| 1. |
- Alvarsson, Jonathan, 1981-
(författare)
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Ligand-based Methods for Data Management and Modelling
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Drug discovery is a complicated and expensive process in the billion dollar range. One way of making the drug development process more efficient is better information handling, modelling and visualisation. The majority of todays drugs are small molecules, which interact with drug targets to cause an effect. Since the 1980s large amounts of compounds have been systematically tested by robots in so called high-throughput screening. Ligand-based drug discovery is based on modelling drug molecules. In the field known as Quantitative Structure–Activity Relationship (QSAR) molecules are described by molecular descriptors which are used for building mathematical models. Based on these models molecular properties can be predicted and using the molecular descriptors molecules can be compared for, e.g., similarity. Bioclipse is a workbench for the life sciences which provides ligand-based tools through a point and click interface. The aims of this thesis were to research, and develop new or improved ligand-based methods and open source software, and to work towards making these tools available for users through the Bioclipse workbench. To this end, a series of molecular signature studies was done and various Bioclipse plugins were developed.An introduction to the field is provided in the thesis summary which is followed by five research papers. Paper I describes the Bioclipse 2 software and the Bioclipse scripting language. In Paper II the laboratory information system Brunn for supporting work with dose-response studies on microtiter plates is described. In Paper III the creation of a molecular fingerprint based on the molecular signature descriptor is presented and the new fingerprints are evaluated for target prediction and found to perform on par with industrial standard commercial molecular fingerprints. In Paper IV the effect of different parameter choices when using the signature fingerprint together with support vector machines (SVM) using the radial basis function (RBF) kernel is explored and reasonable default values are found. In Paper V the performance of SVM based QSAR using large datasets with the molecular signature descriptor is studied, and a QSAR model based on 1.2 million substances is created and made available from the Bioclipse workbench.
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| 2. |
- Andersson, Daniel P
(författare)
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Significance of adipose tissue characteristics for development of metabolic complications in obesity
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Obesity is closely related to development of insulin resistance and dyslipidemia. Intrinsic properties of adipose tissue are also of great importance for obesity related comorbidity. The aim of this thesis was to gain further knowledge of adipose depot specific effects of how fat cell size and lipolysis, as well as removal of a large portion of the visceral fat depot, affect metabolic risk. Methods: All subjects were from a cohort of 81 obese women undergoing gastric bypass operation. Study I and study III were cross-sectional studies using baseline data, whereas study II and IV were longitudinal studies which also included an examination two years post- surgery. Insulin sensitivity was evaluated with hyperinsulinemic euglycemic clamp. Subcutaneous and visceral fat biopsies were obtained to determine mean fat cell size and lipolysis. Results: Study I showed that subcutaneous fat cell size correlated with insulin sensitivity (r= -0.40 p= 0.004) and visceral fat cell size correlated with dyslipidemia (r=0.32-0.38 p= 0.0006-0.003). Subjects with combined hyperplasia (many small fat cells) in both subcutaneous and visceral fat depots had a favorable metabolic profile compared to subjects with combined hypertrophy (few but large fat cells) (p= 0.0001-0.02). Study II focused on changes in fat cell size and insulin sensitivity following weight reduction induced by bariatric surgery in obese women. Changes in subcutaneous fat cell size correlated with improved insulin sensitivity independently of changes in subcutaneous fat mass (r=0.32 p= 0.04). Study III investigated depot specific relations between lipolysis and cardiovascular risk factors. Visceral but not subcutaneous fat cell lipolysis correlated with several cardiovascular risk factors including insulin resistance, high plasma triglycerides and blood pressure (r= 0.28-0.44 p= 0.0001-0.02). Visceral fat cell lipolysis was also increased in subjects with metabolic syndrome (F= 8.3 p= 0.005). Study IV, designed as a randomized double blind controlled trial, investigated the 2-year effects of omentectomy in conjunction with gastric bypass operation on insulin sensitivity and the lipid profile. Eighty-one subjects were included in the study and 62 were re-examined two years post-surgery. Omentectomy did not give any additional positive metabolic effects, neither in the primary outcome measure insulin sensitivity (p= 0.54), nor the secondary outcome measures such as lipid status or weight reduction (p= 0.17-0.98). Conclusion: The studies in this thesis highlight that intrinsic factors of adipose tissue, such as fat cell size and lipolysis, independently of fat mass, are important for metabolic complications in obesity. A mere removal of a substantial part of the visceral fat depot does not enhance improved metabolic outcome after gastric bypass operation, suggesting that a metabolic change in adipose tissue and changes in fat cell size are important to achieve positive effects of fat mass reduction.
