Publikationer från Uppsala Universitet
Not a member yet
127603 research outputs found
Sort by
Targeting loss of heterozygosity in cancer
No full textTherapies targeting driver genes alterations in cancer have reduced treatment toxicities and improved patients’ survival. However, cancer cells develop drug resistance over time. This thesis investigates how the combined knowledge of constitutional genetic variation and tumor chromosomal aberrations may serve in the development of novel therapeutic approaches in cancer. In Paper I we investigated loss of heterozygosity (LOH) at 22q13.2 chromosome which creates the bystander loss of CYP2D6, a polymorphic gene that has frequent inactivating variants. We show that loss of CYP2D6 activity can sensitize tumor cells to talazoparib and validated the finding in patient-derived organoid models. Papers II, III and IV focused on exploiting chromosome 8p22 loss in the NAT2 locus for a novel therapeutical strategy in cancer. In Paper II we aimed to quantitate the number of patients that potentially could benefit from NAT2 LOH-based therapy and develop a method for haplotyping and LOH testing. We estimated which heterozygous patients could be candidates for the therapy in case of NAT2*Rapid loss in their tumors. We demonstrated that multiplexed SMRT sequencing may serve as a suitable haplotyping and LOH resolution method. In Paper III we identified novel compounds for LOH-based treatment where we found 6 novel NAT2 substrates and 43 candidates for validation studies. Paper IV assessed clinically approved cytotoxic compounds based on the cellular NAT2 status. We found that anthracycline antibiotics and HDAC inhibitors are more toxic to cells with rapid NAT2. Doxorubicin, daunorubicin, idarubicin and vorinostat were metabolised by NAT2, a metabolic conversion detected for the first time. We performed target identification to uncover new potential LOH therapy targets in cancer in Paper V. By mining public databases and mapping prevalent alleles, 70 genes with constitutional variants potentially affecting their function, located in commonly lost chromosomal regions, were identified as potential target genes for therapy development
Working life patterns after sickness absence due to depression: A 15-year register-based prospective cohort study
No full textAim: To identify working life patterns after sickness absence (SA) due to depression and sociodemographic, work, and health-related factors associated with them. Methods: The study cohort included 9139 Swedish residents, aged 25–40, with a new SA spell due to depression in 2005. We followed the cohort for 15 years analyzing their yearly dominant labor market outcomes. Sequence analysis was used to identify distinct labor market sequences and cluster analysis – to group similar sequences into working life typologies. For the sociodemographic, work, and health-related factor analysis, we used multinomial logistic regression. Results: We identified 4373 sequences and seven typologies: 1) “Predominant Economic Activity (EA)” (70.7 %), 2) “Predominant EA with Intermittent SA/Disability Pension (DP)” (14.4 %), 3) “Predominant Long-Term SA/DP” (8.0 %), 4) “Long-Term SA/DP Followed by No EA” (2.2 %), 5) “SA/DP with Some EA” (1.6 %), 6) “Emigration” (1.7 %), and 7) “Death” (1.4 %). Factors associated with the predominant long-term SA/DP typology included birth outside Sweden (OR = 1.61, 95 % CI: 1.29–2.01), lower educational attainment (OR = 3.20, 95 % CI: 2.42–4.22), prolonged index SA spell due to depression (OR = 4.81, 95 % CI: 3.71–6.25), prior long-term SA (OR = 3.60, 95 % CI: 2.87–4.50) and unemployment (OR = 2.00, 95 % CI: 1.61–2.48). Living with children (OR = 0.68, 95 % CI: 0.56–0.82) was associated with lower odds of belonging to this typology. Conclusions: Most individuals after SA due to depression maintained their engagement in the labor market suggesting that Sweden's welfare system is supportive of their workforce participation. However, some individuals belonged to long-term SA, DP, and lack of EA typologies indicating a potential path to labor market marginalization
Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases
