Modeling normal and malignant hematopoiesis in vitro. To screen for extrinsic regulators and differentiation therapy.

The incredible thing with blood stem cells, also known as hematopoietic stem cells (HSC), is that they can restore normal hematopoiesis in patients that need a new blood system. Since a prerequisite for successful transplantation is immune compatibility, it requires large donor registries to find a suitable match for a recipient. Unfortunately, there is still a shortage of immune-compatible donors in these registries. Thus one potential approach to improve the quantity and quality of these registries is to expand HSC in umbilical cord blood units. However, robust in vitro expansion of human HSC is not possible yet. Thus, in vitro expansion of HSC is a high-value objective in hematological research.A common reason patients need a new blood system is blood cancer. An added benefit of transferring someone’s else blood system to a cancer patient is that the donor’s immune cells can help eradicate the cancer cells. Because the transfer of a new blood system is not without risks, as the donor’s immune cells also target normal tissues, physicians will only transplant when the cancer treatment is not potent enough to eradicate the cancer cells. Even though the cancer therapies of some AML subtypes are effective today, the prognosis of most cancer types would improve with new therapies. Thus, developing new therapies is another high-value objective in hematological research.Here we addressed both of these objectives by using a mesenchymal stroma-based co-culture model for culturing primary acute myeloid leukemia (AML) cells and HSC to identify differentiation therapy of AML (papers I and II), improve culture conditions of HSC (paper III), and for investigating synthetic lethality in AML (paper IV). Thus, the common thread of the four papers included in this thesis is the use of OP9M2 cells to model normal and malignant hematopoiesis.In paper I, we identified a natural product that induces differentiation in AML through activation of the PKC pathway. Moreover, we show that AML with FLT3-ITD or FLT3 mutations are resistant to differentiation, highlighting the importance of neutralizing the effect of mutated FLT3 in differentiation therapy. This study illustrates how small molecule screening and genetic profiling are powerful tools for developing personalized treatments.Paper II is a small molecule screening protocol based on the OP9M2 co-culture model of primary AML cells. With a flow-cytometry readout, the protocol is highly adjustable to different study objectives, including screening for novel therapeutic agents, drug repurposing, drug synergism, patient selection, mechanism of action analysis, and drug resistance. Methods such as these will continue to be crucial for developing new therapies to improve outcomes for many patient groups.In Paper III, we identified potential regulators of HSC, which we screened by shRNA knockdown in the OP9M2 model. However, it did not identify any candidates, likely due to a sub-optimal screening methodology. Still, the list of potential regulators could be helpful for similar studies. Improving in vitro culture conditions remains a high-value objective as cellular therapies will continue to be essential for treating hematological diseases.Paper IV shows that STAG1 and STAG2 have a synthetic lethal interaction in primary AML cells. Thus, targeting STAG1 or STAG2 in STAG1- or STAG2-null AML is potentially a new precision medicine for molecular targeted therapy. This study shows how an in-depth understanding of disease heterogeneity and subtype-specific weaknesses is critical for developing precision medicine

Impact of Glass Formation on the Thermal Stability of Non-Fullerene Solar Cells

The world is facing immense challenges such as climate change and the depletion of non-renewable resources, making renewable sources of energy essential for a sustainable future. Organic solar cells are emerging as a promising technology; however, their stability requires significant improvement. The nanostructure of the active layer evolves over time, especially during heating, leading to a degradation in device performance. The focus of this thesis is to improve the thermal stability of the active layer.Firstly, the thesis studies the impact of mixing on glass formation by introducing the concept of kinetic fragility to organic semiconductors. Model systems of up to eight perylene derivatives are investigated that demonstrate an unprecedented ability to form a stable molecular glass due to aggregate formation. Next, the thesis discusses the impact of isomers on glass formation, which is illustrated with an anthradithiophene-based compound. Binary mixtures of isomers were also found to form aggregates that stabilize the liquid state. In addition, the thesis describes fragility studies of doped systems and establishes that chemical doping can affect the glass formation of a semiconducting polymer. The doped polymer shows a strong tendency for glass formation which is assigned to restricted motion of oxidized polymer chains. Furthermore, the thesis analyzes mixtures of organic photovoltaic acceptors. Binary mixtures of two indacenodithienothiophene-based acceptors are found to co-crystallize, while mixtures of three to five fused-ring non-fullerene acceptors exhibited a reduced tendency to crystallize. Finally, the thesis discusses the use of acceptor mixtures for improving the thermal stability of organic photovoltaic devices. Ternary solar cell devices with two acceptors are discussed that show a stable nanostructure and improved thermal stability compared to binary devices. The thesis also explores hexanary devices that consist of five acceptor molecules, which exhibit excellent thermal stability. Therefore, the use of multicomponent acceptor mixtures is found to be a powerful tool for creating thermally stable organic solar cells

