Common and rare variant association analyses in amyotrophic lateral sclerosis identify 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. 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

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 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. 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

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

Economic consequences of investing in anti-HCV antiviral treatment from the Italian NHS perspective : a real-world-based analysis of PITER data

OBJECTIVE: We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy. METHODS: A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered. RESULTS: The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively. CONCLUSIONS: This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 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.peer-reviewe

Behavior of photocathodes on superficial modification by electrical breakdown

In this work we present the experimental study and a theoretical approach of the photoemission of rough and smooth photocathodes. The cathode bulk was made of pure yttrium while its surface was morphologically modified. The cathode surface was irradiated by a KrF excimer at normal incidence with the anode-cathode distance set to 5mm. The measurements were performed after electric breakdowns between anode and cathode, induced under high laser energy and high accelerating voltage. This operation was made in order to increase the surface roughness. For the rough cathode the maximum output current was 10.5 A, reached at 25 kV and 12 mJ, with a maximum quantum efficiency value of 1.3×10-4. Instead, under the same experimental conditions the smooth cathode provided an output current of 8.4 A with a maximum quantum efficiency value of 7.0×10-5. We can conclude that in this process the plasma production and the Schottky effect play a fundamental role

Temporal behaviour of photoemission for yttrium cathodes

In this work, the photoemission performance of rough and smooth cathodes is presented. The cathodes were made up of pure yttrium metal bulk. For evaluation of the photocathodes, a KrF excimer laser, operating at 248 nm wavelength, 5 eV photon energy and 23 ns full width at half maximum (FWHM) was used. The targets were tested in a vacuum photodiode cell at 10^(-7) mbar; they were irradiated at normal incidence and the anode-cathode distance was set to 5 mm. The measurements were performed after a series of electric breakdowns between anode and cathode, induced under high laser energy and high accelerating voltage. This operation was performed in order to restore/increase the surface roughness. For the rough cathode, the maximum output current was 10.5 A, reached at 25 kV and 12 mJ laser energy; the maximum quantum efficiency (QE) value was 1.3 x 10^(-4), whereas for the smooth cathode, the maximum output current was 8.4 A and the maximum QE value was 7.0 x 10^(-5), calculated in the same experimental conditions. The temporal behavior of photoemission from these cathodes was studied. Plasma production and Schottky effect played a fundamental role in this process

Temporal quantum efficiency of a micro-structured cathode

In this work the experimental and simulation results of photoemission studies for photoelectrons are presented. The cathode used was a Zn disc having a work function of 4.33 eV. Two different excimer lasers were employed as energy source to apply the photoelectron process: XeCl (308 nm, 10 ns) and KrF (248nm, 23ns). Experimental parameters were the laser fluence (up to 70 mJ/cm2) and the anode-cathode voltage (up to 20 kV). The output current was detected by a resistive shunt having the same value of the characteristic impedance of the system. The best values of global quantum efficiency were approximately 5x10-6 for XeCl and 1x10-4 for KrF laser, while the peaks of the temporal quantum efficiency were 8x10-6 and 1.4x10-4, respectively. The higher efficiency for KrF is ascribed to higher photon energy and to Schottky effect. To enhance the Schottky effect, several electron-beam simulations using OPERA 3-D were carried out to analyze the influence of the geometrical characteristics of the diode

Endocranial volume increases across captive generations in the endangered Mexican wolf

Endangered animals in captivity may display reduced brain sizes due to captive conditions and limited genetic diversity. Captive diets, for example, may differ in nutrition and texture, altering cranial musculature and alleviating constraints on cranial shape development. Changes in brain size are associated with biological fitness, which may limit reintroduction success. Little is known about how changes in brain size progress in highly managed carnivoran populations and whether such traits are retained among reintroduced populations. Here, we measured the endocranial volume of preserved Mexican wolf skulls across captive generations and between captive, wild, and reintroduced populations and assessed endocranial volume dependence on inbreeding and cranial musculature. Endocranial volume increased across captive generations. However, we did not detect a difference among captive, wild, and reintroduced groups, perhaps due to the variability across captive generations. We did not find a relationship between endocranial volume and either inbreeding or cranial musculature, although the captive population displayed an increase in the cross-sectional area of the masseter muscle. We hypothesize that the increase in endocranial volume observed across captive generations may be related to the high-quality nutrition provided in captivity