| 1. |
- Abujrais, Sandy
(författare)
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Exploring the role of tryptophan metabolites in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) : Development and application of high resolution mass spectrometry methods
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a severe systemic disorder characterized by neurological, gastrointestinal, inflammatory symptoms and fatigue. Disregulation in tryptophan (TRP) metabolism and excessive kynurenine pathway activation may cause these symptoms. Thus, this thesis investigates TRP in ME/CFS. TRP, a key amino acid, regulates nervous system, immune system, endocrine system, and energy metabolism. The main pathway of TRP metabolism is kynurenine, with a minor percentage shuttled towards serotonin biosynthesis, a brain-essential neurotransmitter. Kynurenine metabolism generates kynurenic acid (neuroprotective) and quinolinic acid (neurotoxic).Our current knowledge of TRP metabolism in ME/CFS is insufficient. Few studies have quantified TRP in ME/CFS, and even fewer have employed high-resolution mass spectrometry, essential for accurate measurements and comprehensive metabolomics. Additionally, many studies disregarded factors like age and sex, which influence TRP metabolite levels. Lastly, preclinical research on the neuroprotective effects of KYN as a potential treatment is notably lackingTo address these research questions, we developed an accurate and comprehensive analytical method using liquid chromatography coupled with high-resolution mass spectrometry. This method quantifies TRP and its metabolites, along with the vitamins B2 and B6, essential for the enzymes in this pathway. Additionally, we measured the oxidative marker hypoxanthine and the amino acids tyrosine and phenylalanine, which compete with TRP to cross the blood-brain barrier, and limit its availability in the brain. We then employed the, TRP method and untargeted metabolomics, to compare the metabolic profiles of ME/CFS patients with those of healthy individuals, considering age and sex. Moreover, the effects of the menstrual cycle on TRP levels were examined by correlating 11 steroids with TRP metabolites. Additionally, the tissue distribution of kynurenine was investigated following both acute and chronic administration in a preclinical model.The untargeted study found alterations in the vitamin B3, arginine-proline, aspartate-asparagine, L-Adrenaline and S-Adenosyl-L-homocysteine pathways . While, the targeted approach revealed decreased levels of 3-hydroxykynurenine and 3-hydroxyanthranilic acid in ME/CFS patients. In addition, hypoxanthine and phenylalanine was elevated in ME/CFS patients, suggesting hypoxia and altered amino acid metabolism. The study found strong relationships between TRP metabolites and steroids during the menstrual cycle, suggesting hormones affect this pathway. Preclinical findings showed that kynurenine administration resulted in region-specific effects, with a potential neuroprotective effect in the hippocampus. These studies open avenues for further exploration of TRP metabolism, particularly in relation to ME/CFS and the impact of steroid hormones on this metabolic pathway.
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| 2. |
- Aguirre Rivera, Javier, 1989-
(författare)
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Tracking single molecules in uncharted territory : A single-molecule method to study kinetics in live bacteria
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The synthesis of proteins, also known as translation, is a fundamental process in every living organism. The steps in the translation of genetic information to functional proteins have been meticulously studied, mostly using in vitro techniques, yielding a detailed model of their mechanisms. However, the use of minimal cell-free systems allows for the possibility to miss interactions from absent components or that reactions are affected by the buffer composition. The work presented in this thesis opens a way to study the kinetics of complex molecular processes, like protein synthesis, directly inside live bacterial cells in real time. We developed and optimized a method to deliver dye-labeled macromolecules inside live cells and generate a kinetic model of the particle’s interactions based on its diffusion inside the cell.This method facilitated the study of translation elongation and initiation directly in live cells. Our measurements of reaction times of tRNA in the ribosome, agree with previous reports from in vitro techniques. We further applied the method to examine the effects of three aminoglycoside antibiotics and erythromycin directly in live cells. The aminoglycoside antibiotics slowed-down protein synthesis 2- to 4-fold, while the number of elongation cycles per initiation event decreased significantly. In the case of erythromycin, cells showed a 4-fold slower protein synthesis. Additionally, we measured the kinetics of sequence-specific effects of erythromycin: translational arrest, and peptidyl-tRNA drop-off; these in vivo measurements revealed a complex mechanism of action of the drug, in agreement with models suggested by previous experiments. Additionally, we applied the method to measure the effects, on the kinetics of protein synthesis, caused by modifications in the C-terminal tail of the S13 ribosomal protein. Our measurements showed that specific mutations led to different changes in the occupancy and dwell-time of labeled-tRNA in the ribosome.To summarize, the present work will guide the reader through the development of a method to study the kinetics of protein synthesis directly in live bacterial cells, as well as its application to characterize the effects of different antibiotics within the complex environment of a living organism.
