Uppsala University
  • Uppsala, Sweden
Recent publications
Ferroptosis, a form of regulated cell death, has emerged as a crucial process in diverse pathophysiological states, encompassing cancer, neurodegenerative ailments, and ischemia-reperfusion injury. The glutathione (GSH)-dependent lipid peroxidation pathway, chiefly governed by glutathione peroxidase 4 (GPX4), assumes an essential part in driving ferroptosis. GPX4, as the principal orchestrator of ferroptosis, has garnered significant attention across cancer, cardiovascular, and neuroscience domains over the past decade. Noteworthy investigations have elucidated the indispensable functions of ferroptosis in numerous diseases, including tumorigenesis, wherein robust ferroptosis within cells can impede tumor advancement. Recent research has underscored the complex regulatory role of non-coding RNAs (ncRNAs) in regulating the GSH-GPX4 network, thus influencing cellular susceptibility to ferroptosis. This exhaustive review endeavors to probe into the multifaceted processes by which ncRNAs control the GSH-GPX4 network in ferroptosis. Specifically, we delve into the functions of miRNAs, lncRNAs, and circRNAs in regulating GPX4 expression and impacting cellular susceptibility to ferroptosis. Moreover, we discuss the clinical implications of dysregulated interactions between ncRNAs and GPX4 in several conditions, underscoring their capacity as viable targets for therapeutic intervention. Additionally, the review explores emerging strategies aimed at targeting ncRNAs to modulate the GSH-GPX4 pathway and manipulate ferroptosis for therapeutic advantage. A comprehensive understanding of these intricate regulatory networks furnishes insights into innovative therapeutic avenues for diseases associated with perturbed ferroptosis, thereby laying the groundwork for therapeutic interventions targeting ncRNAs in ferroptosis-related pathological conditions.
The electrochemical glucose oxidation reaction (GOR) presents an opportunity to produce hydrogen and high‐value chemical products. Herein, we investigate the effect of Sn in Ni nanoparticles for the GOR to formic acid (FA). Electrochemical results show that the maximum activity is related to the amount of Ni, as Ni sites are responsible for catalyzing the GOR via the NiOOH/Ni(OH)2 pair. However, the GOR kinetics increases with the amount of Sn, associated with an enhancement of the OH⁻ supply to the catalyst surface for Ni(OH)2 reoxidation to NiOOH. NiSn nanoparticles supported on carbon nanotubes (NiSn/CNT) exhibit excellent current densities and direct GOR via C−C cleavage mechanism, obtaining FA with a Faradaic efficiency (FE) of 93 % at 1.45 V vs. reversible hydrogen electrode. GOR selectivity is further studied by varying the applied potential, glucose concentration, reaction time, and temperature. FE toward FA production decreases due to formic overoxidation to carbonates at low glucose concentrations and high applied potentials, while acetic and lactic acids are obtained with high selectivity at high glucose concentrations and 55 °C. Density functional theory calculations show that the SnO2 facilitates the adsorption of glucose on the surface of Ni and promotes the formation of the catalytic active Ni³⁺ species.
Fibrillarin is a key nucleolar S-adenosyl-L-methionine (SAM)-dependent methyltransferase, highly conserved among species in both sequence and function. It is actively involved in numerous cellular processes, particularly in the early stages of pre-ribosomal RNA processing. Although a fibrillarin orthologue has been identified in Giardia, an intestinal protozoan parasite responsible for numerous infections worldwide, its functional and structural features in this parasite remain largely unexplored. In this study, bioinformatics tools were used to analyze the sequence and structure of Giardia fibrillarin to provide insights that could aid future experimental and therapeutic investigations. Taking advantage of the protein sequence of Giardia fibrillarin, multiple bioinformatics tools were employed to estimate its domains, nuclear and nucleolar localization signals (NLS and NoLS), post-translational modifications, phylogeny, and three-dimensional structure. The analysis revealed significant conservation of Giardia fibrillarin, showing close relationships with archaeal and parasitic amoeba orthologs. It retains essential features such as the SAM-dependent methyltransferase domain, a glycine-and arginine-rich domain, and both NLS and NoLS. While the core region of the protein is structurally conserved, the N-terminal region exhibits notable divergence. The potential for inhibition of Giardia fibrillarin by SAM competitors suggests that it could be a promising target for drug development, particularly for strains resistant to current treatments.
