Publikationer från Uppsala Universitet
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Barns röster i skuggan av vuxna : En diskursanalys av barns inflytande
No full textStudiens syfte var att analysera hur barns inflytande och maktrelationer framställs i policydokument samt i barnlitteratur som läromedel över olika tidsperioder och hur synen på barn förändras genom historien. Studien utgick från ett läroplansteoretiskt perspektiv, med särskilt fokus på formuleringsarenan, transformeringsarenan och realiseringsarenan. Genom detta teoretiska ramverk bestod studien av två delstudier som båda tillämpade en kvalitativ metod i form av diskursanalys, men med olika empiriskt material. Den första delstudien analyserade policydokument för att undersöka hur barns inflytande formuleras i dessa texter. Den andra delstudien granskade barnlitteratur som läromedel och undersökte hur barns inflytande och maktrelationer framställs och förändras över tid. Denna studie visar att barns inflytande konstrueras olika beroende på texttyp och sammanhang. Både policydokument och barnlitteratur har en normerande funktion och påverkar hur barns inflytande förstås och praktiseras i förskolan. Resultaten visar att barns inflytande inte är en självklar process, utan något som tolkas, förhandlas och ibland försvaras i det pedagogiska arbetet.
From scission to metastability : Isomeric yield ratios in fission studies
No full textDespite significant advances in nuclear physics, key questions remain open about how a nucleus splits into fragments at scission. The properties of the resulting fission fragments (FF) can be indirectly studied by detecting the products after their de-excitation. During the de-excitation process, FFs emit neutrons and γ-rays until they reach metastable states. Several nuclei have more than one long-lived metastable state, differing in spin and excitation energy, which are called isomers. The ratio of their production rates, known as the isomeric yield ratio (IYR), depends on the properties of the fission fragment and can be used to gain insight into its angular momentum. The IYRs of 22 products of the fission of 232Th induced by 28 MeV α particles were measured at the IGISOL facility at the University of Jyväskylä. Two measurement techniques were used, both relying on the mass-dependent spatial separation of the isomeric states: phase-imaging ion-cyclotron-resonance and multi-reflection time-of-flight mass-spectrometry. By comparing the newly measured IYRs with literature data from photofission and neutron-induced fission, it was found that the angular momentum of the compound nucleus undergoing fission has a significant impact on the fragments angular momentum, while its excitation energy has little to no influence. Additionally, the measured IYRs for yttrium and niobium isotopes showed an anomalously low IYR for 98Y. This unusual behavior is likely due to the shape coexistence in 98Y that was reported in previous studies. Furthermore, a model was developed to test sawtooth-like functional dependencies of the FF angular momentum on mass using the measured IYRs. Preliminary results give support to the observed sawtooth behavior of FF spin as function of mass, recently reported by Wilson et al. (2021), and the finding reported in this thesis regarding the impact of CN spin on the FFs angular momentum. Finally, a study of the level density models implemented in the nuclear model code TALYS is presented, where calculated and experimental IYRs from of a large number of nuclear reactions (excluding fission) from literature are compared. A bias was found in the models that favors the population of the high-spin states. The reason is attributed to a too wide spin-width distribution in the level density
Från papper och penna till dator och tangentbord : En enkätstudie om lärares inställningar av digitala verktyg i skrivundervisningen
No full textSyftet med denna studie är att undersöka lärares erfarenheter och uppfattningar om digitalt skrivande i årskurs F–3, samt identifiera vilka för- och nackdelar som finns. Därav undersöker vi om och hur lärarna använder digitala resurser i klassrummen och deras uppfattningar av det. Vi vill också ta reda på om lärares inställningar var mestadels negativa eller positiva. Studien genomförs genom en enkätundersökning som besvaras av 52 lågstadielärare. Datan från enkäten analyseras statistiskt samt genom en tematisk analys. Studiens teoretiska utgångspunkt är den sociokulturella teorin med extra fokus på begreppen medierande redskap och scaffolding. Resultatet visar att lärarna använder olika metoder och appar i svenskundervisningen. Metoden ASL (att skriva sig till läsning) och appar med funktioner som talsyntes samt ordbehandlingsprogram är vanligt förekommande. Studiens resultat visar att lågstadielärare upplever både positiva och negativa aspekter av digitala verktyg inom skrivundervisningen. De positiva aspekterna som lärarna upplever med verktygen är motivation där eleverna genererar längre texter. Samtidigt lyfter de fram negativa aspekter som minskad finmotorik och distraktion. Vårt resultat visar varierande inställningar hos lärarna angående digitala verktyg i skrivundervisning i svenskämnet. Vår diskussion belyser att en kombination av digitalt och analogt skrivande är viktigt.
