| 1. |
- Andersson, Patrik, 1981-
(författare)
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Four applications of stochastic processes : Contagious disease, credit risk, gambling and bond portfolios
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis consists of four papers on applications of stochastic processes. In Paper I we study an open population SIS (Susceptible - Infective - Susceptible) stochastic epidemic model from the time of introduction of the disease, through a possible outbreak and to extinction. The analysis uses coupling arguments and diffusion approximations. In Paper II we propose a model describing an economy where companies may default due to contagion. The features of the model are analyzed using diffusion approximations. We show that the model can reproduce oscillations in the default rates similar to what has been observed empirically. In Paper III we consider the problem of finding an optimal betting strategy for a house-banked casino card game that is played for several coups before reshuffling. A limit result for the return process is found and the optimal card counting strategy is derived. This continuous time strategy is shown to be a natural generalization of the discrete time strategy where the so called effects of removals are replaced by the infinitesimal generator of the card process. In Paper IV we study interest rate models where the term structure is given by an affine relation and in particular where the driving stochastic processes are so-called generalised Ornstein-Uhlenbeck processes. We show that the return and variance of a portfolio of bonds which are continuously rolled over, also called rolling horizon bonds, can be expressed using the cumulant generating functions of the background driving Lévy processes associated with the OU processes. We also show that if the short rate, in a risk-neutral setting, is given by a linear combination of generalised OU processes, the implied term structure can be expressed in terms of the cumulant generating functions.
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| 2. |
- Golosovskaia, Elena, 1993-
(författare)
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Development of in silico methods to aid chemical risk assessment : focusing on kinetic interactions in mixtures
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The environment and biota are constantly exposed to numerous chemicals through contaminated food, soil, water, and air. These chemicals can be taken up and distributed to reach sensitive tissues where they may cause various effects. Many of these chemicals lack data on their environmental and human health effects. Traditional toxicological tests relying on animal experiments are today being phased out in favor of cell-based and computational methods for early hazard detection and exposure assessment. This thesis focuses on developing computational tools for various stages of chemical risk assessment with a particular focus on bisphenols and per- and polyfluoroalkyl substances (PFAS). In Paper I, quantitative structure-activity relationship (QSAR) models covering molecular targets of the thyroid hormone (TH) system were developed and applied to two data sets to prioritize chemicals of concern for detailed toxicological studies. In Papers II and III, experimental and computational approaches were combined to study toxicokinetics and maternal transfer in zebrafish. Our main focus was to study potential mixture effects on administration, distribution, metabolism, and elimination (ADME) processes, i.e., to reveal if co-exposed chemicals impact each other’s ADME. Physiologically based kinetic (PBK) mixture models were developed to allow translation of external exposure concentrations into tissue concentrations and modelling plausible mechanisms of chemical interactions in a mixture.Main findings of this thesis are summarized as follows:• Application of QSAR models (Paper I) to two chemical inventories revealed that chemicals found in human blood could induce a large iirange of pathways in the TH system whereas chemicals used in Sweden with predicted high exposure index to consumers showed a lower likelihood to induce TH pathways.• Two zebrafish experiments (Paper II and Paper III) did not reveal statistically significant mixture effects on ADME of chemicals.• In Paper II, a PBK mixture model for PFAS accounting for competitive plasma protein binding was developed. The model demonstrated good predictive performance. Competitive plasma protein binding did not affect the predicted internal concentrations.• In Paper III we developed a binary PBK model parametrized for two bisphenols and PFOS showing that competitive plasma protein binding has an effect on ADME of bisphenols at PFOS concentrations at μg/L levels. At these levels internal concentrations of bisphenols were shown to decrease, implying that PFOS outcompeted bisphenols from studied plasma proteins resulting in higher excretion rates.Developed QSAR models showed good predictive power and the ability to identify and prioritize chemicals of concern with confidence. Additionally, PBK models aid in hypotheses testing and predicting exposure concentrations at which co-exposed chemicals could potentially influence each other’s ADME properties. These tools will provide overall early tier data on exposure and effects using non-testing methods in assessment of risks of chemicals.
