This thesis examines methods to enhance the realism of signal strength simulations in a Radio Access Network (RAN) test environment by identifying and analyzing factors that influence signal strength in actual RAN settings. The study addresses different attenuation impacts using three technical reports: 3GPP TR 38.901 for path loss in various area scenarios, ITU-R P.838 for rain attenuation, and ITU-R P.840 for cloud and fog attenuation effects. This thesis also considers inter-cell interference as a proof of concept to understand its impact on signal quality. Key findings indicate that path loss substantially affects signal strength, significantly influenced by frequency, distance between transmitter and receiver, and the environmental context (e.g., rural or urban). Although rain and cloud attenuation also affect signal strength, their impact is minor but increases with higher frequencies. This thesis enriches our understanding of more accurately simulating signal strength in RAN environments by focusing on path loss, rain, cloud attenuation, and inter-cell interference. This work lays a foundation for subsequent studies to expand upon, particularly in integrating diverse attenuation factors, thereby driving forward the precision and reliability of future RAN simulations.

Yes / Ran is a small ras-related GTPase and is highly expressed in aggressive breast carcinoma. Overexpression induces malignant transformation and drives metastatic growth. We have designed a novel series of anti-Ran-GTPase peptides, which prevents Ran hydrolysis and activation, and although they display effectiveness in silico, peptide activity is suboptimal in vitro due to reduced bioavailability and poor delivery. To overcome this drawback, we delivered an anti-Ran-GTPase peptide using encapsulation in PLGA-based nanoparticles (NP). Formulation variables within a double emulsion solvent evaporation technique were controlled to optimise physicochemical properties. NP were spherical and negatively charged with a mean diameter of 182–277 nm. Peptide integrity and stability were maintained after encapsulation and release kinetics followed a sustained profile. We were interested in the relationship between cellular uptake and poly(ethylene glycol) (PEG) in the NP matrix, with results showing enhanced in vitro uptake with increasing PEG content. Peptide-loaded, pegylated (10% PEG)-PLGA NP induced significant cytotoxic and apoptotic effects in MDA-MB-231 breast cancer cells, with no evidence of similar effects in cells pulsed with free peptide. Western blot analysis showed that encapsulated peptide interfered with the proposed signal transduction pathway of the Ran gene. Our novel blockade peptide prevented Ran activation by blockage of regulator of chromosome condensation 1 (RCC1) following peptide release directly in the cytoplasm once endocytosis of the peptide-loaded nanoparticle has occurred. RCC1 blockage was effective only when a nanoparticulate delivery approach was adopted.

Yes / Multidrug resistance (MDR) limits the beneficial outcomes of conventional breast cancer chemotherapy. Ras-related nuclear protein (Ran-GTP) plays a key role in these resistance mechanisms, assisting cancer cells to repair damage to DNA. Herein, we investigate the co-delivery of Ran-RCC1 inhibitory peptide (RAN-IP) and doxorubicin (DOX) to breast cancer cells using liposomal nanocarriers. A liposomal delivery system, co-encapsulating DOX, and RAN-IP, was prepared using a thin-film rehydration technique. Dual-loaded liposomes were optimized by systematic modification of formulation variables. Real-Time-Polymerase Chain Reaction was used to determine Ran-GTP mRNA expression. In vitro cell lines were used to evaluate the effect of loaded liposomes on the viability of breast and lung cancer cell lines. In vivo testing was performed on a murine Solid Ehrlich Carcinoma model. RAN-IP reversed the Ran-expression-mediated MDR by inhibiting the Ran DNA damage repair function. Co-administration of RAN-IP enhanced sensitivity of DOX in breast cancer cell lines. Finally, liposome-mediated co-delivery with RAN-IP improved the anti-tumor effect of DOX in tumor-bearing mice when compared to single therapy. This study is the first to show the simultaneous delivery of RAN-IP and DOX using liposomes can be synergistic with DOX and lead to tumor regression in vitro and in vivo.

