PublicationInteraction between dispersal and behavioural syndromes - empirical approach in a fragmented population of passerine birds( 2015)Daniel, GregoryDispersal is a key life history trait for ecological and evolutionary processes in wild populations. The latest research has particularly focused on the correlation between behavioural traits and dispersal, in order to emphasize the existence of behavioural syndromes of dispersal, and on the estimation of the genetic basis of the dispersal behaviour. Dispersing individuals are not a random part of the population, but are individuals showing particular strategies, that help them to succeed in their dispersal attempt. This thesis has three main aims of research. The first is to show a genetic basis of the dispersal propensity in a fragmented population of collared flycatchers (Ficedulla albicollis). We show, not only, the genetic bases of the dispersal, but also a non-random spatial distribution of relationship between individuals in this population, that might be due to genetic effects on the decision rules of habitat choice in this population. The second aim concerns phenotypic and a genetic correlation between the natal dispersal and a behavioural trait, the nest-defense behaviour, in the alpin swift (Tachymarptis melba). We showed that natal dispersal and nest-defense behaviour were negatively correlated at a phenotypic level, but also at a genetic level in these populations. Finally, the third aim attempts to test the existence of a behavioural syndrome of dispersal, that is if dispersing individuals have a particular behavioural profile, which enable them to colonize new sites, in the collared flycatcher. /
The exmination will be videolinked to seminar room 1003 Evolutionary Biology Centre, EBC, Uppsala University.
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PublicationInteractions between the gut microbiota, short-chain fatty acids and the immune system in pediatric patients undergoing hematopoietic stem cell transplantation( 2015)Nastasi, Claudia"The gut microbiota (GM) is essential for human health and contributes to several diseases; indeed it can be considered an extension of the self and, together with the genetic makeup, determines the physiology of an organism. In this thesis has been studied the peripheral immune system reconstitution in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (aHSCT) in the early phase; in parallel, have been also explored the gut microbiota variations as one of the of primary factors in governing the fate of the immunological recovery, predisposing or protecting from complications such as the onset of acute graft-versus-host disease (GvHD). Has been demonstrated, to our knowledge for the first time, that aHSCT in pediatric patients is associated to a profound modification of the GM ecosystem with a disruption of its mutualistic asset. aGvHD and non-aGvHD subjects showed differences in the process of GM recovery, in members abundance of the phylum Bacteroidetes, and in propionate fecal concentration; the latter are higher in the pre-HSCT composition of non-GvHD subjects than GvHD ones. Short-chain fatty acids (SCFAs), such as acetate, butyrate and propionate, are end-products of microbial fermentation of macronutrients and distribute systemically from the gut to blood. For this reason, has been studied their effect in vitro on human DCs, the key regulators of our immune system and the main player of aGvHD onset. Has been observed that propionate and, particularly, butyrate show a strong and direct immunomodulatory activity on DCs reducing inflammatory markers such as chemokines and interleukins. This study, with the needed caution, suggests that the pre-existing GM structure can be protective against aGvHD onset, exerting its protective role through SCFAs. They, indeed, may regulate cell traffic within secondary lymphoid tissues, influence T cell development during antigen recognition, and, thus, directly shape the immune system."
