This thesis deals with the nature of the Left-Right scale. Theories and ideas about the Left-Right scale have been tested by a mixture of quantitative and qualitative methods. The research questions are, in short, firstly if voters’ preferences on political issues, where economic issues are tested in this specific thesis, can consistently explain voters’ Left-Right self-placement, secondly if this level of explanation can vary depending on changes in national political discourse, and finally if a high level of correlation between issue and Left-Right self-placement facilitates the matching process of parties and voters of similar ideological conviction. A regression is run on data from the World Values Survey and the European Values Study, data which consists of survey questions about attitudes towards economic preferences and self-placement on the Left-Right scale. The selection is restricted to old democracies, as there is some discrepancy between new and old democracies with regards to the capacity of the electorate to relate to the Left-Right scale. The independent variable in this regression is attitudes toward different economic issues, while the dependent variable is self-placement on the Left-Right scale. The first question is answered by the regression, which is if preferences regarding issues can explain self-placement on the Left-Right scale. The answer that is given is that there is indeed a consistent relationship between preferences on economic issues and self-placement on the Left-Right scale, over time. Albeit it is higher for some countries, like Scandinavia, and lower for other countries, like Japan and Ireland. The two remaining questions are answered by case studies, selected through the method of least likely and most likely cases. These are Netherlands, Sweden, Japan and France. In essence, these cases show that the Left-Right scale is indeed flexible, and can adapt to the current political discourse, and that a high relationship between preferences on political issues and self-placement on the Left-Right scale facilitates the matching of voters and parties of similar ideological conviction.

Fabry disease (FD) is an X-linked recessive lysosomal storage disorder (LSD) known to affect approximately 1 in every 40,000 males, and a smaller number of females. FD results from a deficiency of functional α-galactosidase (α-GAL), which leads to the accumulation of terminally α-galactosylated substrates in the lysosome. The predominant treatment is Enzyme Replacement Therapy (ERT), requiring the regular infusion of recombinant human α-GAL. More than half of individuals receiving ERT experience a range of adverse infusion reactions, and it has been reported that as many as 88% of patients receiving ERT develop neutralizing IgG antibodies against the drug. In aim of designing a non-immunogenic treatment candidate for Fabry disease ERT, we have engineered the active sites of α-GAL and another homologous family 27 exoglycosylase named α-N-acetylgalactosaminidase (α-NAGAL) to have interconverted substrate specificities. 11 of 13 active site residues are conserved between these two enzymes, and we have shown that their substrate specificities can be interconverted by mutating the two non-conserved active-site residues. We report the kinetic properties of these two mutants along with wild type controls, and use western blotting to show that both mutant enzymes retain their respective wild type enzyme antigenicity. Structural data obtained by X-ray crystallography on the α-GAL mutant (called α-GALSA ) reveals the mechanism by which substrate specificity is dictated between these two proteins, and provides explanations for the mutant’s reduced catalytic efficiency.

No description available.

This thesis aims to map what arguments are used by the two biggest parties in Swedish politics, The Social Democratic Party and the Moderate Party, when discussing European politics in the European Affairs Committee (EAC) of the Swedish parliament. In order to realise this, frames used by the party representatives in the committee have been analysed. With the typology of Helbling et. al. (2010), a categorisation of four frames is applied, where each frame corresponds with a side of the left-right or the GAL-TAN-dimension. The study is structured by a number of hypotheses constructed based on findings of previous research, comparing both between the parties and changes over time. The results are assessed in relative terms, meaning that the study focuses on the parties’ relative use of frames rather than the absolute. All hypotheses find full or partial support, confirming expectations of previous research made on other European countries. However, some surprising results are found, highlighting new potential research questions for future studies.

The Swedish People’s Party have for over one hundred years functioned as a political tool for the liberals and center-right of the Swedish-speaking minority of Finland. As a party the SPP stands out in comparison to most other European minority parties as not working for regional self-governance or independence, but instead wanting to uphold constitutional language and service rights. The SPP was a part of every coalition government in Finland from 1979 to 2015 and has held multiple ministerial posts despite only having approximately 5% of the votes. The aim of this essay has been to examine the variance in the value based political issues in the SPP to see if there is a divergence on a liberal/conservative divide within the party. With a theoretical framework based on the GAL-TAN political scale, a socially based dimension of measuring party positions, I have operationalized a liberal and conservative stance to Weberian ideal types, and by first e-mail interviewing party representatives to build a frame of issues to investigate, I have then performed an idea based content analysis by examining motions from 2009 to 2017. The results show that, even though there are a divergence between some of the proposals themselves, and in some cases, between the official party line as described in the party program, the differences are too insignificant to draw conclusions from. The conflict between the motions speaking for and against nuclear power stands out as being very even, while the motions concerning Finland joining NATO stands out as being fully for.

Uppsatsen “Nuförtiden får man ju inte säga ett skit” ‘ är en debattanalys av Europaparlamentarikers kritik gentemot politisk korrekthet i EU. Studien tar ett avstamp i tidigare forskning berörande populism, euroscepticism, GAL-TAN dimensionen, och applicerar detta till ett inte tidigare tillämpat teoretiskt perspektiv för denna typ av forskning, politisk korrekthet. Syftet med studien är att beskriva och kategorisera de huvudteser samt argument som förs i kritiken gentemot ett påstått PK-etablissemang i EU:s viktigaste och enda demokratiskt valda organ. De huvudteser som återfanns i argumentationen var följande: att EU består av ett etablissemang som underminerar EU-medborgarnas sanna vilja med PK-het, att EU är i politisk kris då yttrandefriheten förtrycks, att EU bär på en dubbelmoral av vilka åsikter som får uttryckas och inte, att EUs överstatlighet försummar nationernas egna intressen, och att PK- etablissemanget i EU förvrider den objektiva sanningen och kallar sina motståndarna för populister likt ett retoriskt vapen. Det nytillämpade teoretiska perspektivet, PK, bidrar med ett nytt synsätt på den politiska debatten och de dimensioner av sociala normer som tycks styra det politiska talrummet.

[ES] El envejecimiento se concibe como un proceso progresivo de deterioro funcional que se produce a lo largo de la vida. En general, el avance de la edad va acompañado del deterioro de múltiples tejidos, la alteración de la homeostasis y el aumento de la fragilidad. La edad se considera el principal factor de riesgo de un gran número de enfermedades con elevadas tasas de mortalidad, como las patologías cardiovasculares, el cáncer, la fibrosis pulmonar, la esteatosis hepática y los trastornos neurodegenerativos, entre otros. A medida que aumenta la población de edad avanzada, estas patologías son cada vez más frecuentes en nuestra sociedad y constituyen actualmente una de las principales preocupaciones sanitarias en atención primaria. Por consiguiente, comprender los mecanismos que causan el envejecimiento y el consiguiente deterioro de la salud es un reto importante para la comunidad científica, respaldado por un significativo interés socioeconómico. Alcanzar este objetivo permitiría realizar intervenciones específicas contra las enfermedades relacionadas con la edad, promover un envejecimiento saludable y prolongar la vida humana. En este contexto, la senescencia celular se ha convertido en un importante objetivo de investigación, ya que este destino celular se considera un factor que contribuye al deterioro funcional y estructural de los tejidos con el aumento de la edad, dando lugar a enfermedades crónicas. Los trastornos neurodegenerativos son en su mayoría de etiología desconocida, y en la actualidad sólo se dispone de tratamientos paliativos. La neurodegeneración puede deberse a la disminución de la neurogénesis que se produce con el envejecimiento. A este respecto, la vasculatura cerebral representa un componente esencial de los nichos neurogénicos, donde residen las células con capacidad para generar nuevas neuronas. Los microvasos cerebrales contribuyen sustancialmente a preservar la homeostasis y el potencial neurogénico de estas regiones, pero también experimentan cambios estructurales y funcionales con la edad. Sin embargo, aún no está claro si estas alteraciones están relacionadas con la senescencia celular. De ahí que el propósito de esta tesis sea profundizar en los entresijos de la senescencia relacionada con la edad y su impacto en el proceso de envejecimiento cerebral. En este sentido, hemos desarrollado una sonda fluorogénica para la detección in vivo de la actividad ß-Gal, un marcador ampliamente utilizado de senescencia celular. Hemos estimado la carga de células senescentes de forma no invasiva en estudios longitudinales utilizando esta sonda durante el envejecimiento natural y acelerado o durante tratamientos senolíticos. Estos resultados nos han permitido establecer una correlación real entre envejecimiento y senescencia. Por otro lado, hemos centrado nuestros esfuerzos en crear estrategias para detectar la senescencia en las células endoteliales cerebrales y estudiar sus efectos sobre la neurogénesis durante el envejecimiento. Los resultados mostraron que las células endoteliales senescentes a nivel cerebral tienen un impacto perjudicial sobre la neurogénesis y las células madre neurales, lo que sitúa a estas células como diana para futuros estudios sobre el envejecimiento cerebral. / [CA] L'envelliment es concep com un procés progressiu de deterioració funcional que es produeix al llarg de la vida. En general, l'avanç de l'edat va acompanyat de la deterioració de múltiples teixits, l'alteració de l'homeòstasi i l'augment de la fragilitat. L'edat es considera el principal factor de risc d'un gran nombre de malalties amb elevades taxes de mortalitat, com les patologies cardiovasculars, el càncer, la fibrosi pulmonar, la esteatosis hepàtica i els trastorns neurodegeneratius, entre altres. A mesura que augmenta la població d'edat avançada, aquestes patologies són cada vegada més freqüents en la nostra societat i constitueixen actualment les principals preocupacions sanitàries en atenció primària. Per consegüent, comprendre els mecanismes que causen l'envelliment i la consegüent deterioració de la salut és un repte important per a la comunitat científica, recolzat per un significatiu interés socioeconòmic. Aconseguir aquest objectiu permetria realitzar intervencions específiques contra les malalties relacionades amb l'edat, promoure un envelliment saludable i prolongar la vida humana. En aquest context, la senescència cel·lular s'ha convertit en un important objectiu d'investigació, ja que aquest destí cel·lular es considera un factor que contribueix a la deterioració funcional i estructural dels teixits amb l'augment de l'edat, donant lloc a malalties cròniques. Els trastorns neurodegeneratius són en la seua majoria d'etiologia desconeguda, i en l'actualitat només es disposa de tractaments pal·liatius. La neurodegeneración pot deure's a la disminució de la neurogènesi que es produeix amb l'envelliment. Referent a això, la vasculatura cerebral representa un component essencial dels nínxols neurogènics, on resideixen les cèl·lules amb capacitat per a generar noves neurones. Els microvasos cerebrals contribueixen substancialment a preservar l'homeòstasi i el potencial neurogènic d'aquestes regions, però també experimenten canvis estructurals i funcionals amb l'edat. No obstant això, encara no és clar si aquestes alteracions estan relacionades amb la senescència cel·lular. D'aquí ve que el propòsit d'aquesta tesi siga aprofundir en els secrets de la senescència relacionada amb l'edat i el seu impacte en el procés d'envelliment cerebral. En aquest sentit, hem desenvolupat una sonda fluorogénica per a la detecció in vivo de l'activitat ß-Gal, un marcador àmpliament utilitzat de senescència cel·lular. Hem estimat la càrrega de cèl·lules senescentes de forma no invasiva en estudis longitudinals utilitzant aquesta sonda durant l'envelliment natural i accelerat o durant tractaments senolíticos. Aquests resultats ens han permés establir una correlació real entre envelliment i senescència. D'altra banda, hem centrat els nostres esforços a crear estratègies per a detectar la senescència en les cèl·lules endotelials cerebrals i estudiar els seus efectes sobre la neurogènesi durant l'envelliment. Els resultats van mostrar que les cèl·lules endotelials *senescentes a nivell cerebral tenen un impacte perjudicial sobre la neurogènesi i les cèl·lules mare *neurales, la qual cosa situa a aquestes cèl·lules com a diana per a futurs estudis sobre l'envelliment cerebral. / [EN] Ageing