| 1. |
- Blom Västberg, Oskar, 1987-
(författare)
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Five papers on large scale dynamic discrete choice models of transportation
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Travel demand models have long been used as tools by decision makers and researchers to analyse the effects of policies and infrastructure investments. The purpose of this thesis is to develop a travel demand model which is: sensitive to policies affecting timing of trips and time-space constraints; is consistent with microeconomics; and consistently treats the joint choice of the number of trips to perform during day as well as departure time, destination and mode for all trips. This is achieved using a dynamic discrete choice model (DDCM) of travel demand. The model further allows for a joint treatment of within-day travelling and between-day activity scheduling assuming that individuals are influenced by the past and considers the future when deciding what to do on a certain day.Paper I develops and provides estimation techniques for the daily component of the proposed travel demand model and present simulation results provides within sample validation of the model. Paper II extends the model to allow for correlation in preferences over the course of a day using a mixed-logit specification. Paper III introduces a day-to-day connection by using an infinite horizon DDCM. To allow for estimation of the combined model, Paper III develops conditions under which sequential estimation can be used to estimate very large scale DDCM models in situations where: the discrete state variable is partly latent but transitions are observed; the model repeatedly returns to a small set of states; and between these states there is no discounting, random error terms are i.i.d Gumble and transitions in the discrete state variable is deterministic given a decision.Paper IV develops a dynamic discrete continuous choice model for a household deciding on the number of cars to own, their fuel type and the yearly mileage for each car. It thus contributes to bridging the gap between discrete continuous choice models and DDCMs of car ownership.Infinite horizon DDCMs are commonly found in the literature and are used in, e.g., Paper III and IV in this thesis. It has been well established that the discount factor must be strictly less than one for such models to be well defined.Paper V show that it is possible to extend the framework to discount factors greater than one, allowing DDCM's to describe agents that: maximize the average utility per stage (when there is no discounting); value the future greater than the present and thus prefers improving sequences of outcomes implying that they take high costs early and reach a potential terminal state sooner than optimal.
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| 2. |
- Hedner, Erik, 1975-
(författare)
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Bioactive Compounds in the Chemical Defence of Marine Sponges : Structure-Activity Relationships and Pharmacological Targets
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Marine invertebrates, in particular sponges, represent a source of a wide range of secondary metabolites, many of which have been attributed various defensive capabilities against environmental stress factors. In this thesis sponge-derived low-molecular peptide-like compounds and associated analogs are investigated for bioactivity and pharmacological targets. The compound bromobenzisoxazolone barettin (cyclo[(6-bromo-8-(6-bromo-benzioxazol -3(1H)-one)-8-hydroxy)tryptophan)]arginine) was isolated from the sponge Geodia barretti and its ability to inhibit larval settlement of the barnacle Balanus improvisus was determined. With an EC50 value of 15 nM, this compound’s antifouling effect was higher than those of the previously reported brominated dipeptides from Geodia barretti, i.e., barettin and 8,9-dihydrobarettin; moreover, this antifouling effect was demonstrated to be reversible. However, the compound lacked affinity for 5-HT1-7 receptors, whereas barettin possessed specific affinity to 5-HT2A, 5-HT2C and 5-HT4, while 8,9-dihydrobarettin interacted with 5-HT4. In an attempt to evaluate structure-activity relationships synthesized analogs with barettin and dipodazine scaffolds were investigated for antifouling activity. The analog benso[g]dipodazine, with an EC50 value of 34 nM, displayed the highest settlement inhibition. The studies of the structure-activity relationships of sponge-derived compounds were extended to cover analogs of agelasines and agelasimines originally isolated from sponges of the genus Agelas. Synthesized (+)-agelasine D and two structurally close analogs were investigated for cytotoxic and antibacterial activity. The profound cytotoxicity and broad spectrum antibacterial activity found prompted a further investigation of structure-activity relationships in 42 agelasine and agelasimine analogs and several characteristics that increased bioactivity were identified. In conclusion this work has produced new results regarding the potent bioactivity of compounds derived from the sponges Geodia barretti and Agelas spp. and increased SAR knowledge of the fouling inhibition, cytotoxicity and antimicrobial activity of these compounds.
