The gastrointestinal tract (GIT) regulates nutrient uptake, secretes hormones and has a crucial gut flora and enteric nervous system. Of relevance for these functions are the G protein-coupled receptors (GPCRs) and the solute carriers (SLCs). The Adhesion GPCR subfamily is known to mediate neural development and immune system functioning, whereas SLCs transport e.g. amino acids, fatty acids (FAs) and drugs over membranes. We aimed to comprehensively characterize Adhesion GPCR and SLC gene expression along the rat GIT. Using qPCR we measured expression of 78 SLCs as well as all 30 Adhesion GPCRs in a twelve-segment GIT model. 21 of the Adhesion GPCRs had a widespread (≥5 segments) or ubiquitous (≥11 segments) expression. Restricted expression patterns were characteristic for most group VII members. Of the SLCs, we found the majority (56 %) of these transcripts to be expressed in all GIT segments. SLCs were predominantly found in the absorption-responsible gut regions. Both Adhesion GPCRs and SLCs were widely expressed in the rat GIT, suggesting important roles. The distribution of Adhesion GPCRs defines them as a potential pharmacological target. FAs constitute an important energy source and have been implicated in the worldwide obesity increase. FAs and their ratios – indices for activities of e.g. the desaturase enzymes SCD-1 (SCD-16, 16:1n-7/16:0), D6D (18:3n-6/18:2n-6) and D5D (20:4n-6/20:3n-6) – have been associated with e.g. overall mortality and BMI. We examined whether differences in FAs and their indices in five lipid fractions contributed to obesity susceptibility in rats fed a high fat diet (HFD), and the associations of desaturase indices between lipid fractions in animals on different diets. We found that on a HFD, obesity-prone (OP) rats had a higher SCD-16 index and a lower linoleic acid (LA) proportions in subcutaneous adipose tissue (SAT) than obesity-resistant rats. Desaturase indices were significantly correlated between many of the lipid fractions. The higher SCD-16 may indicate higher SCD-1 activity in SAT in OP rats, and combined with lower LA proportions may provide novel insights into HFD-induced obesity. The associations between desaturase indices show that plasma measurements can serve as proxies for some lipid fractions, but the correlations seem to be affected by diet and weight gain.

