| 1. |
- Ghasemi, Rohollah, 1983-
(författare)
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Tribological and Mechanical Behaviour of Lamellar and Compacted Graphite Irons in Engine Applications
- 2015
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There has been much discussion about the beneficial uses of lamellar graphite iron in piston rings–cylinder liner systems, where a good combinations of both thermal and tribological properties are essential. The excellent tribological performance of lamellar iron under such sliding conditions is principally associated with lubrication behaviour of the graphite particles which are distributed as lamellas throughout the matrix. During sliding, graphite particles are extruded and smeared onto the counterfaces, act as solid lubricating agents and form a thin graphite film between the sliding surfaces. Although this process especially, during the running-in period significantly changes the sliding wear response of the components, the exact mechanism behind of this phenomenon has rarely been discussed in previous studies.It is tribologically beneficial to keep the graphite open, particularly in applications where the scuffing issues do matter. In this thesis, the main causes involved in closing the graphite lamellas are discussed, with a focus on matrix plastic deformation that occurs during sliding. In first step, the relationship between graphite lamellae orientation and plastic deformation was investigated. To do so, two piston rings, belonging to the same two-stroke marine engine operated for different periods of time, were selected and compared to the unworn sample. The worn piston rings displayed a substantial decrease in both frequency and area fraction of the graphite lamellas. Most of the lamellas were closed as a result of plastic deformation of matrix. This happening was caused mainly by the interaction between abrasive particles and metallic matrix. Additionally, it was found that graphite lamellas parallel or near-parallel to the sliding direction exhibited maximum closing tendency under sliding condition.In next step, to have a better understanding of the graphite film formation mechanism and matrix deformation role in closing the graphite lamellas, microindentation and microscratch testing were performed on typical lamellar iron. The qualitative results showed a similar mechanism involving in graphite contribution to lubricate the sliding surfaces. Moreover, microindentations made nearby the graphite lamellas demonstrated that the deformation of the matrix causes the formation of cracks in the centre of the graphite lamellas, compressing and then extruding the graphite from its natural position, irrespective of the lamellas′ size. Furthermore, it was found that subsurface graphite orientation had a large influence on the extrusion behaviour, in that, for graphite lamellas oriented towards the indenter, the effect was observed more pronounced.Furthermore, an improved fully ferritic solution strengthened compacted graphite iron was produced for future wear studies. The effects of different Si levels and section thicknesses on tensile properties and hardness were investigated as well. The influence of Si content and section thickness on mechanical properties was revealed by improving the materials strength and slightly enhancing the hardness through increasing Si content. Besides, Si addition up to 4.5 wt% significantly affected the strength and elongation to failure of cast samples.
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| 2. |
- Rosén, Josefin, 1978-
(författare)
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ChemGPS-NP and the Exploration of Biologically Relevant Chemical Space
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chemical space is basically infinite, and comprises all molecules that could possibly exist. Intelligent ways to efficiently navigate through chemical space and to select promising compounds in drug discovery are important tasks, and the focus of this thesis. In this work a new model for chemical space navigation, ChemGPS-NP, was developed. This model is based on a methodology where a global chemical space map is defined through principal component analysis of physico-chemical properties of a reference set of compounds. Through interpolation from the reference set, positions of novel compounds can be defined on this map and interpreted as chemical properties. ChemGPS-NP was demonstrated to be able to chart the entire biologically relevant chemical space, including both drug-like and natural compounds. This is an important improvement considering the present interest in natural products (NPs) in the pharmaceutical industry, as well as the track record of NPs to serve as basis for more than 50% of all marketed drugs. ChemGPS-NP proved able to handle and process large data sets, to aid in efficient selection of test objects, and to extract useful information from the results of high-throughput screening campaigns. Using ChemGPS-NP, it was shown that NPs occupy unique regions of chemical property space in comparison to drug-like compounds, and a number of features distinguishing NPs from medicinal chemistry compounds were identified. ChemGPS-NP was also shown to be able to reliably predict mode of action of anticancer agents based on chemical structure, a finding that has potential to improve cancer research efficiency. Applying a property based similarity search based on calculated eight dimensional Euclidean distances from ChemGPS-NP rendered a tool to identify NP inspired potential leads for drug discovery. Furthermore, ChemGPS-NPWeb, an online version of ChemGPS-NP, was developed, which provides scientists with open access to the tool via http://chemgps.bmc.uu.se/.
