The Facility for Antiproton and Ion Research (FAIR) will be the accelerator-based flagship research facility in many basic sciences and their applications in Europe for the coming decades. FAIR will ...open up unprecedented research opportunities in hadron and nuclear physics, in atomic physics and nuclear astrophysics as well as in applied sciences like materials research, plasma physics and radiation biophysics with applications towards novel medical treatments and space science. FAIR is currently under construction as an international facility at the campus of the GSI Helmholtzzentrum for Heavy-Ion Research in Darmstadt, Germany. While the full science potential of FAIR can only be harvested once the new suite of accelerators and storage rings is completed and operational, some of the experimental detectors and instrumentation are already available and will be used starting in summer 2018 in a dedicated research program at GSI, exploiting also the significantly upgraded GSI accelerator chain. The current manuscript summarizes how FAIR will advance our knowledge in various research fields ranging from a deeper understanding of the fundamental interactions and symmetries in nature to a better understanding of the evolution of the Universe and the objects within.
Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, ...immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in SAMD9L, a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the 10 individuals identified who were heterozygous for either SAMD9L mutation, 3 developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B-, and natural killer (NK)–cell deficiency. Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional in cisSAMD9L truncating mutations. Examination of 1 individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34+ hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-α or IFN-γ induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in 3 individuals. Two carriers also harbored a rare, in trans germ line SAMD9L missense loss-of-function variant, potentially counteracting the SAMD9L mutation. Our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with −7/del(7q), whereas hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.
•Autosomal-dominant SAMD9L gain-of-function mutations predispose to myeloid malignancies involving chromosome 7 aberrations.•Hematopoietic reversions frequently occur postnatally and are associated with milder disease manifestations.
H(2)DCF-DA (dihydrodichlorofluorescein diacetate) is widely used to evaluate 'cellular oxidative stress'. After passing through the plasma membrane, this lipophilic and non-fluorescent compound is ...de-esterified to a hydrophilic alcohol H(2)DCF (dihydrodichlorofluorescein) that may be oxidized to fluorescent DCF (2',7'-dichlorofluorescein) by a process usually considered to involve ROS (reactive oxygen species). It is, however, not always recognized that, being a hydrophilic molecule, H(2)DCF does not cross membranes, except for the outer fenestrated mitochondrial ones. It is also not generally realized that oxidation of H(2)DCF is dependent either on Fenton-type reactions or on unspecific enzymatic oxidation by cytochrome c, for neither superoxide, nor H(2)O(2), directly oxidizes H(2)DCF. Consequently, oxidation of H(2)DCF requires the presence of either cytochrome c or of both redox-active transition metals and H(2)O(2). Redox-active metals exist mainly within lysosomes, whereas cytochrome c resides bound to the outer side of the inner mitochondrial membrane. Following exposure to H(2)DCF-DA, weak mitochondrial fluorescence was found in both the oxidation-resistant ARPE-19 cells and the much more sensitive J774 cells. This fluorescence was only marginally enhanced following short exposure to H(2)O(2), showing that by itself it is unable to oxidize H(2)DCF. Cells that were either exposed to the lysosomotropic detergent MSDH (O-methylserine dodecylamide hydrochloride), exposed to prolonged oxidative stress, or spontaneously apoptotic showed lysosomal permeabilization and strong DCF-induced fluorescence. The results suggest that DCF-dependent fluorescence largely reflects relocation to the cytosol of lysosomal iron and/or mitochondrial cytochrome c.
Abstract Background A 1-h algorithm based on high-sensitivity cardiac troponin T (hs-cTnT) testing at presentation and again 1 h thereafter has been shown to accurately rule out acute myocardial ...infarction. Objectives The goal of the study was to evaluate the diagnostic accuracy of the 1-h algorithm when supplemented with patient history and an electrocardiogram (ECG) (the extended algorithm) for predicting 30-day major adverse cardiac events (MACE) and to compare it with the algorithm using hs-cTnT alone (the troponin algorithm). Methods This prospective observational study enrolled consecutive patients presenting to the emergency department (ED) with chest pain, for whom hs-cTnT testing was ordered at presentation. Hs-cTnT results at 1 h and the ED physician’s assessments of patient history and ECG were collected. The primary outcome was an adjudicated diagnosis of 30-day MACE defined as acute myocardial infarction, unstable angina, cardiogenic shock, ventricular arrhythmia, atrioventricular block, cardiac arrest, or death of a cardiac or unknown cause. Results In the final analysis, 1,038 patients were included. The extended algorithm identified 60% of all patients for rule-out and had a higher sensitivity than the troponin algorithm (97.5% vs. 87.6%; p < 0.001). The negative predictive value was 99.5% and the likelihood ratio was 0.04 with the extended algorithm versus 97.8% and 0.17, respectively, with the troponin algorithm. The extended algorithm ruled-in 14% of patients with a higher sensitivity (75.2% vs. 56.2%; p < 0.001) but a slightly lower specificity (94.0% vs. 96.4%; p < 0.001) than the troponin algorithm. The rule-in arms of both algorithms had a likelihood ratio >10. Conclusions A 1-h combination algorithm allowed fast rule-out and rule-in of 30-day MACE in a majority of ED patients with chest pain and performed better than the troponin-alone algorithm.
Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are ...administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by
-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.