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| 3. |
- Helmfors, Linda, 1983-
(författare)
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Understanding the dual nature of lysozyme: part villain – part hero : A Drosophila melanogaster model of lysozyme amyloidosis
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amyloid proteins are a distinct class of proteins that can misfold into β-sheet rich structures that later mature to form the characteristic species known as amyloid fibrils, and accumulate in tissues in the human body. The misfolding event is often caused by mutations (or outer factors such as changes in pH) that destabilize the native protein structure. The mature amyloid fibrils were initially believed to be associated with diseases connected to protein misfolding such as Alzheimer’s disease (AD), Parkinson’s disease, transthyretin amyloidosis and lysozyme amyloidosis. However, now it is known that many different factors are involved in these diseases such as failure in protein clearance, lysosomal dysfunction and formation of intermediate misfolded protein species, which possess cytotoxic properties, preceding the formation of mature fibrils.In this thesis the amyloidogenic protein lysozyme has been examined in vivo by using Drosophila melanogaster (fruit fly) as a model organism. The effects of over-expressing human lysozyme and amyloidogenic variants in Drosophila have been investigated both in the absence and presence of the serum amyloid P component (SAP), a protein known to interact with amyloid species. In addition, the role of lysozyme in AD has been investigated by co-expressing human lysozyme and amyloid β in Drosophila.The lysozyme protein is an enzyme naturally found in bodily fluids such as tears, breast milk and saliva. It is engaged in the body’s defense and acts by hydrolyzing the cell wall of invading bacteria. Certain disease-associated point mutations in the gene encoding lysozyme destabilize the protein and cause it to misfold which results in systemic amyloidosis. To investigate the in vivo misfolding behavior of lysozyme we developed and established a Drosophila model of lysozyme amyloidosis. SAP is commonly found attached to amyloid deposits in the body; however, the role of SAP in amyloid diseases is unknown. To investigate the effect of SAP in lysozyme misfolding, these two proteins were co-expressed in Drosophila.The amyloid β peptide is involved in AD, building up the plaques found in AD patient brains. These plaques trigger neuroinflammation and since lysozyme is upregulated during various inflammation conditions, a possible role of lysozyme in AD was investigated by overexpressing lysozyme in a Drosophila model of AD. Interaction between lysozyme and the amyloid β protein was also studied by biophysical measurements.During my work with this thesis, the dual nature of lysozyme emerged; on the one hand a villain, twisted by mutations, causing the lysozyme amyloidosis disease. On the other hand a hero, delaying the toxicity and maybe the neurological damage caused by the amyloid β peptide.
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| 4. |
- Jonsson, P. Andreas, 1973-
(författare)
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Superoxide dismutase 1 and amyotrophic lateral sclerosis
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons in the spinal cord, brain stem and motor cortex, leading to paralysis, respiratory failure and death. In about 5% of ALS cases, the disease is associated with mutations in the CuZn-superoxide dismutase (hSOD1) gene. As a rule, ALS caused by hSOD1 mutations is inherited dominantly and the mutant hSOD1s cause ALS by the gain of a noxious property. The present study focused on two hSOD1 mutations with widely differing characters. In Scandinavia, ALS caused by the D90A mutation is inherited in a recessive pattern. Elsewhere, families with dominant inheritance have been found. The properties of D90A mutant hSOD1 are very similar to those of the wild-type protein. The G127insTGGG (G127X) mutation causes a 21 amino acid C-terminal truncation which probably results in an unstable protein. The aim of this thesis was to generate transgenic mice expressing D90A and G127X mutant hSOD1s and to compare these mice with each other and with mice expressing other mutant hSOD1s, in search of a common noxious property. The findings were also compared with the results from studies of human CNS tissue. The cause of the different inheritance patterns associated with D90A mutant hSOD1 was investigated by analyzing erythrocytes from heterozygous individuals from dominant and recessive pedigrees. There was no evidence that a putative protective factor in recessive pedigrees acts by down-regulating the synthesis of D90A mutant hSOD1. In cerebrospinal fluid, there was no difference in hSOD1 content between homozygous D90A patients, ALS patients without hSOD1 mutations and controls. hSOD1 cleaved at the N-terminal end was found in both controls and D90A patients, but the proportion was significantly larger in the latter group. This indicates a difference in degradation routes between mutant and wild-type hSOD1. Both D90A and G127X transgenic mice develop an ALS-like phenotype. Similar to humans, the levels of D90A protein were high. The levels of G127X hSOD1 were very low in the tissues but enriched in the CNS. Similarly, in an ALS patient heterozygous for G127X hSOD1, the levels of the mutant protein were overall very low, but highest in affected CNS areas. Despite the very different levels of mutant hSOD1, both D90A and G127X transgenic mice developed similar levels of detergent-resistant aggregates in the spinal cord when terminally ill. Surprisingly, mice overexpressing wild-type hSOD1 also developed detergent-resistant aggregates, although less and later. Most of the hSOD1 in the CNS of transgenic mice was inactive due to deficient copper charging or because of reduced affinity for the metal. The stabilizing intrasubunit disulfide bond of hSOD1 was partially or completely absent in the different hSOD1s. Both these alterations could increase the propensity of mutant hSOD1s to misfold and form aggregates. The results presented here suggest that the motor neuron degeneration caused by mutant hSOD1s may be attributable to long-term exposure to misfolded, aggregation-prone, disulfide-reduced hSOD1s and that the capacity to degrade such hSOD1s is lower in susceptible CNS areas compared with other tissues. The data also suggest that wild-type hSOD1 has the potential to participate in the pathogenesis of sporadic ALS.
