Heritability enrichment implicates microglia in Parkinson's disease pathogenesis

OBJECTIVE: Understanding how different parts of the immune system contribute to pathogenesis in Parkinson's disease is a burning challenge with important therapeutic implications. We studied enrichment of common variant heritability for Parkinson's disease stratified by immune and brain cell types. METHODS: We used summary statistics from the most recent meta-analysis of genome-wide association studies in Parkinson's disease and partitioned heritability using linkage disequilibrium score regression, stratified for specific cell types as defined by open chromatin regions. We also validated enrichment results using a polygenic risk score approach and intersected disease-associated variants with epigenetic data and expression quantitative loci to nominate and explore a putative microglial locus. RESULTS: We found significant enrichment of Parkinson's disease risk heritability in open chromatin regions of microglia and monocytes. Genomic annotations overlapped substantially between these two cell types, and only the enrichment signal for microglia remained significant in a joint model. We present evidence suggesting P2RY12, a key microglial gene and target for the anti-thrombotic agent clopidogrel, as the likely driver of a significant Parkinson's disease association signal on chromosome 3. INTERPRETATION: Our results provide further support for the importance of immune mechanisms in PD pathogenesis, highlight microglial dysregulation as a contributing etiological factor and nominate a targetable microglial gene candidate as a pathogenic player. Immune processes can be modulated by therapy, with potentially important clinical implications for future treatment in Parkinson's disease

Novel role of extracellular matrix protein 1 (ECM1) in cardiac aging and myocardial infarction

© 2019 Hardy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction The prevalence of heart failure increases in the aging population and following myocardial infarction (MI), yet the extracellular matrix (ECM) remodeling underpinning the development of aging- and MI-associated cardiac fibrosis remains poorly understood. A link between inflammation and fibrosis in the heart has long been appreciated, but has mechanistically remained undefined. We investigated the expression of a novel protein, extracellular matrix protein 1 (ECM1) in the aging and infarcted heart. Methods Young adult (3-month old) and aging (18-month old) C57BL/6 mice were assessed. Young mice were subjected to left anterior descending artery-ligation to induce MI, or transverse aortic constriction (TAC) surgery to induce pressure-overload cardiomyopathy. Left ventricle (LV) tissue was collected early and late post-MI/TAC. Bone marrow cells (BMCs) were isolated from young healthy mice, and subject to flow cytometry. Human cardiac fibroblast (CFb), myocyte, and coronary artery endothelial & smooth muscle cell lines were cultured; human CFbs were treated with recombinant ECM1. Primary mouse CFbs were cultured and treated with recombinant angiotensin-II or TGF-β1. Immunoblotting, qPCR and mRNA fluorescent in-situ hybridization (mRNA-FISH) were conducted on LV tissue and cells. Results ECM1 expression was upregulated in the aging LV, and in the infarct zone of the LV early post-MI. No significant differences in ECM1 expression were found late post-MI or at any time-point post-TAC. ECM1 was not expressed in any resident cardiac cells, but ECM1 was highly expressed in BMCs, with high ECM1 expression in granulocytes. Flow cytometry of bone marrow revealed ECM1 expression in large granular leucocytes. mRNA-FISH revealed that ECM1 was indeed expressed by inflammatory cells in the infarct zone at day-3 post-MI. ECM1 stimulation of CFbs induced ERK1/2 and AKT activation and collagen-I expression, suggesting a pro-fibrotic role. Conclusions ECM1 expression is increased in ageing and infarcted hearts but is not expressed by resident cardiac cells. Instead it is expressed by bone marrow-derived granulocytes. ECM1 is sufficient to induce cardiac fibroblast stimulation in vitro. Our findings suggest ECM1 is released from infiltrating inflammatory cells, which leads to cardiac fibroblast stimulation and fibrosis in aging and MI. ECM1 may be a novel intermediary between inflammation and fibrosis

Can a falling tree make a noise in two forests at the same time?

It is a commonplace to claim that quantum mechanics supports the old idea that a tree falling in a forest makes no sound unless there is a listener present. In fact, this conclusion is far from obvious. Furthermore, if a tunnelling particle is observed in the barrier region, it collapses to a state in which it is no longer tunnelling. Does this imply that while tunnelling, the particle can not have any physical effects? I argue that this is not the case, and moreover, speculate that it may be possible for a particle to have effects on two spacelike separate apparatuses simultaneously. I discuss the measurable consequences of such a feat, and speculate about possible statistical tests which could distinguish this view of quantum mechanics from a ``corpuscular'' one. Brief remarks are made about an experiment underway at Toronto to investigate these issues.Comment: 9 pp, Latex, 3 figs, to appear in Proc. Obsc. Unr. Conf.; Fig 2 postscript repaired on 26.10.9

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~ 25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value < 0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia

Cross-sectional associations between air pollution and chronic bronchitis: an ESCAPE meta-analysis across five cohorts

BACKGROUND: This study aimed to assess associations of outdoor air pollution on prevalence of chronic bronchitis symptoms in adults in five cohort studies (Asthma-E3N, ECRHS, NSHD, SALIA, SAPALDIA) participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE) project. METHODS: Annual average particulate matter (PM10, PM2.5, PMabsorbance, PMcoarse), NO2, nitrogen oxides (NOx) and road traffic measures modelled from ESCAPE measurement campaigns 2008-2011 were assigned to home address at most recent assessments (1998-2011). Symptoms examined were chronic bronchitis (cough and phlegm for &ge;3 months of the year for &ge;2 years), chronic cough (with/without phlegm) and chronic phlegm (with/without cough). Cohort-specific cross-sectional multivariable logistic regression analyses were conducted using common confounder sets (age, sex, smoking, interview season, education), followed by meta-analysis. RESULTS: 15 279 and 10 537 participants respectively were included in the main NO2 and PM analyses at assessments in 1998-2011. Overall, there were no statistically significant associations with any air pollutant or traffic exposure. Sensitivity analyses including in asthmatics only, females only or using back-extrapolated NO2 and PM10 for assessments in 1985-2002 (ECRHS, NSHD, SALIA, SAPALDIA) did not alter conclusions. In never-smokers, all associations were positive, but reached statistical significance only for chronic phlegm with PMcoarse OR 1.31 (1.05 to 1.64) per 5 &micro;g/m(3) increase and PM10 with similar effect size. Sensitivity analyses of older cohorts showed increased risk of chronic cough with PM2.5abs (black carbon) exposures. CONCLUSIONS: Results do not show consistent associations between chronic bronchitis symptoms and current traffic-related air pollution in adult European populations

A precision study of the fine tuning in the DiracNMSSM

Recently the DiracNMSSM has been proposed as a possible solution to reduce the fine tuning in supersymmetry. We determine the degree of fine tuning needed in the DiracNMSSM with and without non-universal gaugino masses and compare it with the fine tuning in the GNMSSM. To apply reasonable cuts on the allowed parameter regions we perform a precise calculation of the Higgs mass. In addition, we include the limits from direct SUSY searches and dark matter abundance. We find that both models are comparable in terms of fine tuning, with the minimal fine tuning in the GNMSSM slightly smaller.Comment: 20 pages + appendices, 10 figure

A Systematic Review of Online Sex Addiction and Clinical Treatments Using CONSORT Evaluation

Researchers have suggested that the advances of the Internet over the past two decades have gradually eliminated traditional offline methods of obtaining sexual material. Additionally, research on cybersex and/or online sex addictions has increased alongside the development of online technology. The present study extended the findings from Griffiths’ (2012) systematic empirical review of online sex addiction by additionally investigating empirical studies that implemented and/or documented clinical treatments for online sex addiction in adults. A total of nine studies were identified and then each underwent a CONSORT evaluation. The main findings of the present review provide some evidence to suggest that some treatments (both psychological and/or pharmacological) provide positive outcomes among those experiencing difficulties with online sex addiction. Similar to Griffiths’ original review, this study recommends that further research is warranted to establish the efficacy of empirically driven treatments for online sex addiction

Consumption patterns of sweet drinks in a population of Australian children and adolescents (2003–2008)

<p>Abstract</p> <p>Background</p> <p>Intake of sweet drinks has previously been associated with the development of overweight and obesity among children and adolescents. The present study aimed to assess the consumption pattern of sweet drinks in a population of children and adolescents in Victoria, Australia.</p> <p>Methods</p> <p>Data on 1,604 children and adolescents (4–18 years) from the comparison groups of two quasi-experimental intervention studies from Victoria, Australia were analysed<it>.</it> Sweet drink consumption (soft drink and fruit juice/cordial) was assessed as one day’s intake and typical intake over the last week or month at two time points between 2003 and 2008 (mean time between measurement: 2.2 years).</p> <p>Results</p> <p>Assessed using dietary recalls, more than 70% of the children and adolescents consumed sweet drinks, with no difference between age groups (p = 0.28). The median intake among consumers was 500 ml and almost a third consumed more than 750 ml per day. More children and adolescents consumed fruit juice/cordial (69%) than soft drink (33%) (p < 0.0001) and in larger volumes (median intake fruit juice/cordial: 500 ml and soft drink: 375 ml). Secular changes in sweet drink consumption were observed with a lower proportion of children and adolescents consuming sweet drinks at time 2 compared to time 1 (significant for age group 8 to <10 years, p = 0.001).</p> <p>Conclusion</p> <p>The proportion of Australian children and adolescents from the state of Victoria consuming sweet drinks has been stable or decreasing, although a high proportion of this sample consumed sweet drinks, especially fruit juice/cordial at both time points.</p