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PublicationMetaphors of cancer in scientific popularisation articles in the English and Spanish press( 2014)Williams Camus, Julia T."This thesis provides an account of the metaphors of cancer in a comparable English and Spanish corpus of 300 press popularisation articles. The aim is to identify relevant source domains that are employed in these articles to conceptualise the disease. Although a number of studies have explored the use of WAR metaphors in the discourse on cancer, there is still little understanding of the actual way cancer is presented metaphorically to the lay public in the press or of the range of source domains that conceptualise the target domain. Thus, in addition to the WAR, VIOLENCE AND AGGRESSION source domain, this study focuses on other metaphorical systems exploited to elucidate such aspects as metastasis, apoptosis, cancer treatments and cancer research. A text analysis was carried out with the aid of a corpus software program. The metaphors in the two subcorpora were compared quantitatively and qualitatively for cross-cultural differences in terms of their functions and patterning. Although cancer knowledge is popularised through similar metaphorical expressions, subtle differences have been identified in terms of metaphor density, choice of metaphor and the functions performed by these expressions. / Esta tesis describe las metáforas del cáncer en un corpus bilingüe inglés-español de 300 artículos de divulgación en la prensa. El objetivo ha sido identificar los distintos dominios fuente relevantes que se emplean en la conceptualización de la enfermedad. Aunque varios trabajos han estudiado las metáforas bélicas utilizadas en el discurso del cáncer, todavía se sabe poco de la forma en la que el cáncer se representa mediante metáforas al público lego y de la variedad de dominios fuente que conceptualizan el dominio meta. Así, además del dominio fuente de la GUERRA, VIOLENCIA Y AGRESIÓN, este estudio se centra en otros sistemas metafóricos empleados para clarificar diversos aspectos como la metástasis, la apoptosis, los tratamientos del cáncer y la investigación oncológica. El análisis textual se ha realizado con la ayuda de un programa informático de análisis de corpus textuales. Las metáforas de ambos subcorpus se han comparado cuantitativa y cualitativamente con el fin de identificar diferencias transculturales en relación a las funciones y a los patrones de las mismas. Aunque el conocimiento sobre el cáncer se divulga a través de expresiones metafóricas similares, se pueden apreciar pequeñas diferencias en relación a la densidad metafórica, la elección de las metáforas y las funciones que estas expresiones desempeñan."
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PublicationMotor control system in Parkinson’s disease: a modeling approach / Approccio modellistico del sistema di controllo motorio nella malattia di parkinson( 2015)Baston, Chiara"Parkinson’s disease is a neurodegenerative disorder due to the death of the dopaminergic neurons of the substantia nigra of the basal ganglia. The process that leads to these neural alterations is still unknown. Parkinson’s disease affects most of all the motor sphere, with a wide array of impairment such as bradykinesia, akinesia, tremor, postural instability and singular phenomena such as freezing of gait. Moreover, in the last few years the fact that the degeneration in the basal ganglia circuitry induces not only motor but also cognitive alterations, not necessarily implicating dementia, and that dopamine loss induces also further implications due to dopamine-driven synaptic plasticity got more attention. At the present moment, no neuroprotective treatment is available, and even if dopamine-replacement therapies as well as electrical deep brain stimulation are able to improve the life conditions of the patients, they often present side effects on the long term, and cannot recover the neural loss, which instead continues to advance. In the present thesis both motor and cognitive aspects of Parkinson’s disease and basal ganglia circuitry were investigated, at first focusing on Parkinson’s disease sensory and balance issues by means of a new instrumented method based on inertial sensor to provide further information about postural control and postural strategies used to attain balance, then applying this newly developed approach to assess balance control in mild and severe patients, both ON and OFF levodopa replacement. Given the inability of levodopa to recover balance issues and the new physiological findings than underline the importance in Parkinson’s disease of non-dopaminergic neurotransmitters, it was therefore developed an original computational model focusing on acetylcholine, the most promising neurotransmitter according to physiology, and its role in synaptic plasticity. The rationale of this thesis is that a multidisciplinary approach could gain insight into Parkinson’s disease features still unresolved."
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PublicationMultimodal (EEG-fMRI) functional connectivity study of levodopa effect in Parkinson’s disease( 2015)Pittau, Francesca"Aim: To assess if the intake of levodopa in patients with Parkinson’s Disease (PD) changes cerebral connectivity, as revealed by simultaneous recording of hemodynamic (functional MRI, or fMRI) and electric (electroencephalogram, EEG) signals. Particularly, we hypothesize that the strongest changes in FC will involve the motor network, which is the most impaired in PD. Methods: Eight patients with diagnosis of PD “probable”, therapy with levodopa exclusively, normal cognitive and affective status, were included. Exclusion criteria were: moderate-severe rest tremor, levodopa induced dyskinesia, evidence of gray or white matter abnormalities on structural MRI. Scalp EEG (64 channels) were acquired inside the scanner (1.5 Tesla) before and after the intake of levodopa. fMRI functional connectivity was computed from four regions of interest: right and left supplementary motor area (SMA) and right and left precentral gyrus (primary motor cortex). Weighted partial directed coherence (w-PDC) was computed in the inverse space after the removal of EEG gradient and cardioballistic artifacts. Results and discussion: fMRI group analysis shows that the intake of levodopa increases hemodynamic functional connectivity among the SMAs / primary motor cortex and: sensory-motor network itself, attention network and default mode network. w-PDC analysis shows that EEG connectivity among regions of the motor network has the tendency to decrease after the intake the levodopa; furthermore, regions belonging to the DMN have the tendency to increase their outflow toward the rest of the brain. These findings, even if in a small sample of patients, suggest that other resting state physiological functional networks, beyond the motor one, are affected in patients with PD. The behavioral and cognitive tasks corresponding to the affected networks could benefit from the intake of levodopa."