Yes / Fifth generation (5G) cellular networks will be comprised of millions of connected devices like wearable devices, Androids, iPhones, tablets and the Internet of Things (IoT) with a plethora of applications generating requests to the network. The 5G cellular networks need to cope with such sky-rocketing tra c requests from these devices to avoid network congestion. As such, cloud radio access networks (C-RAN) has been considered as a paradigm shift for 5G in which requests from mobile devices are processed in the cloud with shared baseband processing. Despite call admission control (CAC) being one of radio resource management techniques to avoid the network congestion, it has recently been overlooked by the community. The CAC technique in 5G C-RAN has a direct impact on the quality of service (QoS) for individual connections and overall system e ciency. In this paper, a novel Fuzzy-Logic based CAC scheme with pre-emption in C-RAN is proposed. In this scheme, cloud bursting technique is proposed to be used during congestion, where some delay tolerant low-priority connections are pre-empted and outsourced to a public cloud with a penalty charge. Simulation results show that the proposed scheme has low blocking probability below 5%, high throughput, low energy consumption and up to 95% of return on revenue.

No / The healthcare sector is now blending with Information and Communications Technology (ICT) using Internet of Things (IoT) to potentially minimise medical errors and reduce healthcare cost. Patients are now embedded with smart devices like body sensors and wearable devices which can monitor their health without the need for a doctor in physical contact. Such smart devices have the downside of low battery power and are unable to transmit their data to the medical personnel when the patient is on the move away from the smart home/smart clinic fixed gateway. A mobile gateway is required which moves with the patient to process the smart device data without depleting the smartphone battery. This paper proposes an Intelligent and Energy Efficient SG based smartphone Gateway for healthcare smart devices (IEE5GG). In IEE5GG, the 5G architecture is adopted and the patient's smartphone is used as a gateway where multiple smart devices are connected e.g. via Bluetooth. To save energy, requests to the smartphone can either be executed on the smartphone gateway or offloaded and executed in the Mobile Edge Computing (MEC) cloud at close proximity to the smartphone in the 5G Base Station (BS) central Unit (gNB-CU) while considering the transmission power, Quality of Service (QoS), smartphone battery level and Central Processing Unit (CPU) load. Results show that the proposed IEE5GG framework saves up to 38% of energy in the healthcare mobile gateway smartphone and reduces healthcare application service time by up to 41%. / British Council Institutional Links grant under the BEIS-managed Newton Fund.

Le cancer épithélial de l’ovaire est le plus létal des cancers gynécologiques. Les tumeurs de l’ovaire se divisent en différentes classes reflétant l’étendue de la maladie. Les tumeurs à faible potentiel de malignité présentent une survie relative à 5 ans de 90%, alors que pour les tumeurs invasives, la survie à 5 ans chute drastiquement à 35-40%. Au laboratoire, nous avons précédemment identifié la protéine Ran, un membre de la superfamille des GTPases Ras, comme marqueur fortement exprimé dans les cancers épithéliaux de l’ovaire de haut grade et de haut stade dont la surexpression est associée à un mauvais pronostic. Ran est déjà connue pour contribuer au transport nucléocytoplasmique et à la progression du cycle cellulaire, mais son rôle dans le cancer ovarien n’est pas bien défini. En utilisant une approche de shRNA inductibles à la tétracycline basée sur les lentivirus, nous avons montré que la diminution de l’expression de Ran dans des lignées cellulaires agressives du cancer de l’ovaire affecte drastiquement la prolifération cellulaire par l’induction d’une apoptose caspase-3 dépendante. Par un essai de tumeurs en xénogreffes, nous avons démontré que la déplétion de Ran résulte en une diminution de la tumorigenèse et que la formation éventuelle de tumeurs est associée à une sélection des cellules tumorales ayant la capacité de ré-exprimer la protéine Ran. Ces résultats suggèrent un rôle critique pour Ran dans la survie et la tumorigénicité des cellules du cancer ovarien, indiquant que Ran pourrait être une cible thérapeutique intéressante. / Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Malignant epithelial tumors can be divided into different classes reflecting the extent of the disease. Low malignant potential (LMP) tumors have a 5 years survival rate of 90-95%. For invasive cancers (TOVs), the survival rate drops dramatically to 35-40%. In the laboratory, we previously identified that Ran protein, a member of the Ras GTPase family, is highly expressed in high grade and high stage serous epithelial ovarian cancers, and that its over-expression is associated with a poor prognosis. Ran is known to contribute to both nucleocytoplasmic transport and cell cycle progression, but its role in ovarian cancer is not well defined. Using a lentivirus-based tetracycline inducible shRNA approach, we show that down-regulation of Ran expression in aggressive ovarian cancer cell lines drastically affects cellular proliferation by inducing a caspase-3 dependent apoptosis. Using a xenograft tumor assay, we demonstrate that depletion of Ran results in decreased tumorigenesis, and eventual tumor formation is associated with the selection of tumor cells able to re-express the Ran protein. These results suggest a critical role for Ran in ovarian cancer cell survival and tumorigenicity and suggest that this critical GTPase may be suitable as a therapeutic target.

