| 1. |
- Ljungström, Viktor, 1986-
(författare)
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Exploring next-generation sequencing in chronic lymphocytic leukemia
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Next-generation sequencing (NGS) techniques have led to major breakthroughs in the characterization of the chronic lymphocytic leukemia (CLL) genome with discovery of recurrent mutations of potential prognostic and/or predictive relevance. However, before NGS can be introduced into clinical practice, the precision of the techniques needs to be studied in better detail. Furthermore, much remains unknown about the genetic mechanisms leading to aggressive disease and resistance to treatment. Hence, in Paper I, the technical performance of a targeted deep sequencing panel including 9 genes was evaluated in 188 CLL patients. We were able to validate 143/155 (92%) selected mutations through Sanger sequencing and 77/82 mutations were concordant in a second targeted sequencing run, indicating that the technique can be introduced in clinical practice. In Paper II we screened 18 NF-κB pathway genes in 315 CLL patients through targeted deep sequencing which revealed a recurrent 4 base-pair deletion in the NFKBIE gene. Screening of NFKBIE in 377 additional cases identified the mutation in ~6% of all CLL patients. We demonstrate that the lesion lead to aberrant NF-κB signaling through impaired interaction with p65 and is associated with unfavorable clinical outcome. In Paper III we sought to delineate the genetic lesions that leads to relapse after fludarabine, cyclophosphamide, and rituximab treatment. Through whole-exome sequencing of pre-treatment and relapse samples from 41 cases we found evidence of frequent selection of subclones harboring driver mutations and subsequent clonal evolution following treatment. We also detected mutations in the ribosomal protein RPS15 in 8 cases (19.5%) and characterization of the mutations through functional assays point to impaired p53 regulation in cells with mutated RPS15. Paper IV aimed at characterizing 70 patients assigned to three major subsets (#1, #2, and #4) through whole-genome sequencing. Besides recurrent exonic driver mutations, we report non-coding regions significantly enriched for mutations in subset #1 and #2 that may facilitate future molecular studies. Collectively, this thesis supports the potential of targeted sequencing for mutational screening of CLL in clinical practice, provides novel insight into the pathobiology of aggressive CLL, and demonstrates the clinical outcome and cellular effects of NFKBIE and RPS15 mutations.
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| 2. |
- Nilforoush, Rasoul
(författare)
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Anchorage in Concrete Structures : Numerical and Experimental Evaluations of Load-Carrying Capacity of Cast-in-Place Headed Anchors and Post-Installed Adhesive Anchors
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Various anchorage systems including both cast-in-place and post-installed anchors have been developed for fastening both non-structural and structural components to concrete structures. The need for increased flexibility in the design of new structures and strengthening of existing concrete structures has led to increased use of various metallic anchors in practice. Although millions of fasteners are used each year in the construction industry around the world, knowledge of the fastening technology remains poor. In a sustainable society, buildings and structures must, from time to time, be adjusted to meet new demands. Loads on structures must, in general, be increased to comply with new demands, and the structural components and the structural connections must also be upgraded. From the structural connection point of view, the adequacy of the current fastenings for the intended increased load must be determined, and inadequate fastenings must either be replaced or upgraded. The current design models are generally believed to be conservative, although the extent of this behavior is not very clear. To address these issues, the current models must be refined to allow the design of new fastenings and also the assessment of current anchorage systems in practice.The research presented in this thesis consists of numerical and experimental studies of the load-carrying capacity of anchors in concrete structures. Two different types of anchors were studied: (I) cast-in-place headed anchors, and (II) post-installed adhesive anchors. This research focused particularly on the tensile load-carrying capacity of cast-in-place headed anchors and also on the sustained tension loading performance of post-installed adhesive anchors. The overall objective of this research was to provide knowledge for the development of improved methods of designing new fastening systems and assessing the current anchorage systems in practice.For the cast-in-place headed anchors (I), the influence of various parameters including the size of anchor head, thickness of concrete member, amount of orthogonal surface reinforcement, presence of concrete cracks, concrete compressive strength, and addition of steel fibers to concrete were studied. Among these parameters, the influence of the anchor head size, member thickness, surface reinforcement, and cracked concrete was initially evaluated via numerical analysis of headed anchors at various embedment depths. Although these parameters have considerable influence on the anchorage capacity and performance, this influence is not explicitly considered by the current design models. The numerical results showed that the tensile breakout capacity