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PublicationNon Invasive Tools for Early Detection of Autism Spectrum Disorders( 2015)Orlandi, Silvia"Autism Spectrum Disorders (ASDs) describe a set of neurodevelopmental disorders. ASD represents a significant public health problem. Currently, ASDs are not diagnosed before the 2nd year of life but an early identification of ASDs would be crucial as interventions are much more effective than specific therapies starting in later childhood. To this aim, cheap an contact-less automatic approaches recently aroused great clinical interest. Among them, the cry and the movements of the newborn, both involving the central nervous system, are proposed as possible indicators of neurological disorders. This PhD work is a first step towards solving this challenging problem. An integrated system is presented enabling the recording of audio (crying) and video (movements) data of the newborn, their automatic analysis with innovative techniques for the extraction of clinically relevant parameters and their classification with data mining techniques. New robust algorithms were developed for the selection of the voiced parts of the cry signal, the estimation of acoustic parameters based on the wavelet transform and the analysis of the infant’s general movements (GMs) through a new body model for segmentation and 2D reconstruction. In addition to a thorough literature review this thesis presents the state of the art on these topics that shows that no studies exist concerning normative ranges for newborn infant cry in the first 6 months of life nor the correlation between cry and movements. Through the new automatic methods a population of control infants (“low-risk”, LR) was compared to a group of “high-risk” (HR) infants, i.e. siblings of children already diagnosed with ASD. A subset of LR infants clinically diagnosed as newborns with Typical Development (TD) and one affected by ASD were compared. The results show that the selected acoustic parameters allow good differentiation between the two groups. This result provides new perspectives both diagnostic and therapeutic"
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PublicationNurses go visiting : ethics and gender in home-based nursing care( 2011)Öresland, StinaThe overall aim of this thesis is to explore how nursing is constructed in home-based nursing care from the viewpoint of patients and nurses who are receiving or giving care. Since nursing both constructs and is in turn constructed by the context in which it serves, language plays a central part in those constructions and in this thesis. The thesis has been guided by social constructionism, meaning that the positions the patients and the nurses inhabits have been considered as social phenomenon constructed in discursive processes. There are two ideas that guided this thesis. One idea was that home-based nursing care promotes the association of caring abilities in relation to nursing, women and the private sphere. Another idea was that the place where the care was carried out has ethical implications. Data was collected from interviews with 10 home-based nurses (study I) working in community in the western part of Sweden and 10 patients cared for in their home by these nurses (study II). Nurses and patients were interviewed about their experiences of giving respectively receiving home-based nursing care. The interviews were transcribed verbatim and analyzed with a discourse analytic method in study I and II. The findings in study I show that the nurses described their subject positions as "guests" and "professionals" and that they have to make a choice between these positions, as it is impossible to perform both positions at the same time. Dependent on the situation, both an ethics of care and an ethics of justice were applied by the nurses, that is, to perform according to the subject positions of "guest" or "professional." In study II, the patients describe their own subject position as "safeguard" and the nurses‟ positions as "substitutes". These subject positions provided the opportunities, and the obstacles, for the patients‟ possibilities to receive care in their home which included which kind of strategies, habits and activities the patients described and what tasks and how they considered or expected the nurses to perform. These findings are discussed within a theoretical framework, i.e. a gendered dichotomy of the private spheres versus the public spheres. Inherent in this framework is a