A theory for the streamwise turbulent fluctuations in high Reynolds number pipe flow

A new theory for the streamwise turbulent fluctuations in fully developed pipe flow is proposed. The theory extends the similarities between the mean flow and the streamwise turbulence fluctuations, as observed in experimental high Reynolds number data, to also include the theoretical derivation. Connecting the derivation of the fluctuations to that of the mean velocity at finite Reynolds number as introduced by Wosnik, Castillo & George (J. Fluid Mech., vol. 421, 2000, pp. 115-145) can explain the logarithmic behaviour as well as the coefficient of the logarithm. The slope of the logarithm, for the fluctuations, depends on the increase of the fluctuations with Reynolds number, which is shown to agree very well with the experimental data. A mesolayer, similar to that introduced by Wosnik et al., exists for the fluctuations for $300\gt {y}^{+ } \gt 800$ , which coincides with the mesolayer for the mean velocities. In the mesolayer, the flow is still affected by viscosity, which shows up as a decrease in the fluctuation

Analytical and Numerical Study of Thermally Stratified Flow above a forest

In order for our energy consumption to be sustainable, we need to rely more and more on renewable energy resources, such as solar power and wind power. In Sweden, 69% of the land area is covered in forest. To open up the possibility of exploiting these forested areas for wind power production, it is desired to gain a better knowledge of the flow situation above forests. An analytical and a numerical study has been carried out, in order to investigate the flow above forests. The thermal stratification of the atmospheric boundary layer has been taken into account to investigate its influence on the characteristics of the flow. The analytical study was performed by analyzing meteorological measurements collected by Göteborg Energi at a site near Töreboda, Sweden, which is mostly covered in forest. In the numerical study, Large Eddy Simulations were carried out. The results obtained from the numerical study were compared to the results of the analytical study. The results showed that the characteristics of the flow varies with thermal stratifiaction. The wind shear was highest with stable stratification, while the turbulence intensity was highest with unstable stratification. The results from the Large Eddy Simulations showed some agreement with the results from the analytical study, but further improvements are needed for better agreement. When investigating the effect of the flow, the results showed that the forest increased both the wind shear and the turbulence intensity. At the site in Töreboda, there were high occurrence of non-favourable wind conditions for wind power, with high wind shear and high turbulence intensity

Students’ Reasoning About Sustainable Development in Relation to Products’ Life Cycles

In this study, we investigate Secondary School students’ reasoning about a product’s life cycle in relation to three dimensions of sustainable development: economic-, social- and ecological sustainable development. Production and consumption are part of a complex socio-technological system that affects nature and life on earth and knowledge about this complex system are required to achieve sustainable development. In technology education, students can get the opportunity to reason about products and their life cycles. Hence, this study aims to explore what emerges in students’ reasoning about products’ life cycles in relation to sustainable development. Data collection was made through two semi-structured interviews where the students participated in focus groups containing 3 and 4 participants in each group. All student responses have been analysed through thematic analysis to explore dimensions of sustainability. Results show that the students reason with regard to all three dimensions of sustainable development. However, the three dimensions occur to a varying extent within the different phases of a product’s life cycle. Additionally, the students also connect dimensions in their reasoning, with both harmonies and contrasted perspective. Participating students’ reasoning indicated traces of an anthropocentric approach. These results have implications for technology education both associated to content and practice, which is an important step towards education for conscious consumers

In vivo detection of lamellocytes in Drosophila melanogaster.

Drosophila has recently become a powerful model organism for studies of innate immunity. The cellular elements of innate immunity in Drosophila, the hemocytes, have been characterized by morphological criteria, molecular markers, and cell-type-specific immunological markers. Here we suggest that an MiET1 GFP-reporter element insertion in the untranslated region of a gene (l1-atilla) - expressed in a subset of hemocytes, the lamellocytes - allows in vivo investigations of lamellocyte differentiation and facilitates genetic screens

A theory for the streamwise turbulent fluctuations in high Reynolds number pipe flow

A new theory for the streamwise turbulent fluctuations in fully developed pipe flow is proposed. The theory extends the similarities between the mean flow and the streamwise turbulence fluctuations, as observed in experimental high Reynolds number data, to also include the theoretical derivation. Connecting the derivation of the fluctuations to that of the mean velocity at finite Reynolds number as introduced by Wosnik, Castillo & George (J. Fluid Mech., vol. 421, 2000, pp. 115-145) can explain the logarithmic behaviour as well as the coefficient of the logarithm. The slope of the logarithm, for the fluctuations, depends on the increase of the fluctuations with Reynolds number, which is shown to agree very well with the experimental data. A mesolayer, similar to that introduced by Wosnik et al., exists for the fluctuations for 300 > y(+) > 800, which coincides with the mesolayer for the mean velocities. In the mesolayer, the flow is still affected by viscosity, which shows up as a decrease in the fluctuations