of headed anchors increases with increasing member thickness and/or increasing size of the anchor head or the use of orthogonal surface reinforcement. However, their capacity decreased considerably in cracked concrete. Based on the numerical results, the current theoretical model for the tensile breakout capacity of headed anchors was extended by incorporating several modification factors that take the influence of the investigated parameters into account. In addition, a supplementary experimental study was performed to verify the numerically obtained findings and the proposed refined model. The experimental results corresponded closely to the numerical results, both in terms of failure load and failure pattern, thereby confirming the validity of the proposed model. The validity of the model was further confirmed through experimental results reported in the literature.Additional experiments were performed to determine the influence of the concrete compressive strength and the addition of steel fiber to concrete on the anchorage capacity and performance. These experiments showed that the anchorage capacity and stiffness increase considerably with increasing concrete compressive strength, but the ductility of the anchor decreases. However, the anchorage capacity and ductility increased significantly with the addition of steel fibers to the concrete mixture. The test results also revealed that the tensile breakout capacity of headed anchors in steel fiber-reinforced concrete is significantly underestimated by the current design model.The long-term performance and creep behavior of the post-installed headed anchors (II) was evaluated from the results of long-time tests on adhesive anchors under sustained loads. In this experimental study, adhesive anchors of various sizes were subjected to various sustained load levels for up to 28 years. The anchors were also exposed to several in-service conditions including indoor temperature, variations in the outdoor temperature and humidity, wetness (i.e., water on the surface of concrete), and the presence of salt (setting accelerant) additives in the concrete. Among the tested in-service conditions, variations in the outdoor temperature and humidity had the most adverse effect on the long-term sustained loading performance of the anchors. Based on the test results, recommendations were proposed for maximum sustained load levels under various conditions. The anchors tested under indoor conditions could carry sustained loads of up to 47% of their mean ultimate short-term capacities. However, compared with these anchors, the anchors tested under outdoor conditions exhibited larger creep deformation and failure occurred at sustained loads higher than 23% of their mean ultimate short-term capacities. Salt additives in concrete and wet conditions had negligible influence on the long-term performance of the anchors, although the wet condition resulted in progressive corrosion of the steel. Based on the experimental results, the suitability of the current testing and approval provisions for qualifying adhesive anchors subjected to long-term sustained tensile loads was evaluated. The evaluations revealed that the current approval provisions are not necessarily reliable for qualifying adhesive anchors for long-term sustained loading applications. Recommendations were given for modifying the current provisions to ensure safe long-term performance of adhesive anchors under sustained loads.
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| 3. |
- Olajos, Fredrik, 1987-
(författare)
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Using environmental DNA to unravel aquatic ecosystem dynamics
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human-induced climate change has led to unprecedented declines in Earth's biodiversity and significant habitat loss. Aquatic ecosystems areespecially at risk, facing pollution, overexploitation, and destruction. Consequently, monitoring biodiversity is critical. Traditional monitoring methods are often low in detection rates, time-consuming, invasive, and harmful to species, which hampers comprehensive biodiversity assessments. Environmental DNA (eDNA) offers a rapid alternative fortaxonomic identification, extracting genetic material from soil, sediments, or water without capturing living organisms, proving useful where traditional methods fall short. However, its integration into aquatic ecology is hampered by unresolved methodological issues.This thesis demonstrates how eDNA can help reconstruct fish colonization histories in lakes post-glacial retreat. I employed species-specific primers with digital droplet PCR and metagenomic shotgun sequencing on ancient DNA from Holocene lake sediments. My findings show the detectability of DNA from ancient fish populations. However, each method exhibited technical limitations that led to varying degrees offalse negatives and false positive results. Additionally, I examined how Northern pike (Esox Lucius) affects ecological speciation in Europeanwhitefish (Coregonus lavaretus), promoting a shift from insectivorous to piscivorous states, enhancing predator biodiversity and biomass. Dietan alyses of piscivorous birds through digital droplet PCR revealed that smaller whitefish support a larger, more diverse bird community. Finally, I compared two molecular techniques for quantifying bird diets from fecal DNA, finding that metabarcoding with a universal fish primer and digital droplet PCR yielded similar results. This research enhances ourunderstanding of the potential and limitations of molecular tools forspecies identification and aids the integration of eDNA into aquatic ecology.