Background Both depression and respiratory disease are common today in young populations. However, little is known about the relationship between them. Aims This study aims to explore the association between depression in childhood to early adulthood and respiratory health outcomes in early adulthood, and the potential underlying mechanisms. Method A prospective study was conducted based on the Swedish BAMSE (Barn, Allergi, Miljö, Stockholm, Epidemiologi [Children, Allergy, Milieu, Stockholm, Epidemiology]) birth cohort ( n = 4089). We identified clinically diagnosed depression through the dispensation of antidepressants, using national register data confirmed by self-reported diagnosis. At the 24-year follow-up, respiratory health was assessed via questionnaires and clinical evaluation. Metabolic and inflammatory profiles were analysed to explore potential mechanisms. Results Among the 2994 participants who provided study data, 403 (13.5%) had depression at any time point from around age 10 to 25 years. Depression was associated with higher risks of any chronic bronchitis symptoms (odds ratio = 1.58, 95% CI 1.21–2.06) and respiratory symptoms (odds ratio = 1.41, 95% CI 1.11–1.80) in early adulthood, independent of body mass index (BMI) and smoking status. Compared to individuals without depression, those with depression had a higher fat mass index (FMI (β = 0.48, 95% CI 0.22–0.74)) and increased blood levels of fibroblast growth factor 21 and Interleukin-6 in early adulthood. These markers together with FMI were found to partly mediate the association between depression and respiratory symptoms (total mediation proportion: 19.8 and 15.4%, respectively, P < 0.01). Conclusions Depression in childhood to early adulthood was associated with an increased risk of respiratory ill-health in early adulthood, independently of smoking. Metabolic and inflammatory dysregulations may underlie this link.
Prior studies have documented that working-class individuals rarely become parliamentarians. We know less about when in the career pipeline to parliament workers disappear, and why. We study these questions using detailed data on the universe of Swedish politicians’ careers over a 50-year period. We find roughly equal-sized declines in the proportion of workers on various rungs of the political career ladder ranging from local to national office. We reject the potential explanations that workers lack political ambition, public service motivation, honesty, or voter support. And while workers’ average high school grades and cognitive test scores are lower, this cannot explain their large promotion disadvantage, a situation that we label a class ceiling. Organizational ties to blue-collar unions help workers advance, but only to lower-level positions in left-leaning parties. We conclude that efforts to improve workers’ numerical representation should apply throughout the career ladder and focus on intra-party processes.
Rechargeable magnesium batteries are promising for future energy storage. However, among other challenges, their practical application is hindered by low coulombic efficiencies of magnesium plating and stripping. Fundamental processes such as the formation, structure, and stability of passivation layers and the influence of different electrolyte components on them are still not fully understood. In this work, we gain unique insights into the initial Mg plating and stripping cycles by comparing Mg bis(trifluoromethanesulfonyl)imide (Mg(TFSI)2)‐ and Mg tetrakis(hexafluoroisopropyloxy)borate (Mg[B(hfip)4]2)‐based electrolytes, each with and without MgCl2, on gold electrodes by highly sensitive operando electrochemical quartz crystal microbalance with dissipation monitoring (EQCM‐D) applying hydrodynamic spectroscopy. With the stable Mg[B(hfip)4]2‐based electrolytes, highly efficient and interphase‐free cycling is possible and passivation layers are attributed to electrolyte contaminants. These are forming and degrading during the so‐called initial conditioning process. With the more reactive Mg(TFSI)2‐based electrolyte, thick passivation layers with small pores are growing during cycling. We demonstrate that the addition of chloride lowers the amount of passivated Mg deposits in these electrolytes and accelerates the currentless dissolution of the passivation layer. This has a positive effect since we observe the most efficient cycling and uniform deposition when no interphase is present on the electrode.