Thesis objectives: The thesis deals with the comparison of wound healing management in acute and subsequent care. The theoretical part presents the knowledge of acute and chronic wounds, wound healing and their phases. Furthermore, the thesis deals with methods of wound treatment. The last chapter of the theoretical part deals with management and the role of a nurse in caring for a patient with a wound. In the empirical part, the first goal was to find out whether nurses from the Hradec Králové Region hospitals know the division and types of wounds. The second goal was to map out the possibilities for nurses to heal wounds. Another aim was to compare the differences between wound healing in acute and subsequent care. The fourth goal mapped the knowledge of nurses about wound healing materials. The following aim was to find out which materials for wound care are available at the hospital of the Hradec Králové Region. The sixth goal was to compare the economic and time-consuming wound healing at the acute and aftercare departments. The last goal of the thesis is to elaborate a seminar within the framework of lifelong education of general nurses on the topic of effective wound healing. Five hypotheses and two research questions were formulated to meet the goals of the thesis. Method for achieving the objectives: The set goals were achieved through quantitative questionnaire research and qualitative observation and interview research, which were chosen to complement the results. The sample included general nurses working in the internal department, the surgical department, the intensive care unit, the anesthesiology-resuscitation department and the aftercare departments in the hospitals of the Hradec Králové region. The total number of respondents was 120. Scientific benefits of the thesis: Overall research shows that nurses have sufficient knowledge of wounds and their treatment, but deficiencies in some areas are still evident. Furthermore, the research shows that nurses do not have enough therapeutic material to work on their workplaces. The interviewed group of general nurses said they think that modern dressing materials have a positive effect on wound healing. The results of the work can be used for practice, in hospital and other health care facilities to improve wound healing. The findings and conclusions: In the tracked file, we verified that the length of treatment of wounds on beds of acute and subsequent care differs (p = 0.002); the results show that the average time of wound dressing is prolonged in subsequent care. Conversely, the availability of dressing materials in the respective departments did not differ (p = 0.159). Furthermore, we found that the economic intensity of the after-care beds is lower, despite the fact that more wound dressings are done than in the acute care.

Submitted by JOSIANE SANTOS DE OLIVEIRA (josianeso) on 2018-05-11T12:40:43Z No. of bitstreams: 1 Felipe Rabuske Costa_.pdf: 3408830 bytes, checksum: 25a67ecb02629c811b5f305a1f2e3d27 (MD5) / Made available in DSpace on 2018-05-11T12:40:43Z (GMT). No. of bitstreams: 1 Felipe Rabuske Costa_.pdf: 3408830 bytes, checksum: 25a67ecb02629c811b5f305a1f2e3d27 (MD5) Previous issue date: 2018-02-28 / Nenhuma / Estima-se que até o ano de 2020, cerca de 50 bilhões de dispositivos móveis estarão conectados a redes sem fio e que 78% de todo o tráfego de dados gerado por esse tipo de dispositivos será conteúdo multimídia. Essas estimativas fomentam o desenvolvimento da quinta geração de redes móveis (5G). Uma das arquiteturas mais recentemente proposta, chamada de Fog Radio Access Networks (F-RAN), dá aos componentes localizados na borda da rede poder de processamento e armazenamento endereçados às atividades da rede. Um dos principais problemas dessa arquitetura é o intenso tráfego de dados no seu canal de comunicação centralizado chamado fronthaul, utilizado