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| 3. |
- Andersson, Elias, 1989-
(författare)
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Enabling industrial energy benchmarking : Process-level energy end-use, key performance indicators, and efficiency potential
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One of the greatest challenges of our time is global climate change. A key strategy for mitigating the emission of greenhouse gases is the improvement of energy efficiency. Manufacturing industry stands for a large share of global energy end-use but has yet to achieve its full energy efficiency potential. A barrier to untapping this potential is the lack of detailed data on industrial energy end-use at the process level, preventing the development of sound, bottom-up energy key performance indicators (KPIs). This hampers the ability to create a profound strategy for improving industrial energy efficiency because it is not known in which end-use processes the largest energy efficiency potential is to be found. Increasing knowledge about energy end-use at the process level also increases the possibility for energy comparisons, i.e. benchmarking, at the process level.This thesis aimed to investigate how to further enable industrial energy benchmarking at the process level, primarily for the pulp and paper and wood industries. Relevant benchmarking requires that data on energy end-use is collected using a common, harmonized categorization of processes and that joint energy KPIs are applied. Therefore, suggestions for standardized categorizations of end-use processes were investigated for the studied industries.Based on the calculations, and under the assumptions made in this thesis for estimating the energy efficiency potential of end-use processes, diversity was found between industries around which type of processes have the largest efficiency potential. It also emerged that, due to the lack of detailed data about energy end-use and lack of information about energy efficiency measures, processes accounting for a significant share of the energy efficiency potential in the wood industry risk being overlooked. It is not certain that current energy policies are sufficient to reach the full potential identified. The lack of information about energy end-use and energy efficiency measures implies that neither industrial actors nor policy-makers are able to develop thorough energy strategies or roadmaps for improved energy efficiency.While the outcomes of this thesis show that a large share of Swedish pulp and paper mills carry out energy benchmarking to some degree, energy managers emphasized that benchmarking in this particular industry is difficult because it requires a deep understanding of the industry’s heterogenous and integrated processes. This thesis proposes a widened perspective on energy benchmarking and its role in industrial energy management; namely, also considering the process of how energy KPIs are implemented within in-house energy management. A process that enhances energy management includes the continuous monitoring, visualization, and revision of KPIs. In this thesis, a method is developed that encourages the bottom-up implementation of energy KPIs in the pulp and paper industry, which further enables industrial energy benchmarking.
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| 4. |
- Andersson, Gustav, 1983-
(författare)
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Influences of paratendinous innervation and non-neuronal substance P in tendinopathy : studies on human tendon tissue and an experimental model of Achilles tendinopathy
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pain of the musculoskeletal system is one of the most common reasons for people seeking medical attention, and is also one of the major factors that prevent patients from working. Chronic tendon pain, tendinopathy, affects millions of workers world-wide, and the Achilles tendon is an important structure often afflicted by this condition. The pathogenesis of tendinopathy is poorly understood, but it is thought to be of multifactoral aetiology. It is known that tendon pain is often accompanied not only by impaired function but also by structural tissue changes, like vascular proliferation, irregular collagen organisation, and hypercellularity, whereby the condition is called tendinosis. In light of the poor knowledge of tendinosis pathophysiology and recent findings of a non-neuronal signalling system in tendon tissue, the contributory role of neuropeptides such as substance P (SP) has gained increased interest. SP, known for afferent pain signalling in the nervous system, also has multiple efferent functions and has been described to be expressed by non-neuronal cells. As pain is the most prominent symptom of tendinopathy, the focus of the studies in this thesis was the innervation patterns of the tissue ventral to the Achilles tendon (i.e. the tissue targeted in many contemporary treatment methods) as well as the distribution of SP and its preferred receptor, the neurokinin-1 receptor (NK-1R), in the tendon tissue itself. It was hereby hypothesised that the source