The use of XLPE as the insulation for power cables has grown steadily since it first introduction more than 30 years ago. Today XLPE is rapidly becoming the preferred insulation system for even the ...highest transmission voltages. This preference is due to the high reliability, low dielectric losses, and low environmental impact that can be achieved with XLPE. The positive effects of high quality insulation materials on improved cable performance have been well known since the start of cable making. The purpose of this paper is to investigate the technical background for the cleanliness levels and to quantify the level of performance required from clean materials. The advantages of clean insulation materials are seen at all voltages. However, this work focuses on the technical basis for the benefits for HV and EHV cables, which typically are designed with a water impervious layer to ensure that the cable remains dry throughout its entire lifetime. The presence of metallic contaminants in MV cable is known to enhance the growth of trees by raising the electric stress level locally. The singular impact of cleanliness on the performance of MV cables is somewhat more complicated as it is influenced both by the cleanliness of the insulation and the ability of the insulation material to resist the growth of water trees.
Kiruna-type apatite-iron-oxide ores are key iron sources for modern industry, yet their origin remains controversial. Diverse ore-forming processes have been discussed, comprising low-temperature ...hydrothermal processes versus a high-temperature origin from magma or magmatic fluids. We present an extensive set of new and combined iron and oxygen isotope data from magnetite of Kiruna-type ores from Sweden, Chile and Iran, and compare them with new global reference data from layered intrusions, active volcanic provinces, and established low-temperature and hydrothermal iron ores. We show that approximately 80% of the magnetite from the investigated Kiruna-type ores exhibit δ
Fe and δ
O ratios that overlap with the volcanic and plutonic reference materials (> 800 °C), whereas ~20%, mainly vein-hosted and disseminated magnetite, match the low-temperature reference samples (≤400 °C). Thus, Kiruna-type ores are dominantly magmatic in origin, but may contain late-stage hydrothermal magnetite populations that can locally overprint primary high-temperature magmatic signatures.
Purpose
This paper aims to expand the emerging field of symbolic green consumer behavior (GCB) by investigating the impact of anticipated conspicuousness of the consumption situation on consumers’ ...choice of organic products. In addition, the paper also explores whether self-monitoring ability and attention to social comparison information (ATSCI) influence GCB in situations of anticipated high conspicuousness.
Design/methodology/approach
Two experiments test the study’s hypotheses.
Findings
The results of both experiments show that the anticipation of conspicuousness has a significant effect on GCB. Moreover, in Experiment 2, this effect is moderated by consumers’ level of ATSCI but not by their self-monitoring ability.
Research limitations/implications
Because ATSCI significantly interacts with green consumption because of the anticipation of a conspicuous setting, although self-monitoring ability does not, we conclude that social identification is an important determinant of green consumption.
Practical implications
Marketers who focus on building green brands could consider designing conspicuous consumption situations to increase GCB.
Social implications
Policymakers could enact change by making the environmental unfriendliness of non-eco-friendly products visible to the public and thus increase the potential for GCB.
Originality/value
The results validate the emerging understanding that green products are consumed for self-enhancement, but also expand the literature by highlighting that a key motivating factor of GCB is the desire to fit in.
Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia-pancytopenia syndrome ...and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9L's normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutation's effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or loss-of-function mutations in SAMD9 or SAMD9L. Furthermore, the complete or partial loss of chromosome 7q may cause myelodysplastic syndrome in these patients. SAMD9 mutations appear to associate with a more severe disease phenotype, including intrauterine growth restriction, developmental delay and hypoplasia of adrenal glands, testes, ovaries or thymus, and most reported patients died in infancy or early childhood due to infections, anemia and/or hemorrhages. SAMD9L mutations have been reported in a few families with balance problems and nystagmus due to cerebellar atrophy, and may lead to similar hematological disease as seen in SAMD9 mutation carriers, from early childhood to adult years. We review the clinical features of these syndromes, discuss the underlying biology, and interpret the genetic findings in some of the affected family members. We provide expert-based recommendations regarding diagnosis, follow-up, and treatment of mutation carriers.
Primary prevention of cardiovascular disease often fails because of poor adherence among practitioners and individuals to prevention guidelines. We aimed to investigate whether ultrasound-based ...pictorial information about subclinical carotid atherosclerosis, targeting both primary care physicians and individuals, improves prevention.
Visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention (VIPVIZA) is a pragmatic, open-label, randomised controlled trial that was integrated within the Västerbotten Intervention Programme, an ongoing population-based cardiovascular disease prevention programme in northern Sweden. Individuals aged 40, 50, or 60 years with one or more conventional risk factors were eligible to participate. Participants underwent clinical examination, blood sampling, and ultrasound assessment of carotid intima media wall thickness and plaque formation. Participants were randomly assigned 1:1 with a computer-generated randomisation list to an intervention group (pictorial representation of carotid ultrasound plus a nurse phone call to confirm understanding) or a control group (not informed). The primary outcomes, Framingham risk score (FRS) and European systematic coronary risk evaluation (SCORE), were assessed after 1 year among participants who were followed up. This study is registered with ClinicalTrials.gov, number NCT01849575.
3532 individuals were enrolled between April 29, 2013, and June 7, 2016, of which 1783 were randomly assigned to the control group and 1749 were assigned to the intervention group. 3175 participants completed the 1-year follow-up. At the 1-year follow-up, FRS and SCORE differed significantly between groups (FRS 1·07 95% CI 0·11 to 2·03, p=0·0017 and SCORE 0·16 0·02 to 0·30, p=0·0010). FRS decreased from baseline to the 1-year follow-up in the intervention group and increased in the control group (−0·58 95% CI −0·86 to −0·30 vs 0·35 0·08 to 0·63). SCORE increased in both groups (0·13 95% CI 0·09 to 0·18 vs 0·27 0·23 to 0·30).
This study provides evidence of the contributory role of pictorial presentation of silent atherosclerosis for prevention of cardiovascular disease. It supports further development of methods to reduce the major problem of low adherence to medication and lifestyle modification.
Västerbotten County Council, the Swedish Research Council, the Heart and Lung Foundation, the Swedish Society of Medicine, and Carl Bennet Ltd, Sweden.
PDF