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| 3. |
- Bergh, Ann-Charlotte, 1980-
(författare)
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Importance of microenvironment and antigen in the regulation of growth and survival of CLL cells
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic lymphocytic leukemia (CLL) cells rapidly die when put in culture implying that microenvironmental signals delivered by accessory cells confer CLL cells with a growth advantage. Recent findings show that CLL cells are antigen experienced and antigen binding play a critical role in the pathogenesis of the disease. The overall aim of this thesis was to study the influence of the microenvironment and antigen binding in CLL.In paper I, we studied the influence of the small redox-regulatory molecule thioredoxin (Trx) on CLL cell survival and proliferation. We found Trx to be highly expressed in CLL lymph nodes (LNs), secreted from stromal cells surrounding proliferating CLL cells in proliferation centers, indicating growth promoting properties. Secreted Trx was also shown to protect CLL cells from apoptosis.In paper II, oxidized LDL was added to subset #1 CLL cells. However, in contrast to our hypothesis, we could not observe activation and proliferation of CLL cells. Instead subset #1 CLL cells were unresponsive/anergic through the B cell receptor (BcR). This anergic state could however be overcome by “wash out” of bound antigen or addition of toll-like receptor 9 stimulation in some patients.Gene expression profiles differ between groups of CLL patients and in peripheral blood (PB) and LN compartment, due to different microenvironments. However, it is not known whether these differences also apply for DNA methylation. In paper III, we identified various genes that were alternatively methylated between IGHV mutated (M) and unmutated (UM) groups. For example prognostic genes, CLLU1 and LPL, genes involved in B cell signaling, IBTK, as well as numerous TGF-β and NF-κB/TNF pathway genes.The intensity and duration of BcR signals are fine-tuned by enhancing or inhibitory coreceptors. SHP-1 inhibits BcR-signals by dephosphorylation. In paper IV, we compared the expression and activity of SHP-1 in CLL cells from LN with matched PB samples. However, in contrast to our hypothesis, SHP-1 activity/phosphorylation status in PB and LN, did not differ significantly.This thesis, add another piece to the puzzle, on how the microenvironment and antigens influence CLL pathogenesis. Since great variations among individuals are seen, further studies in different groups of patients are necessary to elucidate the importance of antigen for the development of CLL.
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| 4. |
- Eriksson, Anders, 1983-
(författare)
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Cathodic Arc Synthesis of Ti-Si-C-N Thin Films : Plasma Analysis and Microstructure Formation
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This Thesis explores the arc deposition process and films of Ti-Si-C-N, inspired by the two ternary systems Ti-Si-N and Ti-C-N, both successfully applied as corrosion and wear resistant films. The correlation between cathode, plasma, and film properties are studied for a comprehensive view on film formation. Novel approaches to adapt arc deposition to form multi-element films are investigated, concluding that the source of C is not a determining factor for film growth. Thus, cubic-phase films of similar properties can be synthesized from processes with either 1) ternary Ti-Si-C cathodes, including the Ti3SiC2 MAX phase, in N2 atmosphere or 2) Ti-Si cathodes in a mixture of N2 and CH4. With the Ti3SiC2 cathodes, superhard (45-50 GPa) cubic-phase (Ti,Si)(C,N) films can be deposited. The structure is nanocrystalline and feather-like, with high Si and C content of 12 and 16 at%, respectively. To isolate the effects of Si on film structure, magnetron sputtered Ti-Si-N films of comparatively low defect density was studied. These films show a strong preference for {200} growth orientation, and can be grown as a single phase solid solution on MgO(001) substrates up to ~9 at% Si, i.e. considerably higher than the ~5 at% Si above which a feather-like nanocrystalline structure forms in arc deposited films. On (011) and (111) growth surfaces, the films self-organize into TiN columns separated by segregated crystalline-to-amorphous SiNx. The conditions for film growth by arc were investigated through plasma studies, showing that plasma properties are dependent on cathode composition as well as phase structure. Plasma generation from Ti-Si cathodes, with up to 25 at% Si, show higher average ion charge states of Ti and Si compared to plasma from elemental cathodes, which may be related to TiSix phases of higher cohesive energies. The ion energy distributions range up to 200 eV. Furthermore, compositional discrepancies between plasma ions and film infer significant contributions to film growth from Si rich neutral species. This is further supported by depositions with a macroparticle filter, intended for growth of films with low surface roughness, where Si and C contents lower than the stoichiometry of Ti3SiC2 cathodes was measured in both plasma and films. Also the substrate geometry is critical for the film composition in plasma based film deposition, as evidenced by the formation of artificial layering from rotating substrate fixtures common in high capacity arc deposition systems. The layers are characterized by modulations in composition and crystallinity, primarily attributed to preferential resputtering in high ion incidence angle segments repeated through rotation.
