Publications
313 results found
Pihlstrøm L, Schottlaender L, Chelban V, et al., 2018, LRP10 in α-synucleinopathies, The Lancet Neurology, Vol: 17, Pages: 1033-1034, ISSN: 1474-4422
Liu AKL, Lim EJ, Ahmed I, et al., 2018, Review: revisiting the human cholinergic nucleus of the diagonal band of Broca, Neuropathology and Applied Neurobiology, Vol: 44, Pages: 647-662, ISSN: 0305-1846
Although the nucleus of the vertical limb of the diagonal band of Broca (nvlDBB) is the second largest cholinergic nucleus in the basal forebrain, after the nucleus basalis of Meynert (nbM), it has not generally been a focus for studies of neurodegenerative disorders. However, the nvlDBB does have an important projection to the hippocampus and discrete lesions of the rostral basal forebrain have been shown to disrupt retrieval memory function, a major deficit seen in patients with Lewy body disorders. One reason for its neglect is that the anatomical boundaries of the nvlDBB are ill defined and this area of the brain is not part of routine diagnostic sampling protocols. We have reviewed the history and anatomy of the nvlDBB and now propose guidelines for distinguishing nvlDBB from other neighbouring cholinergic cell groups for standardising future clinicopathological work. Thorough review of the literature regarding neurodegenerative conditions reveals inconsistent results in terms of cholinergic neuronal loss within the nvlDBB. This is likely to be due to the use of variable neuronal inclusion criteria and omission of cholinergic immunohistochemical markers. Extrapolating from those studies showing significant nvlDBB neuronal loss in Lewy body dementia, we propose an anatomical and functional connection between the cholinergic component of the nvlDBB (Ch2) and the CA2 subfield in the hippocampus which may be especially vulnerable in Lewy body disorders. This article is protected by copyright. All rights reserved.
Sastre M, Gentleman S, Van Leuven F, 2018, TauBI or not TauBI: what was the question?, Brain, Vol: 141, Pages: 2536-2539, ISSN: 1460-2156
Mokretar K, Pease D, Taanman J-W, et al., 2018, Somatic copy number gains of α-synuclein (SNCA) in Parkinson's disease and multiple system atrophy brains, Brain, Vol: 141, Pages: 2419-2431, ISSN: 1460-2156
The α-synuclein protein, encoded by SNCA, has a key role in the pathogenesis of Parkinson's disease and other synucleinopathies. Although usually sporadic, Parkinson's disease can result from inherited copy number variants in SNCA and other genes. We have hypothesized a role of somatic SNCA mutations, leading to mosaicism, in sporadic synucleinopathies. The evidence for mosaicism in healthy and diseased brain is increasing rapidly, with somatic copy number gains of APP reported in Alzheimer's brain. Here we demonstrate somatic SNCA copy number gains in synucleinopathies (Parkinson's disease and multiple system atrophy), focusing on substantia nigra. We selected sporadic cases with relatively young onset or short disease duration, and first excluded high level copy number variant mosaicism by DNA analysis using digital PCR for SNCA, and/or customized array comparative genomic hybridization. To detect low level SNCA copy number variant mosaicism, we used fluorescent in situ hybridization with oligonucleotide custom-designed probes for SNCA, validated on brain and fibroblasts with known copy number variants. We determined SNCA copy number in nigral dopaminergic neurons and other cells in frozen nigra sections from 40 cases with Parkinson's disease and five with multiple system atrophy, and 25 controls, in a blinded fashion. Parkinson's disease cases were significantly more likely than controls to have any SNCA