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| 3. |
- Ahani, Ghafour
(författare)
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Optimal Scheduling for Timely Information in Communication Systems
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The explosive growth of data in information society poses significant challenges in the timely delivery of information in the context of communication networks. Hence, optimal utilization of scarce network resources is crucial. This dissertation contributes to several aspects related to the timely delivery of information, including scheduling of data flows between sources and destinations in a network, scheduling of content caching in a base station of mobile networks, and scheduling of information collection. Two important metrics, namely, delivery deadline and information freshness, are accounted for. Mathematical models and tailored solution approaches are developed via tools from optimization.Five research papers are included in the dissertation. Paper I studies a flow routing and scheduling problem with delivery deadline. This type of problem arises in many applications such as data exchange in scientific projects or data replication in data centers where large amounts of data need to be timely distributed across the globe. Papers II, III, and IV investigate content caching along time in a base station. Content caching at the network’s edge has recently been considered a costefficient way of providing users with their requested information. In Paper II, the schedule for updating the cache is optimized with respect to the content requests of users and the popularity of contents over time. Paper III, as an extension of Paper II, addresses the question of how to keep the cache information fresh, as all contents can not be updated due to the limited capacity of the backhaul link. The freshness of information is quantified via the notion of age of information (AoI). Paper IV investigates joint optimization of content caching as well as recommendation; the latter contributes to satisfying content requests in case of a cache miss. Paper V studies optimal scheduling of information collection from a set of sensor nodes via an unmanned aerial vehicle. The objective is to keep the overall AoI as small as possible.In these studies, analysis of problem complexity is provided, and timeefficient solution algorithms based on column generation, Lagrangian decomposition, and graph labeling are developed. The algorithms also yield a bound of global optimum, that can be used to assess the performance of any given solution. The effectiveness of the algorithms in obtaining nearoptimal solutions is demonstrated via extensive simulations.
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| 4. |
- Ahmed, Taha, 1984-
(författare)
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Nanostructured ZnO and metal chalcogenide films for solar photocatalysis
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The increasing demand for clean energy and safe water resources has driven the development of efficient and sustainable technologies. Among these technologies, photocatalysis using semiconducting materials has emerged as a promising solution for both solar hydrogen generation and water purification. Low-dimensional ZnO, including nanorods, nanoparticles, and quantum confined particles (so called quantum dots), has demonstrated excellent photocatalytic properties due to their large surface area, high electron mobility, and tunable band gap.The work in this thesis aims to investigate the potential of low-dimensional ZnO alone and in combination with CdS and Fe2O3 for solar hydrogen generation and photocatalytic water purification. The thesis includes a comprehensive analysis of the synthesis, characterization, and optimization of low-dimensional ZnO-based photocatalyst systems for solar hydrogen generation and photocatalytic water purification. Additionally, the thesis will evaluate the performance of the ZnO-based photocatalysts under different experimental conditions, either as photoelectrodes or as distributed particle systems for water purification. The work includes detailed size control of ZnO by itself in dimensions below 10 nm using a hydrothermal method, to provide an increased total surface area and introduce quantum confinement effects that increase the band gap to enable degradation of chemical bonds in a model pollutant in a distributed system for water purification. The work also includes a relatively detailed study of the phonon–phonon and electron–phonon coupling as a function of dimension from 10 nm to 150 nm for ZnO using non-resonant and resonant Raman spectroscopy. Ultimately, the thesis aims to provide insight into the potential of low-dimensional ZnO alone and in combination with other inorganic materials for solar hydrogen generation and photocatalytic water purification and pave the way for the development of efficient and sustainable technologies for clean energy and safe water resources.
