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

Development and validation of HERWIG 7 tunes from CMS underlying-event measurements

This paper presents new sets of parameters (“tunes”) for the underlying-event model of the HERWIG7 event generator. These parameters control the description of multiple-parton interactions (MPI) and colour reconnection in HERWIG7, and are obtained from a fit to minimum-bias data collected by the CMS experiment at s=0.9, 7, and 13Te. The tunes are based on the NNPDF 3.1 next-to-next-to-leading-order parton distribution function (PDF) set for the parton shower, and either a leading-order or next-to-next-to-leading-order PDF set for the simulation of MPI and the beam remnants. Predictions utilizing the tunes are produced for event shape observables in electron-positron collisions, and for minimum-bias, inclusive jet, top quark pair, and Z and W boson events in proton-proton collisions, and are compared with data. Each of the new tunes describes the data at a reasonable level, and the tunes using a leading-order PDF for the simulation of MPI provide the best description of the dat

Reactions of the Phthalimide <i>N</i>‑Oxyl Radical (PINO) with Activated Phenols: The Contribution of π‑Stacking Interactions to Hydrogen Atom Transfer Rates

The kinetics of reactions of the phthalimide <i>N</i>-oxyl radical (PINO) with a series of activated phenols (2,2,5,7,8-pentamethylchroman-6-ol (PMC), 2,6-dimethyl- and 2,6-di-<i>tert</i>-butyl-4-substituted phenols) were investigated by laser flash photolysis in CH₃CN and PhCl in order to establish if the reactions with PINO can provide a useful tool for evaluating the radical scavenging ability of phenolic antioxidants. On the basis of the small values of deuterium kinetic isotope effects, the relatively high and negative ρ values in the Hammett correlations and the results of theoretical calculations, we suggest that these reactions proceed by a hydrogen atom transfer (HAT) mechanism having a significant degree of charge transfer resulting from a π-stacked conformation between PINO and the aromatic ring of the phenols. Kinetic solvent effects were analyzed in detail for the hydrogen transfer from 2,4,6-trimethylphenol to PINO and the data obtained are in accordance with the Snelgrove-Ingold equation for HAT. Experimental rate constants for the reactions of PINO with activated phenols are in accordance with those predicted by applying the Marcus cross relation

Ultraclean Derivatized Monodisperse Gold Nanoparticles through Laser Drop Ablation Customization of Polymorph Gold Nanostructures

We report a novel nanosecond laser ablation synthesis for spherical gold nanoparticles as small as 4 nm in only 5 s (532 nm, 0.66 J/cm²), where the desired protecting agent can be selected in a protocol that avoids repeated sample irradiation and undesired exposure of the capping agent during ablation. This method takes advantage of the recently developed synthesis of clean unprotected polymorph and polydisperse gold nanostructures using H₂O₂ as a reducing agent. The laser drop technique provides a unique tool for delivering controlled laser doses to small drops that undergo assisted fall into a solution or suspension of the desired capping agent, yielding monodisperse custom-derivatized composite materials using a simple technique

Ultraclean Derivatized Monodisperse Gold Nanoparticles through Laser Drop Ablation Customization of Polymorph Gold Nanostructures

We report a novel nanosecond laser ablation synthesis for spherical gold nanoparticles as small as 4 nm in only 5 s (532 nm, 0.66 J/cm²), where the desired protecting agent can be selected in a protocol that avoids repeated sample irradiation and undesired exposure of the capping agent during ablation. This method takes advantage of the recently developed synthesis of clean unprotected polymorph and polydisperse gold nanostructures using H₂O₂ as a reducing agent. The laser drop technique provides a unique tool for delivering controlled laser doses to small drops that undergo assisted fall into a solution or suspension of the desired capping agent, yielding monodisperse custom-derivatized composite materials using a simple technique

JHC772798_Supplemental_Material – Supplemental material for Immunolocalization of Advanced Glycation End Products, Mitogen Activated Protein Kinases, and Transforming Growth Factor-β/Smads in Pelvic Organ Prolapse

