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Sökning: WFRF:(Farrer M J)

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  • Föregående 12[3]45Nästa
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21.
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22.
  • O'Hanlon, Simon J., et al. (författare)
  • Recent Asian origin of chytrid fungi causing global amphibian declines
  • 2018
  • Ingår i: Science. - 0036-8075 .- 1095-9203. ; 360:6389, s. 621-
  • Tidskriftsartikel (refereegranskat)abstract
    • Globalized infectious diseases are causing species declines worldwide, but their source often remains elusive. We used whole-genome sequencing to solve the spatiotemporal origins of themost devastating panzootic to date, caused by the fungus Batrachochytrium dendrobatidis, a proximate driver of global amphibian declines. We traced the source of B. dendrobatidis to the Korean peninsula, where one lineage, BdASIA-1, exhibits the genetic hallmarks of an ancestral population that seeded the panzootic. We date the emergence of this pathogen to the early 20th century, coinciding with the global expansion of commercial trade in amphibians, and we show that intercontinental transmission is ongoing. Our findings point to East Asia as a geographic hotspot for B. dendrobatidis biodiversity and the original source of these lineages that now parasitize amphibians worldwide.
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24.
  • Fisher, Matthew C., et al. (författare)
  • Development and worldwide use of non-lethal, and minimal population-level impact, protocols for the isolation of amphibian chytrid fungi
  • 2018
  • Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • Parasitic chytrid fungi have emerged as a significant threat to amphibian species worldwide, necessitating the development of techniques to isolate these pathogens into culture for research purposes. However, early methods of isolating chytrids from their hosts relied on killing amphibians. We modified a pre-existing protocol for isolating chytrids from infected animals to use toe clips and biopsies from toe webbing rather than euthanizing hosts, and distributed the protocol to researchers as part of the BiodivERsA project RACE; here called the RML protocol. In tandem, we developed a lethal procedure for isolating chytrids from tadpole mouthparts. Reviewing a database of use a decade after their inception, we find that these methods have been applied across 5 continents, 23 countries and in 62 amphibian species. Isolation of chytrids by the non-lethal RML protocol occured in 18% of attempts with 207 fungal isolates and three species of chytrid being recovered. Isolation of chytrids from tadpoles occured in 43% of attempts with 334 fungal isolates of one species (Batrachochytrium dendrobatidis) being recovered. Together, these methods have resulted in a significant reduction and refinement of our use of threatened amphibian species and have improved our ability to work with this group of emerging pathogens.
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25.
  • Fuchs, J, et al. (författare)
  • Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication.
  • 2007
  • Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 1526-632X. ; 68:12, s. 916-922
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The " Lister family complex," an extensive Swedish family with autosomal dominant Parkinson disease, was first described by Henry Mjones in 1949. On the basis of clinical, molecular, and genealogic findings on a Swedish and an American family branch, we provide genetic evidence that explains the parkinsonism in this extended pedigree. Methods: Clinical methods included a detailed neurologic exam of the proband of the Swedish family branch, MRI, and ([ 123] I) - beta - CIT SPECT imaging. Genomic analysis included alpha-synuclein sequencing, SNCA real-time PCR dosage, chromosome 4q21 microsatellite analysis, and high-resolution microarray genotyping. The geographic origin and ancestral genealogy of each pedigree were researched in the medical literature and Swedish Parish records. Results: The proband of the Swedish family branch presented with early dysautonomia followed by progressive parkinsonism suggestive of multiple system atrophy. Molecular analysis identified a genomic duplication of < 0.9 Mb encompassing alpha-synuclein and multimerin 1 ( SNCA- MMRN1), flanked by long interspersed repeat sequences ( LINE L1). Microsatellite variability within the genomic interval was identical to that previously described for a Swedish American family with an alpha- synuclein triplication. Subsequent genealogic investigation suggested that both kindreds are ancestrally related to the Lister family complex. Conclusion: Our findings extend clinical, genetic, and genealogical research on the Lister family complex. The genetic basis for familial parkinsonism is an SNCA- MMRN11 multiplication, but whereas SNCA- MMRN1 duplication in the Swedish proband ( Branch J) leads to late- onset autonomic dysfunction and parkinsonism, SNCA- MMRN1 triplication in the Swedish American family ( Branch I) leads to early- onset Parkinson disease and dementia.