para conectar as antenas (F-APs) à rede externa. Dado esse contexto, esse trabalho apresenta o Nuoxus, um modelo de caching de conteúdo multimídia voltado para F-RANs que visa amenizar esse problema. Ao armazenar esse tipo de conteúdo nos nós de rede mais próximos ao usuário, o número de acessos concorrentes ao fronthaul é reduzido, sendo esse um dos fatores agravantes na latência de comunicação na rede. O Nuoxus pode ser executado em qualquer nó da rede que possua capacidade de armazenamento e processamento, ficando responsável por gerenciar o caching de conteúdo desse nó. Sua política de substituição de conteúdo utiliza a similaridade de requisições entre os nós filhos e o restante da rede como um fator para definir a relevância de armazenar o conteúdo requisitado em cache. Além disso, utilizando esse mesmo processo, o Nuoxus sugere, de forma proativa, aos demais nós filhos que apresentam um alto grau de similaridade que façam o caching desse conteúdo, visando um possível futuro acesso. A análise do estado da arte demonstra que até o momento não existe nenhum outro trabalho que explore o histórico de requisições para fazer caching de conteúdo em arquiteturas multicamadas para redes sem fio de forma proativa e sem utilizar algum componente centralizado para fazer coordenação e predição de caching. A fim de comprovar a eficiência do modelo, foi desenvolvido um protótipo utilizando o simulador ns-3. Os resultados obtidos demostram que a utilização do Nuoxus foi capaz de reduzir a latência de rede em cerca de 29.75%. Além disso, quando comparado com outras estratégias de caching, o número de acesso à cache dos componentes de rede aumentou em 53.16% em relação à estratégia que obteve o segundo melhor resultado. / It is estimated that by the year 2020, about 50 billion mobile devices will be connected to wireless networks and 78% of the data traffic of this kind of device will be multimedia content. These estimates foster the development of the 5th generation of mobile networks (5G). One of the most recently proposed architectures, named Fog Radio Access Networks or F-RAN, gives the components located at the edge of the network the processing power and storage capacity to address network activities. One of the main problems of this architecture is the intense data traffic in its centralized component named fronthaul, which is used to connect the antennas (FAPs) to the external network. Given this context, we propose Nuoxus, a multimedia content caching model for F-RANs that aims to mitigate this problem. By storing the content in the nodes closest to the user, the number of concurrent accesses to the fronthaul is reduced, which decreases the communication latency of the network. Nuoxus can run on any network node that has storage and processing capacity, becoming the responsible for managing the cache of that node. Its content replacement policy uses the similarity of requests between the child nodes and the rest of the network as a factor to decide the relevance of storing the requested content in the cache. Furthermore, by using this same process, Nuoxus proactively suggests to the child nodes whose degree of similarity is high to perform the caching of the content, assuming they will access the content at a future time. The State-of-the-art analysis shows that there is no other work that explores the history of requests to cache content in multi-layer architectures for wireless networks in a proactive manner, without using some centralized component to do coordination and prediction of caching. To demonstrate the efficiency of the model, a prototype was developed using the ns 3 simulator. The results obtained demonstrate that the use of Nuoxus reduced network latency in 29.75%. In addition, when compared to other caching strategies, the cache hit increased by 53.16% when compared to the strategy that obtained the second-best result.