of SP affecting the Achilles tendon might be the main cells of the tendon tissue (the tenocytes) as well as paratendinous nerves, and that SP might be involved in tendinosis- development. The studies were conducted, via morphological staining methods including immunohistochemistry and in situ hybridisation, on tendon biopsies from patients suffering from Achilles tendinosis and on those from healthy volunteers. The hypothesis of the thesis was furthermore tested using an experimental animal model (rabbit) of Achilles tendinopathy, which was first validated. The model was based on a previously established overuse protocol of repetitive exercise. In the human biopsies of the tissue ventral to the Achilles tendon, there was a marked occurrence of sympathetic innervation, but also sensory, SP-containing, nerve fibres. NK-1R was expressed on blood vessels and nerve fascicles of the paratendinous tissue, but also on the tenocytes of the tendon tissue proper itself, and notably more so in patients suffering from tendinosis. Furthermore, the human tenocytes displayed not only NK-1R mRNA but also mRNA for SP. The animal model was shown to produce objectively verified tendinosis-like changes, such as hypercellularity and increased vascularity, in the rabbit Achilles tendons, after a minimum of three weeks of the exercise protocol. The contralateral leg of the animals in the model was found to be an unreliable control, as bilateral changes occured. The model furthermore demonstrated that exogenously administered SP triggers an inflammatory response in the paratendinous tissue and accelerates the intratendinous tendinosis-like changes such that they now occur after only one week of the protocol. Injections of saline as a control showed similar results as SP concerning hypercellularity, but did not lead to vascular changes or pronounced paratendinous inflammation. In summary, this thesis concludes that interactions between the peripheral sympathetic and sensory nervous systems may occur in Achilles tendinosis at the level of the ventral paratendinous tissue, a region thought to be of great importance in chronic tendon pain since many successful treatments are directed toward it. Furthermore, the distribution of NK-1R:s in the Achilles tendon described in these studies gives a basis for SP, whether produced by nerves mainly outside the tendon or by tenocytes within the tendon, to affect blood vessels, nerve structures, and/or tendon cells, especially in tendinosis patients. In light of this and of previously known SP-effects, such as stimulation of angiogenesis, pain signalling, and cell proliferation, the proposed involvement of SP in tendinosis development seems likely. Indeed, the animal model of Achilles tendon overuse confirms that SP does induce vascular proliferation and hypercellularity in tendon tissue, thus strengthening theories of SP playing a role in tendinosis pathology.
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| 5. |
- Andersson, Hanna, 1991-
(författare)
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Tradeoffs between self and environment in environmental judgment and decision making
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One of the greatest challenges of today is to change our behavior to act more pro-environmentally to reduce global warming. We need to make sacrifices for the environment, e.g., use a means of transportation that take a longer time but causes less CO2 emission. The present thesis aims to study different factors (intrinsic, extrinsic motivational, and extrinsic motivational-neutral information) that influence us when making tradeoffs between self and environment. Paper I examined how an anchor (a reference price) and an ecolabel influence price judgments. It was found that both a judgment of an objective fact (product price) and a subjective preference (willingness to pay for the product) were affected by an anchor. An eco-label resulted in higher judgments of objective facts. People with higher environmental concern were more affected by an anchor when stating their willingness to pay than their low concern counterparts. In Paper II and Paper III, an interaction between a high anchor and a normative message that put the emissions into context was found when making a tradeoff between CO2 emissions and travel time for a flight (Paper II) or a car journey (Paper III). People with higher concern for the environment gave a longer travel time when they received a high anchor (Paper II and Paper III) or no anchor (Paper III). Paper IV investigated how a survey measuring environmental concern can be divided to different indices and how they predict answers in a tradeoff task. The result suggests that a two-factor structure divided into ecocentric and anthropocentric concern is a possible alternative and that people scoring higher on any of the environmental concern indices were willing to travel for a longer time. Taken together, the results show that normative messages, anchors, and concern for the environment are factors that can influence and interact when people make tradeoffs between self and environment in environmental judgment and decision making.
