2,197 research outputs found
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Neurodegeneration and the ordered assembly of α-synuclein
In 2017, it was two hundred years since James Parkinson
published “An Essay on the Shaking Palsy” and twenty years since
α-synuclein aggregation came to the fore. In 1998, multiple system
atrophy joined Parkinson’s disease and dementia with Lewy bodies
as the third major synucleinopathy. Here we describe the work,
which led to the identification of α-synuclein in Lewy bodies, Lewy
neurites and Papp-Lantos bodies. We also review some of the
findings reported since 1997.MGS is supported by the UK Medical Research Council, Alzheimer’s Research UK, Gates International, Astra Zeneca, Cambridge Biomedical Centre, Addenbrooke’s Hospital Trust, the National Centre for the Replacement, Refinement and Reduction of Animals in Research and Horizon 2020 IMPRiND. MG is an Honorary Professor in the Department of Clinical Neurosciences of the University of Cambridge. He is supported by the UK Medical Research Council (MC_U105184291), the EU Joint Programme – Neurodegenerative Disease Research and Horizon 2020 IMPRiND
A preliminary account of the fishes of the Lower Cretaceous Wessex Formation (Wealden Group, Barremian) of the Isle of Wight, southern England
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Differences in the weighting and choice of evidence for plausible versus implausible causes.
Individuals have difficulty changing their causal beliefs in light of contradictory evidence. We hypothesized that this difficulty arises because people facing implausible causes give greater consideration to causal alternatives, which, because of their use of a positive test strategy, leads to differential weighting of contingency evidence. Across 4 experiments, participants learned about plausible or implausible causes of outcomes. Additionally, we assessed the effects of participants' ability to think of alternative causes of the outcomes. Participants either saw complete frequency information (Experiments 1 and 2) or chose what information to see (Experiments 3 and 4). Consistent with the positive test account, participants given implausible causes were more likely to inquire about the occurrence of the outcome in the absence of the cause (Experiments 3 and 4) than those given plausible causes. Furthermore, they gave less weight to Cells A and B in a 2 × 2 contingency table and gave either equal or less weight to Cells C and D (Experiments 1 and 2). These effects were inconsistently modified by participants' ability to consider alternative causes of the outcome. The total of the observed effects are not predicted by either dominant models of normative causal inference or by the particular positive test account proposed here, but they may be commensurate with a more broadly construed positive test account.This is the author accepted manuscript. The final version is available from the American Psychological Association via http://dx.doi.org/10.1037/a003554
Distribuição do carbono orgânico em Latossolo sob manejo da adubação fosfatada em plantio direto no Cerrado.
O objetivo deste trabalho foi avaliar a distribuição vertical e horizontal do carbono orgânico do solo (CO) sob cinco manejos da adubação fosfatada, no sistema plantio direto. O experimento foi instalado sob Latossolo Vermelho, cultivado durante oito anos com soja ou milho, com milheto como planta de cobertura na entressafra. As parcelas foram submetidas aos tratamentos: aplicação de superfosfato triplo a lanço e no sulco, fosfato natural reativo a lanço e no sulco, e ausência de adição de fertilizante fosfatado (testemunha). A adição anual dos adubos fosfatados, na dose de 80 kg ha‑1 de P2O5, foi realizada em solo inicialmente com baixo teor de fósforo disponível. Amostras foram coletadas perpendicularmente à linha de plantio, em sete pontos distanciados a 12,5 cm, e cinco camadas: 0?2,5, 2,5?5,0, 5,0?10, 10?20 e 20?30 cm. O conteúdo e a distribuição do CO são afetados pela adubação fosfatada, tanto vertical quanto horizontalmente, com os maiores conteúdos observados nos tratamentos com adubos fosfatados. Em comparação com a testemunha, o superfosfato triplo apresentou maior conteúdo de CO até a camada de 5,0?10 cm, e o fosfato natural reativo até 10?20 cm. A aplicação de fósforo em sulcos proporciona maior volume de solo com teores adequados de CO, em comparação à aplicação a lanço
Long-term in vivo imaging of fibrillar tau in the retina of P301S transgenic mice.