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26.
  • Springer, W, et al. (författare)
  • Heterozygous PINK1 p.G411S mutation increases risk for Parkinson's disease (PD)
  • 2016
  • Ingår i: Movement Disorders. - : John Wiley & Sons Inc.. - 0885-3185. ; 31:Suppl. S2, s. 282-282
  • Konferensbidrag (refereegranskat)abstract
    • Objective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype.
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27.
  • Deming, Yuetiva, et al. (författare)
  • Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers
  • 2017
  • Ingår i: Acta Neuropathologica. - : Springer. - 0001-6322. ; 133:5
  • Tidskriftsartikel (refereegranskat)abstract
    • More than 20 genetic loci have been associated with risk for Alzheimer’s disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case–control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = −0.059, P = 2.08 × 10−8) and within SERPINB1 on 6p25 (β = −0.025, P = 1.72 × 10−8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10−2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10−2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10−3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.
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28.
  • Karyotaki, E., et al. (författare)
  • Predictors of treatment dropout in self-guided web-based interventions for depression: an individual patient data meta-analysis
  • 2015
  • Ingår i: Psychological Medicine. - : CAMBRIDGE UNIV PRESS. - 0033-2917 .- 1469-8978. ; 45:13, s. 2717-2726
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. It is well known that web-based interventions can be effective treatments for depression. However, dropout rates in web-based interventions are typically high, especially in self-guided web-based interventions. Rigorous empirical evidence regarding factors influencing dropout in self-guided web-based interventions is lacking due to small study sample sizes. In this paper we examined predictors of dropout in an individual patient data meta-analysis to gain a better understanding of who may benefit from these interventions. Method. A comprehensive literature search for all randomized controlled trials (RCTs) of psychotherapy for adults with depression from 2006 to January 2013 was conducted. Next, we approached authors to collect the primary data of the selected studies. Predictors of dropout, such as socio-demographic, clinical, and intervention characteristics were examined. Results. Data from 2705 participants across ten RCTs of self-guided web-based interventions for depression were analysed. The multivariate analysis indicated that male gender [relative risk (RR) 1.08], lower educational level (primary education, RR 1.26) and co-morbid anxiety symptoms (RR 1.18) significantly increased the risk of dropping out, while for every additional 4 years of age, the risk of dropping out significantly decreased (RR 0.94). Conclusions. Dropout can be predicted by several variables and is not randomly distributed. This knowledge may inform tailoring of online self-help interventions to prevent dropout in identified groups at risk.
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29.
  • Puschmann, Andreas, et al. (författare)
  • A family with parkinsonism, essential tremor, restless legs syndrome, and depression
  • 2011
  • Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 1526-632X. ; 76:19, s. 1623-1630
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Previous epidemiologic and genetic studies have suggested a link between Parkinson disease (PD), essential tremor (ET), and restless legs syndrome (RLS). Methods: We describe the clinical, PET, and pathologic characteristics of an extensive kindred from Arkansas with hereditary PD, ET, and RLS. The pedigree contains 138 individuals. Sixty-five family members were examined neurologically up to 3 times from 2004 to 2010. Clinical data were collected from medical records and questionnaires. Genetic studies were performed. Five family members underwent multitracer PET. Two individuals with PD were examined postmortem. Results: Eleven family members had PD with generally mild and slowly progressive symptoms. Age at onset was between 39 and 74 years (mean 59.1, SD 13.4). All individuals treated with L-dopa responded positively. Postural or action tremor was present in 6 individuals with PD, and in 19 additional family members. Fifteen persons reported symptoms of RLS. PET showed reduced presynaptic dopamine function typical of sporadic PD in a patient with PD and ET, but not in persons with ET or RLS. The inheritance pattern was autosomal dominant for PD and RLS. No known pathogenic mutation in PD-related genes was found. Fourteen of the family members with PD, ET, or RLS had depression. Neuropathologic examination revealed pallidonigral pigment spheroid degeneration with ubiquitin-positive axonal spheroids, TDP43-positive pathology in the basal ganglia, hippocampus, and brainstem, and only sparse Lewy bodies. Conclusion: Familial forms of PD, ET, RLS, and depression occur in this family. The genetic cause remains to be elucidated. Neurology (R) 2011; 76: 1623-1630
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