L'incessant augment del nombre de seqüències genòmiques, juntament amb l'increment del nombre de tècniques experimentals de les que es disposa, permetrà obtenir el catàleg complet de les funcions cel.lulars de diferents organismes, incloent-hi la nostra espècie. Aquest catàleg definirà els fonaments sobre els que es podrà entendre millor com els organismes funcionen a nivell molecular. Al mateix temps es tindran més pistes sobre els canvis que estan associats amb les malalties. Per tant, la seqüència en brut, tal i com s'obté dels projectes de seqüenciació de genomes, no té cap valor sense les anàlisis i la subsegüent anotació de les característiques que defineixen aquestes funcions. Aquesta tesi presenta la nostra contribució en tres aspectes relacionats de l'anotació dels gens en genomes eucariotes. Primer, la comparació a nivell de seqüència entre els genomes humà i de ratolí es va dur a terme mitjançant un protocol semi-automàtic. El programa de predicció de gens SGP2 es va desenvolupar a partir d'elements d'aquest protocol. El concepte al darrera de l'SGP2 és que les regions de similaritat obtingudes amb el programa TBLASTX, es fan servir per augmentar la puntuació dels exons predits pel programa geneid, amb el que s obtenen conjunts d'anotacions més acurats d'estructures gèniques. SGP2 té una especificitat que és prou gran com per que es puguin validar experimentalment via RT-PCR. La validació de llocs d'splicing emprant la tècnica de la RT-PCR és un bon exemple de com la combinació d'aproximacions computacionals i experimentals produeix millors resultats que per separat. S'ha dut a terme l'anàlisi descriptiva a nivell de seqüència dels llocs d'splicing obtinguts sobre un conjunt fiable de gens ortòlegs per humà, ratolí, rata i pollastre. S'han explorat les diferències a nivell de nucleòtid entre llocs U2 i U12, pel conjunt d'introns ortòlegs que se'n deriva d'aquests gens. S'ha trobat que els senyals d'splicing ortòlegs entre humà i rossegadors, així com entre rossegadors, estan més conservats que els llocs no relacionats. Aquesta conservació addicional pot ser explicada però a nivell de conservació basal dels introns. D'altra banda, s'ha detectat més conservació de l'esperada entre llocs d'splicing ortòlegs entre mamífers i pollastre. Els resultats obtinguts també indiquen que les classes intròniques U2 i U12 han evolucionat independentment des de l'ancestre comú dels mamífers i les aus. Tampoc s'ha trobat cap cas convincent d'interconversió entre aquestes dues classes en el conjunt d'introns ortòlegs generat, ni cap cas de substitució entre els subtipus AT-AC i GT-AG d'introns U12. Al contrari, el pas de GT-AG a GC-AG, i viceversa, en introns U2 no sembla ser inusual. Finalment, s'han implementat una sèrie d'eines de visualització per integrar anotacions obtingudes pels programes de predicció de gens i per les anàlisis comparatives sobre genomes. Una d'aquestes eines, el gff2ps, s'ha emprat en la cartografia dels genomes humà, de la mosca del vinagre i del mosquit de la malària, entre d'altres. El programa gff2aplot i els filtres associats, han facilitat la tasca d'integrar anotacions de seqüència amb els resultats d'eines per la cerca d'homologia, com ara el BLAST. S'ha adaptat també el concepte de pictograma a l'anàlisi comparativa de llocs d splicing ortòlegs, amb el desenvolupament del programa compi. / El aumento incesante del número de secuencias genómicas, junto con el incremento del número de técnicas experimentales de las que se dispone, permitirá la obtención del catálogo completo de las funciones celulares de los diferentes organismos, incluida nuestra especie. Este catálogo definirá las bases sobre las que se pueda entender mejor el funcionamiento de los organismos a nivel molecular. Al mismo tiempo, se obtendrán más pistas sobre los cambios asociados a enfermedades. Por tanto, la secuencia en bruto, tal y como se obtiene en los proyectos de secuenciación masiva, no tiene ningún valor sin los análisis y la posterior anotación de las características que definen estas funciones. Esta tesis presenta nuestra contribución a tres aspectos relacionados de la anotación de los genes en genomas eucariotas. Primero, la comparación a nivel de secuencia entre el genoma humano y el de ratón se llevó a cabo mediante un protocolo semi-automático. El programa de predicción de genes SGP2 se desarrolló a partir de elementos de dicho protocolo. El concepto sobre el que se fundamenta el SGP2 es que las regiones de similaridad obtenidas con el programa TBLASTX, se utilizan para aumentar la puntuación de los exones predichos por el programa geneid, con lo que se obtienen conjuntos más precisos de anotaciones de estructuras génicas. SGP2 tiene una especificidad suficiente como para validar esas anotaciones experimentalmente vía RT-PCR. La validación de los sitios de splicing mediante el uso de la técnica de la RT-PCR es un buen ejemplo de cómo la combinación de aproximaciones computacionales y experimentales produce mejores resultados que por separado. Se ha llevado a cabo el análisis descriptivo a nivel de secuencia de los sitios de splicing obtenidos sobre un conjunto fiable de genes ortólogos para humano, ratón, rata y pollo. Se han explorado las diferencias a nivel de nucleótido entre sitios U2 y U12 para el conjunto de intrones ortólogos derivado de esos genes. Se ha visto que las señales de splicing ortólogas entre humanos y roedores, así como entre roedores, están más conservadas que las no ortólogas. Esta conservación puede ser explicada en parte a nivel de conservación basal de los intrones. Por otro lado, se ha detectado mayor conservación de la esperada entre sitios de splicing ortólogos entre mamíferos y pollo. Los resultados obtenidos indican también que las clases intrónicas U2 y U12 han evolucionado independientemente desde el ancestro común de mamíferos y aves. Tampoco se ha hallado ningún caso convincente de interconversión entre estas dos clases en el conjunto de intrones ortólogos generado, ni ningún caso de substitución entre los subtipos AT-AC y GT-AG en intrones U12. Por el contrario, el paso de GT-AG a GC-AG, y viceversa, en intrones U2 no parece ser inusual. Finalmente, se han implementado una serie de herramientas de visualización para integrar anotaciones obtenidas por los programas de predicción de genes y por los análisis comparativos sobre genomas. Una de estas herramientas, gff2ps, se ha utilizado para cartografiar los genomas humano, de la mosca del vinagre y del mosquito de la malaria. El programa gff2aplot y los filtros asociados, han facilitado la tarea de integrar anotaciones a nivel de secuencia con los resultados obtenidos por herramientas de búsqueda de homología, como BLAST. Se ha adaptado también el concepto de pictograma al análisis comparativo de los sitios de splicing ortólogos, con el desarrollo del programa compi. / The constantly increasing amount of available genome sequences, along with an increasing number of experimental techniques, will help to produce the complete catalog of cellular functions for different organisms, including humans. Such a catalog will define the base from which we will better understand how organisms work at the molecular level. At the same time it will shed light on which changes are associated with disease. Therefore, the raw sequence from genome sequencing projects is worthless without the complete analysis and further annotation of the genomic features that define those functions. This dissertation presents our contribution to three related aspects of gene annotation on eukaryotic genomes. First, a comparison at sequence level of human and mouse genomes was performed by developing a semi-automatic analysis pipeline. The SGP2 gene-finding tool was developed from procedures used in this pipeline. The concept behind SGP2 is that similarity regions obtained by TBLASTX are used to increase the score of exons predicted by geneid, in order to produce a more accurate set of gene structures. SGP2 provides a specificity that is high enough for its predictions to be experimentally verified by RT-PCR. The RT-PCR validation of predicted splice junctions also serves as example of how combined computational and experimental approaches will yield the best results. Then, we performed a descriptive analysis at sequence level of the splice site signals from a reliable set of orthologous genes for human, mouse, rat and chicken. We have explored the differences at nucleotide sequence level between U2 and U12 for the set of orthologous introns derived from those genes. We found that orthologous splice signals between human and rodents and within rodents are more conserved than unrelated splice sites. However, additional conservation can be explained mostly by background intron conservation. Additional conservation over background is detectable in orthologous mammalian and chicken splice sites. Our results also indicate that the U2 and U12 intron classes have evolved independently since the split of mammals and birds. We found neither convincing case of interconversion between these two classes in our sets of orthologous introns, nor any single case of switching between AT-AC and GT-AG subtypes within U12 introns. In contrast, switching between GT-AG and GC-AG U2 subtypes does not appear to be unusual. Finally, we implemented visualization tools to integrate annotation features for gene- finding and comparative analyses. One of those tools, gff2ps, was used to draw the whole genome maps for human, fruitfly and mosquito. gff2aplot and the accompanying parsers facilitate the task of integrating sequence annotations with the output of homologybased tools, like BLAST.We have also adapted the concept of pictograms to the comparative analysis of orthologous splice sites, by developing compi.