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| 5. |
- Hellqvist, Eva, 1978-
(författare)
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Antigen interaction with B cells in two proliferative disorders : CLL and MGUS
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of the work presented in this thesis was to elucidate B cell interaction with antigen in the two B cell proliferative disorders chronic lymphocytic leukemia (CLL) and monoclonal gammopathy of undetermined significance (MGUS). In the first part we investigated the antigen specificity of CLL cells and characterized Epstein-Barr virus (EBV)-transformed CLL cell lines with regard to phenotype and genotype. The second part consists of studies on the antigen presenting capacity of myelin protein zero (P0) specific MGUS B cells and their relation to T cells and development of polyneuropathy.The aim of the work presented in this thesis was to elucidate B cell interaction with antigen in the two B cell proliferative disorders chronic lymphocytic leukemia (CLL) and monoclonal gammopathy of undetermined significance (MGUS). In the first part we investigated the antigen specificity of CLL cells and characterized Epstein-Barr virus (EBV)-transformed CLL cell lines with regard to phenotype and genotype. The second part consists of studies on the antigen presenting capacity of myelin protein zero (P0) specific MGUS B cells and their relation to T cells and development of polyneuropathy.CLL cells are considered antigen experienced and different patient-derived CLL cells expressing B cell receptors (BCR) with highly homologous antigen binding sites are believed to have been selected by a common antigen at some point during the leukemogenesis. In paper I we investigated the antigen specificity of CLL-cell derived antibodies (Abs) with various IGHV gene usage and stereotyped BCR subset belonging. Identified CLL antigens included vimentin, filamin B, cofilin-1, proline rich acidic protein-1, cardiolipin, oxidized low density lipoprotein and Streptococcus pneumoniae capsular polysaccharides. Many of the CLL Abs studied displayed an oligo- or polyreactive antigen binding pattern and the identified antigens were either associated with apoptotic cells or microbial infection. This is similar to what has been described for innate natural antibodies, possibly indicating that CLL cells are derived from a natural-antibody- producing B cell population. Further characterization of CLL homology subset-2 antigen specificity showed binding to glands in human gastric mucosa corpus tissue sections for a CLL homology subset-2 Ab with HCDR3 motif-1, suggesting that this CLL subset recognize an autoantigen much like the CLL Abs tested in Paper I.Characterization of EBV-transformed CLL and normal lymphoblastoid cell lines (LCLs) in paper II showed that eight of the CLL cell lines were verified to be of authentic neoplastic origin. Indication for a biclonal CLL was found in two of the cell lines and two of the presumably normal LCLs turned out to represent the malignant CLL clone. For three cell lines no conclusive evidence for CLL origin could be found emphasizing the importance of verifying the identity of cell lines used in research.
