Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Analysis of macrolide antibiotics in eggs validated according to European Commission Decision 2002/657/EC: a rapid extraction followed by liquid chromatography –tandem mass spectrometry

A direct method able to determine residues of macrolide antibiotics erythromycin, tylosin and tilmicosin in whole eggs is here presented. This method proposed is based on a one-step extraction followed by liquid chromatography-tandem mass spectrometry. Analytes were extracted with acetonitrile from 1 g of egg. No cleanup was found to be necessary. Extraction was effective, since absolute recovery of the analyte in egg at the level of 5 ng/g for tilmicosin and at the Maximum Residue Limit (MRL) for erythromycin and tylosin were 89-103%. Based on the EU Commission Decision 2002/657/EC1, the method was in-house validated in terms of ruggedness, specificity, linearity, within-laboratory reproducibility, decision limit (CCα) and detection capability (CCβ). The within-laboratory reproducibility (n= 18) at MRL level was in the 12-13% range. After validation, a short evaluation of the depletion of erythromycin in eggs was conducted after administration of this drug to laying hens

Environmental contaminants

In Pres

Hydrogen-treated graphitized carbon blacks. Limiting isosteric heats and entropy changes upon adsorption of hydrocarbons

The study of the effects of hydrogen treatment at 1000° on graphitized carbon blacks was extended to the adsorption of nonpolar molecules. Before and after the hydrogen treatment on the Graphon and graphitized Sterling FT (Sterling FT-G) surfaces, the isosteric heats and entropies of adsorption at extremely low surface coverages of ethane, propane, isobutane, butane, pentane, and hexane were determined by chromatography using the eluted pulse technique. Our results were compared with some earlier determinations obtained by chromatography or by static methods. The abnormally high limiting heats and entropy changes of adsorption on untreated Graphon indicated the presence of a small fraction of surface geometric irregularities, where the interaction of an individual adsorbed molecule occurs with more than one plane of'the adsorbing surface. Some experimental data suggest that surface heterogeneities can be identified as cavities with specific dimensions. These irregularities are not found on the Sterling FT-G surface, which we observed as almost completely free of strong adsorption sites. After the hydrogen treatment, the heats and entropy changes of adsorption on Graphon sharply decreased and their values are almost equal to those measured upon adsorption on Sterling FT-G. This agreement shows that the hydrogen treatment is effective in removing not only traces of surface oxides but also topographical irregularities on the carbon surface. The standard integral adsorption entropy values were calculated from retention volume measurements and by using a relation we derived. The close agreement between our values and those derived by a static method makes it evident that the gas chromatography technique can definitely also be of great use in the determination of adsorption entropies at very low surface coverages

Hydrogen-treated graphitized carbon blacks

Abstract The isotherms and isosteric heats of adsorption in the region of very low surface coverages have been measured for propylamine and acetic acid on two graphitized carbon blacks, graphitized Sterling FT and MT, before and after hydrogen treatment at 1000°. In order to obtain adsorption isotherms at very low coverages with good precision, a gas chromatographic method has been adopted. The experimental results confirm the effectiveness of the hydrogen treatment in removing trace amounts of surface oxides and the usefulness of an oxygen-free carbon surface in deriving adsorption isotherms of hydrogen-bonding substances. The removal of chemical impurities causes the extent of propylamine adsorption to be sharply reduced and the shape of the isotherm to be altered. On untreated graphitized carbon blacks, the heat of adsorption of propylamine shows an uninterrupted fall as the surface coverage increases, whereas after the hydrogen treatment, a constant value of 7.5 kcal/mole is obtained. In contrast to the behaviour of propylamine, on treated carbon surfaces the adsorption of acetic acid increases and the heat-coverage curve is steeper than for untreated surfaces. This is because the adsorbate can establish strong lateral interactions on a clean surface. The surface density of chemisorbed oxygen on unpurified graphitized Sterling FT is estimated as two oxygen-containing groups per 104 A2

Determination of chloroaniline traces in environmental waters by selective extraction with two traps in tandem and liquid chromatography

[No abstract available

Gas chromatographic determination at the parts-per-million level of aliphatic amines in aqueous solution

Abstract Modifications of Sterling FT-G and Vulcan, which are two well-known examples oil graphitized carbon blacks (GCB) with suitable amounts of KOH and polyethylene glycols (PEG), e.g., PEG-20 M and PEG-1500, allow the linear elution of free aliphatic amines from C1 to C16 to be performed. In particular, because of the use of such packing materials, the quantitative determination of C1-C4 aliphatic amines in aqueous solution is made possible even at the sub-ppm level. At these high sensitivities, the sole factor affecting in some measure the quality of the chromatographic profile is due to the water disturbance. By varying the liquid-to-solid ratio, gas-liquid-solid (GLS) columns have been evaluated in terms of selectivity and elution time