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| 3. |
- Andersson, Marie, 1962-
(författare)
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Immunopathogenesis of relapsing fever borreliosis
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Relapsing fever (RF) is caused by different species of Borrelia transmitted by soft ticks or by the human body louse. Illness is characterized by reappearing peaks of high concentrations of spirochetes in blood, concordant with fever peaks separated by asymptomatic periods. Neuroborreliosis is one of the most severe manifestations of RF borreliosis. To understand the immune response during early RF, we analyzed immune cells in brain and kidney of mice infected with B. crocidurae during the acute infection. Our results indicate that brain defense is comprised primarily of innate immune cells. Despite the infiltration of innate immune cells, Borrelia was not completely eradicated. A failure of the host brain to clear the bacteria may give the pathogen a niche where it can persist. Using our mouse model, we revealed that Borrelia duttonii could persist in the mouse brain for up to 270 days, without being present in the circulation. The infection was silent with no change in host gene expression, and the spirochetes could re-enter the circulation after immunosuppression. We propose that the brain is used by the pathogen to evade host immunity and serves as a possible natural reservoir for B. duttonii, a spirochete that has rarely been found in any mammalian host other than man. Borrelia-induced complications during pregnancy have been reported, and are especially common in RF. In our established mouse model of gestational RF, we could show that the fetuses suffered from severe pathology and growth retardation, probably as a consequence of placental destruction. We could also show trans-placental transmission of the bacteria leading to neonatal RF. Surprisingly, pregnant dams had a lower bacterial load and less severe disease, showing that pregnancy has a protective effect during RF. We have used the gestational RF model to investigate host factors favoring disease resolution. Because the spleen is the primary organ responsible for trapping and removing blood-borne pathogens, we have compared temporal changes in spleen immune cell populations and cytokine/chemokine induction during the infection. Spleens of pregnant mice had earlier neutrophil infiltration, as well as faster and higher production of pro-inflammatory mediators. This rapid, robust response suggests a more effective host defense. Thus, an enhanced pro-inflammatory response during pregnancy imparts a distinct advantage in controlling the severity of relapsing fever infection.
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| 4. |
- Andersson, Rassmus
(författare)
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Discovering new ground in ion transport: Exploring coordination effects in polymer electrolytes : – From method development to battery implementation
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The exponentially increasing demand for portable and stationary energy storage devices is pushing the development of lithium-ion batteries (LIBs). This requires safer and more sustainable electrolytes where solid polymer electrolytes (SPEs) are a viable alternative to the flammable liquid electrolytes used nowadays. However, SPEs are characterized by poor ionic conductivity compared to their liquid equivalents, preventing large-scale implementation. Furthermore, to meet the increasing production rate of batteries, alternative battery chemistries based on more abundant resources than Li are explored. To address these matters, a fundamental understanding of ion transport in SPEs for a range of relevant cations is vital in the development process.In the thesis, the ion transport is explored on a fundamental level for Li+ in addition to cations “beyond Li” such as Na+, K+ and Mg2+ in polyether-, polyester- and polycarbonate-based SPEs, where the core encompasses the connection between the ion coordination strength and the transference number (T+). New methods to investigate these properties have been developed especially targeting these more challenging cations. To study the ion coordination strength, two qualitative and one quantitative methods based on NMR and FTIR, are presented. In addition, eNMR and EIS have been combined to determine T+.Regardless of the cation investigated, the strongest coordination was observed for polyethylene oxide, stemming from its chelating effect on the cations. In contrast, poly(trimethylene carbonate) exhibited the weakest coordination, while poly(ε-caprolactone) fell in between. A direct correlation between the coordination strength and the T+ was also recognized, where strong interactions are accompanied by low T+ and vice versa. Moreover, the divalent Mg2+ displayed particularly interesting transport characteristics, where the [MgTFSI]+ speciation appears to be a large contributor to the net Mg mobility. Lastly, the outcome of incorporating an ion-conducting polymer as the soft segment in polyurethanes is that the transport mechanism of the pure SPE remains. In combination with sustained long-term cycling in lithium metal batteries, the polyurethanes illustrate opportunities for new designs by adjusting the soft segments. Similarly, the properties of poly(1-oxoheptamethylene) can be controlled by tuning its saturation degree, which is crucial for the ion conduction and mechanical properties in lithium metal batteries, since it highly affects the crystallinity and the crosslinking of the systems.In summary, this thesis contributes toward the understanding of ion transport in systems belonging to “next-generation” batteries, where SPEs for lithium-metal batteries as well as for cations “beyond Li” are considered to play an important part.