Tauopathies are widespread neurodegenerative disorders characterised by the intracellular accumulation of hyperphosphorylated tau. Especially in Alzheimer's disease, pathological alterations in the retina are discussed as potential biomarkers to improve early diagnosis of the disease. Using mice expressing human mutant P301S tau, we demonstrate for the first time a straightforward optical approach for the in vivo detection of fibrillar tau in the retina. Longitudinal examinations of individual animals revealed the fate of single cells containing fibrillar tau and the progression of tau pathology over several months. This technique is most suitable to monitor therapeutic interventions aimed at reducing the accumulation of fibrillar tau. In order to evaluate if this approach can be translated to human diagnosis, we tried to detect fibrillar protein aggregates in the post-mortem retinas of patients that had suffered from Alzheimer's disease or Progressive Supranuclear Palsy. Even though we could detect hyperphosphorylated tau, we did not observe any fibrillar tau or Aß aggregates. In contradiction to previous studies, our observations do not support the notion that Aβ or tau in the retina are of diagnostic value in Alzheimer's disease
The novel MAPT mutation K298E:mechanisms of mutant tau toxicity, brain pathology and tau expression in induced fibroblast-derived neurons
Frontotemporal lobar degeneration (FTLD) consists of a group of neurodegenerative diseases characterized by behavioural and executive impairment, language disorders and motor dysfunction. About 20-30 % of cases are inherited in a dominant manner. Mutations in the microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T). Here we report a novel MAPT mutation (K298E) in exon 10 in a patient with FTDP-17T. Neuropathological studies of post-mortem brain showed widespread neuronal loss and gliosis and abundant deposition of hyperphosphorylated tau in neurons and glia. Molecular studies demonstrated that the K298E mutation affects both protein function and alternative mRNA splicing. Fibroblasts from a skin biopsy of the proband taken at post-mortem were directly induced into neurons (iNs) and expressed both 3-repeat and 4-repeat tau isoforms. As well as contributing new knowledge on MAPT mutations in FTDP-17T, this is the first example of the successful generation of iNs from skin cells retrieved post-mortem
Increase in Tau Pathology in P290S Mapt Knock-In Mice Crossed with AppNL-G-F Mice
Alzheimer's Disease (AD) is characterized by the pathological assembly of Aβ peptide, which deposits into extracellular plaques, and tau, which accumulates in intraneuronal inclusions. To investigate the link between Aβ and tau pathologies, experimental models featuring both pathologies are needed. We developed a mouse model featuring both tau and Aβ pathologies by knocking the P290S mutation into murine Mapt and crossing these MaptP290S KI mice with the AppNL-G-F KI line. MaptP290S KI mice developed a small number of tau inclusions, which increased with age. The amount of tau pathology was significantly larger in AppNL-G-FxMaptP290S KI mice from 18-months of age onwards. Tau pathology was higher in limbic areas, including hippocampus, amygdala and piriform/entorhinal cortex. We also observed AT100-and Gallyas-Braak-silver-positive dystrophic neurites containing assembled filamentous tau, as visualized by in situ EM. Using a cell-based tau seeding assay, we showed that sarkosyl-insoluble brain extracts from both 18-month-old MaptP290S KI and AppNL-G-FxMaptP290S KI mice were seed-competent, with brain extracts from double KI mice seeding significantly more than those from the MaptP290S KI mice. Finally, we showed that AppNL-G-FxMaptP290S KI mice had neurodegeneration in the piriform cortex from 18-months of age. We suggest that AppNL-G-F x MaptP290S KI mice provide a good model for studying the interactions of aggregation-prone tau, Aβ, neuritic plaques, neurodegeneration and aging
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