discussion of the findings related to the habits that are essential in the nurses‟ and the patients‟ constructions of subject positions. In study III, metaphors used by home-based nurses‟ were explored as a means to discover values and norms held by nurses working in home-based nursing care. Ten interviews with nurses working in home-based nursing care (the same interviews as in study I) were analyzed and interpreted with a metaphor analytic method. In the analysis metaphoric linguistic expressions (MLE) were explored and patterns of MLEs formed two entailments. After exploring MLEs and entailments on an explicit surface level the analysis went to a broader underlying dimension of conceptual metaphors identifying the overall metaphor: "Home-based nursing care is an endless journey". The metaphor "Home-based nursing care is an endless journey" exposed home-based nursing care in constant motion, thereby requiring nurses to adjust to circumstances. This adjustment required ethical maturity based on experience, knowledge, and creativity. The study III focuses on the importance of further developing reflections over experiences related to everyday ethical issues. In study IV, the findings from study I were the starting point for a philosophical exploration of the concept "guest" and its relation to other adjacent concepts such as hosts and hospitality. The question to be answered was as follows: In what ways can home-based nurses‟ description of being "guests" in patients‟ home be understood? The exploration was based on Derrida‟s philosophy of unconditional and conditional hospitality, Levinas‟ philosophy of "face" and "the Other" and Arendt‟s philosophy of "go visiting". The findings indicated that the concept "guest" was not appropriate for the nurses to use when describing their position in home-based nursing care, since the concept was problematic for the content and the complexity of home-based nursing care. The findings also showed that exposing concepts as binaries is fruitful since they show relationship between concepts. Just illuminating the concept "guest" did not reveal the power relationship between the "guest" and the "host" and their relationship to hospitality. The distinction between diverse ethical perspectives could be seen as problematic or as an opportunity. According to this study, the nurses used a plurality of different ethical ideas, such as an ethics of care, an ethics of justice, an ethics of virtue and an "everyday ethics." A possible interpretation could be that this was a sign of a difficulty to maintain distinction between ethical theories in clinical practice. Ethical issues in the private sphere are less commonly explored compared to ethical issues in the public sphere, for example in hospital care. As showed in this thesis, the distinction between the private and the public spheres was problematic. It does not describe two spatially separate spheres, but rather it describes functionally dependent activities, interests and relations, such as diverse areas of ethical ideas and "feminine" and "masculine" positions. Home-based nursing care is a complex area and discourse analysis of the relation between home-based nursing care, subject positions, ethics and gender is more or less lacking. Exploring home-based nursing care outgoing from discourse analytic perspectives and methods is rewarding for nurses‟ practice, education and research as it opens up new perspectives of home-based nursing care.
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PublicationNutrient Transporter Inhibition Disrupts Mammary and Intestinal Polarized Epithelial Function( 2016)Alcorn, Jane"The transporters primarily responsible for transporting important nutrients involved in energy metabolism have a wide substrate specificity setting up the potential for drug-nutrient transporter interactions. Pharmacological inhibition of nutrient transport across the lactating mammary and neonatal intestinal epithelial barrier can directly and indirectly affect growth and maturation of the developing neonate by either reducing the uptake of important nutrients by the neonate or by disrupting epithelial barrier integrity. My thesis focused on two transporters, OCTN2 and MCT1, expressed in immortalized intestinal and mammary epithelial cell cultures to assess the effects of their pharmacological inhibition on L-carnitine and butyrate flux, respectively, and polarized epithelial barrier integrity. Human colorectal adenocarcinoma (Caco-2) and bovine mammary (BME-UV) cell