Coming dissertations at Uppsala university
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”Det är liksom en stor grej som händer just nu i våra liv” : Psykisk hälsa och stigma bland ungdomar
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-535659
Adolescents’ mental health is a current public health issue. However, research, on adolescents’ views on different aspects of mental health, and the prevalence of mental well-being, mental illness and related stigma, among adolescents is limited in Sweden. The overall aim of this thesis was to explore perceptions and status of mental health and stigma related to mental health problems among adolescents in a Swedish context.
Study I and II were based on qualitative interviews with 32 adolescents on the Swedish island Gotland. Study I indicated that the adolescents had a complex understanding of various mental health concepts but labelled mental well-being as ‘feeling good’ and mental illness as ‘feeling bad’. In Study II, the adolescents described mental health problems as common due to current living conditions, e.g. stress related to school performance and social media and an increased openness about mental health problems. Stigmatisation of people with mental health problems was perceived as problematic, caused by lack of experience and knowledge, but also as related to rumour spreading and stereotypical gender norms.
Study III and IV were based on the Life and Health Youth survey, conducted in secondary schools located on Gotland. In study III, the results according to the dual-factor model of mental health showed that most adolescents had vulnerable mental health status (47.5%), while 36.2% had complete mental health. A smaller proportion had troubled (13,9%) or symptomatic but content (2,5%) mental health status. Associations were observed between mental health status and gender, grades, truancy, stress level, resilience, and subjective social status in school.
In study IV, the factor structure and internal consistency was acceptable for the modified Attitudes About Mental Illness and its Treatment scale, but the adolescents perceived it as difficult to answer. Further, negative attitudes towards people with mental health problems were present, and more common among boys and foreign-born adolescents.
The findings of this thesis suggests the two-factor model of mental health and the three-part description of stigma, including stereotypes, prejudice and discrimination, to be applicable among adolescents. Further, the findings suggest a need for promotion of mental well-being and prevention of mental health problems such as interventions to reduce school-related stress, increase resilience and promote societal knowledge about mental health, stigma and gender stereotypes among adolescents. The findings also motivate support to adolescents with low mental wellbeing and minor mental health problems as well as to adolescents who have friends with mental health problems.
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Targeting pathological alpha-synuclein : Protein engineering towards improved antibody-based therapeutics and their delivery to the brain
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-536149
The aggregation of alpha-synuclein (αSyn) into oligomers and fibrils is central to the disease progression of Parkinson’s disease and related pathologies, where αSyn aggregates spread between neurons and cause neurodegeneration. To this date, there is no treatment available that could interfere with the aggregation of αSyn to potentially stop the disease progression. Among the major limitations in the development of therapeutics against αSyn aggregation are the low extracellular concentration of αSyn, the low selectivity of therapeutics for the pathologically relevant αSyn species, and the lacking detailed knowledge about the actual pathological αSyn species.
In this thesis, different engineered antibodies and αSyn mutants were investigated with the aim to identify better strategies of antibody-based treatment of αSyn aggregation.
In Paper I, we engineered multivalent antibodies based on the αSyn aggregate-specific antibody SynO2 to enhance the antibody’s binding strength to a wide range of soluble αSyn aggregates. We could show that the higher valency increased the binding strength to αSyn aggregates up to 20-fold.
In Paper II, we aimed to improve the design of the antibody RmAb158-scFv8D3 to enhance its TfR-mediated brain uptake. By drastically reducing the linker length between the therapeutic antibody and its TfR-targeting scFv8D3, we showed a two-fold enhanced transcytosis across an in vitro BBB model.
In Paper III, we fused a negatively charged peptide to the αSyn aggregate-specific antibodies SynO2 and 9E4 to test whether those fusion antibodies had the potential to bind with higher avidity to αSyn aggregates. Our results showed lower binding strengths compared with the parental antibodies.
In Paper IV, we designed αSyn mutants with a stabilized beta-hairpin conformation to produce stable, small αSyn oligomers closely resembling native, pathological αSyn oligomers. We showed that two of the mutants formed exclusively pentameric and hexameric oligomers under conditions that promoted fibrillation of wild-type αSyn.
In conclusion, this thesis shows that increasing the valency of an antibody is a possible strategy to enhance its binding strength to αSyn aggregates. However, to effectively target pathologically relevant αSyn species, a more selective targeting approach may be required, possibly through a conformational epitope exclusive to αSyn oligomers.
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Development of Injectable ECM-Polymer Hydrogels : Enhancing Corneal and Cardiac Repair with Encapsulated Extracellular Vesicles
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-536323
The field of medicine has traditionally relied solely on small molecular drugs and conventional surgical procedures. However, recent advancements have shifted the focus toward innovative approaches, such as tissue engineering and regenerative medicine, which aim to overcome the limitations of traditional treatments through personalized and precision medicine. This thesis investigates tissue repair strategies using minimally invasive methods, specifically through the application of injectable biomaterials with or without cell-derived therapeutic factors. To this end, a series of novel injectable hydrogels were developed, alongside protocols for the reliable isolation of extracellular vesicles. These components were then integrated to create injectable therapeutic hydrogels. In Paper I, an injectable collagen-based hydrogel was developed. The injectable hydrogel maintained its shape in aqueous buffers, was biodegradable by the body's own enzymes, and supported the encapsulation and attachment of model cells. In Paper II, the collagen hydrogel from Paper I was further developed for use as a corneal sealant in corneal perforations. The hydrogel retained its beneficial properties of being shape-holding, biodegradable, and supporting cell attachment. Additionally, it exhibited increased transparency and tunable mechanical properties through minor adjustments in stoichiometry. It also successfully withstood burst pressures exceeding normal intraocular pressure levels and demonstrated adhesive properties comparable to fibrin glue, while supporting corneal epithelialization. Altogether, showing promise as an injectable corneal sealant. In Paper III, extracellular vesicles from corneal epithelial cells were isolated, purified and characterized based on their size, morphology, surface protein pattern and protein content. Corneal epithelial extracellular vesicles are thought to promote wound healing which could be confirmed with a functional in vitro scratch assay. These therapeutic EVs were then encapsulated within the collagen hydrogel developed in Paper II. Release studies indicated that while a fraction of the EVs was released by simple diffusion, the majority were released on-demand through enzymatic degradation of the hydrogel. This presents a novel treatment strategy for corneal perforations by combining the tissue adhesive with therapeutic factors. In Paper IV, extracellular vesicles derived from induced pluripotent stem cells (iPSCs) were isolated and shown to promote cardiac function after injury. These EVs were encapsulated in viscous ECM-polymer solutions and injected into the left ventricle of mouse hearts, demonstrating that the viscous polymer solutions enhanced the retention of EVs in cardiac tissue over an extended period.
In summary, this thesis investigates the potential of injectable hydrogels, both alone and in combination with extracellular vesicles, as treatments for corneal and cardiac injuries.