No description available.

Diss. (sammanfattning) Umeå : Umeå universitet, 2010.

Le travail présenté dans cette thèse concerne la mise en oeuvre numérique de techniques temporelles pour des applications en compatibilité électromagnétique (CEM) impulsionnelle, essentiellement pour des études en chambre réverbérante à brassage de modes (CRBM). Prenant le contre-pied des approches fréquentielles, adaptées par nature aux études de cavités résonantes, l’idée directrice de ce mémoire a été d’étudier des moyens temporels originaux d’investigation de CRBM en vue de proposer de nouveaux paradigmes pour la caractérisation d’équipements. Originellement développé en acoustique, le processus de retournement temporel (RT) récemment appliqué aux ondes électromagnétiques permet une focalisation spatiale et temporelle de ces dernières d’autant meilleur que le milieu de propagation est réverbérant. Les chambres réverbérantes (CR) sont ainsi des endroits idéaux pour l’application du processus de RT. Après une nécessaire étude des nombreux paramètres qui gouvernent ce dernier couplée à la définition de méthodologies numériques spécifiques, les applications du RT en CRBM sont exposées. En particulier, l’intérêt d’une focalisation sélective pour des tests en susceptibilité rayonnée est démontré. L’importance des coefficients d’absorption et de diffraction des équipements en CRBM justifie leur caractérisation précise et efficace. À cette fin, la mise en oeuvre d’un calcul temporel de section efficace totale de diffraction (TSCS en anglais) est détaillée. L’application de cette nouvelle technique à différentes formes de brasseurs de modes permet au final de confronter ces résultats avec ceux obtenus à l’aide de tests normatifs CEM. / The work presented in this thesis concerns the use of time techniques for impulsive ElectroMagnetic Compatibility (EMC) applications, mainly for Modes Stirred Reverberation Chamber (MSRC) studies. Contrary to approaches from frequency domain, obviously well-fitted for studies in resonant cavities, the main idea of this thesis was to study an original time method for MSRC investigation to propose new paradigms for equipment characterization. Originally developed in acoustics, the Time Reversal (TR) process recently applied to electromagnetic waves allows focusing it both in time and space. The process quality is even higher if the propagation environment is reverberant. Thus, the Reverberation Chambers (RC) are an ideal locations for TR implementation. After a study of parameters involved in the TR process coupled with the definition of specific numerical methods, the applications of TR in MSRC are exposed. In particular, the interest of selective focusing for radiated susceptibility tests is demonstrated. The importance of absorption and diffraction coefficients for MSRC equipment justifies their accurate and efficient characterization. To this end, the implementation of a temporal calculation of the Total Scattering Cross Section (TSCS) in RC is detailed. The application of this new technique to different forms of stirrers allows finally to face these results with those obtained from standard EMC test.

