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Coming theses from other universities

  • Novel approaches using electrocardiographic imaging for early detection of ARVC in patients and relatives and symptoms preceding sudden death Author: Varvara Kommata Link: Publication date: 2022-05-23 14:26

    Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited disease of the myocardium, predominantly affecting the right ventricle (RV). Arrhythmias are common among patients with the disease and Sudden Cardiac Death (SCD) can occur even in early stages. 

    The overall purpose of this thesis was to investigate the effectiveness of new diagnostic methods in detecting early abnormalities in genetically predisposed individuals and to emphasize the importance of early diagnosis. 

    The analysis of body surface mapping (BSM) signals recorded using a 252-lead vest revealed abnormal repolarisation patterns in all ARVC patients, but also in 25% of family members who were carriers of the family pathogenic variant (M-carriers). The abnormal repolarization patterns preceded repolarization abnormalities on 12-leads electrocardiogram (ECG). Depolarization abnormalities were also detected by the analysis of body surface signals. The QRS dispersion calculated by the body surface signals was significantly higher among ARVC patients compared with controls. 20% of M-carriers presented also with a slightly elevated QRS dispersion. ECG based QRS dispersion could not adequately differentiate ARVC patients from controls. Thus, the higher resolution of the BSM system permitted the detection of repolarization and depolarization abnormalities even in early stages of the disease.

    The analysis of reconstructed epicardial signals using Electrocardiographic Imaging (ECGI) revealed terminal ventricular epicardial activation (the last 20msecs) located only in parts of RV, as opposed to controls, where the right ventricular outflow tract (RVOT) and cardiac base (both right and left ventricle) were activated last. The total ventricular activation time and the RV activation time were both longer in ARVC patients, whereas the area activated during the last 20 msecs was smaller. Similar pattern with delayed conduction in limited areas of the RV were also observed in 50% of the M-carriers. This subgroup presented also smaller area of terminal ventricular activation and longer RV activation time, but the total ventricular activation was normal. 

    Through nationwide registries, the first SCD cohort due to ARVC in Sweden was described. Cardiac related symptoms were common (68%) prior to death and 36% of cases had sought medical care the last six months prior to death. A family history of SCD was present in 45% of the cases.  The careful clinical evaluation of young individuals seeking with cardiac related symptoms and the evaluation of both medical and family history is crucial.

    In conclusion, new technologies, using multiple electrodes for the recording of body surface signals and the reconstruction of the epicardial signals have shown promising results in detecting early repolarization and depolarization abnormalities and could facilitate the early diagnosis in M-carriers.

  • The neurotoxin β-N-methylamino-L-alanine (BMAA) and 2,4-diaminobutyric acid (DAB) : possible risk of human exposure, and the effect and function in diatoms Author: Sea-Yong Kim Link: Publication date: 2022-05-20 09:00

    The toxic secondary metabolites β-N-methylamino-L-alanine (BMAA) and 2,4-diaminobutyric acid (DAB) produced by phytoplankton groups such as cyanobacteria, diatoms and dinoflagellates are known to cause neurotoxicity in vertebrates. BMAA has been linked to development of the neurodegenerative diseases amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC) and Alzheimer's disease. Despite these risks, previous studies have focused mostly on food webs in aquatic ecosystems as a possible source of human exposure to BMAA and DAB. Moreover, most studies in regard to the producer of BMAA and DAB are biased towards cyanobacteria.

    The first aim of this thesis was to investigate the possible risk of human exposure to BMAA via the agro-aqua cycle that artificially interconnects agriculture and aquaculture. Two groups of commercial chickens, fed on either standard feed or standard feed mixed with blue mussel meat, were investigated. The results show that BMAA can be transferred to and accumulated in the chickens through the mixed fodder. It has been suggested that the consumption of chicken may cause a risk of human exposure to BMAA if the chickens are fed with the fodder mixed with mussel meat (Paper I).

    The second aim was to assess the effect of biotic stresses (i.e. predation, competition) as possible causative factors to regulate the production of BMAA and/or DAB in diatoms, and assess the toxic effect of BMAA and/or DAB on predator and competitor (if specific production patterns occur for either toxin). The production of DAB was specially regulated only in the diatom T. pseudonana as responses to the predation and the competition. The toxic effect of DAB was significant on the population growth of the copepod Tigriopus sp. as predator, and the growth of cell numbers in T. pseudonana as competitor. However, given the environmental relevance of the DAB effect, the results suggest that DAB may play an important role in the defense mechanisms of the diatom T. pseudonana (Paper II and III).

    The last aim was to study the effect and function of BMAA in the diatom Phaeodactylum tricornutum. P. tricornutum was exposed to different concentrations of BMAA. The results showed concentration dependent responses to BMAA. The following were observed when the growth (i.e. cell number) of P. tricornutum was arrested due to exogenous BMAA; oxidative stress, reduced carbon fixation, increase in intracellular Chl a, alterations in GS-GOGAT, and suppressed urea cycle. The results suggest that BMAA represents a toxic secondary metabolite capable of controlling the growth of P. tricornutum via oxidative stress and alterations in the activity of photosynthesis and nitrogen metabolism (Paper IV).

  • Imaging the molecular pathways of neurodegeneration : New pathologies of SCA7 Author: Frida Niss Link: Publication date: 2022-05-20 09:00

    Spinocerebellar Ataxia type 7 (SCA7) is a genetic neurodegenerative disease with lethal outcome that affects the cerebellum and retina of patients. This thesis focuses on characterising molecular pathological pathways that cause toxicity and cell death in SCA7. Using primarily an inducible cell model and patient fibroblasts I found that the three RNA binding proteins FUS, TDP-43 and TIA1 are co-sequestered into aggregates formed by the SCA7 causing protein, ATXN7. Consequently I investigated the cellular functions in which these proteins have important roles. I found that FUS’ ability to regulate mRNAs is altered due to mislocalisation, DNA damage is increased, and that stress granules (SGs) are induced in a SCA7 cell model and in patient fibroblasts. Surprisingly, I also found that ATXN7 was present within SGs, and that SGs exhibited an altered shape upon induction of mutant ATXN7. I also participated in developing a microscopy-based method for monitoring chromatin organisation in live cells called FRIC. FRIC is able to detect even subtle changes to peripheral chromatin organisation, and since ATXN7 is a subunit of the transcription regulational complex SAGA, we used FRIC to investigate the effect of mutant ATXN7 on peripheral chromatin organisation. While we found no evidence that mutant ATXN7 affected peripheral chromatin organisation, the inner nuclear membrane protein Samp1 was found to be important for normal chromatin organisation in the nuclear periphery. Finally, I characterised the effect of mutant ATXN7 expression on the nuclear lamina, nuclear pore complexes, and nucleocytoplasmic transport. I found that although key transport factors such as Ran and Importin ß intermittently co-localised with ATXN7 aggregates, there were no apparent defects in nucleocytoplasmic protein import or nuclear envelope integrity. 

    In summation, my investigations resulted in new findings that may be built upon to find key targets for treating SCA7 patients.