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| 5. |
- Aihara, Aya, 1989-
(författare)
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Aeroacoustic Prediction for Vertical Axis Wind Turbines
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis investigates the aerodynamic and aeroacoustic prediction of vertical axis wind turbines, using computational fluid dynamics simulations. Noise pollution from wind turbines is one of the disadvantages of wind energy, calling for strategies to reduce noise levels. Yet for vertical axis wind turbines in particular, there is insufficient knowledge of how to identify sound sources and mitigate the sound level. The aim of this study is to predict aerodynamic noise, using large eddy simulation and acoustic analogy, so as to better understand the mechanism of sound generation for vertical axis wind turbines. First, the prediction method is validated for a static single blade in stall. This model is able to capture the dominant frequency, but it does not well reproduce the broadband characteristics. Next, the aerodynamic behavior of the 12 kW H-rotor vertical axis wind turbine is studied, whereby the focus is on the importance of properly modeling the strut influence for an accurate prediction of the blade forces. To achieve this, the flow field is solved for three different tip speed ratios. The results show that the struts significantly affect on the force distribution along the blade. The reduction of the blade force is observed to occur not only at the attachment points of the struts, but also over a large area of the blade section in the downwind side where the blade interacts with the wake created in the upwind. Finally, the noise radiated from the vertical axis wind turbine operating at high tip speed ratio is predicted. Measurements are conducted to validate the prediction, with the experimental data representing the broadband noise characteristics dominant at around 800 Hz. The prediction reproduces the sound pressure level observed at a radial distance of 1.4 rotor diameter, with a few decibels difference. However, these discrepancies become more pronounced at double distance, which can be considered to arise due to the effect of the ground reflection being ignored. The simulation furthermore indicates, that the main sound sources are emitted when the blade rotates in the downwind. It is suggested that future work should properly consider the atmospheric turbulence for more accurate predictions.
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| 6. |
- Alghamdi, Fayiq, 1985-
(författare)
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Dimensions of Professionalism : A Study of Computer Science Teaching in Saudi Arabia
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In Saudi Arabia, new computing education programs have been introduced in alignment with the Saudi Vision 2030, which is a plan launched in 2017 to reduce Saudi Arabia's reliance on oil, diversify its economy, and develop its health, education, recreation, infrastructure and tourism. Computer science is a rapidly changing area, which places high demands on teachers in the subject to develop both their subject and pedagogical competence. This thesis explores computer science teachers’ perspectives on professional development from three viewpoints—the Saudi Teaching Competencies Standard, engagement in teachers’ awards and self-directed learning. The thesis examines the efforts of computer science teachers as they develop new pedagogies during their teaching careers as a result of the new regulations. The main question is ‘How do Saudi Arabian computer science teachers develop their teaching professionalism?’ Conclusions draw on the outcomes of four sub-studies. A mixed-methods approach consisting of interviews and questionnaires was used to collect data. The participants comprised 389 computer science teachers from different Saudi Arabian cities with different demographics and different teaching experience. The analysis drew on a theoretical framework that integrates elements of the Theory of Reasoned Action, the Theory of Planned Behaviour and the Adult Learning Theory. A model for pedagogical change was developed and used to understand how and why computer science teachers change their educational pedagogy. The model explains the teachers’ shift in pedagogy and answers the question of how and why computer science teachers adopt a new pedagogical strategy. The studies show that both internal and external factors motivate the study participants to engage in competency development. In the Saudi model, the Saudi Teaching Competencies Standard and awards are external factors as they include a preparatory period of intensive skills development. Teachers' experience from this informs the picture of Saudi teachers' training that is presented in the dissertation. Indeed, the trial participants stated that they mainly used self-directed learning for their competence development, drawing on internal motivation. One reason for this was that they felt that many of the skills development programs offered lacked timeliness and relevance. The studies on which the dissertation is based have been conducted in Saudi Arabia, but the results also provide insights into general challenges associated with regulating teachers' competence and the design of in-service training for teachers. The results clearly point out the importance of teachers' participation in the development of the profession in order for changes to be accepted and incorporated into their profession. Behavior change theories can be used to understand and predict how new regulations and pedagogical strategies will be received, and if they are likely to be accepted or rejected by teachers. These theories, therefore, constitute a useful tool in regulating teaching and the teaching profession.