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| 4. |
- Sanchez Preciado, Deycy Janeth, 1975-
(författare)
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Developing Technology Transfer Processes in rural contexts : The case of Cauca in Colombia
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This doctoral thesis addresses the technology transfer process in rural developing economies. Technology transfer refers to the movement of physical artifacts and knowledge from a transferor (e.g. a university) to a recipient (e.g. a cooperative or a producer). Many rural developing economies depend on rural enterprises engaged in small-scale production. These enterprises usually have limited market reach, inadequate financial margins, and low value added products. In this context, technology transfer commonly features large information and knowledge asymmetry between the transferors and recipients, the recipients’ dependence on government financial support, and the recipients’ underdeveloped business skills. Despite the importance of technology transfer for production improvements by enterprises in rural economies, little is known about how the two sides interact when technologies to fit the small-scale production context are transferred. To address this knowledge gap, this thesis focuses on how rural enterprises adapt and use technologies that are collaboratively developed with universities with the support of governments and non-governmental organisations (NGOs). Empirically, the thesis analyses technology transfer aimed at improving silk, fish, and coffee production in Cauca, a region in Colombia. The thesis uses Situated Learning Theory, action research, and case study methodology. The thesis shows that i) intermediaries broker and facilitate (organise) the interaction between universities and cooperatives and rural enterprises; ii) there are seven features that enable technology transfer in rural developing economies and iii) ‘systems’ of technology transfer evolve in rural developing economies through analysis of problem formulation and problem solving as the mechanisms.
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| 5. |
- Awad, Amar, 1988-
(författare)
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Functional brain imaging of sensorimotor dysfunction and restoration : investigations of discomplete spinal cord injury and deep brain stimulation for essential tremor
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The nervous system exists to generate adaptive behaviour by processing sensory input from the body and the environment in order to produce appropriate motor output, and vice versa. Consequently, sensorimotor dysfunction is the basis of disability in most neurological pathologies. In the current thesis, I explore two conditions with different types and degrees of sensorimotor dysfunction by means of functional magnetic resonance imaging (fMRI). In part 1, I assess residual sensory connections to the brain in clinically complete spinal cord injury (SCI) with seemingly complete loss of sensorimotor function below the injury level. In part 2, fMRI is combined with deep brain stimulation (DBS) to investigate interventional mechanisms of restoring dysfunctional sensorimotor control in essential tremor (ET).Part 1: SCI disrupts the communication between the brain and below-injury body parts, but rarely results in complete anatomical transection of the spinal cord. In studies I and II, we demonstrate somatosensory cortex activation due to somatosensory (tactile and nociceptive) stimulation on below-level insensate body parts in clinically complete SCI. The results from studies I and II indicate preserved somatosensory conduction across the spinal lesion in some cases of clinically complete SCI, as classified according to international standards. This subgroup is referred to as sensory discomplete SCI, which represents a distinct injury phenotype with an intermediate degree of injury severity between clinically complete and incomplete SCI.Part 2: ET is effectively treated with DBS in the caudal zona incerta, but the neural mechanisms underlying the treatment effect are poorly understood. By exploring DBS mechanisms with fMRI, DBS was shown to cause modulation in the activity of the sensorimotor cerebello-cerebral regions during motor tasks (study III), but did not modulate the functional connectivity during resting-state (study IV).fMRI is a valuable tool to investigate sensorimotor dysfunction and restoration in SCI and DBS-treated ET. There is evidence for sensory discomplete SCI in about half of the patients with clinically complete SCI. DBS modulates DBS modulation of the activity in the sensorimotor cerebello-cerebral circuit during motor tasks, but not during resting-state, is action-dependent.