Malondialdehyde (MDA) is a mutagenic and carcinogenic product of lipid peroxidation which has also been found at elevated levels in smokers. MDA reacts with nucleic acid bases to form pyrimidopurinone DNA adducts, of which 3-(2-deoxy-β-D-erythro-pentofuranosyl)pyrimidol[1,2-α]purin-10(3H)-one (M1dG) is the most abundant and has been linked to smoking. Mutations in the TP53 tumour suppressor gene are associated with half of all cancers. This research applied a multidisciplinary approach to investigate the toxic effects of MDA on the human lung fibroblasts MRC5, which have an intact p53 response, and their SV40 transformed counterpart, MRC5 SV2, which have a sequestered p53 response. Both cell lines were treated with MDA (0-1000 µM) for 24 and 48 h and subjected to a variety of analyses to examine cell proliferation, cell viability, cellular and nuclear morphology, apoptosis, p53 protein expression, DNA topography and M1dG adduct detection. For the first time, mutation sequencing of the 5’ untranslated region (UTR) of the TP53 gene in response to MDA treatment was carried out. The main findings were that both cell lines showed reduced proliferation and viability with increasing concentrations of MDA, the cell surface and nuclear morphology were altered, and levels of apoptosis and p53 protein expression appeared to increase. A LC MS-MS method for detection of M1dG adducts was developed and adducts were detected in CT-DNA treated with MDA in a dose-dependent manner. DNA appeared to become more fragmented with increasing MDA concentration, and the number of mutations in the 5’ UTR region of the TP53 gene also increased. The majority of mutations observed were insertions, compared to lung cancer mutation data where the majority were G to T transversions. This was unexpected, suggesting that tobacco smoke compounds have a different role in mutagenesis than endogenous lipid peroxidation. Thus, MDA has been found to have a clear effect on human lung fibroblasts at both the cellular and DNA level.

No description available.

Background: Gait initiation is a major issue in Parkinson’s disease (PD). Moreover, the effect of current treatment on motor deficits vary alongside individual differences and disease severity. In some cases, postural instability has been documented as a major side-effect and refractory symptom to dopaminergic medication. Despite these shortcomings, research involving other forms of therapy including deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS), has evidenced the improvement of postural deficits in PD. In this regard, there is a strong rational for the modulation of subcortical brain activity via the application of non-invasive transcranial direct current stimulation (tDCS) to interconnected cortical brain structures. Purpose: Therefore, we sought to determine the effect of tDCS applied to the supplementary motor area (SMA), on gait initiation preparation and performance in PD. Methods: A within subjects repeated measures quasi-experimental design was used to investigate the effects of a 10-minute sham-controlled tDCS intervention. Clinically diagnosed participants (n=12) with idiopathic PD were tested on medication during two sessions that bookended one week. Those who had previously undergone other forms of brain stimulation, had diabetes, severe freezing of gait, or any other neurological or functional limitations that could interfere with gait initiation were excluded from the study. Statistical Analyses/Results: Two-way repeated measures ANOVAs with Bonferroni corrections and a post-hoc analyses when appropriate, revealed a significant reduction in the magnitude of center of pressure (CoP) displacement and velocity in the mediolateral (ML) direction following tDCS. Conclusions: Findings from this study provide insights that may guide scientific research regarding the effects of tDCS on gait initiation among those with PD. Additionally, our work may highlight the importance of ML postural stability for individuals with comorbid and/or pharmacologically induced postural instabilities.

This thesis explores to what extent Multinomial Naive Bayes (MNB) and Support Vector Machines (SVM) classifiers can be used to determine the polarity of news, specifically the news coverage of Sweden by the Russian state-funded news outlets RT and Sputnik. Three experiments are conducted.  In the first experiment, an MNB and an SVM classifier are trained with the Large Movie Review Dataset (Maas et al., 2011) with a varying number of samples to determine how training data size affects classifier performance.  In the second experiment, the classifiers are trained with 300 positive, negative, and neutral news articles (Agarwal et al., 2019) and tested on 95 RT and Sputnik news articles about Sweden (Bengtsson, 2019) to determine if the domain specificity of the training data outweighs its limited size.  In the third experiment, the movie-trained classifiers are put up against the domain-specific classifiers to determine if well-trained classifiers from another domain perform better than relatively untrained, domain-specific classifiers.  Four different types of feature sets (unigrams, unigrams without stop words removal, bigrams, trigrams) were used in the experiments. Some of the model parameters (TF-IDF vs. feature count and SVM’s C parameter) were optimized with 10-fold cross-validation.  Other than the superior performance of SVM, the results highlight the need for comprehensive and domain-specific training data when conducting machine learning tasks, as well as the benefits of feature engineering, and to a limited extent, the removal of stop words. Interestingly, the classifiers performed the best on the negative news articles, which made up most of the test set (and possibly of Russian news coverage of Sweden in general).

