Publikationer från Uppsala Universitet
Not a member yet
127603 research outputs found
Sort by
Interpreting mammalian synonymous site conservation in light of the unwanted transcript hypothesis
No full textMammalian genomes are biased towards GC bases at third codon positions, likely due to a GC-biased ancestral genome and the selectively neutral recombination-related process of GC-biased gene conversion. The unwanted transcript hypothesis posits that this high GC content at synonymous sites may be beneficial for protecting against spurious transcripts, particularly in species with low effective population sizes. Utilising a 240 placental mammal genome alignment and single-base resolution conservation scores, we interpret sequence conservation at mammalian four-fold degenerate sites in this context and find evidence in support of the unwanted transcript hypothesis, including a strong GC bias, high conservation at sites relating to exon splicing, less human genetic variation at conserved four-fold degenerate sites, and conservation of sites important for epigenetic regulation of developmental genes. Additionally, we show that high conservation of four-fold degenerate sites in essential developmental genes, including homeobox genes, likely relates to the low mutation rates experienced by these genes
MINCE III. Detailed chemical analysis of the UVES sample
No full textContext; The Measuring at Intermediate Metallicity Neutron-Capture Elements (MINCE) project aims to provide high-quality neutron-capture abundances measurements for several hundred stars at an intermediate metallicity of -2.5 < [Fe/H] < -1.5. This project will shed light on the origin of the neutron-capture elements and the chemical enrichment of the Milky Way. Aims: The goal of this work is to chemically characterize the second sample of the MINCE project and compare the abundances with the galactic chemical evolution model at our disposal. Methods: We performed a standard abundance analysis based on one-dimensional (1D) local thermodynamic equilibrium (LTE) model atmospheres based on high-resolution and high-signal-to-noise-ratio (S/N) spectra from Ultraviolet and Visual Echelle Spectrograph (UVES). Results: We provide the kinematic classification (i.e., thin disk, thick disk, thin-to-thick disk, halo, Gaia Sausage Enceladus, Sequoia) of 99 stars and the atmospheric parameters for almost all stars. We derived the abundances for light elements (from Na to Zn) and neutron-capture elements (Rb, Sr, Y, Zr, Ba, La, Ce, Pr, Nd, Sm, and Eu) for a subsample of 32 stars in the metallicity range of -2.5 < [Fe/H] < -1.00. In the subsample of 32 stars, we identified eight active stars exhibiting (inverse) P-Cygni profile and one Li-rich star, CD 28-11039. We find a general agreement between the chemical abundances and the stochastic model computed for the chemical evolution of the Milky Way halo for elements Mg, Ca, Si, Ti, Sc, Mn, Co, Ni, Zn, Rb, Sr, Y, Zr, Ba, La, and Eu . Conclusions: The MINCE project has already significantly increased the number of neutron-capture elements measurements in the intermediate metallicity range. The results from this sample are in perfect agreement with the previous MINCE sample. The good agreement between the chemical abundances and the chemical evolution model of the Galaxy supports the nucleosynthetic processes adopted to describe the origin of the n-capture elements
Generalized local systems and the Maslov class of exact Lagrangians
No full textThis PhD-thesis in symplectic topology consists of an introduction and two research papers. The goal of the thesis is to investigate the Maslov class for exact Lagrangians in Weinstein domains. In the introduction we give some history, introduce the research area and explain everything that is needed to understand the main results of the papers. Afterwards we give a short summary of the papers and their main results. Finally we state some open questions that the author was not able to answer during his time as a student. In Paper I we reprove with new methods the well known fact that the Maslov class vanishes for closed exact Lagrangians in cotangent bundles of closed manifolds. We also further extend that result to closed exact Lagrangians in slightly more general Weinstein domains built by attaching sub-critical handles in a certain way to cotangent bundles. The proof uses Floer theory with coefficients in path local systems which is a theory developed in the paper that builds on previous works by Abouzaid, Barraud and Cornea. In paper II we show that the main result of Paper I does not hold if we allow the handles that build the Weinstein domains to be critical. For instance we show that to any Weinstein domain one can attach a one-handle and a critical handle and then find a closed exact Lagrangian with non vanishing Maslov class. In the proof we construct the Lagrangians with explicit formulas and explicitly compute their Maslov class
Gleason scores provide more accurate prognostic information than grade groups
