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| 2. |
- Thörn, Ingrid, 1957-, et al.
(författare)
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Minimal residual disease assessment in childhood acute lymphoblastic leukemia : Results of a Swedish multi-centre study comparing real-time PCR and multi-colour flow cytometry
- 2009
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In this Swedish multi-center study of early treatment response in childhood acute lymphoblastic leukemia (ALL), we evaluated the concordance between multicolour flow cytometry (FCM) and real-time quantitative polymerase chain reaction (RQ-PCR) for assessment of minimal residual disease (MRD). Multiple time points (i.e. day 15, 29, 50 and 106) were evaluated with the NOPHO (Nordic Society of Pediatric Hematology and Oncology) ALL 2000 treatment protocol as backbone. During 2002-2006, 334 children were diagnosed with ALL, where 228 had paired samples taken at any of the four time points. With the detection level of 0.1%, the concordance between RQ-PCR and FCM was 90% in the 726 paired samples analyzed. At day 29, the correlation between the methods was greater with MRD levels >0.1% (rs=0.7, p<0.001) than below (rs=0.2, p=0.024). MRD levels higher than 0.1% at day 29 was a significant predictor of higher risk of having a bone marrow relapse. This was true both for BCP ALL and T-ALL analysed with either FCM or RQ-PCR, although RQ-PCR was a better discriminator than FCM in T-ALL. However, using the NOPHO ALL 2000 protocol, our data indicate that a higher cut-off value (0.2%) should be applied in BCP ALL when using RQ-PCR as MRD method. In contrast, MRD levels ≥ 0.1%, analysed with either method late during induction therapy, was not a predictor of isolated extramedullary relapse. We therefore conclude that MRD assessment by RQ-PCR based IG/TCR rearrangement and multicolour FCM monitoring can be used as a clinical tool if the aim is to find childhood ALL cases with increased risk of having bone marrow relapses.
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| 3. |
- Thörnerup, Ingrid, et al.
(författare)
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Minimal residual disease assessment in childhood acute lymphoblastic leukaemia: a Swedish multi-centre study comparing real-time polymerase chain reaction and multicolour flow cytometry.
- 2011
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 152:6, s. 743-753
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Tidskriftsartikel (refereegranskat)abstract
- Minimal residual disease (MRD) assessment is a powerful prognostic factor for determining the risk of relapse in childhood acute lymphoblastic leukaemia (ALL). In this Swedish multi-centre study of childhood ALL diagnosed between 2002 and 2006, the MRD levels were analysed in 726 follow-up samples in 228 children using real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes and multicolour flow cytometry (FCM). Using an MRD threshold of 0·1%, which was the sensitivity level reached in all analyses, the concordance between RQ-PCR and FCM MRD values at day 29 was 84%. In B-cell precursor ALL, an MRD level of ≥0·1% at day 29 predicted a higher risk of bone marrow relapse (BMR) with both methods, although FCM was a better discriminator. However, considering the higher median MRD values achieved with RQ-PCR, a higher MRD cut-off (≥0·2%) improved the predictive capacity of RQ-PCR. In T-ALL, RQ-PCR was notably superior to FCM in predicting risk of BMR. That notwithstanding, MRD levels of ≥0·1%, detected by either method at day 29, could not predict isolated extramedullary relapse. In conclusion, the concordance between RQ-PCR and FCM was high and hence both methods are valuable clinical tools for identifying childhood ALL cases with increased risk of BMR.
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| 4. |
- Abdel-Fattah, Wael R., et al.
(författare)
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Growth-regulated co-occupancy of Mediator and Lsm3 at intronic ribosomal protein genes
- 2024
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Ingår i: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 52:11, s. 6220-6233
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Tidskriftsartikel (refereegranskat)abstract
- Mediator is a well-known transcriptional co-regulator and serves as an adaptor between gene-specific regulatory proteins and RNA polymerase II. Studies on the chromatin-bound form of Mediator revealed interactions with additional protein complexes involved in various transcription-related processes, such as the Lsm2–8 complex that is part of the spliceosomal U6 small nuclear ribonucleoprotein complex. Here, we employ Chromatin Immunoprecipitation sequencing (ChIP-seq) of chromatin associated with the Lsm3 protein and the Med1 or Med15 Mediator subunits. We identify 86 genes co-occupied by both Lsm3 and Mediator, of which 73 were intron-containing ribosomal protein genes. In logarithmically growing cells, Mediator primarily binds to their promoter regions but also shows a second, less pronounced occupancy at their 3́-exons. During the late exponential phase, we observe a near-complete transition of Mediator from these promoters to a position in their 3́-ends, overlapping the Lsm3 binding sites ∼250 bp downstream of their last intron–exon boundaries. Using an unbiased RNA sequencing approach, we show that transition of Mediator from promoters to the last exon of these genes correlates to reduction of both their messenger RNA levels and splicing ratios, indicating that the Mediator and Lsm complexes cooperate to control growth-regulated expression of intron-containing ribosomal protein genes at the levels of transcription and splicing.