TV distribution and stream content delivery of video over the Internet, since is made up of complex networks including Content Delivery Networks (CDNs), cables and end-point user devices, that is very prone to issues appearing in different levels of the network ending up affecting the final customer’s TV services. When a problem affects the customer, and this prevents from having a proper TV delivery service in devices used for stream purposes, the issue is reported through a call, a TV case is opened and the company’s customer handling agents start supervising it to solve the problem as soon as possible. The goal of this research work is to present an ML-based solution that predicts the Resolution Times (RTs) of the TV cases in each TV delivery service type, therefore how long the cases will take to be solved. The approach taken to provide meaningful results consisted in utilizing four Machine Learning (ML) algorithms to create 480 models for each of the two scenarios. The results revealed that Random Forest (RF) and, specially, Gradient Boosting Machine (GBM) performed exceptionally well. Surprisingly, hyperparameter tuning didn’t significantly improve the RT as expected. Some challenges included the initial data preprocessing and some uncertainty in hyperparameter tuning approaches. Thanks to these predicted times, the company is now able to better inform their costumers on how long the problem is expected to last until is resolved. This real case scenario also considers how the company processes the available data and manages the problem. The research work consists in, first, a literature review on the prediction of RT of Trouble Ticket (TT) and customer churn in telecommunication companies, as well as the study of the company’s available data for the problem. Later, the research focuses in analysing the provided dataset for the experimentation, the preprocessing of the this data according to the industry standards and, finally, the predictions and analysis of the obtained performance metrics. The proposed solution is designed to offer an improved resolution for the company’s specified task. Future work could involve increasing the number of TV cases per service for improving the results and exploring the link between resolution times and customer churn decisions. / TV-distribution och leverans av strömningsinnehåll via internet består av komplexa nätverk, inklusive CDNs, kablar och slutanvändarutrustning. Detta gör det känsligt för problem på olika nätverksnivåer som kan påverka slutkundens TV-tjänster. När ett problem påverkar kunden och hindrar en korrekt TV-leveranstjänst rapporteras det genom ett samtal. Ett ärende öppnas, och företagets kundhanteringsagenter övervakar det för att lösa problemet så snabbt som möjligt. Målet med detta forskningsarbete är att presentera en maskininlärningsbaserad lösning som förutsäger löstiderna (RTs) för TV-ärenden inom varje TV-leveranstjänsttyp, det vill säga hur lång tid ärendena kommer att ta att lösa. För att få meningsfulla resultat användes fyra maskininlärningsalgoritmer för att skapa 480 modeller för var och en av de två scenarierna. Resultaten visade att Random Forest (RF) och framför allt Gradient Boosting Machine (GBM) presterade exceptionellt bra. Överraskande nog förbättrade inte finjusteringen av hyperparametrar RT som förväntat. Vissa utmaningar inkluderade den initiala dataförbehandlingen och osäkerhet i metoder för hyperparametertuning. Tack vare dessa förutsagda tider kan företaget nu bättre informera sina kunder om hur länge problemet förväntas vara olöst. Denna verkliga fallstudie tar också hänsyn till hur företaget hanterar tillgängliga data och problemet. Forskningsarbetet börjar med en litteraturgenomgång om förutsägelse av RT för Trouble Ticket (TT) och kundavhopp inom telekommunikationsföretag samt studier av företagets tillgängliga data för problemet. Därefter fokuserar forskningen på att analysera den tillhandahållna datamängden för experiment, förbehandling av datan enligt branschstandarder och till sist förutsägelser och analys av de erhållna prestandamätvärdena. Den föreslagna lösningen är utformad för att erbjuda en förbättrad lösning för företagets angivna uppgift. Framtida arbete kan innebära att öka antalet TV-ärenden per tjänst för att förbättra resultaten och utforska sambandet mellan löstider och kundavhoppbeslut.