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| 6. |
- Andersson, Patrik
(författare)
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Development of new NMR techniques and structural characterization of complexes between the N-terminal domain of the E. coli arginine repressor and operator DNA
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis includes the development of new solution NMR methods for the study of biomolecules and the characterization of complexes between the N-terminal domain of the E. coli arginine repressor (ArgR-N) and operator DNA. [alpha]/[beta]-half-filter were designed as spin-state selective pulse sequence elements for the rapid measurement of one-bond coupling constants. The spectral editing of IS cross-peak multiplets into separate subspectra retains the sensitivity of the parent experiment recorded without decoupling during acquisition while maintaining the resolution of the decoupled experiment. Incorporation of the filters into HSQC- and HMQC-type experiments with and without sensitivity enhancement is demonstrated. The original TROSY experiment was re-examined and a generalized version presented, which allows the spin-state selective editing of the multiplet components of 1H-15N groups into four different subspectra without any loss of sensitivity, A gain of [IMAGE] in sensitivity is possible if only two of the four components are selected. The time-shared X([omega]1)-half-filter reduces the loss of magnetization by relaxation by utilizing the filter delay for simultaneous chemical shift evolution. A timeshared 13C([omega]1)-half-filtered 1H NOESY of a 2:1 complex between 13 C-labelled ArgR-N and 16-mer operator DNA showed an increased signal intensity of 30% over the conventional filter. The full-length E. coli arginine repressor (ArgR) binds to DNA as a hexamer. DNA-binding is mediated by pairs of N-terminal domains of ArgR (ArgR-N) which bind to largely palindromic sites, referred to as ARG-boxes, on the operator DNA. NMR data collected for the 2:1 complex between ArgR-N and 16-mer operator DNA include chemical shift perturbation, amide 1H protection from solvent and a relaxation enhancing agent in the solution, relaxation enhancement by spin-labelled DNA and residual dipolar couplings, The interaction surface of the protein was found to include parts of the N-terminal half of helix 3 and the preceding loop, the N-terminal of helix 1, the flexible N-terminus and the sidechain of Gln26. The orientation of the ArgR-N molecules in the 2:1 complex brings the [beta]-fingers in spatial proximity near the centre of the ARG-box. A model of the 2:1 complex is proposed which accounts for most of the NMR and available biochemical data.
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| 7. |
- Andersson, Patrik
(författare)
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Functional role of a constitutively active dioxin/Ah receptor in a transgenic mouse model
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The dioxin/ Aryl hydrocarbon receptor is a ligand-activated transcription factor that mediates most (if not all) of the toxic effects of the group of highly potent environmental pollutants collectively called dioxins and PCBs, including the highly toxic compound 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD). The toxic effects include immune suppression, endocrine disruption, impaired reproduction and carcinogenesis. In addition, the Ah receptor regulates expression of several genes, most of which are xenobiotic metabolizing enzymes such as CYP1A1. Although the high toxicity of these compounds has been known for more than three decades, the mechanism(s) of action behind the wide spectrum of effects is yet not known. Moreover, although the Ah receptor was cloned more than ten years ago, a physiological role or ligand has not unambiguously been identified. A transgenic mouse model that expresses a constitutively active Ah receptor (CA-AhR) was therefore developed. The aim of this study was to characterize the functional role of this receptor in these mice. Homozygous CA-AhR mice were fertile and the CA-AhR was expressed in several tissues such as thymus, spleen, liver, lungs and heart as well as in all parts of the gastrointestinal tract. In CA-AhR mice, unexposed to any exogenous Ah receptor ligand, expression of the Ah receptor target gene CYP1A1 was induced in all of these organs, indicating that the CA-AhR was transcriptionally active in a constitutive manner. In addition, effects observed in most experimental animals after TCDD exposure, such as decreased thymus weight and increased liver weight were also observed in the CA- AhR mice. Increased mortality was observed from six months of age in the CA-AhR mice. This correlated with the development of cystic stomach tumors that penetrated all layers of the glandular stomach. These tumors consisted of differentiated cells, such as foveolar, parietal and cardio-pyloral type of cells. Immunohistochemical analysis demonstrated expression of CYP1A1 and the proliferation marker PCNA. Intestinal and squamous metaplasia was also observed in the tumors. Some tumors were surrounded by a region of connective and fatty tissue together with lymphatic foci and vessels, reminiscent of hamartomatous lesions observed in humans. Wild-type animals orally treated with TCDD demonstrated an expansion of the zone of proliferating cells normally found in the narrow isthmus-region of the stomach to include the entire parietal-chief cell region. Moreover, the parietal/chief cell region was decreased in the stomach of CA-AhR mice and this was associated with foveolar hyperplasia. To identify dysregulated genes in the CA-AhR mouse stomachs, RNA from three months old animals was subjected suppressive subtraction analysis. Osteopontin gene expression was found to be down- regulated in the glandular stomach but also in other organs of CA-AhR mice. TCDD exposure of wild-type and mutant mouse hepatoma cells demonstrated a rapid but transient decrease in osteopontin expression that was dependent on functional Ah receptor and Amt. Moreover, FACS analysis of lymphoid cells revealed that the CD5-expressing peritoneal population of B cells (B1a) was substantially reduced in CA-AhR mice. Taken together, these results demonstrate that expression of the CA-AhR in mice resulted in a number of effects. In particular, the development of wen-differentiated stomach tumors indicates a role of the receptor in regulation of gastric epithelial cell homeostasis.