Heteroresistance - from clinical implications to genetic mechanisms
No full textAntibiotic heteroresistance (HR) is a phenotype characterized by the presence of low frequency subpopulations with increased resistance present in a more susceptible main population of bacteria. The clinical impact of the phenotype is not clear, but in vitro, in vivo and clinical studies suggest that HR increases the risk of treatment failure. To further complicate the situation, HR often evades detection by commonly used diagnostic methods. The phenotype can be caused by several different genetic mechanisms, and one main mechanism is tandem gene amplification of resistance genes. In this thesis, questions regarding clinical implications, prevalence, diagnostics and genetic mechanisms are adressed in three papers. In Paper I, the prevalence, classification and clinical outcomes of breakpoint crossing HR (BCHR) in 255 Escherichia coli bloodstream infection isolates were investigated for three clinically relevant antibiotics in a retrospective study. The BCHR prevalences for cefotaxime, gentamicin and piperacillin-tazobactam were <1%, 43% and 9%, respectively. Out of 125 BCHR isolates 96% (120/125) were classified as suceptible by disk diffusion. Patients with BCHR infections that were treated with the corresponding antibiotic had higher odds for admittance to the intensive care unit and mortality for gentamicin, and for admittance to the intermediate care unit for piperacillin-tazobactam. In Paper II, we predicted the HR phenotype from whole genome sequencing data utilizing machine learning algorithms. 467 clinical isolates of E. coli phenotyped for piperacillin-tazobactam HR were included. The best performing model detected HR isolates with 100% sensitivity and 84.6% specificity. Genetic analysis of the resistant subpopulations showed that copy number increases of resistance genes, either due to amplifications or increased plasmid copy number, were the main HR mechanisms. In Paper III, the population distribution of resistance gene tandem amplifications in a HR E. coli isolate was resolved and studied, using a new method combining genetic engineering and Nanopore long read sequencing. The distribution of amplifications correlated with the observed HR phenotype. Mathematical modelling suggested that indirect resistance mechanisms could affect the distribution of amplification copy numbers. In conclusion, these findings advance the understanding of the prevalence, clinical outcome, diagnostics and genetic mechanisms of the HR phenotype. The presented methodologies in Paper II and III can aid in developing better diagnostics for detection of HR, and in further investigations of the parameters that shapes the HR population and how these populations impact the clinical outcomes of antibiotic treatment
Microbiome dysbiosis in SARS-CoV-2 infection : implication for pathophysiology and management strategies of COVID-19
No full textThe emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), in late 2019 initiated a global health crisis marked by widespread infection, significant mortality, and long-term health implications. While SARS-CoV-2 primarily targets the respiratory system, recent findings indicate that it also significantly disrupts the human microbiome, particularly the gut microbiota, contributing to disease severity, systemic inflammation, immune dysregulation, and increased susceptibility to secondary infections and chronic conditions. Dysbiosis, or microbial imbalance, exacerbates the clinical outcomes of COVID-19 and has been linked to long-COVID, a condition affecting a significant proportion of survivors and manifesting with over 200 symptoms across multiple organ systems. Despite the growing recognition of microbiome alterations in COVID-19, the precise mechanisms by which SARS-CoV-2 interacts with the microbiome and influences disease progression remain poorly understood. This narrative review investigates the impact of SARS-CoV-2 on host-microbiota dynamics and evaluates its implications in disease severity and for developing personalized therapeutic strategies for COVID-19. Furthermore, it highlights the dual role of the microbiome in modulating disease progression, and as a promising target for advancing diagnostic, prognostic, and therapeutic approaches in managing COVID-19
Linker-Determined Folding and Hydrophobic Interactions Explain a Major Difference in PROTAC Cell Permeability
No full textThe ability to adopt folded conformations that have a low solvent-accessible 3D polar surface area has been found to be important for PROTACs to display a high passive cell permeability. We have studied two VHL PROTACs that differ only by the replacement of two methylene groups in the linker by oxygen atoms but that displayed vast differences in their cell permeability. MD simulations and NMR spectroscopy revealed an unexpected, environment-dependent conformational behavior for the low-permeability PROTAC that has an alkyl linker. Hydrophobic interactions enforced extended and polar conformations for this PROTAC in nonpolar media, explaining its low cell permeability. In water, hydrophobic collapse around the linker led to folded and less polar conformations. In contrast, the highly permeable PROTAC having a PEG linker adopted conformations of similar shapes and polarities in polar and nonpolar environments
Nonlocal coherent states in an infinite array of boson sites
