| 1. |
- Ihse, Elisabet, 1977-
(författare)
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Two Types of Fibrils in ATTR Amyloidosis : Implications for Clinical Phenotype and Treatment Outcome
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic amyloidoses are a group of lethal diseases where proteins aggregate into fibrillar structures, called amyloid fibrils, that deposits throughout the body. Transthyretin (TTR) causes one type of amyloidosis, in which the aggregates mainly infiltrate nervous and cardiac tissue. Almost a hundred different mutations in the TTR gene are known to trigger the disease, but wild-type (wt) TTR is also incorporated into the fibrils, and may alone form amyloid. Patients with the TTRV30M mutation show, for unknown reasons, two clinical phenotypes. Some have an early onset of disease without cardiomyopathy while others have a late onset and cardiomyopathy. It has previously been described that amyloid fibrils formed from TTRV30M can have two different compositions; either with truncated molecules beside full-length TTR (type A) or only-full-length molecules (type B). In this thesis, the clinical importance of the two types of amyloid fibrils was investigated. We found that the fibril composition types are correlated to the two clinical phenotypes seen among TTRV30M patients, with type A fibrils present in late onset patients and type B fibrils in early onset patients. The only treatment for hereditary TTR amyloidosis has been liver transplantation, whereby the liver producing the mutant TTR is replaced by an organ only producing wt protein. However, in some patients, cardiac symptoms progress post-transplantationally. We demonstrated that the propensity to incorporate wtTTR differs between fibril types and tissue types in TTRV30M patients, with cardiac amyloid of type A having the highest tendency. This offers an explanation to why particularly cardiac amyloidosis develops after transplantation, and suggests which patients that are at risk for such development. By examining patients with other mutations than TTRV30M, we showed that, in contrast to the general belief, a fibril composition with truncated TTR is very common and might even be the general rule. This may explain why TTRV30M patients often have a better outcome after liver transplantation than patients with other mutations. In conclusion, this thesis has contributed with one piece to the puzzle of understanding the differences in clinical phenotype and treatment response between TTR amyloidosis patients, by demonstrating corresponding differences at a molecular level.
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| 2. |
- Mohseni, Farzad, 1981-
(författare)
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Power to gas : Bridging renewable electricity to the transport sector
- 2012
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Globally, transport accounts for a significant part of the total energy utilization and is heavily dominated by fossil fuels. The main challenge is how the greenhouse gas emissions in road transport can be addressed. Moreover, the use of fossil fuels in road transport makes most countries or regions dependent on those with oil and/or gas assets. With that said, the question arises of what can be done to reduce the levels of greenhouse gas emissions and furthermore reduce dependency on oil? One angle is to study what source of energy is used.Biomass is considered to be an important energy contributor in future transport and has been a reliable energy source for a long time. However, it is commonly known that biomass alone cannot sustain the energy needs in the transport sector by far.This work presents an alternative where renewable electricity could play a significant role in road transport within a relatively short time period. Today the amount of electricity used in road transport is negligible but has a potential to contribute substantially. It is suggested that the electricity should be stored, or “packaged” in a chemical manner, as a way of conserving the electrical energy. One way of doing so is to chemically synthesize fuels. It has been investigated how a fossil free transport system could be designed, to reach high levels of self-sufficiency. According to the studies, renewable electricity could have the single most important role in such a system. Among the synthetic fuels, synthetic methane (also called synthetic biogas) is the main focus of the thesis. Hydrogen is obtained through water electrolysis, driven by electricity (preferable renewable), and reacted with carbon dioxide to produce synthetic methane. The concept of the mentioned process goes under the name Power to Gas. The electricity to fuel efficiency of such a process reaches about 50 %, but if utilizing excess heat produced during the electrolysis and the reaction, the total process efficiency can reach much higher levels.The economics of the process is as important as the technology itself in terms of large scale implementation. The price of electricity and biogas are the most important influences on the economic viability. The minimum “spread” between purchase and selling price can be determined to obtain a general perception of the economic feasibility. In this case biogas must be sold about 2.6 times higher than purchased electricity per kWh.
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| 3. |
- Bergström, Joakim, 1972-
(författare)
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Apolipoprotein A-IV and Transthyretin in Swedish Forms of Systemic Amyloidosis
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Over 20 different plasma proteins have been shown to have the capacity to undergo conformational changes and self-assemble into highly stable and insoluble amyloid fibrils. One, transthyretin (TTR), consists of 127 amino acid residues arranged in eight β-strands (named A to H) and is involved in two different clinical forms of amyloidosis. In familial amyloidotic polyneuropathy (FAP), mutated TTR is found in the amyloid deposits while in senile systemic amyloidosis (SSA) only wild type TTR is present in the amyloid deposits.In this study, we have identified a novel form of amyloidosis that is caused by the deposition of an N-terminal fragment of apolipoprotein A-IV (apoA-IV). Interestingly, apoA-IV amyloid was found deposited in a patient that also suffered from SSA. Thus, this patient had two biochemically distinct and concurrent forms of amyloidosis that were derived from apoA-IV and TTR. We have also discovered that two different morphological deposition patterns (identified as patterns A and B) exist in TTR-derived amyloidosis. Pattern A, observed in all SSA patients studied and in half of the FAP patients examined contained large homogenous deposits that were composed of short randomly oriented fibrils. In contrast, pattern B was observed in the remaining FAP patients and was represented by smaller-sized deposits that consisted of longer fibrils that were arranged in parallel bundles. The predominant TTR component deposited also differed between the two amyloid patterns. Amyloid pattern A contained mainly C-terminal TTR fragments while pattern B amyloid consisted of full-length TTR. Our findings suggest that two different mechanisms of fibril formation may exist in TTR-derived amyloidosis. We have found two epitopes, corresponding to strand C and H that are surface-exposed in TTR-derived amyloid fibrils but hidden and part of the hydrophobic core in the native molecular structure. This indicates that TTR undergoes partial unfolding during fibril formation.