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| 8. |
- Andersson, Patrik
(författare)
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Mechanisms of tumor microenvironment in promoting metastasis
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tumor tissues contain diverse cell populations that relentlessly cross-communicate with each other in the tumor microenvironment. In addition to malignant cells, infiltration of other host cells including inflammatory cells, fibroblasts, and cells in the vessel walls in tumors significantly contribute to tumor growth and metastasis. The diversity of cell populations in the tumor microenvironment determines the production of various growth factors and cytokines, which are often upregulated. Although these signaling molecules interact with their specific receptors to trigger signaling events in the targeted cells, they often crosstalk to each other to elicit additive or synergistic effects in the tumor tissue. This thesis work provides several examples of such complex interactions between various cellular and signaling components in the tumor microenvironment in promoting metastasis. We particularly focused our research on angiogenesis-related signaling events to identify molecular mechanisms underlying tumor metastasis. In paper I, we show that expression levels of PDGF-BB in tumor cells can serve as a surrogate marker for drug response. One of the most surprising findings is that high levels of tumor cell-derived PDGF-BB ablates pericytes from the tumor microvasculature. Mechanistically, tumor cell-derived PDGF-BB attracts pericytes from the vessel wall toward tumor cells, leaving the endothelium unprotected. Ablation of pericytes leads to exposure of primitive microvessels susceptible for tumor cell intravasation. As a result, inhibition of the PDGF-BB-PDGFR signaling in high PDGF-BB-producing tumors prevents tumor cell intravasation and metastasis. Conversely, inhibition of the PDGF-BB-PDGFR signaling in PDGF-BB negative tumors ablates pericytes from the tumor microvasculature and promotes tumor metastasis. Therefore, PDGF-BB levels may serve as a potential surrogate marker for predicting anti-PDGF therapeutic outcomes. In paper II, we uncover a novel mechanism of pericytes in promoting tumor metastasis. In PDGF-BB-activated pericytes, genome-wide profiling shows that IL-33 is the most upregulated gene among all genes. ST2 as a receptor for IL-33 is abundantly expressed in macrophages. In various in vitro and in vivo experimental settings, IL-33 promotes the polarization of macrophages to an M2 subtype. Gain- and loss-of-function experimental data show that IL-33-activated macrophages promote tumor metastasis. Together, this work reveals a previously unknown mechanism underlying pericyte-mediated tumor metastasis and targeting the PDGF-PDGFR-IL-33-ST2 signaling axis provides a novel therapeutic option for treatment of cancer patients. Paper III identifies VEGF-B; a VEGFR-1 exclusive binding ligand, as a promoter of tumor metastasis through a VEGF-A-independent mechanism. VEGF-B remodels tumor vessels to become pseudonormalized and highly leaky by ablating pericytes from tumor vessels. The highly leaky tumor vessels permit tumor cell intravasation into the circulation and facilitate metastasis. Importantly, high expression levels of VEGF-B in cancer patients correlate with poor prognosis. In the last paper, we show that FGF-2 and VEGF-C collaboratively promote lymphangiogenesis. For the first time, we show that the VEGFR3 signaling is crucial for non-VEGF-C-induced lymphatic networks. Importantly, FGF-2 and VEGF-C synergistically promotes metastasis. Altogether, this thesis work uncovered several novel mechanisms underlying tumor metastasis and targeting these signaling pathways may offer new opportunities for effective treatment of cancer patients.