Rechargeable magnesium batteries are promising for future energy storage. However, among other challenges, their practical application is hindered by low coulombic efficiencies of magnesium plating and stripping. Fundamental processes such as the formation, structure, and stability of passivation layers and the influence of different electrolyte components on them are still not fully understood. In this work, we gain unique insights into the initial Mg plating and stripping cycles by comparing Mg bis(trifluoromethanesulfonyl)imide (Mg(TFSI)2)‐ and Mg tetrakis(hexafluoroisopropyloxy)borate (Mg[B(hfip)4]2)‐based electrolytes, each with and without MgCl2, on gold electrodes by highly sensitive operando electrochemical quartz crystal microbalance with dissipation monitoring (EQCM‐D) applying hydrodynamic spectroscopy. With the stable Mg[B(hfip)4]2‐based electrolytes, highly efficient and interphase‐free cycling is possible and passivation layers are attributed to electrolyte contaminants. These are forming and degrading during the so‐called initial conditioning process. With the more reactive Mg(TFSI)2‐based electrolyte, thick passivation layers with small pores are growing during cycling. We demonstrate that the addition of chloride lowers the amount of passivated Mg deposits in these electrolytes and accelerates the currentless dissolution of the passivation layer. This has a positive effect since we observe the most efficient cycling and uniform deposition when no interphase is present on the electrode.
Nervous system cancers exhibit diverse transcriptional cell states influenced by normal development, injury response, and growth. However, the understanding of these states’ regulation and pharmacological relevance remains limited. Here we present “single-cell regulatory-driven clustering” (scregclust), a method that reconstructs cellular regulatory programs from extensive collections of single-cell RNA sequencing (scRNA-seq) data from both tumors and developing tissues. The algorithm efficiently divides target genes into modules, predicting key transcription factors and kinases with minimal computational time. Applying this method to adult and childhood brain cancers, we identify critical regulators and suggest interventions that could improve temozolomide treatment in glioblastoma. Additionally, our integrative analysis reveals a meta-module regulated by SPI1 and IRF8 linked to an immune-mediated mesenchymal-like state. Finally, scregclust’s flexibility is demonstrated across 15 tumor types, uncovering both pan-cancer and specific regulators. The algorithm is provided as an easy-to-use R package that facilitates the exploration of regulatory programs underlying cell plasticity.
On a Weierstraß elliptic surface X, we define a “limit” of Bridgeland stability conditions, denoted as ZlZ^l-stability, by moving the polarisation towards the fiber direction in the ample cone while keeping the volume of the polarisation fixed. We describe conditions under which a slope stable torsion-free sheaf is taken by a Fourier-Mukai transform to a ZlZ^l-stable object, and describe a modification upon which a ZlZ^l-semistable object is taken by the inverse Fourier-Mukai transform to a slope semistable torsion-free sheaf. We also study wall-crossing for Bridgeland stability, and show that 1-dimensional twisted Gieseker semistable sheaves are taken by a Fourier-Mukai transform to Bridgeland semistable objects.