lines were grown into monolayers on 12-well tissue culture plates and subsequently exposed to the presence or absence of OCTN2 and MCT1 inhibitors for 6, 12, and 24 hours as well as 7 days. Failure to obtain a polarized mammary monolayer prevented the analysis of the direct effects of nutrient transport inhibition on nutrient flux forcing the focus on the indirect effects. To assess polarized epithelial barrier integrity, transepithelial electrical resistance and Lucifer yellow rejection rates were measured at each time point. No trend was noted between control and treated groups. To assess the acute and chronic effects of pharmacological exposure on polarized epithelial function, a limited appraisal of nutrient transporter expression and cellular homeostasis parameters was conducted. Following exposure at each time point, mRNA expression of OCTN1, OCTN2, MCT1, MCT2 and GADPH were measured using qPCR. Low mRNA yields resulted in an inability to assess transporter expression levels in the epithelial systems. Cellular homeostasis parameters were analyzed using the CellTiter-Glo Luminescent Cell Viability Assay, pH-Xtra Glycolysis Assay and MitoXpress Xtra Oxygen Consumption Assay. These assays measured ATP synthesis, glycolytic flux and cellular respiration, respectively. No significant trend was noted in ATP synthesis between control and treated groups. An upward trend in both glycolytic flux and cellular respiration was noted in treatment with both inhibitors in both cell lines. Complications in obtaining polarized monolayer forced the focus on the indirect affects, therefore, obtaining and utilizing a more accurate portrayal of the lactating mammary and neonatal intestinal epithelium is critical in answering this research question as both of these systems are highly synthetic and complex. By doing so, a more accurate representation of the effects of pharmacological inhibition of nutrient transporters essential for energy metabolism can be identified."
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PublicationPolypurine Reverse Hoogsteen hairpins: stability, lack of immunogenicity and gene silencing in cancer therapy( 2015)Villalobos Alberú, Xenia"This work is focused on the study of the stability and immunogenic properties of the Polypurine Reverse Hoogsteen hairpins (PPRHs), and on their use as a gene-silencing tool. PPRHs are non-modified DNA molecules formed by two antiparallel polypurine strands linked by a pentathymidine loop that allows the formation of intramolecular reverse Hoogsteen bonds between both strands. Previously in our laboratory it was demonstrated that these hairpins bind to their polypyrimidine target in a dsDNA via Watson-Crick bonds, displacing the polypurine strand of the target duplex. The effect of PPRHs in cells and their mechanism of action were first described using PPRHs designed against the template and coding strands of the DHFR gene. A PPRH against survivin was further validated in a xenograft tumor model, establishing the proof of principle for the use of PPRHs as a therapeutic tool. In this work we increased the knowledge we have about PPRHs. We were able to establish that PPRHs, unlike siRNAs, are very stable molecules in different types of serum and inside the cells. We also established that PPRHs do not induce the innate immune response, since they do not induce the levels of neither the transcription factors IRF3 and NF-κB, nor the proinflammatory cytokines IL-6, TNF-α, IFN-α, IFN-β, IL-1β, and IL-18. Additionally, unlike siRNAs, PPRHs did not trigger the activation of the inflammasome. Another element that we studied was the modification of the PPRH structure, since it has been shown that circular structures can provide advantages over linear structures. Therefore, we analyzed the efficacy of two other types of PPRH: i) nicked-circle-PPRHs, a new structure in which a second loop was introduced to form a nearly circular sequence, and ii) PPRHs made out of RNA (RNA-PPRHs). To broaden the applicability of PPRHs in cancer therapy, we evaluated their capacity to silence genes involved in a variety of biological functions linked to cancer hallmarks. The genes selected were: BCL2, MDM2, MYC, TOP1 and MTOR, and the validation of the PPRHs was performed in different cancer cells lines (PC3, MIA PaCa2, HCT116, SKBR3, MCF7 and MDA-MB-468). Regardless of the gene or cell line tested, PPRHs were able to decrease cell survival and mRNA expression levels, and to increase apoptosis, to a greater or lesser