No full textProstate cancer grade is currently often reported both by Gleason scores and by grouping of the scores into five socalled International Society of Urological Pathology (ISUP) grades (also known as grade groups). Using population-based registry data from 172,112 men diagnosed with prostate cancer on needle biopsy, we recently investigated the outcome of Gleason score 8-10 prostate cancer with death due to prostate cancer and death from any cause as endpoints. There was a prognostic heterogeneity between Gleason scores 3+5, 4+4 and 5+3 (ISUP grade 4) and between Gleason scores 4+5, 5+4 and 5+5 (ISUP grade 5). This heterogeneity was lost when the grades collapsed into ISUP grades 4 and 5, respectively. On the other hand, there was also a prognostic overlap between these ISUP grades. The outcome of Gleason score 5+3 and 4+5 cancers was very similar. The prostatespecific mortality of Gleason scores 5+3 and 4+5 was 0.32 (95% confidence interval 0.27-0.36) and 0.30 (0.29-0.31), respectively, after 5 years and 0.44 (0.39-0.49) and 0.45 (0.44-0.46), respectively, after 10 years. The findings emphasise the importance of reporting the Gleason grades and scores for more accurate prognostic information of highly heterogeneous high-grade prostate cancers. It also questions the clinical value of the current recommendations of grouping of Gleason scores into ISUP grades or grade groups
Biomarkers of dietary PUFA intake in childhood and adolescence in relation to cardiometabolic risk factors in young adulthood : a prospective cohort study in Sweden
No full textBackground: PUFAs, especially from vegetable fat sources, have been suggested to contribute to weight regulation and be protective to cardiometabolic health. However, a few longitudinal studies on childhood exposure are available, with short follow-up time and conflicting results. Objectives: To study the relationship between plasma proportions of PUFA in childhood and adolescence and cardiometabolic risk factors in young adulthood, such as obesity, body composition, blood pressure (BP), and blood lipids in a prospective cohort study. Methods: We included n = 688 participants of the BAMSE (Barn, Allergi, Miljo<euro>, Stockholm, Epidemiologi) cohort in Stockholm, Sweden, with data on plasma phospholipid proportions of n-3 and n-6 fatty acids [alpha-linolenic acid (ALA), EPA, docosapentaenoic acid, DHA, linoleic acid (LA), and arachidonic acid (AA)] at 8 and 16 y and body mass index (BMI), waist circumference, fat mass %, BP, and blood lipids at 24 y. Associations between PUFAs and cardiometabolic health outcomes were assessed with sex-stratified multivariable-adjusted linear and logistic regression models. Results: In females, LA and ALA at 16 y were inversely associated with BMI [B:-0.35 (-0.54,-0.17) and B:-6.1 (-11,-1.5), respectively], and similarly with waist circumference and fat mass at 24 y. Also in females, LA was inversely associated with BP, triglycerides, LDL-cholesterol), and total cholesterol (e.g., B-0.044 [-0.079,-0.0099] for LA at 16 y and LDL-cholesterol), whereas ALA was only inversely associated with LDL-cholesterol. No associations were found between long chain n-3 fatty acids or AA and any of the studied outcomes. Conclusions: Plasma phospholipid proportions of LA and ALA, biomarkers of vegetable oil intake, during childhood and adolescence were inversely associated with measures of obesity and cardiometabolic health in young adulthood, with a potential sex difference. These findings accord with short-term feeding trials suggesting a possible preventive role of LA on body fat accumulation
Large scale investigation of GPCR molecular dynamics data uncovers allosteric sites and lateral gateways
No full textG protein-coupled receptors (GPCRs) constitute a functionally diverse protein family and are targets for a broad spectrum of pharmaceuticals. Technological progress in X-ray crystallography and cryogenic electron microscopy has enabled extensive, high-resolution structural characterisation of GPCRs in different conformational states. However, as highly dynamic events underlie GPCR signalling, a complete understanding of GPCR functionality requires insights into their conformational dynamics. Here, we present a large dataset of molecular dynamics simulations covering 60% of currently available GPCR structures. Our analysis reveals extensive local "breathing" motions of the receptor on a nano- to microsecond timescale and provides access to numerous previously unexplored receptor conformational states. Furthermore, we reveal that receptor flexibility impacts the shape of allosteric drug binding sites, which frequently adopt partially or completely closed states in the absence of a molecular modulator. We demonstrate that exploring membrane lipid dynamics and their interaction with GPCRs is an efficient approach to expose such hidden allosteric sites and even lateral ligand entrance gateways. The obtained insights and generated dataset on conformations, allosteric sites and lateral entrance gates in GPCRs allows us to better understand the functionality of these receptors and opens new therapeutic avenues for drug-targeting strategies
Network effects of partial reshoring in the internationalization process
No full textA growing number of firms is considering reshoring as an option to cope with the increasingly complex international business environment. However, especially when concerning only part of the activities outsourced to suppliers, reshoring may harm the firm’s business relationships in the host country and restrain access to essential resources and capabilities. This paper examines the impact that reshoring outsourced activities has on the host-country network. Building on a case study and key concepts from the business network view of internationalization, the study reveals concurring but contrasting effects for the reshoring firm: the tangible commitment of the firm and its structural embeddedness in the foreign market diminish, while the intangible commitment and relational embeddedness simultaneously increase. Accordingly, the resulting host-country network counts fewer but deeper relationships. The study advances our knowledge of both internationalization and reshoring. The former is extended by furthering the understanding of the network and nonlinear views of internationalization, while the latter by exposing the multidirectional network effects of partial reshoring and discussing it in relation to recent global disruptions