Symbiotic relationships between eukaryotes and prokaryotes played pivotal roles in the evolution of life and drove the emergence of specialized symbiotic structures in animals, plants and fungi. The host-evolved symbiotic structures of microbial eukaryotes – the vast majority of such hosts in nature – remain largely unstudied. Here we describe highly structured symbiosomes within three free-living anaerobic protists (Anaeramoeba spp.). We dissect this symbiosis using complete genome sequencing and transcriptomics of host and symbiont cells coupled with fluorescence in situ hybridization, and 3D reconstruction using focused-ion-beam scanning electron microscopy. The emergence of the symbiosome is underpinned by expansion of gene families encoding regulators of membrane trafficking and phagosomal maturation and extensive bacteria-to-eukaryote lateral transfer. The symbionts reside deep within a symbiosomal membrane network that enables metabolic syntrophy by precisely positioning sulfate-reducing bacteria alongside host hydrogenosomes. Importantly, the symbionts maintain connections to the Anaeramoeba plasma membrane, blurring traditional boundaries between ecto- and endosymbiosis.
Quantifying fair national shares of the remaining global carbon budget has proven challenging. Here, we propose an indicator—additional carbon accountability—that quantifies countries’ responsibility for mitigation and CO2 removal in addition to achieving their own targets. Considering carbon debts since 1990 and future claims based on countries’ emission pathways, the indicator uses an equal cumulative per capita emissions approach to allocate accountability for closing the mitigation gap among countries with a positive total excessive carbon claim. The carbon budget is exceeded by 576 Gigatonnes of fossil CO2 when limiting warming below 1.5 °C (50% probability). Additional carbon accountability is highest for the United States and China, and highest per capita for the United Arab Emirates and Russia. Assumptions on carbon debts strongly impact the results for most countries. The ability to pay for this accountability is challenging for Iran, Kazakhstan and several BRICS+ members, in contrast to the G7 members.
Background The effect of milk on the risk of ischemic heart disease (IHD) and acute myocardial infarction (MI) is unclear. We aimed to examine the association between non-fermented and fermented milk consumption on these endpoints and investigate the relationship between milk intake and cardiometabolic-related proteins in plasma. Methods Our study is based on two Swedish prospective cohort studies that included 59,998 women and 40,777 men without IHD or cancer at baseline who provided repeated measures of diet and lifestyle factors and plasma proteomics data in two subcohorts. Through registry linkage, 17,896 cases with IHD were documented during up to 33 years of follow-up, including 10,714 with MI. We used time-updated multivariable Cox regression analysis to examine non-fermented or fermented milk intake with time to IHD or MI. Using high-throughput multiplex immunoassays, 276 cardiometabolic plasma proteins were measured in two subcohorts. We applied multivariable-adjusted regression models using a discovery-replication design to examine protein associations with increasing consumption of non-fermented or fermented milk. Results The results for non-fermented milk differed by sex (p-value for interaction = 0.01). In women, we found a pattern of successively greater risk of IHD and MI at non-fermented milk intake levels higher than 1.5 glasses/day. Compared with an intake of 0.5 glass/day (100 mL/day), non-fermented milk intake of 2 glasses/day in women conferred a multivariable-adjusted hazard ratio (HR) of 1.05 (95% CI 1.01–1.08) for IHD, an intake of 3 glasses/day an HR of 1.12 (95% CI 1.06–1.19), and an intake of 4 glasses/day an HR of 1.21 (95% CI 1.10–1.32). Findings were similar for whole, medium-fat, and low-fat milk. We did not detect higher risks of IHD with increasing milk intakes in men. Fermented milk intake was unrelated to the risk of IHD or MI in either sex. Increasing non-fermented milk intake in women was robustly associated with a higher concentration of plasma ACE2 and a lower concentration of FGF21. Conclusions We show a positive association between high amounts of non-fermented milk intake and IHD in women but not men. We suggest metabolic pathways related to ACE2 and FGF21 potentially underlie the association. Graphical abstract Our analysis of two large cohort studies involving 100,775 participants and 17,896 clinically confirmed IHD events supports a dose–response positive association between non-fermented milk intake higher than 300 mL/day with higher rates of IHD (and acute MI specifically) in women, but not in men. The higher risk of IHD with high milk intake in women was evident, irrespective of the fat content of the milk. Fermented milk intake was unrelated to the risk of IHD in both women and men. Non-fermented milk intake was associated in different directions with circulating levels of ACE2 and FGF21 in women—two essential cardiometabolic proteins, also related to IHD in women in our study.