Le cancer épithélial de l’ovaire est le plus létal des cancers gynécologiques. Les tumeurs de l’ovaire se divisent en différentes classes reflétant l’étendue de la maladie. Les tumeurs à faible potentiel de malignité présentent une survie relative à 5 ans de 90%, alors que pour les tumeurs invasives, la survie à 5 ans chute drastiquement à 35-40%. Au laboratoire, nous avons précédemment identifié la protéine Ran, un membre de la superfamille des GTPases Ras, comme marqueur fortement exprimé dans les cancers épithéliaux de l’ovaire de haut grade et de haut stade dont la surexpression est associée à un mauvais pronostic. Ran est déjà connue pour contribuer au transport nucléocytoplasmique et à la progression du cycle cellulaire, mais son rôle dans le cancer ovarien n’est pas bien défini. En utilisant une approche de shRNA inductibles à la tétracycline basée sur les lentivirus, nous avons montré que la diminution de l’expression de Ran dans des lignées cellulaires agressives du cancer de l’ovaire affecte drastiquement la prolifération cellulaire par l’induction d’une apoptose caspase-3 dépendante. Par un essai de tumeurs en xénogreffes, nous avons démontré que la déplétion de Ran résulte en une diminution de la tumorigenèse et que la formation éventuelle de tumeurs est associée à une sélection des cellules tumorales ayant la capacité de ré-exprimer la protéine Ran. Ces résultats suggèrent un rôle critique pour Ran dans la survie et la tumorigénicité des cellules du cancer ovarien, indiquant que Ran pourrait être une cible thérapeutique intéressante. / Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Malignant epithelial tumors can be divided into different classes reflecting the extent of the disease. Low malignant potential (LMP) tumors have a 5 years survival rate of 90-95%. For invasive cancers (TOVs), the survival rate drops dramatically to 35-40%. In the laboratory, we previously identified that Ran protein, a member of the Ras GTPase family, is highly expressed in high grade and high stage serous epithelial ovarian cancers, and that its over-expression is associated with a poor prognosis. Ran is known to contribute to both nucleocytoplasmic transport and cell cycle progression, but its role in ovarian cancer is not well defined. Using a lentivirus-based tetracycline inducible shRNA approach, we show that down-regulation of Ran expression in aggressive ovarian cancer cell lines drastically affects cellular proliferation by inducing a caspase-3 dependent apoptosis. Using a xenograft tumor assay, we demonstrate that depletion of Ran results in decreased tumorigenesis, and eventual tumor formation is associated with the selection of tumor cells able to re-express the Ran protein. These results suggest a critical role for Ran in ovarian cancer cell survival and tumorigenicity and suggest that this critical GTPase may be suitable as a therapeutic target.

[ES] El equilibrio de la homeostasis de proteínas es esencial para asegurar la funcionalidad celular. La expresión de proteínas propensas a plegarse mal induce la formación de agregados tóxicos que alteran el correcto funcionamiento de estos sistemas de control, lo que conduce a un desequilibrio de la homeostasis de proteínas, y por consiguiente a una afectación patológica. Varias enfermedades neurodegenerativas, como la enfermedad de Huntington (EH), Parkinson, Alzheimer, entre otras, tienen en común esta marca patológica molecular. Especialmente, la EH pertenece a un grupo de patologías producidas por proteínas que contienen expansiones de poliQs (varias ataxias espinocerebelosas, la atrofia muscular bulbar y espinal y la atrofia dentatorubro-pálidoluisiana), que hacen que estos péptidos sean propensos a la agregación, y causen los problemas que hemos descrito. A pesar de que estas enfermedades son genéticas, y se conoce su causa molecular, se cree que la presencia de variantes alélicas en otros genes puede exacerbar o ralentizar la agregación de proteínas con poliQs. Por tanto, la identificación de estos genes permitirá profundizar en los mecanismos moduladores de la dinámica de agregación de poliQs e identificar dianas terapéuticas frente a la toxicidad de poliQs. También es ampliamente conocido que el ARN que porta tripletes CAG tiene carácter patogénico. En este trabajo hemos desarrollado modelos, empleando C. elegans, que muestran signos indirectos de que están expresando transcritos CAG patogénicos, puesto que los tejidos diana están alterados. Usamos uno de estos modelos, que perturba la función de las neuronas GABAérgicas del gusano, para realizar un cribado de 85 compuestos farmacológicos, que nos llevó a identificar cuatro compuestos que reducían los defectos motores en estos animales. Además de poliQs y transcritos CAG, también se producen péptidos derivados de una traducción no canónica, conocida como traducción