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| 7. |
- Ali, Hasan, 1985-
(författare)
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Towards atomically resolved magnetic measurements in the transmission electron microscope : A study of structure and magnetic moments in thin films
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The magnetic properties of thin metallic films are significantly different from the bulk properties due to the presence of interfaces. The properties shown by such thin films are influenced by the atomic level structure of the films and the interfaces. Transmission electron microscope (TEM) has the potential to analyse the structure and the magnetic properties of such systems with atomic resolution. In this work, the TEM is employed to characterize the structure of the Fe/V and Fe/Ni multilayers and the technique of electron magnetic circular dichroism (EMCD) is developed to obtain the quantitative magnetic measurements with high spatial resolution.From TEM analysis of short period Fe/V multilayers, a coherent superlattice structure is found. In short period Fe/Ni multilayer samples with different repeat frequency, only the TEM technique could verify the existence of the multilayer structure in the thinnest layers. The methods of scanning TEM imaging and electron energy loss spectroscopy (EELS) results were used and refined to determine interdiffusion at the interfaces. The confirmation of the multilayer structure helped to explain the saturation magnetization of these samples.Electron magnetic circular dichroism (EMCD) has the potential to quantitatively measure the magnetic moments of the materials with atomic resolution, but the technique presents several challenges. First, the EMCD measurements need to acquire two EELS spectra at two different scattering angles. These spectra are mostly acquired one after the other which makes it difficult to guaranty the identical experimental conditions and the spatial registration between the two acquisitions. We have developed a technique to simultaneously acquire the two angle-resolved EELS spectra in a single acquisition. This not only ensures the accuracy of the measurements but also improves the signal to noise ratio as compared to the previously used methods. The second important question is the effect of crystal orientations on the measured EMCD signals, considering the fact that the crystal orientation of a real crystal does not remain the same in the measured area. We developed the methodology to simultaneously acquire the EMCD signals and the local crystal orientations with high precision and experimentally showed that the crystal tilt significantly changes the magnetic signal. The third challenge is to obtain EMCD measurements with atomic resolution which is hampered by the need of high beam convergence angles. We further developed the simultaneous acquisition technique to obtain the quantitative EMCD measurements with beam convergence angles corresponding to atomic size electron probes.
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| 8. |
- Ali, Muhammad, 1990-
(författare)
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Identification of SLiMs: Mapping and characterizing motif-based protein interactions
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During the last twenty years it has become evident that about 35-40% of amino acids in the proteome are in regions that have evolved to remain unstructured. These intrinsically disordered regions contain short linear motifs (SLiMs), which serve as docking sites for protein-protein interactions. SLiMs often mediate low-to-medium affinity interactions that are transient in their nature. The characteristics of SLiM-based interactions make them difficult to be captured using conventional approaches like affinity-purification coupled to mass spectrometry or yeast-two-hybrid. We therefore used and developed a dedicated method for large-scale screening of SLiM-based interactions termed proteomic peptide phage display (ProP-PD).Using ProP-PD, We identified large sets of ligands, for the binding pocket of shank1 PDZ domain, containing C-terminal or internal binding motifs and established the consensus motifs to be xTxL/F-COOH and xTxFx respectively. We further validated interactions using biophysical affinity determinations and pulldown experiments. Using X-ray crystallization, we uncovered that shank1 PDZ binds to internal xTxFx motifs using a binding mode similar to that for C-terminal peptides.Adding a level of complexity, we explored interactions of the multiple binding pocket containing FERM domains from four closely related proteins: ezrin, radixin, moesin and merlin. We found hundreds of FERM ligands, which contained binding motifs of at least four different classes. By combining docking simulations with experiments, we established ligands binding to different pockets, and uncovered a complex interplay between distinct pockets.We further developed an optimized version of a phage library that displays intrinsically disordered regions of the human proteome. We benchmarked the library using a set of protein domains and reported better recovery of known SLiM-based interactions. Furthermore, we highlighted the functional aspects of identified SLiMs, in the case of nuclear localization signals, found for binding to importin-subunit alpha-3. Finally, we validated predicted binding of SLiMs in the Sars-CoV-2 host receptor ACE2, which illustrates the importance of fundamental knowledge for SLiMs and their binding partners.This work, taken together, contributes with method development for expansion of motifs based interactomes and provide insights into the plastic yet selective nature of peptide binding proteins.