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| 5. |
- Andersson, Tony P. M., 1973-
(författare)
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Melanophore signaling : regulation and application
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Melanophores are pigment-containing cells responsible for quick physiological color changes in lower vertebrates due to redistribution of melanosomes, pigment granules. We have studied melanophores from African clawed frog, Xenopus laevis. Classically, melanosomes can be stimulated to aggregate in the cell center by the hormone melatonin via a process involving activation of the inhibitory Gi/o protein and inhibition of adenylate cyclase/cAMP/protein kinase A pathway. In addition, tyrosine phosphorylations have been shown to be crucial for aggregation. In this thesis, we demonstrate that mitogen-activated protein kinase (MAPK) are activated and phosphoinositol 3-kinase (PI3-K) are involved in melatonininduced aggregation. Inhibition of MAPK kinase or PI3-K inhibits MAPK activation, tyrosine phosphorylation of a 280-kDa protein and aggregation. Further, PI3-K inhibition is less dramatic in fish Labrus melanophores. Together with findings that phosphodiesterase (PDE) 4 and/or PDE2 are involved in keeping the aggregated state in Xenopus, we suggest that active PI3-K via MAPK stimulates PDE, thus lowering cAMP. We also use latrunculin A to induce aggregation via disruption of actin filaments. Kinetic studies indicate that melatonin and latrunculin share final downstream target, possibly inactivate myosin-V leading to melanosome aggregation. As biosensor application, a new computer screen assisted technique suitable for bioassays is demonstrated using melanophores to monitor kinetic responses of melanosome movement and blood plasma sample detection of the asthma drug and ß2 adrenergic agonist formoterol. We also used melanophores to examine the efficacy of enantiomers of formoterol. We confirm that (R;R)-formoterol is more potent than (S;S)-formoterol, in guinea pig tracheal ring preparations, cultured melanophores, and radioligand binding on COS-7 cells, but demonstrate and calculate that (S;S)-formoterol has more efficacy than previously described. Characterization of melanophores are important for biosensor applications, i e to understand mechanisms of drugs, and will probably also increase the knowledge of cell signaling in other cell systems.
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| 6. |
- Jansson, Stefan P.O. 1959-
(författare)
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A Longitudinal Study of Diabetes Mellitus : With Special Reference to Incidence and Prevalence, and to Determinants of Macrovascular Complications and Mortality
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objectives. To investigate diabetes prevalence, incidence, mortality trends, the effects of hyperglycaemia and blood pressure, diabetes and hypertension treatment, and the effect of screening detection on total and cardiovascular disease (CVD), myocardial infarction (MI) and stroke incidence.Study population and methods. Between 1972 and 2001 all patients with diabetes, some detected clinically and some by case-finding procedures (screening), were entered in a diabetes register at Laxå Primary Health Care Center in Sweden. The register included information on medical treatment and laboratory data as well as information on mortality and morbidity from National Registers. The register was supplemented with five non-diabetic subjects, matched to each diabetes patients by age, sex, and year of detection.Results. During the study period 776 new diabetes cases was found, 36 type 1 diabetes mellitus and 740 type 2 diabetes mellitus. Age standardised incidence and prevalence rates for type 1 and type 2 diabetes did not increase over time. Diabetic patients had 17% higher mortality rate than non-diabetic persons, 22% in women and 13% in men. The corresponding over-mortality in CVD was 33%, 41% in women and 27% in men. CVD mortality decreased across time in non-diabetic subjects and in diabetic men but not in diabetic women. Results regarding coronary heart disease (CHD) were similar. CVD incidence increased with fasting blood glucose (FBG), body mass index (BMI), mean arterial blood pressure (MABP), and decreased with metformin treatment and sulfonylurea. Myocardial infarction incidence increased with FBG, BMI and MABP, and decreased with metformin treatment. Stroke incidence increased with MABP. There was no difference in prognoses between those detected by screening or clinically.Conclusions. Diabetes prevalence and incidence did not change over time. The over-mortality according to diabetes was moderate. CVD and MI during follow up were negatively affected by hypertension and hyperglycaemia, and positively by pharmacological diabetic treatment. For stroke no pharmacological protective effect was seen. Screening did not improve prognosis.