gains in dopaminergic neurons (P = 0.0036), and overall (P = 0.0052). The average proportion of dopaminergic neurons with gains in each nigra was significantly higher in Parkinson's disease than controls (0.78% versus 0.45%; P = 0.017). There was a negative correlation between the proportion of dopaminergic neurons with gains and onset age in Parkinson's disease (P = 0.013), but not with disease duration, or age of death in cases or controls. Cases with tremor at onset were less likely to have gains (P = 0.035). All multiple system atrophy cases had gains
Arena JD, Johnson VE, Trojanowski JQ, et al., 2018, TAU ASTROGLIOPATHY CONSISTENT WITH ARTAG IS A COMMON FEATURE OF REPETITIVE MILD AND LATE SINGLE SEVERE TBI IN HUMANS, 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, Publisher: MARY ANN LIEBERT, INC, Pages: A140-A140, ISSN: 0897-7151
Jabbari E, Woodside J, Tan M, et al., 2018, Variation at the TRIM11 locus modifies Progressive Supranuclear Palsy phenotype, Annals of Neurology, Vol: 84, Pages: 485-496, ISSN: 0364-5134
OBJECTIVE: The basis for clinical variation related to underlying Progressive Supranuclear Palsy (PSP) pathology is unknown. We performed a genome wide association study (GWAS) to identify genetic determinants of PSP phenotype. METHODS: Two independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson's syndrome (RS) and non-RS groups. We carried out separate logistic regression GWAS to compare RS and non-RS groups and then combined datasets to carry out a whole cohort analysis (RS=367, non-RS=130). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from a recent GWAS. We assessed the expression/co-expression patterns of our identified genes and used our data to carry out gene-based association testing. RESULTS: Our lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome wide significance in our whole cohort analysis - OR 5.5 (3.2-10.0), p-value 1.7x10-9 . rs564309 is an intronic variant of the tripartite motif-containing protein 11 (TRIM11) gene, a component of the ubiquitin proteasome system (UPS). In our third cohort, minor allele frequencies of surrogate SNPs in high linkage disequilibrium with rs564309 replicated our findings. Gene based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed neuronally, in the cerebellum and basal ganglia. INTERPRETATION: Our study suggests that the TRIM11 locus is a genetic modifier of PSP phenotype and potentially adds further evidence for the UPS having a key role in tau pathology, therefore representing a target for disease modifying therapies. This article is protected by copyright. All rights reserved.
Calsolaro V, Fan Z, Veronese M, et al., 2018, Novel third generation microglial marker flutriciclamide ([18F]GE180) in Alzheimer’s disease and mild cognitive impairment, Alzheimer's and Dementia, Vol: 14, Pages: P506-P506, ISSN: 1552-5260
Lai HM, Liu AKL, Ng HHM, et al., 2018, Author correction: Next generation histology methods for three-dimensional imaging of fresh and archival human brain tissues, Nature Communications, Vol: 9, Pages: 2726-2726, ISSN: 2041-1723
In the original version of this Article, the concentration of boric acid buffer for the SDS clearing solution was given incorrectly as '1 M sodium borate' and should have read '0.2 M boric acid'. Also, the composition of PBST incorrectly read '1% Triton X-100 (vol/vol) and 0.1% sodium azide (wt/vol)' and should have read '0.1% Triton X-100 (vol/vol) and 0.01% sodium azide (wt/vol)'. Further, the pH of the OPTIClear solution was not stated, and should have read 'with a pH between 7 to 8 adjusted with hydrochloric acid'. These errors have been corrected in both the PDF and HTML versions of the Article.