<p>Supplemental material, JHC772798_Supplemental_Material for Immunolocalization of Advanced Glycation End Products, Mitogen Activated Protein Kinases, and Transforming Growth Factor-β/Smads in Pelvic Organ Prolapse by Antonella Vetuschi, Simona Pompili, Anna Gallone, Angela D’Alfonso, Maria Gabriella Carbone, Gaspare Carta, Claudio Festuccia, Eugenio Gaudio, Alessandro Colapietro and Roberta Sferra in Journal of Histochemistry & Cytochemistry</p

The Length of SNCA Rep1 Microsatellite May Influence Cognitive Evolution in Parkinson’s Disease

BackgroundAlpha-synuclein is a constituent of Lewy bodies and mutations of its gene cause familial Parkinson’s disease (PD). A previous study showed that a variant of the alpha-synuclein gene (SNCA), namely the 263 bp allele of Rep1 was associated with faster motor progression in PD. On the contrary, a recent report failed to detect a detrimental effect of Rep1 263 on both motor and cognitive outcomes in PD. Aim of this study was to evaluate the influence of the Rep1 variants on disease progression in PD patients.MethodsWe recruited and genotyped for SNCA Rep1 426 PD patients with age at onset ≥40 years and disease duration ≥4 years. We then analyzed frequency and time of occurrence of wearing-off, dyskinesia, freezing of gait, visual hallucinations, and dementia using a multivariate Cox’s proportional hazards regression model.ResultsSNCA Rep1 263 carriers showed significantly increased risk of both dementia (HR = 3.03) and visual hallucinations (HR = 2.69) compared to 263 non-carriers. Risk of motor complications did not differ in the two groups.ConclusionSNCA Rep1 263 allele is associated with a worse cognitive outcome in PD

The length of SNCA Rep1 microsatellite may influence cognitive evolution in Parkinson's disease

Background: Alpha-synuclein is a constituent of Lewy bodies and mutations of its gene cause familial Parkinson's disease (PD). A previous study showed that a variant of the alpha-synuclein gene (SNCA), namely the 263 bp allele of Rep1 was associated with faster motor progression in PD. On the contrary, a recent report failed to detect a detrimental effect of Rep1 263 on both motor and cognitive outcomes in PD. Aim of this study was to evaluate the influence of the Rep1 variants on disease progression in PD patients. Methods: We recruited and genotyped for SNCA Rep1 426 PD patients with age at onset 6540 years and disease duration 654 years. We then analyzed frequency and time of occurrence of wearing-off, dyskinesia, freezing of gait, visual hallucinations, and dementia using a multivariate Cox's proportional hazards regression model. Results: SNCA Rep1 263 carriers showed significantly increased risk of both dementia (HR = 3.03) and visual hallucinations (HR = 2.69) compared to 263 non-carriers. Risk of motor complications did not differ in the two groups. Conclusion: SNCA Rep1 263 allele is associated with a worse cognitive outcome in PD

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Background<p>Alpha-synuclein is a constituent of Lewy bodies and mutations of its gene cause familial Parkinson’s disease (PD). A previous study showed that a variant of the alpha-synuclein gene (SNCA), namely the 263 bp allele of Rep1 was associated with faster motor progression in PD. On the contrary, a recent report failed to detect a detrimental effect of Rep1 263 on both motor and cognitive outcomes in PD. Aim of this study was to evaluate the influence of the Rep1 variants on disease progression in PD patients.</p>Methods<p>We recruited and genotyped for SNCA Rep1 426 PD patients with age at onset ≥40 years and disease duration ≥4 years. We then analyzed frequency and time of occurrence of wearing-off, dyskinesia, freezing of gait, visual hallucinations, and dementia using a multivariate Cox’s proportional hazards regression model.</p>Results<p>SNCA Rep1 263 carriers showed significantly increased risk of both dementia (HR = 3.03) and visual hallucinations (HR = 2.69) compared to 263 non-carriers. Risk of motor complications did not differ in the two groups.</p>Conclusion<p>SNCA Rep1 263 allele is associated with a worse cognitive outcome in PD.</p