The pharmacokinetics of vancomycin exhibit significant inter-individual variability, particularly among elderly patients. This study aims to develop a predictive model that integrates machine learning with population pharmacokinetics (popPK) to facilitate personalized medication management for this demographic. A retrospective analysis incorporating 33 features, including popPK parameters such as clearance and volume of distribution. A combination of multiple algorithms and Shapley Additive Explanations was utilized for feature selection to identify the most influential factors affecting drug concentrations. The performance of each algorithm with popPK parameters was superior to that without popPK parameters. Our final ensemble model, composed of support vector regression, light gradient boosting machine, and categorical boosting in a 6:3:1 ratio, included 16 optimized features. This model demonstrated superior predictive accuracy compared to models utilizing all features, with testing group metrics including an R2 of 0.656, mean absolute error of 3.458, mean square error of 28.103, absolute accuracy within ± 5 mg/L of 81.82%, and relative accuracy within ± 30% of 76.62%. This study presents a rapid and cost-effective predictive model for estimating vancomycin plasma concentrations in elderly patients. The model offers a valuable tool for clinicians to accurately determine effective plasma concentration ranges and tailor individualized dosing regimens, thereby enhancing therapeutic outcomes and safety.
Light–matter interaction at the nanoscale in magnetic alloys and heterostructures is a topic of intense research in view of potential applications in high-density magnetic recording. While the element-specific dynamics of electron spins is directly accessible to resonant x-ray pulses with femtosecond time structure, the possible element-specific atomic motion remains largely unexplored. We use ultrafast electron diffraction (UED) to probe the temporal evolution of lattice Bragg peaks of FePt nanoparticles embedded in a carbon matrix following excitation by an optical femtosecond laser pulse. The diffraction interference between Fe and Pt sublattices enables us to demonstrate that the Fe mean square vibration amplitudes are significantly larger that those of Pt as expected from their different atomic mass. Both are found to increase as energy is transferred from the laser-excited electrons to the lattice. Contrary to this intuitive behavior, we observe a laser-induced lattice expansion that is larger for Pt than for Fe atoms during the first picosecond after laser excitation. This effect points to the strain-wave driven lattice expansion with the longitudinal acoustic Pt motion dominating that of Fe.
Recent seismic tomography unveiled complex mantle plume structures diverging from the originally proposed single, narrow, and vertically-oriented plume conduits, which necessitates new perspectives on the mechanism of hotspot motion. While several recent endeavours have focused on Pacific hotspots’ motion, knowledge of others remains limited. Here we constrain the motions of the Kerguelen hotspot within the Indian Ocean by obtaining robust ⁴⁰Ar/³⁹Ar ages for the Ninetyeast Ridge, Earth’s longest linear volcanic ridge. These data indicate varying volcanic progression rates along the ridge, contrasting to a constant rate as previously documented. Combined with constraints on the Indian Plate motion and seafloor spreading, we reveal four periods of motions of the hotspot caused by its interactions with the Indian–Antarctic spreading ridge. This suggests that mantle plume lateral flows are susceptible to changes in shallow mantle convection due to the existence of horizontal ponding zones and vertical conduits, especially in the shallow asthenosphere.
In this paper, we investigate extensions between graded Verma modules in the Bernstein–Gelfand–Gelfand category O\mathcal{O} . In particular, we determine exactly which information about extensions between graded Verma modules is given by the coefficients of the R -polynomials. We also give some upper bounds for the dimensions of graded extensions between Verma modules in terms of Kazhdan–Lusztig combinatorics. We completely determine all extensions between Verma module in the regular block of category O\mathcal{O} for sl4\mathfrak{sl}_4 and construct various “unexpected” higher extensions between Verma modules.
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Carina Schlebusch
  • Department of Organismal Biology
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