is conceived as a progressive process of functional decline that occurs over the course of life. In general, advancing age is accompanied by the deterioration of multiple tissues, altered homeostasis and increased frailty. Age is considered to be the main risk factor for a large number of diseases with high mortality rates, such as cardiovascular pathologies, cancer, pulmonary fibrosis, hepatic steatosis, and neurodegenerative disorders, among others. As the elderly population grows, these pathologies are becoming increasingly prevalent in our society and are now the leading health concerns in primary care. Consequently, comprehending the mechanisms that cause ageing and resulting health decline is a major challenge for the scientific community, backed by significant socio-economic interest. Achieving this goal would allow for targeted interventions against age-related diseases, promote healthy ageing, and extend human lifespan. In this context, cellular senescence has emerged as an important research target, as this cellular fate is considered a contributing factor to the functional and structural deterioration of tissues with increasing age, leading to chronic diseases. Neurodegenerative disorders are mostly of unknown etiology, and only palliative treatments are currently available. Neurodegeneration may be prompted by the decline in neurogenesis that occurs with ageing. In this regard, the brain vasculature represents an essential component of the neurogenic niches, where cells with the capacity to generate new neurons reside. Brain microvessels contribute substantially to preserving the homeostasis and neurogenic potential of these regions, but they also undergo structural and functional changes with age. However, whether these alterations are linked to cellular senescence it is not yet clear. Hence, the purpose of this thesis is to delve deeper into the intricacies of age-related senescence and its impact on the process of brain ageing. In this regard, we have developed a fluorogenic probe for the in vivo detection of ß-Gal activity, a widely used marker of cellular senescence. We have estimated the senescent cell burden non-invasively in longitudinal studies using this probe during natural and accelerated ageing or during senolytic treatments. These results have allowed us to establish a real correlation between ageing and global senescence. On the other hand, we have focused our efforts on creating strategies to detect senescence in brain endothelial cells and to study its effects on neurogenesis during ageing. The results showed that senescent endothelial cells at the brain level have a detrimental impact on neurogenesis and neural stem cells, positioning these cells as a target for future studies on brain ageing. / This PhD thesis has been supported by a pre-doctoral scholarship from the Spanish Ministry of Universities, “Programa de Formación del Profesorado Universitario (FPU)”, and a technical expert contract funded by the European Commission. The research has been funded by the following research projects led by Ramón Mártinez Máñez: - Gobierno de España (RTI2018-100910-B-C41 and PID2021-126304OB-C41). - Generalitat Valenciana (PROMETEO 2018/024 and CIPROM/2021/007). - CIBER-BBN- Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (CB06/01/2012). And by the following research projects led by Isabel Fariñas: - 2014-2018. Estudio de células madre en el ámbito de las investigaciones básicas en terapia celular. Fundación Botín-Banco de Santander. - 2018-2021. Regulación del comportamiento de las células madre neurales por el medio sistémico: el nicho extendido. MINECO (SAF2017-86690-R). - 2016-ongoing. CIBER en Enfermedades Neurodegenerativas (CIBERNED). ISCIII (Programa de Investigación Cooperativa, CB06/05/0086). - 2017-2021. Efectos directos y remotos de la respuesta inflamatoria sobre las células madre neurales. Generalitat Valenciana (Proyectos de Excelencia, PROMETEO/2017/030). - 2017-2021. RETIC de terapia celular ISCIII (RD16/0011/0017). - 2021-2024 Regulación molecular de la heterogeneidad celular en los nichos neurogénicos adultos MICINN (PID2020- 117937GB-I00). - 2021-2025. Una aproximación multidisciplinar al estudio de la respuesta al daño genómico en células madre neurales: de levadura a mamíferos y vuelta. Generalitat Valenciana. Programa Prometeo de Proyectos de Excelencia (PROMETEO/2021/028). / Rojas Vázquez, S. (2023). Impact of Brain Endothelial Senescence on Neurogenesis: Application of Novel Strategies for Age-Related Senescence Detection [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/194629

No description available.