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| 7. |
- Larsson, Johan P.
(författare)
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Nonmarket Interactions and Density Externalities
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The four individual papers in this thesis all explore some aspect of the relationship between productivity and the density of economic activity.The first paper (co-authored with Martin Andersson, and Johan Klaesson) establishes the general relationship between regional density and average labor productivity; a relationship that is particularly strong for workers in interactive professions. In the paper, we also caution that much of the observed differences are not causal effects of density, but driven by sorting of actors todense environments.Paper number two (co-authored with Martin Andersson, and Johan Klaesson) addresses the attenuation of density externalities with space. Using data on the neighborhood-level, and information on first- and second-order neighboring areas, we conclude that the neighborhood effects are stronger for highly educated workers, and that the attenuation of the effect is sharp.In the third paper, I estimate an individual-level wage equation to assess appropriate levels of aggregation when analyzing density externalities. I conclude that failure to use data on the neighborhood level will severely understate the benefits of working in the central parts of modern cities.The fourth paper departs from the conclusions of the previous chapters, and asks whether firms position themselves to benefit from density externalities. Judging by job switching patterns, the attenuation of density externalities are a real issue for the metropolitan workforce. Employees, especially those in interactive professions, tend to move short distances between employers, consistent with clustering to take advantage of significant but sharply attenuating human capital externalities.
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| 8. |
- Nydahl, Helena, 1990-
(författare)
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Communication of life cycle assessment results : life cycle key performance indicators
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The global warming that we are on track for will result in a severe loss of natural capital leading to significant losses in economic capital when urban infrastructure is destroyed, agricultural productivity declines and poverty spread among other disasters. Climate change due to emissions does not only affect the polluter, the hazardous effects becomes evident on a global level. An essential tool to enable decision‑making with concern to the welfare of the global commons is life cycle assessment (LCA). LCA compile and evaluate the inputs, outputs, and potential environmental impacts of a product system throughout its life cycle. The reviewed literature frames a gap regarding interpretation of LCA-results and inquire for guidelines that address a wide range of stakeholders to enable informed decision-making with regard to the welfare of the global commons. Some studies even argue that an apparent weakness of LCA-result communication is the understanding of what the results mean for the economic key performance indicators (KPIs) of the stakeholder. Thus, this thesis aims to contribute to the development of guidelines for interpretation of LCA-results by introducing an approach for communicating LCA-results that is compatible with the economically driven nature of stakeholders. The specific research questions (RQ) of this thesis are: (RQ1) How can well-established economic KPIs be utilised to quantify environmental impact? and (RQ2) How does incorporation of monetary valuation of environmental impacts and related environmental aspects affect the LCA-result and communication of results?These research questions have led to life cycle key performance indicators (LC‑KPIs) that quantify life cycle economic and environmental impacts in a way that take after the traditional economic KPIs of the stakeholders, which is outlined as essential to improve the understanding of LCA-results. The LC‑KPIs utilize the traditional economic KPIs of return on investment (ROI) and annual yield (AY). Additionally, to manage the large amount of non-commensurate units of holistic life cycle sustainability assessment, monetary valuation has been applied. Hence, contributing to the research area of monetary valuation in LCA by introducing and testing new approaches.The introduced LC-KPIs have been specified for building LCA and exemplified by applying them to a number of Swedish case buildings. The result show that the climate-economic assessment of building refurbishment differs compared to the traditional economic assessment when monetary valuation is utilized in LCA with the LC-KPI of ROIEconomy+. However, in the comparative assessment of building refurbishment and new construction, the LCA‑result does not change compared to the traditional economic assessment when monetary valuation is utilized in LCA with the LC-KPI of ELCCA. This is explained by the high costs associated with the investment and energy use of buildings and may not be the case if products with lower investment and energy use costs and high life cycle greenhouse-gas emissions would be studied. Still, if a purely environmental assessment of a product is wished for, the LC-KPI should only include monetary valuation of environmental impact factors and exclude traditional economic performance. Thus, the case study result defines further scope for research on the subject of monetary valuation in LCA and inquire for a wider spectrum of LC-KPIs that utilizes monetary valuation.The introduced approach of this thesis contribute to the development of guidelines for interpretation of LCA-results. Nevertheless, there are still challenges that needs to be addressed in the development of robust LCA-result interpretation. Still, the LC‑KPIs used in this thesis address the “cognitive logics” of a wide range of stakeholders and provide an approach for communication of LCA-results which improve the understanding of LCA-results.