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| 6. |
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| 7. |
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| 8. |
- Sahaf, Bita
(författare)
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Thioredoxin system in normal and transformed human cells
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Thioredoxin (Trx) and thioredoxin reductase (TrxR), together with NADPH, constitute the Trx system, a major antioxidant entity that helps maintain a reducing environment within living cells. Trx designates a family of proteins that are related on the basis of structure and function. Human full-length Trx is a 12 kDa redox-active protein that contains the evolutionarily conserved active site sequence Cys-Gly Pro-Cys. Truncated Trx is a shorter, 10 kDa form of human Trx that shows complete homology to the N-terminal 80 or 84 amino acids of 12 kDa Trx. Truncated Trx displays no reducing activity, even though it contains an intact active site. Human TrxR is a homodimeric, FAD-containing, selenoprotein that reduces oxidized Trx back to the enzymatically active form by consuming NADPH. Expression of human Trx and TrxR is induced by a variety of stressors. The Trx system functions directly and indirectly in important biological features such as DNA synthesis, gene expression, co-cytokine activity, chemokine properties, scavenging reactive oxygen intermediates, apoptosis, and growth regulation.Aims: The overall objective of this research was to examine the regulation and biological role of the Trx system in normal and transformed cells, and a possible connection with tumorigenesis. The specific aims were as follows: i) to study the presence and function of full-length and truncated Trx in normal and transformed human cells; ii) to assess the expression and function of TrxR; iii) to investigate the functional importance of truncated Trx; iv) to examine the regulatory mechanisms behind secretion of Trx, truncated Trx, and TrxR; v) to study full-length secreted Trx in human plasma.Methods: Using Köhler and Milstein hybridoma technology, monoclonal antibodies against full-length and truncated Trx, as well as TrxR, were developed and applied in various immunological methods to detect the proteins in and secreted from normal and transformed human cells.Results: Using selective monoclonal antibodies distinct intracellular localization of full-length and truncated Trx was shown. The latter was present in lower amounts, primarily associated with the plasma membrane; only small amounts of the 12 kDa were present on the plasma membrane. Moreover, we found that human TrxR was secreted from normal and transformed cells via a Golgi-dependent pathway. Using sensitive EUSPOT, TrxR release was quantified at the single-cell level and found to be inducible. TrxR was detected in plasma from healthy blood donors, and this protein was overexpressed in transformed cells, compared to their normal counterparts. Truncated 10 kDa Trx was present in and secreted from normal and transformed cells. Treatment of normal peripheral blood monocytes with LPS, IL-1, IFN-γ, PMA, ionomycin, and the thiol oxidant diarnide induced secretion of Trx. Trx was found within platelets, and liberation of this Trx was induced by diamide, implying a novel mechanism for release of Trx.Conclusions: Monoclonal antibodies were generated against full-length and truncated Trx as well as TrxR and proved to be useful tools for investigating these proteins. Full-length and truncated Trx were found to have different cellular functions, suggesting that C-temrinal truncation regulates the activity of Trx. Secretion of TrxR and the presence of thls enzyme in plasma imply that the Trx system has both intracellular and extracellular functions. The presence of Trx in platelets indicates participation of the protein in coagulation and possibly also in the effects of platelets that maintain the reducing capacity of human plasma.
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| 9. |
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| 10. |
- de Alwis, Manudul Pahansen, 1980-
(författare)
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Towards consonance in working conditions, health and performance aboard high-performance marine craft
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The High-Performance Marine Craft (HPMC) is a complex man-machine system dealing with the stochastic nature of the sea. The occupants of these craft are challenged by the strenuous work environments resulting in various detrimental conditions and reducing the overall performance of the system. The sophisticated craft, designed and developed for high operational demands, are underused due to the human limitations while occupants confronting various psychophysical impairments. A balance is required between the craft and human to get the most out of the system as an ensemble. Achieving that, the knowledge is essential about the human response to the working conditions aboard HPMC which is lacking in the scientific community.In this context, a research program has been commenced to investigate working conditions aboard HPMC and the response of the craft occupants in terms of health and performance. The thesis presents the research as a holistic approach to integrate the exposure-response relationship into HPMC design and operation.An epidemiological study is designed and executed to identify and quantify the risk associated with the working conditions aboard HPMC. As the first step, two web-based questionnaire tools are developed, validated and pilot tested for cross-sectional and longitudinal investigation of health and performance in HPMC occupants. Then a sample of HPMC occupants is investigated for work-related and individual risk factors relating to their work-exposure, health and performance in a cross-sectional cohort study. The prevalence of health impairments and performance degradation is determined while estimating their association with work exposure. Following that, another sample of HPMC occupants is longitudinally examined in a prospective cohort study for their work exposure, health and performance estimating the incidence of adverse health effects and its association with the occupational exposure to shock and vibration. Finally, a method is developed for a decision support feedback system continuously updating the crew during real-time operations on the severity of expected high-intensity short-duration impacts as well as the accumulated vibration exposure aboard HPMC.The cross-sectional study shows that the prevalence of musculoskeletal pain (MSP) among HPMC occupants is comparatively high and that the exposure to severe conditions aboard semi-displacement and planing craft increases the risk of MSP. The latter also increases the risk of performance degradation. The longitudinal study indicates an incidence of MSP and performance degradation in HPMC occupants. It also suggests that the accumulation of occupational exposure to shock and vibration aboard HPMC is a factor increasing the risk of MSP incidence while quantifying the level of risk. The introduced method for real-time crew feedback is capable of capturing the exposure severity and informing it to the crew in a sufficiently short time.The research has successfully achieved the objectives. It has also highlighted the areas that need further improvements and suggested the domains that require extended investigations.
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