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| 5. |
- Jonsson, R. Daniel, 1972-
(författare)
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Analysing Sustainable Urban Transport and Land-Use : Modelling tools and appraisal frameworks
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sustainable development and climate change is high on the agenda for most cities around the world today. Urban transport is at the heart of these changes. Increasingly, it is recognised that not only is the emission of pollutants and greenhouse gases a problem, but also the detrimental effects of congestion and social exclusion. In order to address these issues, it will be necessary for cities to make strategic long term decisions regarding the future infrastructure and land use, not only in terms of what will be built, but also on measures that affect how these systems are used.This thesis is focused on the decision support tools that we need in order to make well informed decisions. Models that predict the performance of future scenarios, and appraisal frameworks that help evaluate whether these outcomes are desirable or not. The first two papers experiment with different ways of bringing some aspects of sustainability into the appraisal frameworks used to analyse long term strategies. Paper I addresses intergenerational fairness, and Paper II focuses on the emission of greenhouse gases. Paper III develops a model, Scapes, that can help us to better understand the daily travel behaviour, through an activity based approach. By explicitly modelling space-time constraints, and travel time uncertainty in a microeconomic framework, we can get a better understanding of how people can respond to, and value, changes in the transport system. Papers IV and V describe a new integrated land use and transport model, LandScapes.The policy implications from the studies in Papers I, II, and V are that it will be very difficult for Stockholm to reduce its emissions of CO2. Particularly, predicted economic and population growth will inevitably lead to more transport. It is likely that a range of different policies will be necessary to solve that problem. At the same time, we must not forget that decreasing CO2 emissions, although important, is not the only objective Stockholm has. To cope with the increasing travel demand from a growing population, it may well be necessary to build new infrastructure as well. This thesis does not prescribe any such relative valuation between conflicting objectives. It only helps bring them to the fore.
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| 6. |
- Lorenzo Varela, Juan Manuel, 1987-
(författare)
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Learning about the unobservable : The role of attitudes, measurement errors, norms and perceptions in user behaviour.
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Unobservable factors are important to understand user behaviour. Moreover, they contain information to help design services that willsolve today’s challenges. Yet, we have barely scratched the surface ofthe underlying mechanisms ruling user behaviour. For decades, userbehaviour analysis has focused on the capabilities of observable variables,as well as assumptions of regular preferences and rational behaviourto explain user choices; and amalgamated unobservable factorsinto ”black-box” variables. As a response, the field of behaviouraleconomics has produced an array of so-called choice anomalies, wherepeople seem not to be fully rational. Furthermore, as a consequence of the ”digital revolution”, nowwe harvest data on an unprecedented scale -both in quantity andresolution- that is nurturing the golden age of analytics. This explosionof analytics contributes to reveal fascinating patterns of humanbehaviour and shows that when users face difficult choices, predictionsbased only on observable variables result in wider gaps between observedand predicted behaviour, than predictions including observableand unobservable factors. Impacts of the ”digital revolution” are not limited to data and analyticsbut they have filtered through the whole tissue of society. Forinstance, telecommunications allow users to telework, and telework allowsusers to change their travel patterns, which in turn contributes toincrease the overall system complexity. In addition to the new worlddynamics facilitated by Information and Communications Technology,megatrends such as hyper-urbanization or increase demand of personalisedtransport services are imposing pressures on transport networksat a furious pace, which also contributes to increase the complexity ofthe choices needed in order to navigate the networks efficiently. In an effort to alleviate these pressures, new mobility services suchas electric and autonomous vehicles; bicycle and car sharing schemes;mobility as a service; vacuum rail systems or even flying cars are evolving. Each of these services entails a different set of observable variableslike travel time and cost, but also a completely different set of unobservableones such as expectations, normative beliefs or perceptionsthat will impact user behaviour. Hence, a good understanding of theimpact of underlying, unobservable, factors -especially when servicesare radically different from what users know and have experienced inthe past- will help us to predict user behaviour in uncharted scenarios. Unobservable factors are elusive by nature, hence to incorporatethem into our models is an arduous task. Furthermore, there is evidence showing that the importance of these factors might differ across time and space, as user preferences, perceptions, normative beliefs, etc.are influenced by local conditions and cultures. As a consequence, we have witnessed a surge of