DNA Modifications and Alzheimer's Disease

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this recordAlzheimer's disease (AD) is a complex neurodegenerative disease, affecting millions of people worldwide. While a number of studies have focused on identifying genetic variants that contribute to the development and progression of late-onset AD, the majority of these only have a relatively small effect size. There are also a number of other risk factors, for example, age, gender, and other comorbidities; however, how these influence disease risk is not known. Therefore, in recent years, research has begun to investigate epigenetic mechanisms for a potential role in disease etiology. In this chapter, we discuss the current state of play for research into DNA modifications in AD, the most well studied being 5-methylcytosine (5-mC). We describe the earlier studies of candidate genes and global measures of DNA modifications in human AD samples, in addition to studies in mouse models of AD. We focus on recent epigenome-wide association studies (EWAS) in human AD, using microarray technology, examining a number of key study design issues pertinent to such studies. Finally, we discuss how new technological advances could further progress the research field

Detection of high levels of congenital transmission of toxoplasma gondii in natural urban populations of mus domesticus

The relative importance of different transmission routes of Toxoplasma gondii has been a matter for debate. This ubiquitous parasite is generally thought to be transmitted by infective oocysts excreted by the definitive host, the cat. Ingestion of undercooked meat has also been considered an important route of transmission in many mammals while congenital transmission has generally been considered relatively rare. Experimental studies demonstrate the ability of T. gondii to be transmitted congenitally, but few studies have investigated the frequency of this transmission route in natural populations. We use PCR amplification of the SAG1 gene to investigate the frequency of congenital transmission in a wild population of mice (Mus domesticus) and show that congenital transmission is occurring in 75% of pregnancies in this population. Furthermore, for infected pregnant mice, transmission occurs to at least one foetus in 100% of cases while variable penetrance of congenital infection is observed. These high levels of congenital transmission in this wild population of mice, taken together with other recent data on congenital transmission in sheep, suggests that this phenomenon might be more widespread than previously thought

Elucidating novel dysfunctional pathways in Alzheimer's disease by integrating loci identified in genetic and epigenetic studies

PublishedReviewJournalThis is the author accepted manuscript. The final version is freely available from Elsevier via the DOI in this record.© 2016 The Authors.Alzheimer's disease is a complex neurodegenerative disorder. A large number of genome-wide association studies have been performed, which have been supplemented more recently by the first epigenome-wide association studies, leading to the identification of a number of novel loci altered in disease. Twin studies have shown monozygotic twin discordance for Alzheimer's disease (Gatz et al., 2006), leading to the conclusion that a combination of genetic and epigenetic mechanisms is likely to be involved in disease etiology (Lunnon & Mill, 2013). This review focuses on identifying overlapping pathways between published genome-wide association studies and epigenome-wide association studies, highlighting dysfunctional synaptic, lipid metabolism, plasma membrane/cytoskeleton, mitochondrial, and immune cell activation pathways. Identifying common pathways altered in genetic and epigenetic studies will aid our understanding of disease mechanisms and identify potential novel targets for pharmacological intervention.This work was funded by a grant from Bristol Research into Alzheimer's and Care of the Elderly and the Alzheimer's Society (grant AS-PG-14-038) to KL

The prevalence of Neospora caninum and co-infection with Toxoplasma gondii by PCR analysis in naturally occurring mammal populations

Neospora caninum and Toxoplasma gondii are closely related intracellular protozoan parasites associated with bovine and ovine abortion respectively. Little is known about the extent of Neospora/Toxoplasma co-infection in naturally infected populations of animals. Using nested PCR techniques, based on primers from the Nc5 region of N. caninum and SAG1 for T. gondii, the prevalence of N. caninum and its co-infection with T. gondii were investigated in populations of Mus domesticus, Rattus norvegicus and aborted lambs (Ovis aries). A low frequency of infection with N. caninum was detected in the Mus domesticus (3%) and Rattus norvegicus (4·4%) populations. A relatively high frequency of infection with N. caninum was detected in the brains of aborted lambs (18·9%). There was no significant relationship between N. caninum and T. gondii co-infection. Investigation of the tissue distribution of Neospora, in aborted lambs, showed that Neospora could not be detected in tissues other than brain and this was in contrast to Toxoplasma where the parasite could be frequently detected in a range of tissues