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| 9. |
- Åstrand, Anders P, 1961-
(författare)
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A Tactile Resonance Sensor System for Detection of Prostate Cancer ex vivo : Design and Evaluation on Tissue Models and Human Prostate
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background The most common form of cancer among males in Europe and the USA is prostate cancer, PCa. Surgical removal of the prostate is the most common form of curative treatment. PCa can be suspected by a blood test for a specific prostate antigen, a PSA-test, and a digital rectal examination, DRE where the physician palpates the prostate through the rectum. Stiff nodules that can be detected during the DRE, and elevated levels of PSA are indications for PCa, and a reason for further examination. Biopsies are taken from the prostate by guidance of a transrectal ultrasound. Superficial cancer tumours can indicate that the cancer has spread to other parts of the body. Tactile resonance sensors can be used to detect areas of different stiffness in soft tissue. Healthy prostate tissue is usually of different stiffness compared to tissue with PCa.AimThe general aim of this doctoral thesis was to design and evaluate a flexible tactile resonance sensor system (TRSS) for detection of cancer in soft human tissue, specifically prostate cancer. The ability to detect cancer tumours located under the surface was evaluated through measurements on tissue phantoms such as silicone and biological tissues. Finally measurements on resected whole prostate glands were made for the detection of cancer tumours.Methods The sensor principle was based on an oscillating piezoelectric element that was indented into the soft tissue. The measured parameters were the change in resonance frequency, Δf, and the contact force F during indentation. From these, a specific stiffness parameter was obtained. The overall accuracy of the TRSS was obtained and the performance of the TRSS was also evaluated on tissue models made of silicone, biological tissue and resected whole human prostates in order to detect presence of PCa. Prostate glands are generally spherical and a special rotatable sample holder was included in the TRSS. Spherically shaped objects and uneven surfaces call for special attention to the contact angle between the sensor-tip and the measured surface, which has been evaluated. The indentation velocity and the depth sensitivity of the sensor were evaluated as well as the effect on the measurements caused by the force with which spherical samples were held in place in the sample holder. Measurements were made on silicone models and biological tissue of chicken and pork muscles, with embedded stiff silicone nodules, both on flat and spherical shaped samples. Finally, measurements were made on two excised whole human prostates.ResultsA contact angle deviating ≤ 10° from the perpendicular of the surface of the measured object was acceptable for reliable measurements of the stiffness parameter. The sensor could detect stiff nodules ≤ 4 mm under the surface with a small indentation depth of 0.4 to 0.8 mm.Measurements on the surface of resected human prostate glands showed that the TRSS could detect stiff areas (p < 0.05), which were confirmed by histopathological evaluation to be cancer tumours on, and under the surface.Conclusions A flexible resonance sensor system was designed and evaluated on soft tissue models as well as resected whole prostate glands. Evaluations on the tissue models showed that the TRSS can detect stiffer volumes hidden below the surface on both flat and spherical samples. The measurements on resected human prostate glands showed that PCa could be detected both on and under the surface of the gland. Thus the TRSS provides a promising instrument aimed for stiffness measurements of soft human tissue that could contribute to a future quantitative palpation method with the purpose of diagnosing cancer.
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