Medulloblastoma, a malignant brain tumour primarily diagnosed during childhood, has recently been the focus of intensive molecular profiling efforts, profoundly advancing our understanding of ...biologically and clinically heterogeneous disease subgroups. Genomic, epigenomic, transcriptomic and proteomic landscapes have now been mapped for an unprecedented number of bulk samples from patients with medulloblastoma and, more recently, for single medulloblastoma cells. These efforts have provided pivotal new insights into the diverse molecular mechanisms presumed to drive tumour initiation, maintenance and recurrence across individual subgroups and subtypes. Translational opportunities stemming from this knowledge are continuing to evolve, providing a framework for improved diagnostic and therapeutic interventions. In this Review, we summarize recent advances derived from this continued molecular characterization of medulloblastoma and contextualize this progress towards the deployment of more effective, molecularly informed treatments for affected patients.
Ticagrelor, a direct-acting P2Y12-receptor antagonist, is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). To identify single-nucleotide polymorphisms (SNPs) ...associated with pharmacokinetics of ticagrelor and clinical outcomes, we performed a genome-wide association study (GWAS) in patients treated with ticagrelor in the PLATO trial.
A two-stage design was used for the GWAS with discovery (discovery phase: n = 1812) and replication cohorts (replication phase: n = 1941). The steady-state area under the curve (AUCss) values, estimated by the population pharmacokinetic (PK) models, were log transformed and analysed on a genome-wide scale using linear regression. SNPs were analysed against clinical events using Cox-regression in 4990 patients. An SNP (rs113681054) in SLCO1B1 was associated with levels of ticagrelor (P = 1.1 × 10(-6)) and ARC (P = 4.6 × 10(-13)). This SNP is in linkage disequilibrium with a functional variant (rs4149056) that results in decreased OATP1B1 transporter activity. Ticagrelor levels were also associated with two independent SNPs (rs62471956, P = 7.7 × 10(-15) and rs56324128, P = 9.7 × 10(-12)) in the CYP3A4 region. Further, ARC levels were associated with rs61361928 (P = 3.0 × 10(-14)) in UGT2B7. At all loci, the effects were small. None of the identified SNPs that affected ticagrelor PK were associated with the primary composite outcome (cardiovascular death myocardial infarction, and stroke), non-CABG-related bleeds or investigator-reported dyspnoea.
In patients with ACS, ticagrelor pharmacokinetics is influenced by three genetic loci (SLCO1B1, UGT2B7, and CYP3A4). However, the modest genetic effects on ticagrelor plasma levels did not translate into any detectable effect on efficacy or safety during ticagrelor treatment.
NCT00391872.
The mechanisms controlling the conversion of spider silk proteins into insoluble fibres, which happens in a fraction of a second and in a defined region of the silk glands, are still unresolved. The ...N-terminal domain changes conformation and forms a homodimer when pH is lowered from 7 to 6; however, the molecular details still remain to be determined. Here we investigate site-directed mutants of the N-terminal domain from Euprosthenops australis major ampullate spidroin 1 and find that the charged residues D40, R60 and K65 mediate intersubunit electrostatic interactions. Protonation of E79 and E119 is required for structural conversions of the subunits into a dimer conformation, and subsequent protonation of E84 around pH 5.7 leads to the formation of a fully stable dimer. These residues are highly conserved, indicating that the now proposed three-step mechanism prevents premature aggregation of spidroins and enables fast formation of spider silk fibres in general.
Abstract
Background
Despite advances in life expectancy, low socioeconomic status is associated with a shorter lifespan. This study was conducted to investigate socioeconomic differences in mortality ...by comparing preventable with non-preventable causes of death in 39 506 participants from the Swedish Twin Registry born before 1935.
Methods
Childhood social class, own education, own social class and social mobility were used as separate indicators of socioeconomic status. These data were linked to the Swedish Cause of Death Register. Cause of death was categorized as preventable or non-preventable mortality according to indicators presented in the Avoidable Mortality in the European Union (AMIEHS) atlas. Using Cox proportional hazard models, we tested the association between the socioeconomic measures and all-cause mortality, preventable mortality and non-preventable mortality. Additional co-twin control analyses indicated whether the associations reflected genetic confounding.
Results
The social gradient for mortality was most prominent for the adult socioeconomic measures. There was a social gradient in both preventable mortality and non-preventable mortality, but with an indication of a moderately stronger effect in preventable causes of death. In analyses of social mobility, those who experienced life-time low socioeconomic status (SES) or downward social mobility had an increased mortality risk compared with those with life-time high SES and upward social mobility. Adjustments for genetic confounding did not change the observed associations for education, social class or social mobility and mortality. In the co-twin control analyses of reared-apart twins, the association between childhood social class and mortality weakened, indicating possible genetic influences on this association.