Fan Z, Dani M, Femminella GD, et al., 2018, Parametric mapping using spectral analysis for11C-PBR28 PET reveals neuroinflammation in mild cognitive impairment subjects, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 45, Pages: 1432-1441, ISSN: 1619-7070
PURPOSE: Neuroinflammation and microglial activation play an important role in amnestic mild cognitive impairment (MCI) and Alzheimer's disease. In this study, we investigated the spatial distribution of neuroinflammation in MCI subjects, using spectral analysis (SA) to generate parametric maps and quantify11C-PBR28 PET, and compared these with compartmental and other kinetic models of quantification. METHODS: Thirteen MCI and nine healthy controls were enrolled in this study. Subjects underwent11C-PBR28 PET scans with arterial cannulation. Spectral analysis with an arterial plasma input function was used to generate11C-PBR28 parametric maps. These maps were then compared with regional11C-PBR28 VT(volume of distribution) using a two-tissue compartment model and Logan graphic analysis. Amyloid load was also assessed with18F-Flutemetamol PET. RESULTS: With SA, three component peaks were identified in addition to blood volume. The11C-PBR28 impulse response function (IRF) at 90 min produced the lowest coefficient of variation. Single-subject analysis using this IRF demonstrated microglial activation in five out of seven amyloid-positive MCI subjects. IRF parametric maps of11C-PBR28 uptake revealed a group-wise significant increase in neuroinflammation in amyloid-positive MCI subjects versus HC in multiple cortical association areas, and particularly in the temporal lobe. Interestingly, compartmental analysis detected group-wise increase in11C-PBR28 binding in the thalamus of amyloid-positive MCI subjects, while Logan parametric maps did not perform well. CONCLUSIONS: This study demonstrates for the first time that spectral analysis can be used to generate parametric maps of11C-PBR28 uptake, and is able to detect microglial activation in amyloid-positive MCI subjects. IRF parametric maps of11C-PBR28 uptake allow voxel-wise single-subject analysis and could be used to evaluate microglial activation in individual subjects.
Harrison CH, Buckland GR, Brooks SE, et al., 2018, A novel method to visualise the three-dimensional organisation of the human cerebral cortical vasculature, Journal of Anatomy, Vol: 232, Pages: 1025-1030, ISSN: 1469-7580
Current tissue-clearing protocols for imaging in three dimensions (3D) are typically applied to optimally fixed, small-volume rodent brain tissue - which is not representative of the tissue found in diagnostic neuropathology laboratories. We present a method to visualise the cerebral cortical vasculature in 3D in human post-mortem brain tissue which had been preserved in formalin for many years. Tissue blocks of cerebral cortex from two control cases, two Alzheimer's brains and two cases from Alzheimer's patients immunised against Aβ42 were stained with fluorescent Lycopersicon esculentum agglutinin (Tomato lectin), dehydrated and cleared using an adapted three-dimensional imaging of solvent cleared organs (3DISCO) protocol to visualise the vascular endothelium. Tissue was imaged using light sheet and confocal microscopy and reconstructed in 3D using amira software. The method permits visualisation of the arrangement of the parallel penetrating cortical vasculature in the human brain. The presence of four vascular features including anastomosis, U-shaped vessels, spiralling and loops were revealed. In summary, we present a low cost and simple method to visualise the human cerebral vasculature in 3D compatible with prolonged fixation times (years), allowing study of vascular involvement in a range of normative and pathological states.
Lai HM, Liu KL, Ng HHM, et al., 2018, Next generation histology methods for three-dimensional imaging of fresh and archival human brain tissues, Nature Communications, Vol: 9, ISSN: 2041-1723
Modern clearing techniques for the three-dimensional (3D) visualization of neural tissue microstructure have been very effective when used on rodent brain but very few studies haveutilized them on human brain material, mainly due to the inherent difficulties in processing post26mortem tissue. Here, we develop a tissue clearing solution, OPTIClear, optimised for fresh and archival human brain tissue, including formalin-fixed paraffin-embedded material. In light ofpractical challenges with immunostaining in tissue clearing, we adapt the use of cresyl violet for visualization of neurons in cleared tissue, with the potential for 3D quantification in regions ofinterest. Furthermore, we use lipophilic tracers for tracing of neuronal processes in post-mortem tissue, enabling the study of the morphology of human dendritic spines in 3D. The development ofthese different strategies for human tissue clearing has wide applicability and, we hope, will provide a baseline for further technique development.
Goldfinger M, Tilley B, Mediratta S, et al., 2018, Boxing and the brain: disruption of the neurovascular unit in chronic traumatic encephalopathy, 119th Meeting of the British-Neuropathological-Society (BNS) / Epilepsy Neuropathology Symposium, Publisher: WILEY, Pages: 29-29, ISSN: 0305-1846
Gentleman S, Liu AKL, 2018, Neuropathological Assessment as an Endpoint in Clinical Trial Design., Methods Mol Biol, Vol: 1750, Pages: 271-279
Different neurodegenerative conditions can have complex, overlapping clinical presentations that make accurate diagnosis during life very challenging. For this reason, confirmation of the clinical diagnosis still requires postmortem verification. This is particularly relevant for clinical trials of novel therapeutics where it is important to ascertain what disease and/or pathology modifying effects the therapeutics have had. Furthermore, it is important to confirm that patients in the trial actually had the correct clinical diagnosis as this will have a major bearing on the interpretation of trial results. Here we present a simple protocol for pathological assessment of neurodegenerative changes.
Woerman AL, Kazmi SA, Patel S, et al., 2017, MSA prions exhibit remarkable stability and resistance to inactivation., Acta Neuropathologica, Vol: 135, Pages: 49-63, ISSN: 1432-0533
In multiple system atrophy (MSA), progressive neurodegeneration results from the protein α-synuclein misfolding into a self-templating prion conformation that spreads throughout the brain. MSA prions are transmissible to transgenic (Tg) mice expressing mutated human α-synuclein (TgM83(+/-)), inducing neurological disease following intracranial inoculation with brain homogenate from deceased patient samples. Noting the similarities between α-synuclein prions and PrP scrapie (PrP(Sc)) prions responsible for Creutzfeldt-Jakob disease (CJD), we investigated MSA transmission under conditions known to result in PrP(Sc) transmission. When peripherally exposed to MSA via the peritoneal cavity, hind leg muscle, and tongue, TgM83(+/-) mice developed neurological signs accompanied by α-synuclein prions in the brain. Iatrogenic CJD, resulting from PrP(Sc) prion adherence to surgical steel instruments, has been investigated by incubating steel sutures in contaminated brain homogenate before implantation into mouse brain. Mice studied using this model for MSA developed disease, whereas wire incubated in control homogenate had no effect on the animals. Notably, formalin fixation did not inactivate α-synuclein prions. Formalin-fixed MSA patient samples also transmitted disease to TgM83(+/-) mice, even after incubating in fixative for 244 months. Finally, at least 10% sarkosyl was found to be the concentration necessary to partially inactivate MSA prions. These results demonstrate the robustness of α-synuclein prions to denaturation. Moreover, they establish the parallel characteristics between PrP(Sc) and α-synuclein prions, arguing that clinicians should exercise caution when working with materials that might contain α-synuclein prions to prevent disease.
Fan Z, Dani M, Femminella G, et al., 2017, Regional kinetic modelling application for TSPO PET tracer [11C]PBR28, Alzheimer's and Dementia, Vol: 13, Pages: P289-P289, ISSN: 1552-5260
Calsolaro V, Fan Z, Femminella G, et al., 2017, Microglial activation in Alzheimer’s disease detected by novel third generation translocator protein tracer flutriciclamide ([18F]GE180), Alzheimer's and Dementia, Vol: 13, Pages: P922-P922, ISSN: 1552-5260
Donat CK, Scott G, Gentleman S, et al., 2017, Microglial activation in traumatic brain injury, Frontiers in Aging Neuroscience, Vol: 9, ISSN: 1663-4365
Microglia have a variety of functions in the brain, including synaptic pruning, CNS repair and mediating the immune response against peripheral infection. Microglia rapidly become activated in response to CNS damage. Depending on the nature of the stimulus, microglia can take a number of activation states, which correspond to altered microglia morphology, gene expression and function. It has been reported that early microglia activation following traumatic brain injury (TBI) may contribute to the restoration of homeostasis in the brain. On the other hand, if they remain chronically activated, such cells display a classically activated phenotype, releasing pro-inflammatory molecules, resulting in further tissue damage and contributing potentially to neurodegeneration. However, new evidence suggests that this classification is over-simplistic and the balance of activation states can vary at different points. In this article, we review the role of microglia in TBI, analyzing their distribution, morphology and functional phenotype over time in animal models and in humans. Animal studies have allowed genetic and pharmacological manipulations of microglia activation, in order to define their role. In addition, we describe investigations on the in vivo imaging of microglia using translocator protein (TSPO) PET and autoradiography, showing that microglial activation can occur in regions far remote from sites of focal injuries, in humans and animal models of TBI. Finally, we outline some novel potential therapeutic approaches that prime microglia/macrophages toward the beneficial restorative microglial phenotype after TBI.