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| 5. |
- Adli, Erik, et al.
(författare)
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Progress Of The Ess Proton Beam Imaging Systems
- 2022
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Ingår i: LINAC2022. - : ACoW Publishing. ; , s. 395-398
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Konferensbidrag (refereegranskat)abstract
- The ESS Target Proton Beam Imaging Systems has the objective to image the 5 MW ESS proton beam as it entersthe spallation target. The imaging systems has to operate in a harsh radiation environment, leading to a number of challenges : development of radiation hard photon sources, long and aperture-restricted optical paths and fast electronics required to provide rapid information in case of beam anomalies. This paper outlines how main challenges of the imaging systems have been addressed, and the status of deployment as ESS gets closer to beam.
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| 6. |
- Aguilar, Ximena, 1978-
(författare)
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Folding and interaction studies of subunits in protein complexes
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Proteins function as worker molecules in the cell and their natural environment is crowded. How they fold in a cell-like environment and how they recognize their interacting partners in such conditions, are questions that underlie the work of this thesis.Two distinct subjects were investigated using a combination of biochemical- and biophysical methods. First, the unfolding/dissociation of a heptameric protein (cpn10) in the presence of the crowding agent Ficoll 70. Ficoll 70 was used to mimic the crowded environment in the cell and it has been used previously to study macromolecular crowding effects, or excluded volume effects, in protein folding studies. Second, the conformational changes upon interaction between the Mediator subunit Med25 and the transcription factor Dreb2a from Arabidopsis thaliana. Mediator is a transcriptional co-regulator complex which is conserved from yeast to humans. The molecular mechanisms of its action are however not entirely understood. It has been proposed that the Mediator complex conveys regulatory signals from promoter-bound transcription factors (activators/repressors) to the RNA polymerase II machinery through conformational rearrangements.The results from the folding study showed that cpn10 was stabilized in the presence of Ficoll 70 during thermal- and chemical induced unfolding (GuHCl). The thermal transition midpoint increased by 4°C, and the chemical midpoint by 0.5 M GuHCl as compared to buffer conditions. Also the heptamer-monomer dissociation was affected in the presence of Ficoll 70, the transition midpoint was lower in Ficoll 70 (3.1 μM) compared to in buffer (8.1 μM) thus indicating tighter binding in crowded conditions. The coupled unfolding/dissociation free energy for the heptamer increased by about 36 kJ/mol in Ficoll. Altogether, the results revealed that the stability effect on cpn10 due to macromolecular crowding was larger in the individual monomers (33%) than at the monomer-monomer interfaces (8%).The results from the interaction study indicated conformational changes upon interaction between the A. thaliana Med25 ACtivator Interaction Domain (ACID) and Dreb2a. Structural changes were probed to originate from unstructured Dreb2a and not from the Med25-ACID. Human Med25-ACID was also found to interact with the plant-specific Dreb2a, even though the ACIDs from human and A. thaliana share low sequence homology. Moreover, the human Med25-interacting transcription factor VP16 was found to interact with A. thaliana Med25. Finally, NMR, ITC and pull-down experiments showed that the unrelated transcription factors Dreb2a andVP16 interact with overlapping regions in the ACIDs of A. thaliana and human Med25.The results presented in this thesis contribute to previous reports in two different aspects. Firstly, they lend support to the findings that the intracellular environment affects the biophysical properties of proteins. It will therefore be important to continue comparing results between in vitro and cell-like conditions to measure the magnitude of such effects and to improve the understanding of protein folding and thereby misfolding of proteins in cells. Better knowledge of protein misfolding mechanisms is critical since they are associated to several neurodegenerative diseases such as Alzheimer’s and Parkinson's. Secondly, our results substantiate the notion that transcription factors are able to bind multiple targets and that they gain structure upon binding. They also show that subunits of the conserved Mediator complex, despite low sequence homologies, retain a conserved structure and function when comparing evolutionary diverged species.
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| 7. |
- Aguilar, Ximena, 1978-, et al.
(författare)
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Interaction Studies of the Human and Arabidopsis thaliana Med25-ACID Proteins with the Herpes Simplex Virus VP16-and Plant-Specific Dreb2a Transcription Factors
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:5, s. e98575-
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Tidskriftsartikel (refereegranskat)abstract
- Mediator is an evolutionary conserved multi-protein complex present in all eukaryotes. It functions as a transcriptional coregulator by conveying signals from activators and repressors to the RNA polymerase II transcription machinery. The Arabidopsis thaliana Med25 (aMed25) ACtivation Interaction Domain (ACID) interacts with the Dreb2a activator which is involved in plant stress response pathways, while Human Med25-ACID (hMed25) interacts with the herpes simplex virus VP16 activator. Despite low sequence similarity, hMed25-ACID also interacts with the plant-specific Dreb2a transcriptional activator protein. We have used GST pull-down-, surface plasmon resonance-, isothermal titration calorimetry and NMR chemical shift experiments to characterize interactions between Dreb2a and VP16, with the hMed25 and aMed25-ACIDs. We found that VP16 interacts with aMed25-ACID with similar affinity as with hMed25-ACID and that the binding surface on aMed25-ACID overlaps with the binding site for Dreb2a. We also show that the Dreb2a interaction region in hMed25-ACID overlaps with the earlier reported VP16 binding site. In addition, we show that hMed25-ACID/Dreb2a and aMed25-ACID/Dreb2a display similar binding affinities but different binding energetics. Our results therefore indicate that interaction between transcriptional regulators and their target proteins in Mediator are less dependent on the primary sequences in the interaction domains but that these domains fold into similar structures upon interaction.