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| 9. |
- Alipour, Mehdi
(författare)
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Rethinking Dynamic Instruction Scheduling and Retirement for Efficient Microarchitectures
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Out-of-order execution is one of the main micro-architectural techniques used to improve the performance of both single- and multi-threaded processors. The application of such a processor varies from mobile devices to server computers. This technique achieves higher performance by finding independent instructions and hiding execution latency and uses the cycles which otherwise would be wasted or caused a CPU stall. To accomplish this, it uses scheduling resources including the ROB, IQ, LSQ and physical registers, to store and prioritize instructions.The pipeline of an out-of-order processor has three macro-stages: the front-end, the scheduler, and the back-end. The front-end fetches instructions, places them in the out-of-order resources, and analyzes them to prepare for their execution. The scheduler identifies which instructions are ready for execution and prioritizes them for scheduling. The back-end updates the processor state with the results of the oldest completed instructions, deallocates the resources and commits the instructions in the program order to maintain correct execution.Since out-of-order execution needs to be able to choose any available instructions for execution, its scheduling resources must have complex circuits for identifying and prioritizing instructions, which makes them very expansive, therefore, limited. Due to their cost, the scheduling resources are constrained in size. This limited size leads to two stall points respectively at the front-end and the back-end of the pipeline. The front-end can stall due to fully allocated resources and therefore no more new instructions can be placed in the scheduler. The back-end can stall due to the unfinished execution of an instruction at the head of the ROB which prevents other resources from being deallocated, preventing new instructions from being inserted into the pipeline.To address these two stalls, this thesis focuses on reducing the time instructions occupy the scheduling resources. Our front-end technique tackles IQ pressure while our back-end approach considers the rest of the resources. To reduce front-end stalls we reduce the pressure on the IQ for both storing (depth) and issuing (width) instructions by bypassing them to cheaper storage structures. To reduce back-end stalls, we explore how we can retire instructions earlier, and out-of-order, to reduce the pressure on the out-of-order resource.
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| 10. |
- Ament-Velásquez, Sandra Lorena, M.Sc. 1988-
(författare)
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Drivers of evolutionary change in Podospora anserina
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Genomic diversity is shaped by a myriad of forces acting in different directions. Some genes work in concert with the interests of the organism, often shaped by natural selection, while others follow their own interests. The latter genes are considered “selfish”, behaving either neutrally to the host, or causing it harm. In this thesis, I focused on genes that have substantial fitness effects on the fungus Podospora anserina and relatives, but whose effects are very contrasting. In Papers I and II, I explored the evolution of a particular type of selfish genetic elements that cause meiotic drive. Meiotic drivers manipulate the outcome of meiosis to achieve overrepresentation in the progeny, thus increasing their likelihood of invading and propagating in a population. In P. anserina there are multiple meiotic drivers but their genetic basis was previously unknown. In Paper I, we demonstrated that drive is caused by members of the Spok gene family. We discovered two new Spok genes, Spok3 and Spok4, which locate in different chromosomes in different strains. In Paper II, we showed that Spok3 and Spok4 are found on a gigantic (up to 247 Kb long) variant of Enterprise, a Crypton-like transposable element. Enterprise likely mobilize through the action of a putative tyrosine-recombinase that we call Kirc. When carrying the Spoks, this element has double selfish properties: transposition and meiotic drive. In addition, we found that homologs of the Spoks (Paper I) and of Kirc (Paper II) are widespread in fungi but their phylogenies are discordant with that of the species, suggesting that they have undergone horizontal gene transfer. In Papers III and IV, I turned the focus into genes that have an adaptive function. In fungi, the het genes control conspecific self/non-self recognition. Such genes are expected to evolve under frequency-dependent balancing selection. In Paper III, we found evidence of balancing selection acting on some het genes across the P. anserina species complex. Unexpectedly, we also discovered that het genes of the HNWD gene family are duplicated in a transposon-like manner, broadening our understanding of their potential fitness effects. Finally, in Paper IV we show how het genes with pleiotropic effects on sexual recognition lead to the evolution of strong reproductive isolation, and hence speciation. Overall, the results of my thesis highlight the functional intersection between mobile selfish genetic elements and other genes, either selfish or adaptive, and their effects on genome architecture and population structure.
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