Lai HM, Ng W-L, Gentleman SM, et al., 2017, Chemical probes for visualizing intact animal and human brain tissue, Cell Chemical Biology, Vol: 24, Pages: 659-672, ISSN: 2451-9456
Newly developed tissue clearing techniques can be used to render intact tissues transparent. When combined with fluorescent labeling technologies and optical sectioning microscopy, this allows visualization of fine structure in three dimensions. Gene-transfection techniques have proved very useful in visualizing cellular structures in animal models, but they are not applicable to human brain tissue. Here, we discuss the characteristics of an ideal chemical fluorescent probe for use in brain and other cleared tissues, and offer a comprehensive overview of currently available chemical probes. We describe their working principles and compare their performance with the goal of simplifying probe selection for neuropathologists and stimulating probe development by chemists. We propose several approaches for the development of innovative chemical labeling methods which, when combined with tissue clearing, have the potential to revolutionize how we study the structure and function of the human brain.
Kovacs GG, Xie SX, Lee EB, et al., 2017, Multisite assessment of aging-related Tau astrogliopathy (ARTAG), Journal of Neuropathology and Experimental Neurology, Vol: 76, Pages: 605-619, ISSN: 1554-6578
Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was >60% with a kappa value of 0.55 (95% CI 0.433–0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457–0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37–0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341–0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534–0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.
Liu K, Lai HM, Chang RCC, et al., 2017, Free-of-acrylamide SDS-based Tissue Clearing (FASTClear): A novel protocol of tissue clearing for three-dimensional visualisation of human brain tissues, Neuropathology and Applied Neurobiology, Vol: 43, Pages: 346-351, ISSN: 1365-2990
Lai HM, Liu AKL, Ng HHM, et al., 2017, Development of next generation histological methods for three-dimensional interrogation of the human brain, 118th Meeting of the British-Neuropathological-Society, Publisher: WILEY, Pages: 44-45, ISSN: 0305-1846
Chau TW, Liu AKL, Lim EJ, et al., 2017, Cognitive decline and hippocampal CA2 pathology in Lewy body disorders, 118th Meeting of the British-Neuropathological-Society, Publisher: WILEY, Pages: 11-12, ISSN: 0305-1846
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Alexandris A, Walker L, Liu AKL, et al., 2017, Differential expression of galanin in the cholinergic basal forebrain in Lewy body disorders and Alzheimer's disease, 118th Meeting of the British-Neuropathological-Society, Publisher: WILEY, Pages: 12-12, ISSN: 0305-1846
Liu AKL, Lai HM, Goldfinger MH, et al., 2017, Exploration of human brain anatomy in three-dimensions using the next generation histological pipeline, 118th Meeting of the British-Neuropathological-Society, Publisher: WILEY, Pages: 28-29, ISSN: 0305-1846
Goldfinger MH, Ling H, Holton JL, et al., 2017, Chronic Traumatic Encephalopathy: Unearthing pathology in archival tissue, 118th Meeting of the British-Neuropathological-Society, Publisher: WILEY, Pages: 56-56, ISSN: 0305-1846
Forte AE, Gentleman SM, Dini D, 2016, On the characterisation of the heterogeneous mechanical response of human brain tissue, Biomechanics and Modeling in Mechanobiology, Vol: 16, Pages: 907-920, ISSN: 1617-7959
The mechanical characterization of brain tissue is a complex task scientists have tried to accomplish for over fifty years. The resultsin literatureoften differ by orders of magnitudebecause of the lack of a standard testing protocol. Different testing conditions (including humidity, temperature, strain rate),the methodologyadopted,the variety of the speciesanalysed, are all potential sources of discrepancies in the measurements.In this work we present a rigorous experimental investigation on the mechanical properties of human brain, covering both grey and white matter. The influence of testing conditions isalso shown and thoroughly discussed. The material characterisation performed is finally adopted to provide inputs toa mathematical formulation suitable fornumerical simulations of brain deformation during surgical procedures.
