No Association Between MTHFR A1298C and MTRR A66G Polymorphisms, and MS in an Australian Cohort

Multiple sclerosis (MS) is a complex neurological disease that affects the central nervous system (CNS) resulting in debilitating neuropathology. Pathogenesis is primarily defined by CNS inflammation and demyelination of nerve axons. Methionine synthase reductase (MTRR) is an enzyme that catalyzes the remethylation of homocysteine (Hcy) to methionine via cobalamin and folate dependant reactions. Cobalamin acts as an intermediate methyl carrier between methylenetetrahydrofolate reductase (MTHFR) and Hcy. MTRR plays a critical role in maintaining cobalamin in an active form and is consequently an important determinant of total plasma Hcy (pHcy) concentrations. Elevated intracellular pHcy levels have been suggested to play a role in CNS dysfunction, neurodegenerative, and cerebrovascular diseases. Our investigation entailed the genotyping of a cohort of 140 cases and matched controls for MTRR and MTHFR, by restriction length polymorphism (RFLP) techniques. Two polymorphisms: MTRR A66G and MTHFR A1298C were investigated in an Australian age and gender matched case-control study. No significant allelic frequency difference was observed between cases and controls at the α = 0.05 level (MTRR χ^2 = 0.005, P = 0.95, MTHFR χ^2 = 1.15, P = 0.28). Our preliminary findings suggest no association between the MTRR A66G and MTHFR A1298C polymorphisms and MS

Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability

Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing

This research was supported by the Australian Research Council (DP160102400), the Australian National Health and Medical Research Council (1078037, 1078901, 1103418, 1107258, 1127440 and 1113400), and the Sylvia & Charles Viertel Charitable Foundation. Riccardo Marioni was supported by Alzheimer’s Research UK Major Project Grant [ARUK-PG2017B-10]. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping and DNA methylation profiling of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland, and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” ((STRADL) Reference 104036/Z/14/Z).Peer reviewedPublisher PD

Biofilters as effective pathogen barriers for greywater reuse

Greywater is an alternative water resource, having many favourable characteristics over stormwater or wastewater. In particular, it can be supplied consistently and generated close to desirable end-use applications. Although greywater is considered to contain a low level of contamination, treatment is still required before the end-use, and passive filtration such as biofiltration became a popular option due to its low maintenance and low energy consumption. To this end, a laboratory experiment was conducted with synthetic greywater over 12 months to test the influence of operational characteristics and design factors on pathogen removal from greywater. The role of plants types, saturated zone, and the absence/inclusion of antimicrobial material were tested in a total of 80 biofilter columns. The results showed that the biofilters obtained a median E. coli logarithmic removal of 3.0 across the tested configurations and produced quality of water that meets indoor non-potable use standard (NRMMC, 2006). Further, the infiltration rate and event size were found to significantly influence E. coli removal in greywater biofilters (ANOVA, p < 0.05). The presence of antimicrobial media also significantly improved E. coli removal (up to 1.4 log) compared to non-amended media (ANOVA, p < 0.05). Vegetation also played a significant role in removing E. coli (ANOVA < 0.05). This study successfully suggested the great potential for the application of biofilters to greywater treatment and identified key design factors for consideration prior to implementation.</p

Factors affecting Leverage: An empirical analysis of Mauritius companies

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Dual-mode stormwater-greywater biofilters:The impact of alternating water sources on treatment performance

The intermittent nature of stormwater runoff impacts the treatment performance of biofilters, also known as stormwater biofiltration or bioretention systems and raingardens. During extended dry periods, which are common even in temperate climates, plants can perish, creating unattractive and non-functional systems that might leach pollutants during the next rainfall event. The current solution is to irrigate during long dry spells, which is costly and unsustainable as biofilters become more widespread. This paper presents the development of dual-mode biofilters, where stormwater and greywater are treated within the same system. Fifty columns, utilising eight plant species, including understory and climbing ornamentals, and designs with and without a carbon source in the submerged zone, were subjected to alternating greywater and stormwater inflows over five months. Six sampling events investigated treatment performance across these switching inflows and an extended dry period (atypical event). Good removal of total suspended solids (>83%), biochemical oxygen demand (>86%) and some heavy metals (e.g. lead >96%) were reported irrespective of design. Plant species selection was critical for the removal of nitrogen (2 to 79%) and phosphorus (12 to 75%) under dual-mode operation. However, following the extended dry period, plants with the lowest nutrient outflow concentrations also experienced some of the highest sediment and carbon concentrations, suggesting that a mixture of plant species may be beneficial for withstanding abnormal conditions. Differences between the treatment performance of designs with and without a carbon source were negligible, with potential benefits possibly negated due to the increased root mass that comes with age (systems were approximately two years old) and the release of carbon from root exudates. The results demonstrate the potential for dual-mode stormwater-greywater biofilters as an alternative to single-mode systems as they can provide effective treatment, along with greater volumes of treated water, while maintaining system performance throughout the year.</p

Phosphorus Fate and Dynamics in Greywater Biofiltration Systems

Phosphorus, a critical environmental pollutant, is effectively removed from stormwater by biofiltration systems, mainly via sedimentation and straining. However, the fate of dissolved inflow phosphorus concentrations in these systems is unknown. Given the growing interest in using biofiltration systems to treat other polluted waters, for example greywater, such an understanding is imperative to optimize designs for successful long-term performance. A mass balance method and a radiotracer, ³²P (as H₃PO₄), were used to investigate the partitioning of phosphorus (concentrations of 2.5–3.5 mg/L, >80% was in dissolved inorganic form) between the various biofilter components at the laboratory scale. Planted columns maintained a phosphorus removal efficiency of >95% over the 15-week study period. Plant storage was found to be the dominant phosphorus sink (64% on average). Approximately 60% of the phosphorus retained in the filter media was recovered in the top 0–6 cm. The ³²P tracer results indicate that adsorption is the immediate primary fate of dissolved phosphorus in the system (up to 57% of input P). Plant assimilation occurs at other times, potentially liberating sorption sites for processing of subsequent incoming phosphorus. Plants with high nutrient uptake capacities and the ability to efficiently extract soil phosphorus, for example <i>Carex appressa</i>, are, thus, recommended for use in greywater biofilters

Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era

Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.Other UBCNon UBCReviewedFacult