Predictors of ophthalmology career success (POCS) study

OBJECTIVE: Ophthalmology is the busiest outpatient specialty with demand predicted to rise over 40% in the next 20 years. A significant increase in the number of trainee ophthalmologists is required to fill currently vacant consultant posts and meet the UK’s workforce demands by 2038. Our aim was to understand what determines success in ophthalmology training, in order to inform future ophthalmologists, refine recruitment and facilitate workforce planning. METHODS AND ANALYSIS: This was a retrospective longitudinal cohort study using routinely collected data available from UK Medical Education Database (UKMED) (https://www.ukmed.ac.uk/). Data were analysed on 1350 candidates who had applied for ophthalmology specialty training (OST) between 2012 and 2018, as well as 495 candidates who had attempted Fellow of the Royal College of Ophthalmologists (FRCOphth) Part 1 between 2013 and 2018. Participants who had not obtained their primary medical qualification from the UK medical schools were excluded. Primary outcome measures included gaining a place on the OST programme and passing the FRCOphth Part 1 examination on first attempt. RESULTS: Higher education performance measure decile scores at medical school are strongly predictive in securing an OST post and passing the part 1 examination first time (p<0.001). Candidates who attempt FRCOphth Part 1 prior to their ST1 application are more likely to get a place on OST on first attempt. Socioeconomic factors, gender and ethnicity do not influence success in OST entry. Male trainees are more likely to pass FRCOphth Part 1 on their first attempt. CONCLUSION: This study is the first quantitative assessment of the factors that determine success in OST recruitment and ophthalmology postgraduate examinations in the UK. Similar studies should be undertaken in all other medical and surgical specialties to understand what factors predict success

Decadal Evolution of Ocean Thermal Anomalies in the North Atlantic: The Effects of Ekman, Overturning, and Horizontal Transport

Basin-scale thermal anomalies in the North Atlantic, extending to depths of 1–2 km, are more pronounced than the background warming over the last 60 years. A dynamical analysis based on reanalyses of historical data from 1965 to 2000 suggests that these thermal anomalies are formed by ocean heat convergences, augmented by the poorly known air–sea fluxes. The heat convergence is separated into contributions from the horizontal circulation and the meridional overturning circulation (MOC), the latter further separated into Ekman and MOC transport minus Ekman transport (MOC-Ekman) cells. The subtropical thermal anomalies are mainly controlled by wind-induced changes in the Ekman heat convergence, while the subpolar thermal anomalies are controlled by the MOC-Ekman heat convergence; the horizontal heat convergence is generally weaker, only becoming significant within the subpolar gyre. These thermal anomalies often have an opposing sign between the subtropical and subpolar gyres, associated with opposing changes in the meridional volume transport driving the Ekman and MOC-Ekman heat convergences. These changes in gyre-scale convergences in heat transport are probably induced by the winds, as they correlate with the zonal wind stress at gyre boundaries

10- m imaging of the bipolar protoplanetary nebula Mz-3

A 10-µm image is presented of the bipolar protoplanetary nebula Mz-3 made at the 3.9-m Anglo-Australian Telescope using the NIMPOL mid-infrared imaging polarimeter. The image shows extended emission from warm (110–130 K) dust both to the north and to the south of the central star, which correlates well with the visible bipolar lobes. The observed surface brightness of this emission is consistent with radiative heating of the dust by both direct stellar illumination and trapped Lyman α photons. Emission in excess of the point-source profile indicates that there is also an extended shell of dust surrounding the central star

Evolutionary dynamics of avian influenza A virus in the natural reservoir

Poster Presentations: Animal Influenza EcologyAvian influenza viruses were thought to exist in a form of evolutionary stasis within their natural reservoirs, i.e. waterfowls. However, a recent study demonstrated very high evolutionary rates, with epidemic-like population growth, for individual influenza subtypes in both aquatic birds and poultry, suggesting the stasis theory may be incorrect. Yet the evolutionary dynamics of the influenza gene pool within one species of migratory waterfowl remains unclear. We therefore tested influenza virus population behavior by estimating rates of nucleotide substitution of the internal genes from different subtypes of influenza viruses exclusively from mallard ducks …postprin

Blood methylomic signatures of presymptomatic dementia in elderly subjects with type 2 diabetes mellitus

Author version of article. The version of record is avilable from the publisher via doi: doi:10.1016/j.neurobiolaging.2014.12.023. Copyright © 2015 Elsevier Inc. All rights reserved.Available online 24 December 2014Due to an aging population, the incidence of dementia is steadily rising. The ability to identify early markers in blood, which appear before the onset of clinical symptoms is of considerable interest to allow early intervention, particularly in "high risk" groups such as those with type 2 diabetes. Here, we present a longitudinal study of genome-wide DNA methylation in whole blood from 18 elderly individuals with type 2 diabetes who developed presymptomatic dementia within an 18-month period following baseline assessment and 18 age-, sex-, and education-matched controls who maintained normal cognitive function. We identified a significant overlap in methylomic differences between groups at baseline and follow-up, with 8 CpG sites being consistently differentially methylated above our nominal significance threshold before symptoms at baseline and at 18 months follow up, after a diagnosis of presymptomatic dementia. Finally, we report a significant overlap between DNA methylation differences identified in converters, only after they develop symptoms of dementia, with differences at the same loci in blood samples from patients with clinically diagnosed Alzheimer's disease compared with unaffected control subjects.National Institute for Health Research (NIHR)Helen Bader FoundationLeroy Schecter FoundationBrightFocus Foundatio