L'eau des fleuves, des rivières, des lacs et des réservoirs ne représente que 0,26 % des 2,5 % (35 millions de km3) d'eau douce disponibles à l’état liquide sur Terre, or sa qualité et quantité ont fortement diminué ces dernières années. Sa dégradation a des conséquences sur l'agriculture, la santé, l'environnement et l'économie des territoires et est aujourd'hui au centre des préoccupations sociétales. Les objectifs de la présente thèse sont pour trois fleuves localisés dans le Bouclier des Guyanes, au nord de l'Amérique du Sud (le Maroni, l'Oyapock, l'Orénoque): (i) d'utiliser et d'adapter des outils novateurs de télédétection pour suivre et quantifier, sur du long terme, leurs charges sédimentaires en suspension, (ii) d'évaluer l'existence de tendances spatio-temporelles, ainsi que de ruptures dans les chroniques de données, (iii) de quantifier la part organique et minérale de ces charges, (iv) d'apprécier le rôle des facteurs naturels (débits et précipitations) et anthropiques (surfaces urbaines, agricoles et minières) sur les tendances observées et enfin, (v) de discuter de seuils de charges pour le suivi de la qualité de l'eau. Les résultats ont montré qu'il est possible de suivre les concentrations de matières en suspension, pour les fleuves Orénoque et Maroni avec une erreur relative de 32 et 25% respectivement. Sur la période 2000-2016, des tendances spatio-temporelles régulières ont été observées pour l'Orénoque, alors qu'elles sont en augmentation pour le Maroni avec une rupture en 2009 et en diminution pour l'Oyapock depuis 2008 (données in situ). Un lien fort avec l'augmentation de la déforestation pour les surfaces minières et les précipitations est observé pour le Maroni alors que pour l'Oyapock les tendances sont liées aux débits.Pour les deux années d'études (2014-2016), les charges minérales ont représenté la plus forte fraction des particules transportées dans les eaux du Maroni au Saut Hermina (en moyenne 93 %) et de l'Oyapock au Saut Maripa (en moyenne 82 %) avec une grande variabilité selon les mois de la teneur en carbone dans les matières transportées et pour les deux fleuves. Enfin, les rapports C/N et C/Chl-a ont dévoilé des matières organiques d'origine principalement endogène avec une forte biomasse chlorophyllienne surtout durant les basses eaux. / The water of rivers, lakes and reservoirs represents only 0.26 % of the 2.5 % (35 million of km3) of fresh water available on the liquid state on Earth, but its quality and quantity strongly decreased these last years. Her degradation has consequences on the farming, the health, the environment and the economy of territories and is now in the center of the societal concerns. The objectives of the present thesis are for three rivers located in the Guiana Shield, in the North of South America (the Maroni, the Oyapock, the Orinoco): i) to use and to adapt innovative tools of remote detection to follow and quantify, on the long term, their sedimentary loads, ii) to estimate the existence of spatiotemporal trends, as well as breaks in the chronicles of data, iii) to quantify the organic and mineral part of these loads, iv) to appreciate the role of the natural (discharge and precipitation) and the anthropological factors (urban, agricultural and mining surfaces) on the observed trends and finally, v) to discuss thresholds of concentrations for the quality monitoring of the river water.The results showed that it is possible to follow the concentrations of suspension materials, for rivers Maroni and Orinoco with a relative error of 25 and 32 % respectively. Over the period 2000-2016, regular spatiotemporal trends were observed for the Orinoco, while they are increasing for Maroni with a break in 2009 and in decrease for the Oyapock since 2008 (in situ data). A strong link with the increase of the deforestation for the mining surfaces and the precipitation is observed for the Maroni catchment while for the Oyapock the trend is explained by the specific water discharge.For two years of studies (2014-2016), the mineral loads represented the strongest fraction of particles transported in the Maroni River at Saut Hermina (on average 93 %) and in the Oyapock River at Saut Maripa (on average 82 %) with a high variability according to the months of the content in carbon in the transported materials and for both rivers. Finally, report C/N and C/Chl-a revealed organic matters of mainly endogenous origin with a strong chlorophyll biomass and especially during the low water period.