Sastre M, Ries M, Loiola R, et al., 2016, The anti-inflammatory Annexin A1 induces the clearance and degradation of the Amyloid-β peptide, Journal of Neuroinflammation, Vol: 13, ISSN: 1742-2094
Background: The toxicity of amyloid-β (Aβ) peptide present in the brain of Alzheimer’s disease (AD) patients is thought to be mediated via the increased secretion of pro-inflammatory mediators, which can lead to neuronal dysfunction and cell death. In addition, we have previously shown that inflammation can affect Aβ generation. More recently, we have reported that in vitro administration of the anti-inflammatory mediator Annexin A1 (ANXA1) following an inflammatory challenge suppressed microglial activation and this effect was mediated through Formyl Peptide Receptor Like-1 (FPRL1/FPR2) signalling. The aim of this study was to determine the potential role of ANXA1 in the generation and clearance of Aβ. Methods: We first compared ANXA1 protein expression in the brains of AD patients and healthy controls as well as in the 5XFAD model of AD. To determine the role of ANXA1 in the processing of amyloid precursor protein (APP) and the degradation of Aβ, N2a neuroblastoma cells were treated with human recombinant ANXA1 or transfected with ANXA1 siRNA. We also investigated the effect of ANXA1 on Aβ phagocytosis and microglial activation in BV2 cells treated with synthetic Aβ. Results: Our data show that ANXA1 is increased in the brains of AD patients and animal models of AD at early stages. ANXA1 was able to reduce the levels of Aβ by increasing its enzymatic degradation by neprilysin in N2a cells and to stimulate Aβ phagocytosis by microglia. These effects were mediated through FPRL1 receptors. In addition, ANXA1 inhibited the Aβ-stimulated secretion of inflammatory mediators by microglia. Conclusions: These data suggest that ANXA1 plays a pivotal role in Aβ clearance and supports the use of ANXA1 as potential pharmacological tool for AD therapeutics.
Lai HM, Liu K, Ng WL, et al., 2016, Rationalisation and validation of an acrylamide-free procedure in three-dimensional histological imaging, PLOS One, Vol: 11, ISSN: 1932-6203
Three-dimensional visualization of intact tissues is now being achieved by turning tissues transparent. CLARITY is a unique tissue clearing technique, which features the use of detergents to remove lipids from fixed tissues to achieve optical transparency. To preserve tissue integrity, an acrylamide-based hydrogel has been proposed to embed the tissue. In this study, we examined the rationale behind the use of acrylamide in CLARITY, and presented evidence to suggest that the omission of acrylamide-hydrogel embedding in CLARITY does not alter the preservation of tissue morphology and molecular information in fixed tissues. We therefore propose a novel and simplified workflow for formaldehyde-fixed tissue clearing, which will facilitate the laboratory implementation of this technique. Furthermore, we have investigated the basic tissue clearing process in detail and have highlighted some areas for targeted improvement of technologies essential for the emerging subject of three-dimensional histology.
Liu K, Goldfinger MH, Questari HE, et al., 2016, ARTAG in the basal forebrain: Widening the constellation of astrocytic tau pathology, Acta Neuropathologica Communications, Vol: 4, ISSN: 2051-5960
Parr C, Carzaniga R, Gentleman SM, et al., 2016, Glycogen Synthase Kinase 3 Inhibition Promotes Lysosomal Biogenesis and Autophagic Degradation of the Amyloid-beta Precursor Protein (vol 32, pg 4410, 2012), Molecular and Cellular Biology, Vol: 36, ISSN: 1098-5549
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