RAN. En relación a esto, hemos profundizado en la identificación y modelización de estos péptidos en C. elegans mediante la expresión de expansiones CAG fusionadas a proteínas fluorescentes para su detección in vivo. Además hemos empleado otros modelos ya existentes, para caracterizar potenciales dianas terapéuticas, como AMPK, la cual puede ser activada por diferentes sustancias. Sin embargo, algunas sustancias, como la metformina o el salicilato, son pleiotrópicas. Por tanto, hemos caracterizado la activación sinérgica de AMPK, mediante metformina y salicilato, para reducir el estrés por agregados de poliQs, con lo que podríamos evitar que otras dianas resulten activadas. Por último, hemos demostrado que este tratamiento sinérgico reduce la toxicidad inducida por la α -sinucleína implicada en la enfermedad de Parkinson. Por otro lado, hemos caracterizado en C. elegans un nuevo alelo que potencia la la agregación de poliQs, vlt10, en el gen unc-1. Nuestros resultados sugieren que la mutación unc-1(vlt10) perturba la sinapsis eléctrica entre las neuronas sensoriales IL2 y ASJ, induciendo un exceso de señalización hormonal que requiere la función de la sulfotransferasa SSU-1. También hemos demostrado que la diana de esta señal es un receptor nuclear llamado NHR-1. En este mismo capítulo, hemos identificado otra ruta de señalización hormonal, mediada por otro receptor nuclear (DAF-12), que tiene un papel protector. Se desconoce qué hormona modula la actividad de NHR-1. Sin embargo, hemos identificado que algunos de los genes regulados por NHR-1 están relacionados con el metabolismo lipídico. Además, hemos observado que la disrupción de unc-1 induce la acumulación de lípidos en los gusanos, pero a la vez estos animales contienen menos ácidos grasos totales. Esto sugiere que las grasas juegan un papel fundamental en la modulación de la agregación de poliQs, y quizás señala posibles dianas terapéuticas contra enfermedades causadas / [CA] L'equilibri de l'homeòstasi de proteïnes és essencial per a assegurar la funcionalitat cel·lular. L'expressió de proteïnes propenses a plegar-se malament indueix la formació d'agregats tòxics i altera el correcte funcionament dels sistemes de control, cosa que condueix a un desequilibri de l'homeòstasi de proteïnes, i per consegüent a una afectació patològica. Diverses malalties neurodegeneratives, com la malaltia de Huntington (MH), Parkinson i Alzheimer, entre altres, tenen en comú aquesta signatura patològica. Especialment, la MH pertany a un grup de patologies produïdes per proteïnes que contenen expansions de poliQs (s'inclouen diverses atàxies espinocerebel·loses 1, 2, 3, 6, 7 i 17, l'atròfia muscular bulbar i espinal, i l'atròfia dentatorúbrica-pàl·lidaluisiana), que fan que aquests pèptids siguen propensos a l'agregació, i causen els problemes que hem descrit. Malgrat que aquestes malalties són genètiques i es coneix la seva causa molecular, es creu que la presència de variants al·lèliques en gens pot incrementar o alentir l'agregació de proteïnes amb poliQs. Per tant, la identificació de gens modificadors permet aprofundir en els mecanismes moduladors de la dinàmica d'agregació de poliQs ens permet trobar dianes terapèutiques enfront de la toxicitat de poliQs. També és àmpliament conegut que l'ARN que contenen expansions CAG té caràcter patogènic. Per tant, hem desenvolupat models, utilitzant C. elegans, en els quals es mostren signes indirectes que expressen transcrits patogènics, ja que els teixits diana revelen una funcionalitat alterada. Utilitzant aquests models, que alteren la funció de les neurones GABAèrgiques del cuc, hem realitzat un cribratge de 85 compostos farmacològics, que ens va portar a identificar quatre compostos que reduïen els defectes motors en aquests animals. A més de poliQs i l'ARN que conté expansions de CAG, es produeixen pèptids derivats d'una traducció no canònica, coneguda com a traducció RAN. En relació amb això, hem aprofundit en la identificació i modelització d'aquests pèptids en C. elegans mitjançant l'expressió d'expansions CAG fusionades a proteïnes fluorescents per a la seva detecció in vivo. A més hem emprat models ja generats, per a caracteritzar potencials dianes terapèutiques, com AMPK puga ser activat per diversos fàrmacs. No obstant això, alguns activadors, com la metformina o el salicilat, són substàncies pleiotròpiques. Per tant, hem caracteritzat l'activació sinèrgic de AMPK, mitjançant metformina i salicilat, per a reduir l'estrés induït per agregats de poliQs i s'evita l'activació de dianes no desitjades. I finalment, hem demostrat que aquest tractament sinèrgic podria ser utilitzat per a reduir proteïnes tòxiques com la α-sinucleína, causant de la malaltia de Parkinson. D'altra banda, hem caracteritzat un nou modulador de l'agregació de poliQs, vlt10, en el gen unc-1, que produeix un augment