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| 6. |
- Herdenberg, Carl, 1982-
(författare)
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Molecular and physiological functions of LRIG proteins and netrin-1 in health and disease
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family has three members, LRIG1, LRIG2, and LRIG3, that encode three structurally similar transmembrane proteins. LRIG1 is a receptor tyrosine kinase regulator, tumor suppressor, and stem cell marker in the skin, intestine, and brain. LRIG2 and LRIG3 have been less studied but shown to interact with LRIG1. The different roles and mechanisms of action of LRIG proteins have not yet been fully elucidated. In Caenorhabditis elegans (C. elegans), the LRIG homolog SMA-10 regulates bone morphogenetic protein (BMP) signaling; however, this function has not been demonstrated for mammalian LRIG proteins. In mice, the gene encoding the neurodevelopmental guidance cue netrin-1, Ntn1, interacts with Lrig3 in inner ear development. The physical interactions between LRIG proteins and other proteins are mostly unknown. Here, we describe an LRIG1-centered protein interaction network that regulates growth factor receptor levels. The LRIG1 interactome comprised LRIG2 and LRIG3 as well as many unanticipated proteins. An unbiased pathological examination of female mice with different Lrig3 genotypes (homozygous, heterozygous, or knockout) revealed a reduced incidence of spontaneous fatty liver and lymphocytic hyperplasia of the spleen in Lrig3-null mice. Female Lrig3-null mice also had a lower incidence of microvesicular cytoplasm in the liver after eight weeks on a high-fat diet. To further explore the molecular and physiological functions of LRIG proteins, we generated Lrig-null (Lrig1-/-;Lrig2-/-;Lrig3-/-) mouse embryonic fibroblasts (MEFs), which displayed a deficiency in adipogenesis caused by impaired BMP signaling. LRIG1 and LRIG3, but not LRIG2, sensitized cells to BMP and rescued the adipogenesis deficiency in Lrig-null MEFs. In C. elegans, the LRIG homolog sma-10 was needed for proper lipid accumulation. By analyzing data from the UK Biobank and GENiAL cohort, we found that certain LRIG1 gene variants were associated with a higher body mass index (BMI) yet protected against type 2 diabetes. This effect was probably mediated by altered adipocyte morphology. CRISPR/Cas9-mediated ablation of Ntn1 revealed that the BMP-promoting function of LRIG1 and LRIG3 was opposed by netrin-1, which functioned as an inhibitor of BMP signaling via its receptor neogenin.In summary, the present thesis describes a novel LRIG protein interaction network, the regulation of BMP signaling by LRIG proteins and netrin-1, and an important function of LRIG proteins in regulating fat metabolism with implications for human metabolic health.
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| 7. |
- Kosmack Vaara, Elsa
(författare)
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Exploring the Aesthetics of Felt Time
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- By building a felt time repertoire, designers can sensitively feed a sense of time into their design work. And this in turn can help them produce an interaction gestalt that is richer, more sensual. My research on this suggests that this is not entirely easy, however. One has to develop a ‘feel’ for time. My research exploration began when I worked on designing a biofeedback data system, Affective Health, struggling with the tension and division between clocktime and the users’ unceasingly changing, ‘felt’ experiences. By turning to artistic practice, of music and culinary arts, I hoped to find keys to this question. Through connecting interaction-design research to these practices, I could start unfolding possibilities of temporal aesthetics in interaction design. I point to a space where designers can expand their understanding of felt time and playfully explore the sense of time that interactive systems and physical materials can deliver. Through the aspects below I point to the importance of being sensitive to felt forms and expressions of time to approach the temporal gestalt in interaction. • Through my research I have strived to move outside clocktime and re-imagine the sense of time that interactive systems deliver.• One part of this space is felt rhythms and how they shape temporal experiences.• In common to those rhythms are the rest and pause moments that form their vitality.• One way of working with rhythm is to see how felt shapes and rhythms of time resonate through the temporal gestalt in interaction.• Aesthetic sensitivity, felt timers, can help us to orient ourselves in time.• By approaching time as plastic: time as a form and shape that we can hold on to, squeeze and weave together, we can start finding tools for remoulding the sense of time in systems, artefacts and services.• Finally, I have worked with aesthetic transformations that can encourage people to start experiencing temporality from new perspectives and with a different approach.