interest in behavioural economics over the past two decades, due to its ability to increase the explanatory and predictive power of models based on economic theory by adding a more psychologically plausible foundation. This thesis contributes to the existing body of literature in TransportScience in the areas of user perceptions, measurement errors, and the influence of attitudes and social norms in the adoption of new mobility solutions. The work builds on the behavioural economics theoretical framework, underpinned by economic theory, discrete choice analysis -rational behaviour and random utility maximization-, as well as social and cognitive psychology. Methodological contributions include a framework to systematically test differences in user preferences for a set of public transport modes, relating to observed and unobserved attributes; and a framework to assess the magnitude of unobservable measurement errors in the input variables of large-scale travel demand models. On an empirical dimension, findings support the existence of a ”rail factor”, the impact of modelling assumptions on parameter estimates of hybrid choice models, the presence of larger measurement errors in the cost variables than in the time variables, -which in turn translates into diluted parameters that under-estimate the response to pricing interventions-, and that the model with the best fit does not guarantee better parameter estimates. Therefore, I expect this thesis to be of interest not only to modellers, but also to decision makers; and that its findings will contribute to the design of the mobility solutions that users need and desire, but also that will benefit society as a whole.
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| 7. |
- Öhmark, Sara, 1980-
(författare)
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Winter browsing by moose and hares in subarctic birch forest : Scale dependency and responses to food addition
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Despite their difference in body size and morphology, the moose (Alces alces) andthe mountain hare (Lepus timidus) sustain themselves during winter on similar plantspecies and plant parts in in subarctic environments, namely apical twigs ofmountain birch (Betula pubescens ssp. czerepanovii). Herbivores must select areas anditems of food that provide sufficient intake rates and food nutritional quality whilebalancing this against their intake of dietary fiber and potentially detrimental plantsecondary metabolites. This selection takes place simultaneously at multiple spatialscales, from individual plants and plant parts to patches of food and parts of the wider landscape. While the herbivores must consider their need for food to sustaindaily activities, for body growth and reproduction it is also necessary to avoid predators and harsh environmental conditions. For managers, an understanding of key factors for animal foraging distributions is pivotal to reach intended goals ofmanagement and conservation plans. Knowledge in this area is also important formodels to make accurate predictions of foraging responses of herbivores to resource distributions. The mountain birch forest displays a naturally heterogeneous distribution of trees and shrubs which presents herbivores with a challenge to findgood feeding areas. In an investigation of the spatial distribution of moose browsing on birch and willows (Salix spp.) in two winter seasons separated in time by 14 years,it was found that moose browsing patterns in 1996 were correlated to those observed in 2010. It was also found that moose browsing was spatially clustered within the same distances (1000-2500 m) as densities of willow and birch, but at other spatial scales, browsing was mostly randomly distributed. It was concluded that foragedensity is a cue for moose but only at certain spatial scales. Similarly, a comparison of foraging distribution by hare and moose showed that high birch density was a key factor for both species. In spite of this, hares and moose used different parts ofthe same environment because they respond to food resource distribution at different spatial scales. Hares fed from smaller plants, and focused their foraging activity on smaller spatial scales than moose. These results emphasize the importance of taking into account the distribution of food resources at spatial scales relevant for each species in plans for conservation and management. In an experimental study it was found that intensified browsing on natural forage by mountain hares can be induced locally through placement of food. The induced browsing varied with the amount and quality of the added food, but also with thedensity of natural food plants and natural foraging distribution by hares. Finally, ina last experiment habitat preference of mountain hares across edges between open and forested areas was studied. The results were not consistent; hares utilized baitto a greater extent within forested areas than bait placed on a nearby lake ice, butbait on mires and heaths was either preferred over bait in nearby forest, or utilizedto a similar extent. A possible explanation is that hares have knowledge of their environment such that both forested areas and subarctic mires and heaths are partof its natural home range, whilst the extreme environment on the lake ice is not. During recent decades arctic areas have had an increase in vegetation density andwill be affected by future climate warming and therefore, factors that determineforaging ecology of key herbivores need to be identified. This thesis sheds some light on these factors in relation to spatial scale and forage distribution for two high profile herbivores in the subarctic.
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