No full textA regular coherent state (CS) is a special type of quantum state for boson particles placed in a single site. The defining feature of the CS is that it is an eigenmode of the annihilation operator. The construction easily generalizes to the case of a finite number of sites. However, the challenge is altogether different when one considers an infinite array of sites. In this work we demonstrate a mathematically rigorous construction that resolves the latter case. The resulting nonlocal coherent states (NCS) are simultaneous eigenmodes for all of the infinitely many annihilation operators acting in the infinite array's Fock space. Our construction fundamentally relies on Dirichlet series-based analysis and number theoretic arguments
Preceding Options Affect Subsequent Listwise but Not Pairwise Choice, Even for Experts
No full textRecent theories of decision-making, such as Decision by Sampling, suggest that people lack stable preferences. Instead, preferences are malleable and constructed in the moment by comparisons of target attributes to small samples of attribute values active in working memory. Manipulating the distribution of attribute values observed before a choice has therefore been suggested to affect subsequent choices. In a series of four experiments, we investigate if prior exposure to different distributions of attribute values affect subsequent pairwise, two-alternative forced choices and listwise choices between multiple options. We also investigate if these suggested effects are attenuated by domain expertise. We typically find that listwise choices are affected by prior experience of attributes in the predicted manner but that the pairwise choices are not. This occurs even when we hold range constant, and the effect is reduced but not eliminated by substantial domain expertise. We propose that this format dependence of the malleability of choices is an important challenge for any theory of their cognitive origin
Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells
No full textThe interplay between drug-sensitive and drug-resistant cancer cells has been observed to impact cell-to-cell interactions in experimental settings. However, the role that space plays in these interactions remains unclear. In this study, we develop mathematical models to investigate how spatial factors affect cell-to-cell competition between drug-sensitive and drug-resistant cancer cells in silico. We develop two baseline models to study cells from the epithelial FaDu cell line subjected to two drugs, specifically the ATR inhibitor ceralasertib and the PARP inhibitor olaparib, that target DNA damage response pathways. Our baseline models are: (1) a temporally resolved ordinary differential equation (ODE) model, and (2) a spatio-temporally resolved agent-based model (ABM). The models simulate cells in well-mixed and spatially structured cell systems, respectively. The ODE model is calibrated against in vitro data and is thereafter mapped onto the baseline ABM which, in turn, is extended to enable a simulation-based investigation on how spatial factors impact cell-to-cell competition. Simulation results from the extended ABMs demonstrate that the in silico treatment responses are simultaneously affected by: (i) the initial spatial cell configurations, (ii) the initial fraction of drug-resistant cells, (iii) the drugs to which cells express resistance, (iv) drug combinations, (v) drug doses, and (vi) the doubling time of drug-resistant cells compared to the doubling time of drug-sensitive cells. These results reveal that spatial structures of the simulated cancer cells affect both cell-to-cell interactions, and the impact that these interactions have on the ensuing population dynamics. This leads us to suggest that the role that space plays in cell-to-cell interactions should be further investigated and quantified in experimental settings
Elucidation of short linear motif‑based interactions of the MIT and rhodanese domains of the ubiquitin‑specific protease 8
No full textUbiquitin-specific protease 8 (USP8) is a deubiquitinating enzyme with essential functions in protein trafficking and stability. It is a multidomain protein, with an N-terminal MIT (microtubule interacting and trafficking) domain, followed by a non-catalytic rhodanese (Rhod) domain, a long intrinsically disordered region, and a C-terminal catalytic domain. The N-terminal MIT domain of USP8 is known to mediate protein-protein interactions through binding to short linear motifs. The non-catalytic Rhod domain is also involved in protein-protein interactions, however detailed insights into these interactions remain limited. In this study we explore the short linear motif-based interactions of the MIT and Rhod domains of USP8 using a combination of proteomic peptide-phage display, peptide arrays and deep mutational scanning. We show that the MIT domain can bind ligands with a general [DE][LIF]x{2,3}R[FYIL]xxL[LV] consensus motif. We uncover that the rhodanese domain of USP8 is a peptide-binding domain, and define two distinct binding motifs (Rx[LI]xGxxxPxxL and G[LV][DE][IM]WExKxxxLxE) for this domain by deep mutational scanning of two different peptide ligands. Using the motif information, we predict binding sites within known USP8 interactors and substrates and validate interactions through peptide array analysis. Our findings demonstrate that both the USP8 MIT and rhodanese domains are peptide-binding domains that can be bound by degenerate and distinct binding motifs. The detailed information on the peptide binding preference of the two N-terminal domains of USP8 provide novel insights into the molecular recognition events that underlie the function of this essential deubiquitinating enzyme