No full textObjective: Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren disease (pSS), and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study was aimed at elucidating the genetics underlying these common features. Methods: We performed targeted DNA sequencing of coding and regulatory regions from approximately 1,900 immune-related genes in a large cohort of 2,292 well-characterized Scandinavian patients with SIADs with SLE, pSS, and myositis as well as 1,252 controls. A gene-based functionally weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in silico functional analyses and in vitro reporter experiments. Results: Case–control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case–case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by antinuclear antibodies and anti–double-stranded DNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that dual-specificity phosphatase 1 (DUSP1) protective genetic variants lead to increased gene expression and potentially to anti-inflammatory effects on the SIAD-associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported down-regulation of the MAPK signaling-related gene DUSP1 in other skin disorders. Conclusion: Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks
The Weinberg operator at same-sign muon-muon colliders
No full textThe Standard Model (SM) of particle physics describes how fundamental particles interact. Experimental observations are well-explained by the SM but some questions still remain. One of these questions has to do with neutrinos: how are their masses generated and how do we treat the masses? The Standard Model Effective Field Theory (SMEFT) is an effective field theory that provides a possible answer. The SMEFT Lagrangian expands the SM Lagrangian in canonical dimensions of 1/Λ, where Λ ≫ mW is the scale of New Physics (NP). The SM Lagrangian has dimension D = 4, but the SMEFT Lagrangian allows for higher dimension terms. At D = 5, the so-called “Weinberg operator” generates Majorana neutrino masses. In this project I investigate the possibility of probing the Weinberg operator at a same-sign muon-muon collider. I simulate the Weinberg operator using MadGraph5 and discuss the possibility of observing it in a potential future collider
General strategy for boosting the performance of speed-tunable rotary molecular motors with visible light
No full textLight-driven molecular rotary motors perform chirality-controlled unidirectional rotations fueled by light and heat. This unique function renders them appealing for the construction of dynamic molecular systems, actuating materials, and molecular machines. Achieving a combination of high photoefficiency, visible-light responsiveness, synthetic accessibility, and easy tuning of dynamic properties within a single scaffold is critical for these applications but remains a longstanding challenge. Herein, a series of highly photoefficient visible-light-responsive molecular motors (MMs), featuring various rotary speeds, was obtained by a convenient one-step formylation of their parent motors. This strategy greatly improves all aspects of the performance of MMs-red-shifted wavelengths of excitation, high photoisomerization quantum yields, and high photostationary state distributions of isomers-beyond the state-of-the-art light-responsive MM systems. The development of this late-stage functionalization strategy of MMs opens avenues for the construction of high-performance molecular machines and devices for applications in materials science and biological systems, representing a major advance in the synthetic toolbox of molecular machines
Exploring and increased acetate biosynthesis in Synechocystis PCC 6803 through insertion of a heterologous phosphoketolase and overexpressing phosphotransacetylase
No full textAcetate is a biological anion with many applications in the chemical and food industries. In addition to being a common microbial fermentative end-product, acetate can be produced by photosynthetic cyanobacteria from CO2 using solar energy. Using wild-type cells of the unicellular model cyanobacterium Synechocystis PCC 6803 only low levels of acetate are observed outside the cells. By inserting a heterologous phosphoketolase (PKPa) in the acs locus, encoding acetyl-CoA synthetase responsible for the irreversible conversion of acetate to acetyl-CoA, an increased level of 40 times was observed. Metabolite analyses indicate an enhanced Calvin-Benson-Bassham cycle, based on increased levels of glyceraldehyde 3-phosphate and fructose-1,6-biphosphate, while the decreased levels of 3-phosphoglycerate and pyruvate suggest a quick consumption of the fixed carbon. Acetyl-P and erythrose-4-phosphate showed significantly increased levels, as products of phosphoketolase, while acetylCoA remained stable through the experiment. The results of intra- and extra-cellular acetate levels clearly demonstrate an efficient excretion of produced acetate from the cells in the engineered strain. Knock-out of ach and pta showed a reduction in acetate production however, it was not as low as in cells with a single knock-out of ach. Overexpressing acetyl-CoA hydrolase (Ach) and acetate kinase (AckA) did not significantly increase production. In contrast, overexpressing phosphotransacetylase (Pta) in cells containing an inserted PKPa resulted in 80 times more acetate reaching 2.3 g/L after 14 days of cultivation