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| 4. |
- Chen, Yang
(författare)
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Novel cycles using carbon dioxide as working fluid : new ways to utilize energy from low-grade heat sources
- 2006
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This licentiate thesis proposes and analyzes three carbon dioxide novel cycles, namely: the carbon dioxide transcritical power cycle, the carbon dioxide Brayton cycle and the carbon dioxide cooling and power combined cycle. Due to the different characteristics of each cycle, the three cycles are suitable for different applications. The CO2 transcritical power cycle is suitable for harvesting energy from low-grade heat sources, near which a low temperature heat sink is accessible. The CO2 Brayton cycle is suitable for harvesting the energy from relatively high-grade heat sources when there is no low temperature heat sink available. The CO2 cooling and power combined cycle is suitable for applications, where both power and cooling are needed (e.g. automobile applications, in which the cycle can utilize the energy in the engine exhaust gasses to produce power and provide cooling/heating to the mobile compartment room at the same time). Several models have been developed using the software known as Engineering Equation Solver (EES)1 for both cycle analysis and computer aided heat exchanger design. Different cycle working conditions have been simulated and different working parameters’ influence on the cycle performance has been explained. In addition, Refprop 7.02 is used for calculating the working fluid properties and the CFD tool Femlab has been employed to investigate the particular phenomena influencing the heat exchanger performance.
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| 5. |
- Enqvist, Stina
(författare)
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Influence of Genes and Post-translational Modifications in the Pathogenesis of Light Chain Amyloidosis
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amyloid is formed when a normally soluble protein undergoes conformational changes that results in self-aggregation. The pathogenic protein in light chain amyloidosis is an immunoglobulin light chain produced by a plasma cell clone mainly in the bone marrow. The light chain is transported via the circulation to various organs and tissues but deposits only in certain locations. The disease is very heterogenous and every patient can be considered to have their own disease, since symptoms and outcome vary enormously. In this thesis I have tried to elucidate some factors involved in the pathogenesis of light chain amyloidosis. Firstly, we investigated the impact of the germ line origin for tissue affinity and found out that even though it is important other factors like posttranslational modifications are also of relevance. Secondly we describe familial-like light chain amyloidosis in Sweden, affecting a father and son. The inheritance is hard to explain but we believe that genetic factors that might be involved in the rearrangement of light chain genes or that familial immunopathies predispose certain families for development of light chain amyloidosis. Thirdly, we wanted to study if cleavage of the light chain occurs before or after deposition, since purified light chain amyloid contains full-length, and N- and C-terminal fragments of the protein. The cleavage pattern in 1-5 organs from 6 patients was analyzed by Western blot with three antisera directed against one epitope in the N-terminal and two epitopes in the N- and C-terminal part of the protein. By using these antisera we could determine to which part of the light chain molecule the fragment belonged. We found fragments that could be aligned to compose the whole light chain. The finding indicates that cleavage occurs after deposition. Finally, we wanted to investigate if lambda amyloid fibrils contain small C-terminal fragments from the constant domain, earlier been detected in patients with kappa light chain amyloidosis. In concordance, we identified the same fragments in lambda patients and could demonstrate that these fragments made fibrils in vitro. The role of the small C-terminal peptides for the development of light chain amyloidosis must be further investigated.
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| 6. |
- Larsson, Annika, 1975-
(författare)
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Medin amyloid - a matter close to the heart : Studies on medin amyloid formation and involvement in aortic pathology
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amyloidoses are a group of protein misfolding diseases characterized by deposits of insoluble fibrillar protein aggregates. Medin amyloid, which is the focus of this thesis, appears in the media of the thoracic aorta in nearly all individuals over 50 years. The fibrils are derived from a 50 amino acid residue fragment of the precursor protein lactadherin. How medin amyloid arises is unknown, but in paper I we demonstrated, with immunohistochemical and in vitro binding experiments, that both lactadherin and medin interact with elastin, implying that the elastic fibre is central in amyloid formation. In paper II, we further showed that the last 18-19 amino acid residues constitute the amyloid-promoting region. In paper III, the consequence of medin deposition was investigated. Aortic specimens from patients with thoracic aorta aneurysm and dissection were examined for medin content. The tissue findings indicated that the two disease groups contained more medin oligomers than normal aortas. Interestingly, recent reports demonstrate that the toxicity of amyloid proteins is attributed to prefibrillar oligomeric aggregates rather than to mature fibrils. In support of this finding, we observed that prefibrillar medin, in contrast to medin fibrils, was toxic in cell culture. Amyloid formation is a nucleation-dependent process. Addition of preformed fibrils to an amyloid protein solution dramatically accelerates fibrillation, a phenomenon called seeding. In paper IV, serum amyloid A-derived (AA) amyloid was found co-localized with medin deposits in the aorta. In vitro, medin fibrils enhanced the formation of AA fibrils, indicative of a seeding mechanism. The data are of great importance as they suggest that one type of amyloid is capable of inducing fibrillation and deposition of another amyloid type. In conclusion, the results of this thesis shed light on how medin is formed, the function of lactadherin and the consequences of medin deposition for aortic pathology.
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