La sénescence est un important mécanisme cellulaire qui prévient la tumorigenèse et se caractérise par un arrêt permanent du cycle cellulaire orchestré principalement par les inhibiteurs des cycline-kinases dépendantes (i.e p16INK4a). La sénescence est une caractéristique importante du vieillissement, mais un déséquilibre dans son induction peut être délétère pour la régénération tissulaire et paradoxalement pour la progression tumorale. L'irradiation (IR) est couramment utilisée comme approche thérapeutique dans le cancer. Chez les enfants survivants du cancer, l’exposition à l’irradiation et à la chimiothérapie entrainent le développement d’importants effets secondaires, lesquels sont associés à une forme de vieillissement prématuré. La formation de cellules sénescentes, en inhibant la prolifération tissulaire et en sécrétant des cytokines proinflammatoires, pourrait être en être responsable. Notre groupe a précédemment démontré que le gène p16INK4a est augmenté de manière tardive (environ 8 semaines) suite à une exposition à l’irradiation. Il n'a pas encore été étudié si cette expression retardée survient en réponse aux dommages causés par l'irradiation sur l’homéostasie tissulaire ou à titre de mécanismes de suppression tumorale. Un objectif de cette thèse visait donc à déterminer s’il était possible de moduler/inhiber l’expression de p16INK4a dans le but d’accroitre la régénération tissulaire sans nécessairement accroitre les risques d’incidence du cancer. En effet, ceci pourrait être possible dans la mesure ou la sénescence induite par p16INK4a est également irréversible in vivo. Nos résultats ont démontré que l’inhibition de l’expression de p16INKa (suite à l’administration de tamoxifen chez les souris p16L/LCre), induit à la fois une augmentation de la régénération tissulaire mais malheureusement également une augmentation de l’incidence du cancer. Nous voulions également connaitre l’impact de l’accumulation de ces cellules sénescentes sur les tissus, plus spécifiquement sur la fonction des cellules immunitaires de la rate. Nous avons démontré que des altérations (dépendantes de p16INK4a) au sein du microenvironnement splénique pouvaient altérer les fonctions intrinsèques des macrophages, des cellules dendritiques et des lymphocytes T. En outre, l'élimination systémique des cellules p16INK4a positives (modèle de sourie p16-3MR) a conduit à une restauration partielle de la fonction de ces cellules immunitaires. La combinaison de ces données nous permet de mieux comprendre le rôle et la fonction du gène p16INK4a dans le processus de sénescence induite par l’irradiation. Nos résultats suggèrent qu’il est envisageable d’utiliser des agents pharmacologiques tels que des composés sénolytiques, capables d’induire l’apoptose chez les cellules sénescentes spécifiquement, afin de potentiellement diminuer les effets du vieillissement prématuré induit par la sénescence cellulaire chez les survivants du cancer. / Senescence is an important cellular mechanism that prevents tumorigenesis and is characterized by a permanent cell cycle arrest orchestrated by cyclin-dependent kinases inhibitors (i.e p16INK4a). Senescence is an important hallmark of aging and unbalanced levels of senescence is considered deleterious for tissue regeneration, and paradoxically for tumor progression. Irradiation (IR) is commonly used therapeutic approach in cancer treatment. Together with surgery and chemotherapy, it has helped to increase the life expectancy of patients and, in some cases, leads to complete remission. However, long-after therapy, children who survive cancer encounter alterations in the integrity of tissues/organs associated with premature aging. The accumulation of senescent cells may be responsible for this accelerated aging by limiting tissue proliferation and secreting pro-inflammatory cytokines. Our group has previously demonstrated that the p16INK4a gene is increased in a delayed manner (approximately 8 weeks) following exposure to IR. It has not yet been investigated whether this delayed expression occurs in response to IR-induce damage of tissue homeostasis or as tumor suppression mechanisms. One objective of this thesis was to determine whether it was possible to modulate / inhibit the expression of p16INK4a in order to increase tissue regeneration without necessarily increasing the risk of cancer incidence. Indeed, this may be possible since p16INK4a-induced senescence is also irreversible in vivo. Our results demonstrated that the inhibition of p16INK4a expression in conditional-p16INK4a null mice , induces both an increase in tissue regeneration but unfortunately also an increase in the incidence of cancer. We also wanted to know the impact of the accumulation of these senescent cells on the tissues, more specifically on the function of the immune cells in the spleen. We have demonstrated that alterations (p16INK4a-dependent) within the splenic microenvironment can alter the intrinsic functions of macrophages, dendritic cells and T cells. In addition, the systemic elimination of p16INK4a positive cells (mouse model p16-3MR) has led to a partial restoration of the function of these immune cells. The combination of these data allows us to better understand the role and function of the p16INK4a gene in the irradiation-induced senescence process. Our results suggest that it is conceivable to use pharmacological agents such as senolytic compounds, capable of inducing apoptosis in senescent cells specifically, in order to potentially reduce the effects of premature aging induced by cellular senescence in cancer survivors.