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| 8. |
- Aid, Graham, 1980-
(författare)
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Operationalizing Industrial Ecology in the Waste Sector : Roles and tactics for circular value innovation
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The take-make-waste approach to resource management in human production and consumption systems is contributing to a variety of environmental and social problems worldwide. Additionally, as the world’s population and affluence increase, so do the negative impacts of poor resource management. Lifting the waste management (WM) sector into a new phase of development, which takes its lead from the ideals of Industrial Ecology and circular economy, is seen by many scholars and practitioners as one potential to assist in alleviating these impacts. While there are many studies on how more efficient inter-organizational resource management is (or could be) constructed, there are relatively few business development studies which have explored novel approaches (from roles to tactics) that WM organizations might operationalize toward more efficient resource management.The aim of this thesis is to contribute to the development of knowledge and understanding of how the waste management sector can operationalize more effective and efficient resource management. In approaching this aim, two research questions guided the exploration of: 1) novel roles for WM and 2) support tactics for such roles. Grounded in the broader context of Industrial Ecology (IE) and Business Development, five studies were performed. Two studies, focused on the novel roles of inter-organizational resource management and high value secondary resource extraction, were performed through literature review and interviews, and market driver analysis respectively. In exploring support tactics, two design and proof of concept studies were carried out to investigate data analysis tools for inter-organizational resource management, and one long-term action research engagement project was coordinated to study hands-on inter-organizational collaboration tactics.The studies highlighted that the Swedish WM sector holds some key capacities for operationalizing (and in some cases, is already developing) the novel resource management roles identified: industrial symbiosis facilitator, eco-industrial park manager, holistic facility management, and high value resource extractor. However, depending on the portfolio of services to be performed in such roles, several capacities may need to be developed or strengthened. Main opportunities seen for these roles were – staying ahead of market developments, and aligning activities with organizational goals. The main general risk related to these roles was insufficient returns on investment. Looking forward, the main enablers identified were policy leadership for more balanced market mechanisms, increasing use of external knowledge, developing long term partnerships, lobbying, stockpiling resources, and carefully crafting new business models.The tools developed for strategically applying external information toward the identification of opportunities within new roles showed tactical potential. However, their implementation in broader development processes has yet to be fully validated. The hands-on exploration of change oriented collaboration, highlighted collective system framing and goal setting and face-to-face interaction as key activities for inter-organizational approaches within roles such as industrial symbiosis facilitator.Throughout the studies, several novel roles were investigated. Each of these roles will need to be individually evaluated by directing bodies of WM organizations, and evaluated from the organization’s vision and strategy. If certain roles are chosen to be explored in more detail, they will need to be developed within full business models - addressing issues such as income structure, internal processes and capacities to be developed, and key customers. Through applying IE and business development concepts and findings, WM organizations have possibilities to translate ambitious visions into novel offerings.
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| 9. |
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| 10. |
- Andersson, Martin
(författare)
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Churning losses and efficiency in gearboxes
- 2014
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Efficient transmissions systems are key to producing competitive motor vehicles that have a smaller environmental impact. Gears are the main components in vehicle transmissions and although they are already highly efficient, there is still room for improvement. In this study, the focus falls on the lubricant used to create separating films between gears and todissipate heat. When driving, the gears churn this lubricant, giving rise to power losses that are related to the amount and properties of the lubricant. However, any attempt to reduce these losses must not compromise the required lubrication and heat dissipation. Paper A reports on the use of an FZG gear test rig to investigate power losses and heat generation for different gear immersion depths, surface roughness and coatings. The results show that lower gear roughness reduces gear mesh losses and heat generation. A polishing affect was obtained when a non-coated gear ran against a coated gear.The aim of the research reported in paper B was to increase the accuracy of efficiency testing. It investigated how and whether repeated disassembly and re-assembly of the same test equipment, as well as test performance and rig conditions, affect the measured torque loss in an FZG gear test rig. It was shown that the measured torque loss changes between one assembly and another. Repeatability between tests is crucial for accurate conclusions.The aim of the research reported in paper C was to study whether gear efficiency could be increased by a running-in procedure, which would reduce the need for a coolant. A back-to-back gear test rig was used to test two running-in loads. Higher gear mesh efficiency was seen when a higher running-in load was used.
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