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| 9. |
- Andersson, Patrik, 1974
(författare)
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Modelling Interfacial Details in Tyre/Road Contact — Adhesion Forces and Non-Linear Contact Stiffness
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rolling resistance, noise generation, and wear are all determined by the interaction process between the rolling automotive vehicle tyre and the road. A deep understandingof the interaction process is needed for optimisation aiming at reducing these effects. Details in the tyre/road contact interface are considered in the presented work; non-linear contact stiffness and adherence forces at the interface areinvestigated and modelled. A description of the tyre structure and especially its tread layer is required for contact modelling. The dynamic responses of smooth and patterned passenger-car tyres are experimentally investigated. Experimental results are used to validate a high-frequency tyre model based on the elastic field equations, which includes the local deformation of the tread. The separation process when tyre tread blocks are rapidly separated from road surfaces is investigated in an experiment. This process is described with the aid ofthe total contact force and noise generation. Based on the experimental results, a model for the adherence force as a function of load, load duration, and unloading rate is proposed.Optimisation of the tyre/road interaction including interfacial details requires time-domain contact models including a wide range of length-scales. The strategyis to divide the contact problem into different ranges of length-scales. A model based on statistical description of the contact geometry is used on the smallest length-scales. A tread block in contact with the road surface is modelled on intermediate length-scales, and on the largest length-scales is a contact model of the complete tyre structure rolling over the road surface. The two latter models use a numerical time-domain contact formulation with a discretised contact geometry. These three models are connected via constitutive relations between contact pressure and relative displacements, incorporated as non-linear springs between the contact elements. The modelling approach is still under development but preliminary results are presented.
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| 10. |
- Andersson, Patrik, 1967-
(författare)
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Physico-chemical characteristics and quantitative structure-activity relationships of PCBs
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The polychlorinated biphenyls (PCBs) comprise a group of 209 congeners varying in the number of chlorine atoms and substitution patterns. These compounds tend to be biomagnified in foodwebs and have been shown to induce an array of effects in exposed organisms. The structural characteristics of the PCBs influence their potency as well as mechanism of action. In order to assess the biological potency of these compounds a multi-step quantitative structure-activity relationship (QSAR) procedure was used in the project described in this thesis.The ultraviolet absorption (UV) spectra were measured for all 209 PCBs, and digitised for use as physico-chemical descriptors. Interpretations of the spectra using principal component analysis (PCA) showed the number of ortho chlorine atoms and para-para substitution patterns to be significant. Additional physico-chemical descriptors were derived from semi-empirical calculations. These included various molecular energies, the ionisation potential, electron affinity, dipole moments, and the internal barrier of rotation. The internal barrier of rotation was especially useful for describing the conformation of the PCBs on a continuous scale.In total 52 physico-chemical descriptors were compiled and analysed by PCA for the tetra- to hepta-chlorinated congeners. The structural variation within these compounds was condensed into four principal properties derived from a PCA for use as design variables in a statistical design to select congeners representative for these homologue-groups. The 20 selected PCBs have been applied to study structure-specific biochemical responses in a number of bioassays, and to study the biomagnification of the PCBs in various fish species.QSARs were established using partial least squares projections to latent structures (PLS) for the PCBs potency to inhibit intercellular communication, activate respiratory burst, inhibit dopamine uptake in synaptic vesicles, compete with estradiol for binding to estrogen receptors, and induce cytochrome P4501A (CYP1A) related activities. By the systematic use of the designed set of PCBs the biological potency was screened over the chemical domain of the class of compounds. Further, sub-regions of highly potent PCBs were identified for each response measured. For risk assessment of the PCBs potency to induce dioxin-like activities the predicted induction potencies (PIPs) were calculated. In addition, two sets of PCBs were presented that specifically represent congeners of environmental relevance in combination with predicted potency to induce estrogenic and CYP1A related activities.
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