d'agregació de poliQs. Els nostres resultats suggereixen que la mutació unc-1(vlt10) pertorba la sinapsi elèctrica entre les neurones sensorials IL2 i ASJ, induint un excés de senyalització hormonal que requereix la funció de la sulfotransferasa SSU-1. També hem demostrat que la diana d'aquest senyal és un receptor nuclear anomenat NHR-1. En el mateix capítol, hem identificat una altra ruta de senyalització hormonal, mitjançada per un altre receptor nuclear (DAF-12), que té un paper protector. Es desconeix l'hormona que modula l'activitat de NHR-1. No obstant això, hem identificat que alguns del genes regulats per NHR-1 estan relacionats amb el metabolisme lipídic. els resultats han sigut confirmats. També hem observat que la disrupció de unc-1 indueix l'acumulació de lípids en els cucs, però simultàniament aquests animals contenen menys àcids grassos totals. Això suggereix que els greixos juguen un paper fonamental en la modulació de l'agregació de poliQs, i potser assenyala / [EN] The balance of protein homeostasis is essential to ensure cellular functionality. The expression of proteins that are prone to misfolding induces the formation of toxic aggregates, which leads to an imbalance in protein homeostasis and pathological consequences. Several neurodegenerative diseases, such as Huntington disease (HD), Parkinson, Alzheimer, among others, have this molecular pathological mark in common. HD belongs to a group of pathologies produced by proteins that contain expansions of polyQs (several spinocerebellar ataxias 1, 2, 3, 6, 7 and 17, bulbar and spinal muscular atrophy and the dentatorubral-pallidoluysian atrophy), which make these peptides prone to aggregation, and cause the problems described above. Although these diseases are genetic, and their molecular cause is known, it is believed that the presence of allelic variants in other genes can exacerbate or slow the polyQ aggregation. Therefore, the identification of these genes will allow delving into the modulating mechanisms of the polyQ aggregation dynamics and find therapeutic targets against the polyQ toxicity. In addition, RNA that contains CAG triplets is pathogenic. In this work we have developed models using C. elegans that show indirect signs of pathogenic transcript expression since altered functionality was observed in target tissues. We use a model, which disturbs the function of the worm's GABAergic neurons, to screen for 85 pharmacological compounds, which led us to identify four compounds that reduced motor defects in these animals. In addition to polyQs and CAG transcripts, also are produced peptides derived from a non-canonical translation, known as RAN translation. In this regard, we have delved into the identification and modelling of these peptides in C. elegans through the expression of CAG expansions fused to fluorescent proteins to investigate them in vivo. Furthermore, we have used models previously generated to characterize potential therapeutic targets, such as AMPK. This enzyme can be activated using different compounds. However, some activators, such as metformin or salicylate, are pleiotropic substances. Therefore, in the second chapter of this thesis, we have characterised the synergistic activation of AMPK, using metformin and salicylate, to reduce the stress induced by polyQ aggregates and prevent possible unwanted targets from being activated. Finally, we have shown that this synergistic treatment could be used to reduce α-synuclein toxicity, which is involved in Parkinson disease. On the other hand, we have characterised a new allele that enhances polyQ aggregation, vlt10, in the unc-1 gene. Our results suggest that the unc-1(vlt10) mutation disturbs the electrical synapse between sensory neurons IL2 and ASJ, inducing an excess of hormonal signalling that requires the function of the sulfotransferase SSU-1. We have also shown that the target of this signal is the nuclear receptor NHR-1. In the same chapter, we have identified another hormonal signalling pathway, mediated by another nuclear receptor (DAF-12), which has a protective role. It is unknown which hormone modulates the activity of NHR-1. However, we have identified several genes that regulate lipid metabolism and whose expression could be modulated by NHR-1. In addition, we have observed that the disruption of unc-1 induces the accumulation of lipids in worms, but at the same time these animals contain less total fatty acids. Thus, our results suggest that the metabolism of fats play a key role in modulating polyQs aggregation, highlighting potential therapeutic targets against diseases caused by aggregation-prone proteins. / Gómez Escribano, AP. (2021). Modelos de toxicidad inducidos por microsatélites CAG y caracterización de dianas terapéuticas en C. elegans [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/166783 / TESIS