extent. Finally, we also present an approach to increase the specificity of PPRHs that involves the use of a DNA aptamer that has been shown to have an effect in HER2 positve cells. / Este trabajo se centra en el estudio de la estabilidad y potencial inmunogénico de las moléculas llamadas PPRHs (Polypurine Reverse Hoogsteen hairpins), y en su uso como herramienta de silenciamiento génico. Los PPRHs son moléculas de DNA no modificadas. Están formadas por dos cadenas antiparalelas de polipurinas unidas por un bucle pentatimidínico, lo que permite la formación intramolecular de enlaces de Hoogsteen reversos entre ambas cadenas. Anteriormente se demostró que los PPRH son capaces de unirse a una secuencia de dsDNA mediante enlaces de Watson-Crick, formando un triplex que desplaza la cadena polipurínica de la diana. La prueba de principio para el uso de los PPRH como agente terapéuticos se llevó a cabo con un PPRH dirigido al gen de la survivina el cual fue validado tanto in vitro como in vivo. En esta tesis se ha profundizado en el conocimiento de los PPRHs. Se ha establecido que estas moléculas son estables en diferentes tipos de suero, así como intracelularmente. Además se determinó que los PPRHs, no inducen la activación de la respuesta inmune innata, ya que su transfección a una línea monocítica no incrementó los niveles de expresión de los factores de transcripción IRF3 y NF-κB, y tampoco de las citoquinas proinflamatorias IL-6, TNF-α, IFN-α, IFN-β, IL-1β, y IL-18. Además, los PPRHs no indujeron la activación del inflamasoma. También se diseñaron dos estructuras nuevas de PPRH: PPRH circulares y PPRHs basados en RNA, y se estudiaron diversos parámetros como su capacidad de unión a la diana y su citotoxicidad. Para ampliar la aplicabilidad de estas moléculas, se validó el uso de los PPRHs sobre diversos genes relevantes en cáncer: BCL2, MDM2, MYC, TOP1 y MTOR. Esta validación se realizó en diversas líneas tumorales (PC3, MIA PaCa-2, HCT116, SKBR3, MCF7 y MDA-MB-468) observando que los PPRHs fueron capaces de disminuir la supervivencia de las células y la expresión de los genes diana, y de aumentar la apoptosis. Finalmente, se realizó una aproximación para incrementar la especificidad de los PPRHs, la cual incluye el uso de un aptámero de DNA dirigido a la proteína de membrana HER2."
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PublicationPreclinical development of anti-cancer strategies against human HER-2( 2015)Dall'Ora, Massimiliano"HER-2 is a 185 kDa transmembrane receptor tyrosine kinase that belongs to the EGFR family. HER-2 is overexpressed in nearly 25% of human breast cancers and women with this subtype of breast cancer have a worse prognosis and frequently develop metastases. The progressive high number of HER-2-positive breast cancer patients with metastatic spread in the brain (up to half of women) has been attributed to the reduction in mortality, the effectiveness of Trastuzumab in killing metastatic cells in other organs and to its incapability to cross the blood-brain barrier. Apart from full-length-HER-2, a splice variant of HER-2 lacking exon 16 (here referred to as D16) was identified in human HER-2-positive breast cancers. Here, the contribution of HER-2 and D16 to mammary carcinogenesis was investigated in a model transgenic for both genes (F1 model). A dominant role of D16, especially in early stages of tumorigenesis, was suggested and the coexistence of heterogeneous levels of HER-2 and D16 in F1 tumors revealed the undeniable value of F1 strain as preclinical model of HER-2-positive breast cancer, closer resembling the human situation in respect to previous models. The therapeutical efficacy of anti-HER-2 agents, targeting HER-2 receptor (Trastuzumab, Lapatinib, R-LM249) or signaling effectors (Dasatinib, UO126, NVP-BKM120), was investigated in models of local or advanced HER-2-positive breast cancer. In contrast with early studies, data herein collected suggested that the presence of D16 can predict a better response to Trastuzumab and other agents targeting HER-2 receptor or Src activity. Using a multiorgan HER-2-positive metastatic model, the efficacy of NVP-BKM120 (PI3K inhibitor) in blocking the growth of brain metastases and the oncolytic ability of R-LM249 (HER-2-retargeted HSV) to reach and destroy metastatic HER-2-positive cancer cells were shown. Finally, exploiting the definition of “oncoantigen” given to HER-2, the immunopreventive activity of two vaccines on HER-2-positive mammary tumorigenesis was demonstrated."