Amyloid-β nanotubes are associated with prion protein-dependent synaptotoxicity

Growing evidence suggests water-soluble, non-fibrillar forms of amyloid-β protein (Aβ) have important roles in Alzheimer's disease with toxicities mimicked by synthetic Aβ1-42. However, no defined toxic structures acting via specific receptors have been identified and roles of proposed receptors, such as prion protein (PrP), remain controversial. Here we quantify binding to PrP of Aβ1-42 after different durations of aggregation. We show PrP-binding and PrP-dependent inhibition of long-term potentiation (LTP) correlate with the presence of protofibrils. Globular oligomers bind less avidly to PrP and do not inhibit LTP, whereas fibrils inhibit LTP in a PrP-independent manner. That only certain transient Aβ assemblies cause PrP-dependent toxicity explains conflicting reports regarding the involvement of PrP in Aβ-induced impairments. We show that these protofibrils contain a defined nanotubular structure with a previously unidentified triple helical conformation. Blocking the formation of Aβ nanotubes or their interaction with PrP might have a role in treatment of Alzheimer's disease

Corrigendum to: Cohort profile: Extended Cohort for E-health, Environment and DNA (EXCEED)

This is a correction to: International Journal of Epidemiology, Volume 48, Issue 3, June 2019, Pages 678–679j, https://doi.org/10.1093/ije/dyz07

Association analysis of PRNP gene region with chronic wasting disease in Rocky Mountain elk

<p>Abstract</p> <p>Background</p> <p>Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of cervids including white-tailed (<it>Odocoileus virginianus</it>) and mule deer (<it>Odocoileus hemionus</it>), Rocky Mountain elk (<it>Cervus elaphus nelsoni</it>), and moose (<it>Alces alces</it>). A leucine variant at position 132 (132L) in prion protein of Rocky Mountain elk confers a long incubation time with CWD, but not complete resistance. However, variants in regulatory regions outside the open reading frame of <it>PRNP </it>have been associated with varying degrees of susceptibility to prion disease in other species, and some variants have been observed in similar regions of Rocky Mountain elk <it>PRNP</it>. Thus, additional genetic variants might provide increased protection, either alone or in combination with 132L.</p> <p>Findings</p> <p>This study provided genomic sequence of all exons for <it>PRNP </it>of Rocky Mountain elk. Many functional sites in and around the <it>PRNP </it>gene region were sequenced, and this report approximately doubled (to 75) the number of known variants in this region. A haplotype-tagging approach was used to reduce the number of genetic variants required to survey this variation in the <it>PRNP </it>gene region of 559 Rocky Mountain elk. Eight haplotypes were observed with frequencies over 1.0%, and one haplotype was present at 71.2% frequency, reflecting limited genetic diversity in the <it>PRNP </it>gene region.</p> <p>Conclusions</p> <p>The presence of 132L cut odds of CWD by more than half (Odds Ratio = 0.43; P = 0.0031), which was similar to a previous report. However after accounting for 132L, no association with CWD was found for any additional variants in the <it>PRNP </it>region (P > 0.05).</p

Genetic Markers of Obesity Risk: Stronger Associations with Body Composition in Overweight Compared to Normal-Weight Children

Genetic factors are important determinants of overweight. We examined whether there are differential effect sizes depending on children's body composition. We analysed data of n = 4,837 children recorded in the Avon Longitudinal Study of Parents and Children (ALSPAC), applying quantile regression with sex- and age-specific standard deviation scores (SDS) of body mass index (BMI) or with body fat mass index and fat-free mass index at 9 years as outcome variables and an "obesity-risk-allele score" based on eight genetic variants known to be associated with childhood BMI as the explanatory variable. The quantile regression coefficients increased with increasing child's BMI-SDS and fat mass index percentiles, indicating larger effects of the genetic factors at higher percentiles. While the associations with BMI-SDS were of similar size in medium and high BMI quantiles (40th percentile and above), effect sizes with fat mass index increased over the whole fat mass index distribution. For example, the fat mass index of a normal-weight (50th percentile) child was increased by 0.13 kg/m(2) (95% confidence interval (CI): 0.09, 0.16) per additional allele, compared to 0.24 kg/m(2) per allele (95% CI: 0.15, 0.32) in children at the 90th percentile. The genetic associations with fat-free mass index were weaker and the quantile regression effects less pronounced than those on fat mass index. Genetic risk factors for childhood overweight appear to have greater effects on fatter children. Interaction of known genetic factors with environmental or unknown genetic factors might provide a potential explanation of these findings

PECAM-Independent Thioglycollate Peritonitis Is Associated With a Locus on Murine Chromosome 2