Conclusions
Our results indicate that there is an association between low adult socioeconomic status and increased mortality independent of genetic endowment. Thus, we do not find support for indirect social selection as the basis for mortality inequalities in Sweden
New nanomaterials are constantly developed with applications in everything from cosmetics to high tech electronics. Assessing their biological impact has been done by analysis of their adsorbed ...protein corona, in vitro cell assays, and larger scale ecotoxicological studies. This has proved to be a huge challenge due to the wide range of available nanomaterials and their unpredictable behaviour in different environments. Furthermore, the enormous number of experimental variables make comparisons difficult. Concentration is one of these variables and can vary greatly depending on the aim of the study. When analysing the protein corona, concentrations are often higher than in cell assays. Using a combination of complementary techniques, we have characterised 20 nm gold nanoparticles in a concentration level commonly used in cell studies. We compare their behaviour in a commonly used, protein rich medium and one protein poor medium over 24 hours. Under these conditions, the NPs were stable in protein rich environment but underwent gradual aggregation in protein poor medium. We characterise the biomolecular corona in both media. In protein poor medium, we can describe the often overlooked aggregation. The aggregates' morphology is confirmed by cryo-TEM. Finally, in the protein poor medium, by infrared spectroscopy, we have identified the amino acid arginine in the biomolecular corona which drives the aggregation.
Preeclampsia (PE) complicates 3-8% of all pregnancies and manifests clinically as hypertension and proteinuria in the second half of gestation. The pathogenesis of PE is not fully understood but ...recent studies have described the involvement of cell-free fetal hemoglobin (HbF). Hypothesizing that PE is associated with prolonged hemolysis we have studied the response of the cell-free Hb- and heme defense network. Thus, we have investigated the levels of cell-free HbF (both free, denoted HbF, and in complex with Hp, denoted Hp-HbF) as well as the major human endogenous Hb- and heme-scavenging systems: haptoglobin (Hp), hemopexin (Hpx), α1-microglobulin (A1M) and CD163 in plasma of PE women (n = 98) and women with normal pregnancies (n = 47) at term. A significant increase of the mean plasma HbF concentration was observed in women with PE. Plasma levels of Hp and Hpx were statistically significantly reduced, whereas the level of the extravascular heme- and radical scavenger A1M was significantly increased in plasma of women with PE. The Hpx levels significantly correlated with maternal blood pressure. Furthermore, HbF and the related scavenger proteins displayed a potential to be used as clinical biomarkers for more precise diagnosis of PE and are candidates as predictors of identifying pregnancies with increased risk of obstetrical complications. The results support that PE pathophysiology is associated with increased HbF-concentrations and an activation of the physiological Hb-heme defense systems.
Atherosclerotic cardiovascular disease (ACVD) is the leading cause of death worldwide. This study aimed to investigate the association between diet and lifestyle factors, beyond traditional risk ...factors, and the risk of incident ACVD. The Malmö Diet and Cancer study included 30,446 middle-aged individuals. Baseline examinations including a dietary assessment, questionnaire and interviews, were performed between 1991-1996. After excluding individuals with prevalent cardiovascular disease and atrial fibrillation or flutter, 26,990 participants remained. In a previously developed diet quality index, adherence to recommended intake of saturated fat (SFA), polyunsaturated fat (PUFA), fish and shellfish, fiber, vegetables and fruit, and sucrose results in one point per dietary component, with a maximum diet score of six points. Diagnosis of incident ACVD was based on validated diagnoses of coronary artery disease, atherothrombotic ischemic stroke, carotid artery disease or peripheral artery disease. Multivariable Cox regression analysis adjusting for established risk factors was performed to assess hazard ratios (HR) with 95% confidence intervals (CI). After a median follow-up of 21.1 years, 5858 (21.7%) individuals diagnosed with ACVD unrelated to atrial fibrillation or flutter were identified. Higher diet score (HR 0.94/point increase; 95% CI 0.91-0.97;
< 0.001), intake of fish and shellfish (HR 0.95/standard deviation (SD) increment, 95% CI 0.93-0.98), fiber (HR 0.93/SD increment, 95% CI 0.89-0.98) and SFA (HR 0.96/SD increment, 95% CI 0.92-0.99) consumption were associated with decreased risk for incident ACVD. High leisure-time physical activity (HR 0.82, 95% CI 0.74-0.91) was associated with reduced risk and obesity (HR 1.17, 95% CI 1.08-1.27) with increased risk of incident ACVD. The present study strengthens current recommendations of improving diet quality and increasing physical activity in preventing ACVD.