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| 8. |
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| 9. |
- Liu, Dongming, 1987-
(författare)
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Polyethylene – metal oxide particle nanocomposites for future HVDC cable insulation : From interface tailoring to designed performance
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Low-density polyethylene (LDPE) nanocomposites containing metal oxide nanoparticles are considered as promising candidates for insulating materials in future high-voltage direct-current (HVDC) cables. The significant improvement in dielectric properties compared with unfilled polymer is attributed to the large and active interface between the nanoparticles and the polymer. The nanoparticles may also initiate cavitation under stress and potential accelerated aging risks due to the adsorption and inactivation of the protecting antioxidants. This study is focused on the possibilities of achieving well-balanced performances of the polyethylene nanocomposites for HVDC insulation via tailoring the particle interface in the nanocomposites.A facile and versatile surface coating method for metal oxide particles was developed based on silane chemistry. The developed method was successfully applied to 8.5 nm Fe3O4, 25 nm ZnO and 50 nm Al2O3 particles, with the aim to develop uniform coatings that universally could be applied on individual particles rather than aggregates of particles. The surface properties of the coatings were further tailored by applying silanes with terminal alkyl groups of different lengths, including methyl (C1-), octyl (C8-) and octadecyl (C18-) units. Transmission electron microscopy, infrared spectroscopy and thermal gravimetric analysis confirmed the presence of uniform coatings on the particle surface and importantly the coatings were found to be highly porous.The capacity of metal oxide particles to adsorb relevant polar species (e.g. moisture, acetophenone, cumyl alcohol and phenolic antioxidant) was further assessed due to its potential impact on electrical conductivity and long-term stability of the nanocomposites. The oxidative stability of the nanocomposites was affected by the adsorption of phenolic antioxidants on particles and transfer of catalytic impurities (ionic species) from metal oxide particles to polymer matrix. It was found that carefully coated metal oxide particles had much less tendency to adsorb antioxidants. They could, however, adsorb moisture, acetophenone and cumyl alcohol. The coated particles did not emit any destabilizing ionic species into the polymer matrix. The inter-particle distance of the nanocomposites based on C8-coated nanoparticles showed only a small deviation from the ideal, theoretical value, indicating a good particle dispersion in the polymer. Scanning electron microscopy of strained nanocomposite samples suggested the cavitation mainly occurred at the polymer/nanoparticles interface. The microstructural changes at polymer/nanoparticle interface were studied by small-angle X-ray scattering coupled with tensile testing. The polymer/nanoparticle interface was fractal before deformation due to the existence of the bound polymers at the nanoparticle surface. Extensive de-bonding of particles and cavitation were observed when the nanocomposites were stretched beyond a critical strain. It was found that the composites based on carefully coated particles showed higher strain at cavitation than the composites based on uncoated particles. The composites based on C8-coated nanoparticles showed the largest decrease in electrical conductivity and the lowest temperature coefficient of the electrical conductivity among the composite samples studied.
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| 10. |
- Liu-Helmersson, Jing, 1960-
(författare)
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Climate Change, Dengue and Aedes Mosquitoes : Past Trends and Future Scenarios
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Climate change, global travel and trade have facilitated the spread of Aedes mosquitoes and have consequently enabled the diseases they transmit (dengue fever, Chikungunya, Zika and yellow fever) to emerge and re-emerge in uninfected areas. Large dengue outbreaks occurred in Athens in 1927 and in Portuguese island, Madeira in 2012, but there are almost no recent reports of Aedes aegypti, the principal vector, in Europe. A dengue outbreak needs four conditions: sufficient susceptible humans, abundant Aedes vector, dengue virus introduction, and conducive climate. Can Aedes aegypti establish themselves again in Europe in the near future if they are introduced? How do the current and future climate affect dengue transmission globally, and regionally as in Europe? This thesis tries to answer these questions.Methods Two process-based mathematical models were developed in this thesis. Model 1 describes a vector’s ability to transmit dengue – vectorial capacity – based on temperature and diurnal temperature range (DTR). Model 2 describes vector population dynamics based on the lifecycle of Aedes aegypti. From this model, vector abundance was estimated using both climate as a single driver, and climate together with human population and GDP as multiple drivers; vector population growth rate was derived as a threshold condition to estimate the vector’s invasion to a new place.Results Using vectorial capacity, we estimate dengue epidemic potential globally for Aedes aegypti and in Europe for Aedes aegypti and Aedes albopictus. We show that mean temperature and DTR are both important in modelling dengue transmission, especially in a temperate climate zone like Europe. Currently, South Europe is over the threshold for dengue epidemics if sufficient dengue vectors are present. Aedes aegypti is on the borderline of invasion into the southern tip of Europe. However, by end of this century, the invasion of Aedes aegypti may reach as far north as the middle of Europe under the business-as-usual climate scenario. Or it may be restricted to the south Europe from the middle of the century if the low carbon emission – Paris Agreement – is implemented to limit global warming to below 2°C.Conclusion Climate change will increase the area and time window for Aedes aegypti’s invasion and consequently the dengue epidemic potential globally, and in Europe in particular. Successfully achieving the Paris Agreement would considerably change the future risk scenario of a highly competent vector – Aedes aegypti’s – invasion into Europe. Therefore, the risk of transmission of dengue and other infectious diseases to the mainland of Europe depends largely on human efforts to mitigate climate change.
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