Background: Previous studies have demonstrated that knockout or inhibition of Platelet/Endothelial Cell Adhesion Molecule (PECAM, CD31) in a number of murine strains results in impaired inflammatory responses, but that no such phenotype is seen in the C57BL/6 (B6) murine background. Methodology/Principal Findings: We have undertaken a quantitative trait locus (QTL) mapping effort between FVB/n (FVB) and B6 mice deficient for PECAM to identify the gene or genes responsible for this unique feature of B6 mice. We have identified a locus on murine chromosome 2 at approximately 35.8 Mb that is strongly associated (LOD score = 9.0) with inflammatory responses in the absence of PECAM. Conclusions/Significance: These data potentiate further study of the diapedesis machinery, as well as potential identification of new components of this machinery. As such, this study is an important step to better understanding the processes of inflammation

An alternative to the hand searching gold standard: validating methodological search filters using relative recall

BACKGROUND: Search filters or hedges play an important role in evidence-based medicine but their development depends on the availability of a "gold standard" – a reference standard against which to establish the performance of the filter. We demonstrate the feasibility of using relative recall of included studies from multiple systematic reviews to validate methodological search filters as an alternative to validation against a gold standard formed through hand searching. METHODS: We identified 105 Cochrane reviews that used the Highly Sensitive Search Strategy (HSSS), included randomized or quasi-randomized controlled trials, and reported their included studies. We measured the ability of two published and one novel variant of the HSSS to retrieve the MEDLINE-index studies included in these reviews. RESULTS: The systematic reviews were comprehensive in their searches. 72% of included primary studies were indexed in MEDLINE. Relative recall of the three strategies ranged from .98 to .91 across all reviews and more comprehensive strategies showed higher recall. CONCLUSION: An approach using relative recall instead of a hand searching gold standard proved feasible and produced recall figures that were congruent with previously published figures for the HSSS. This technique would permit validation of a methodological filter using a collection of approximately 100 studies of the chosen design drawn from the included studies of multiple systematic reviews that used comprehensive search strategies

Effects of music on arousal during imagery in elite shooters: A pilot study

© 2017 Kuan 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. Beneficial effects of music on several performance-related aspects of sport have been reported, but the processes involved are not well understood. The purpose of the present study was to investigate effects of relaxing and arousing classical music on physiological indicators and subjective perceptions of arousal during imagery of a sport task. First, appropriate music excerpts were selected. Then, 12 skilled shooters performed shooting imagery while listening to the three preselected music excerpts in randomized order. Participants' galvanic skin response, peripheral temperature, and electromyography were monitored during music played concurrently with imagery. Subjective music ratings and physiological measures showed, as hypothesized, that unfamiliar relaxing music was the most relaxing and unfamiliar arousing music was the most arousing. Researchers should examine the impact of unfamiliar relaxing and arousing music played during imagery on subsequent performance in diverse sports. Practitioners can apply unfamiliar relaxing and arousing music with imagery to manipulate arousal level.This present study was support by the Fundamental Research Grant Scheme, Ministry of Higher Education, Ministry of Education, Malaysia (FRGS/1/2014/SS02/USM/03/1)

Experimental Evidence for Reduced Rodent Diversity Causing Increased Hantavirus Prevalence

Emerging and re-emerging infectious diseases have become a major global environmental problem with important public health, economic, and political consequences. The etiologic agents of most emerging infectious diseases are zoonotic, and anthropogenic environmental changes that affect wildlife communities are increasingly implicated in disease emergence and spread. Although increased disease incidence has been correlated with biodiversity loss for several zoonoses, experimental tests in these systems are lacking. We manipulated small-mammal biodiversity by removing non-reservoir species in replicated field plots in Panama, where zoonotic hantaviruses are endemic. Both infection prevalence of hantaviruses in wild reservoir (rodent) populations and reservoir population density increased where small-mammal species diversity was reduced. Regardless of other variables that affect the prevalence of directly transmitted infections in natural communities, high biodiversity is important in reducing transmission of zoonotic pathogens among wildlife hosts. Our results have wide applications in both conservation biology and infectious disease management

Detecting broad domains and narrow peaks in ChIP-seq data with hiddenDomains

Abstract Background Correctly identifying genomic regions enriched with histone modifications and transcription factors is key to understanding their regulatory and developmental roles. Conceptually, these regions are divided into two categories, narrow peaks and broad domains, and different algorithms are used to identify each one. Datasets that span these two categories are often analyzed with a single program for peak calling combined with an ad hoc method for domains. Results We developed hiddenDomains, which identifies both peaks and domains, and compare it to the leading algorithms using H3K27me3, H3K36me3, GABP, ESR1 and FOXA ChIP-seq datasets. The output from the programs was compared to qPCR-validated enriched and depleted sites, predicted transcription factor binding sites, and highly-transcribed gene bodies. With every method, hiddenDomains, performed as well as, if not better than algorithms dedicated to a specific type of analysis. Conclusions hiddenDomains performs as well as the best domain and peak calling algorithms, making it ideal for analyzing ChIP-seq datasets, especially those that contain a mixture of peaks and domains