Bayesian composite Lp-quantile regression
No full textLP-quantiles are a class of generalized quantiles defined as minimizers of an asymmetric power function. They include both quantiles, P = 1, and expectiles, P = 2, as special cases. This paper studies composite LP-quantile regression, simultaneously extending single LP-quantile regression and composite quantile regression. A Bayesian approach is considered, where a novel parameterization of the skewed exponential power distribution is utilized. Further, a Laplace prior on the regression coefficients allows for variable selection. Through a Monte Carlo study and applications to empirical data, the proposed method is shown to outperform Bayesian composite quantile regression in most aspects
Kvinnor i regeringen : En kvantitativ studie som undersöker gender-washing genom kvinnlig representation och makt i regeringen
No full textDenna studie undersöker kvantitativt fenomenet gender-washing i icke-demokratiska, biståndsberoende stater genom att undersöka kvinnors representation och makt i regeringen i både demokratier och icke-demokratier. Efter det kalla krigets slut ledde den globala uppmärksamheten på jämställdhet till genomförandet av reformer som syftade till att öka kvinnors politiska deltagande. Många icke-demokratiska stater verkar ha genomfört sådana reformer i första hand i syfte att stärka deras internationella anseende, snarare än som en åtgärd för att främja kvinnors representation och inflytande i politiken. Med anledning av detta undersöker studien om det finns tecken på att icke-demokratier bedriver genderwashing, ett verktyg där stater implementerar jämställdhetsreformer för att stärka sin image och minska extern kritik. Genom att analysera data från främst WhoGov-paneldataset (1966- 2023), som inkluderar information om kön och prestige hos ministrar i 177 länder, jämför studien den genomsnittliga andelen kvinnor och deras makt i demokratiska och ickedemokratiska regeringar. Fokusperioden är 1995- 2023, en tid då det internationella jämställdhetsarbetet blev mer synligt. Studien syftar till att ge nya insikter i hur biståndsberoende och jämställdhetsreformer samspelar, och bidra till förståelsen av hur ickedemokratiska regimer använder jämställdhetspolitik för att åstadkomma politiska fördelar
Forum play : Working with climate anxiety
No full textThis chapter outlines a workshop on how to navigate climate anxiety. It is designed for university students with forum play as a key activity. It opens for unfolding climate-related emotions in a university classroom, revealing the worries from a ‘shadow zone’ through them being recognised, accepted, and expressed. The form of forum play used here allows students to slow down events, freeze them, try out different solutions, and deepen their awareness of the issues at stake. As a warm-up, this chapter introduces a walking practice including an introspective, embodied reflection on personal emotions and experiences of climate change
Högstadielärares syn på fältarbete i geografi och dess organisatoriska utmaningar : En kvalitativ studie om högstadielärares syn på och användning av fältarbete i geografiundervisning
No full textDenna studie undersöker högstadielärares uppfattningar och användning av fältarbete i geografiundervisningensamt de faktorer som påverkar dess genomförande. Studien bygger på kvalitativa intervjuer med sju lärare fråntvå skolor och analyseras utifrån Kolbs teori om erfarenhetsbaserat lärande, Ajzens teori om planerat beteendeoch Peters och O’Connors teori om organisatoriska begränsningar.Resultaten visar att lärarna ser fältarbete som en värdefull metod för att konkretisera geografiska koncept ochengagera elever. Samtidigt hindras dess användning av begränsningar som tidsbrist, brist på resurser ochorganisatoriska utmaningar. Lärare med ämnesbehörighet uttrycker större trygghet i att använda metoden, medande utan behörighet ofta avstår på grund av osäkerhet och bristande erfarenhet. Studien betonar behovet avfortbildning, förbättrade resurser och ökat organisatoriskt stöd för att stärka fältarbetets roll igeografiundervisninge