GWAS identifies genetic loci, lifestyle factors and circulating biomarkers that are risk factors for sarcoidosis
No full textSarcoidosis is a complex inflammatory disease with a strong genetic component. Here, we perform a genome-wide association study in 9755 sarcoidosis cases to identify risk loci and map associated genes. We then use transcriptome-wide association studies and enrichment analyses to explore pathways involved in sarcoidosis and use Mendelian randomization to examine associations with modifiable factors and circulating biomarkers. We identify 28 genomic loci associated with sarcoidosis, with the C1orf141-IL23R locus showing the largest effect size. We observe gene expression patterns related to sarcoidosis in the spleen, whole blood, and lung, and highlight 75 tissue-specific genes through transcriptome-wide association studies. Furthermore, we use enrichment analysis to establish key roles for T cell activation, leukocyte adhesion, and cytokine production in sarcoidosis. Additionally, we find associations between sarcoidosis and genetically predicted body mass index, interleukin-23 receptor, and eight circulating proteins
Population pharmacokinetics and dosing of dispersible moxifloxacin formulation in children with rifampicin‐resistant tuberculosis
No full textAims: Moxifloxacin is a priority drug for treating rifampicin-resistant tuberculosis (RR-TB). We assessed the pharmacokinetics of a child-friendly, dispersible 100 mg tablet moxifloxacin formulation (dispersed in water) compared to the standard 400 mg non-dispersible formulation (crushed and suspended in water) in children and evaluated current dosing recommendations. Methods: The CATALYST trial investigated the pharmacokinetics of moxifloxacin in children with RR-TB. Children were enrolled in South Africa, India and the Philippines. Intensive pharmacokinetic sampling was undertaken while children were taking the standard non-dispersible 400 mg moxifloxacin tablet formulation and repeated after switching to the novel dispersible formulation. Pharmacokinetic data were analysed using population pharmacokinetic modelling. Simulations were per- formed to evaluate moxifloxacin exposures in children compared to consensus adult reference exposures using current World Health Organization (WHO)-recommended doses and more recent model-based doses. Results: Thirty-six children were enrolled [median age 4.8 (range 0.4–15) years and weight 15.6 (range 6.9–42.1) kg]. A two-compartment disposition model with first- order elimination and delayed absorption was developed. The bioavailability of dis- persible versus standard formulations fulfilled standard bioequivalence criterion (ratio 1.05 with 90% confidence interval 0.95–1.15). Simulations showed WHO- recommended doses achieved exposures similar to those in adults in children >10 kg, while children <10 kg may require 33%–56% higher doses to reach adult reference exposures. Conclusions: Dosing recommendations for children can be the same for the dispers- ible paediatric and standard non-dispersible adult moxifloxacin formulation. The cur- rent WHO dosing recommendation risks underdosing moxifloxacin in children <10 kg. We propose optimized moxifloxacin doses for both formulations.The epub version of the article is published with DOI 10.1002/bcp.70005</p
Tyre wear particles and metals in highway roadside ditches : Occurrence and potential transport pathways
No full textTyre wear particles (TWP) pose significant environmental concerns, necessitating a comprehensive understanding of their environmental distribution for accurate risk assessment. Roadside soil has not been extensively studied for TWP occurrence and distribution. This study aims to characterise the occurrence and distribution of TWP and associated metals in roadside soils and to investigate the correlations between these contaminants. Soil samples were collected from two road ditches along a Swedish national motorway at varying depths and distances from the contamination source. TWP in fractions <500 mu m were analysed using PYR-GC/MS. Results indicated that TWP concentrations in soil samples ranged from 0.74 +/- 0.20 to 12.40 +/- 1.88 mg/kg d.w., consistent with other studies, and decreased with distance from the road, similar to Zn. In one ditch, TWP concentrations remained constant with depth, unlike concentrations of Co and Cr, which increased, while in the other ditch, TWP and most metals did not decrease with depth or distance from the outlet. Strong correlations were found between concentrations of TWP and Zn in one, but not the other, where Zn might have followed different transport due to leaching. Metal correlations in both ditches suggest traffic-related but not necessarily tyre wear origins. These findings are crucial for risk assessments of traffic-related pollutants, particularly TWP, and their spread into soils