Electrocardiogram (ECG) and measurement of plasma brain natriuretic peptides (BNP) are established markers of right ventricular dysfunction (RVD) in the setting of acute pulmonary embolism (PE) but ...their value at long-term follow-up is largely unknown. The purpose of this prospective study was to determine the prevalence of ECG abnormalities, describe levels of N-terminal proBNP (NT-proBNP), and establish their association with dyspnea at long-term follow-up after PE.OBJECTIVESElectrocardiogram (ECG) and measurement of plasma brain natriuretic peptides (BNP) are established markers of right ventricular dysfunction (RVD) in the setting of acute pulmonary embolism (PE) but their value at long-term follow-up is largely unknown. The purpose of this prospective study was to determine the prevalence of ECG abnormalities, describe levels of N-terminal proBNP (NT-proBNP), and establish their association with dyspnea at long-term follow-up after PE.All Swedish patients diagnosed with acute PE in 2005 (n = 5793) were identified through the Swedish National Patient Registry. Surviving patients in 2007 (n = 3510) were invited to participate. Of these, 2105 subjects responded to a questionnaire about dyspnea and comorbidities. Subjects with dyspnea or risk factors for development of chronic thromboembolic pulmonary hypertension were included in the study in a secondary step, which involved collection of blood samples and ECG registration.DESIGNAll Swedish patients diagnosed with acute PE in 2005 (n = 5793) were identified through the Swedish National Patient Registry. Surviving patients in 2007 (n = 3510) were invited to participate. Of these, 2105 subjects responded to a questionnaire about dyspnea and comorbidities. Subjects with dyspnea or risk factors for development of chronic thromboembolic pulmonary hypertension were included in the study in a secondary step, which involved collection of blood samples and ECG registration.Altogether 49.3% had a completely normal ECG. The remaining participants had a variety of abnormalities, 7.2% had atrial fibrillation/flutter (AF). ECG with any sign of RVD was found in 7.2% of subjects. Right bundle branch block was the most common RVD sign with a prevalence of 6.4%. An abnormal ECG was associated with dyspnea. AF was associated with dyspnea, whereas ECG signs of RVD were not. 61.2% of subjects had NT-proBNP levels above clinical cut-off (>125 ng/L). The degree of dyspnea did not associate independently with NT-proBNP levels.RESULTSAltogether 49.3% had a completely normal ECG. The remaining participants had a variety of abnormalities, 7.2% had atrial fibrillation/flutter (AF). ECG with any sign of RVD was found in 7.2% of subjects. Right bundle branch block was the most common RVD sign with a prevalence of 6.4%. An abnormal ECG was associated with dyspnea. AF was associated with dyspnea, whereas ECG signs of RVD were not. 61.2% of subjects had NT-proBNP levels above clinical cut-off (>125 ng/L). The degree of dyspnea did not associate independently with NT-proBNP levels.We conclude that the value of ECG and NT-proBNP in long term follow-up after PE lies mostly in differential diagnostics.CONCLUSIONSWe conclude that the value of ECG and NT-proBNP in long term follow-up after PE lies mostly in differential diagnostics.
Electrostatic forces are important for protein folding and are favored targets of protein engineering. However, interactions between charged residues are difficult to study because of the complex ...network of interactions found in most proteins. We have designed a purposely simple system to investigate this problem by systematically introducing individual and pairs of charged and titratable residues in a protein otherwise free of such residues. We used constant pH molecular dynamics simulations, NMR spectroscopy, and thermodynamic double mutant cycles to probe the structure and energetics of the interaction between the charged residues. We found that the partial burial of surface charges contributes to a shift in pK a value, causing an aspartate to titrate in the neutral pH range. Additionally, the interaction between pairs of residues was found to be highly context dependent, with some pairs having no apparent preferential interaction, while other pairs would engage in coupled titration forming a highly stabilized salt bridge. We find good agreement between experiments and simulations and use the simulations to rationalize our observations and to provide a detailed mechanistic understanding of the electrostatic interactions.
Landslides as major geo-hazards in Sweden adversely impact on nearby environments and socio-economics. In this paper, a landslide susceptibility map using a proposed subdivision approach for a large ...area in southwest Sweden has been produced. The map has been generated by means of an artificial neural network (ANN) model developed using fourteen causative factors extracted from topographic and geomorphologic, geological, land use, hydrology and hydrogeology characteristics. The landslide inventory map includes 242 events identified from different validated resources and interpreted aerial photographs. The weights of the causative factors employed were analyzed and verified using accepted mathematical criteria, sensitivity analysis, previous studies, and actual landslides. The high accuracy achieved using the ANN model demonstrates a consistent criterion for future landslide susceptibility zonation. Comparisons with earlier susceptibility assessments in the area show the model to be a cost-effective and potentially vital tool for urban planners in developing cities and municipalities.
•An ANN model for landslide susceptibility was developed and optimized.•A novel subdivision approach for landslide hazard assessment was introduced.•Detailed discussion comparing with previous studies and projects.•A cost-effective high-resolution map for decision makers and planners was generated.
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