Fibrils from Designed Non-Amyloid-Related Synthetic Peptides Induce AA-Amyloidosis during Inflammation in an Animal Model

Background: Mouse AA-amyloidosis is a transmissible disease by a prion-like mechanism where amyloid fibrils act by seeding. Synthetic peptides with no amyloid relationship can assemble into amyloid-like fibrils and these may have seeding capacity for amyloid proteins. Principal Findings: Several synthetic peptides, designed for nanotechnology, have been examined for their ability to produce fibrils with Congo red affinity and concomitant green birefringence, affinity for thioflavin S and to accelerate AAamyloidosis in mice. It is shown that some amphiphilic fibril-forming peptides not only produced Congo red birefringence and showed affinity for thioflavin S, but they also shortened the lag phase for systemic AA-amyloidosis in mice when they were given intravenously at the time of inflammatory induction with silver nitride. Peptides, not forming amyloid-like fibrils, did not have such properties. Conclusions: These observations should caution researchers and those who work with synthetic peptides and thei

Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs

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On the role of forests and the forest sector for climate change mitigation in Sweden

We analyse the short- and long-term consequences for atmospheric greenhouse gas (GHG) concentrations of forest management strategies and forest product uses in Sweden by comparing the modelled consequences of forest resource use vs. increased conservation at different levels of GHG savings from carbon sequestration and product substitution with bioenergy and other forest products. Increased forest set-asides for conservation resulted in larger GHG reductions only in the short term and only when substitution effects were low. In all other cases, forest use was more beneficial. In all scenarios, annual carbon dioxide (CO2) sequestration rates declined in conservation forests as they mature, eventually approaching a steady state. Forest set-asides are thus associated with increasing opportunity costs corresponding to foregone wood production and associated mitigation losses. Substitution and sequestration rates under all other forest management strategies rise, providing support for sustained harvest and cumulative mitigation gains. The impact of increased fertilization was everywhere beneficial to the climate and surpassed the mitigation potential of the other scenarios. Climate change can have large—positive or negative—influence on outcomes. Despite uncertainties, the results indicate potentially large benefits from forest use for wood production. These benefits, however, are not clearly linked with forestry in UNFCCC reporting, and the European Union\u27s Land Use, Land-Use Change and Forestry carbon accounting, framework may even prevent their full realization. These reporting and accounting frameworks may further have the consequence of encouraging land set-asides and reduced forest use at the expense of future biomass production. Further, carbon leakage and resulting biodiversity impacts due to increased use of more GHG-intensive products, including imported products associated with deforestation and land degradation, are inadequately assessed. Considerable opportunity to better mobilize the climate change mitigation potential of Swedish forests therefore remains

Surgery outcome modelling in concomitant esotropia treatment - a pilot study

Background: Many surgical formulas have been developed and proposed based on the experience of surgeons to improve the predictability of strabismus surgery. However, the consent among strabismus surgeons regarding the dose effect of the extra-ocular muscle recession or resection was not achieved yet and the disagreement about the appropriate amount of strabismus surgery still exists. Our study aimed to propose to elaborate an postoperative angle of deviation (PAD) predictive model using simple potential predictors for esotropia treatment. Methods: The analytical prospective clinical study was conducted from April 2016 to July 2019, on a sample of 160 patients (aged between 2–58) with concomitant esotropia who underwent strabismus surgery in Clinical Republican Hospital ”Timofei Mosneaga” and Children Hospital “Emilian Cotaga” from Republic of Moldova. The correlations of patients’ age, strabismus type, amblyopia degree, RsL, RcL, preoperative angle of deviation (PreAD) with PAD were estimated using Pearson’s correlation analysis. Multiple linear regression analysis, multi-collinearity analysis, model stability (bootstrapping 1000 samples) and residual analysis were performed. Results: Correlation analysis named to identify potential predictors for esotropia surgery outcome revealed the following significant associations with preoperative angle of squint (p ≤0.001. effect size 0.06). amblyopia degree (p ≤0.001 (effect size 0.32) and EOM recession amount (p= 0.24. (effect size 0.31). PAD modeling showed the PreAD, EOM RsL and EOM RcL predictive ability for esotropia surgery outcome prediction. Conclusions: In our study we propose a mathematical models as potential instruments for postoperative angle of deviation modelling in esotropia surgery. The correlation analysis of the factors associated with postoperative drift after 6 months of follow-up

When Is a Principal Charged With an Agent’s Knowledge?

Question: Detecting species presence in vegetation and making visual assessment of abundances involve a certain amount of skill, and therefore subjectivity. We evaluated the magnitude of the error in data, and its consequences for evaluating temporal trends. Location: Swedish forest vegetation. Methods: Vegetation data were collected independently by two observers in 342 permanent 100-m2 plots in mature boreal forests. Each plot was visited by one observer from a group of 36 and one of two quality assessment observers. The cover class of 29 taxa was recorded, and presence/absence for an additional 50. Results: Overall, one third of each occurrence was missed by one of the two observers, but with large differences among species. There were more missed occurrences at low abundances. Species occurring at low abundance when present tended to be frequently overlooked. Variance component analyses indicated that cover data on 5 of 17 species had a significant observer bias. Observer-explained variance was < 10% in 15 of 17 species. Conclusion: The substantial number of missed occurrences suggests poor power in detecting changes based on presence/absence data. The magnitude of observer bias in cover estimates was relatively small, compared with random error, and therefore potentially analytically tractable. Data in this monitoring system could be improved by a more structured working model during field work.Original publication: Milberg, P., Bergstedt, J., Fridman, J., Odell, G & Westerberg, L., Systematic and random variation in vegetation monitoring data, 2008, Journal of Vegetation Science, (19), 633-644. http://dx.doi.org/10.3170/2008-8-18423. Copyright: Opulus Press, http://www.opuluspress.se/index.ph

Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.This work was supported by grants from the Fondation Leducq (CADgenomics: Understanding CAD Genes, 12CVD02), the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (e:AtheroSysMed, grant 01ZX1313A-2014 and SysInflame, grant 01ZX1306A), and the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no HEALTH-F2-2013-601456 (CVgenes-at-target). Further grants were received from the DFG as part of the Sonderforschungsbereich CRC 1123 (B2). T.K. was supported by a DZHK Rotation Grant. I.B. was supported by the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ‘Inflammation at Interfaces’. F.W.A. is supported by a Dekker scholarship-Junior Staff Member 2014T001 - Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction