| 1. |
- Cossarizza, A., et al.
(författare)
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Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
- 2019
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 49:10, s. 1457-1973
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Tidskriftsartikel (refereegranskat)abstract
- These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
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| 2. |
- van Rheenen, Wouter, et al.
(författare)
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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
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Tidskriftsartikel (refereegranskat)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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| 3. |
- Huang, X. F., et al.
(författare)
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Genomewide Association Study of Acute Anterior Uveitis Identifies New Susceptibility Loci
- 2020
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404 .- 1552-5783. ; 61:6
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. Acute anterior uveitis (AAU) is a common intraocular inflammatory disease. AAU occurs in 30% to 50% of patients with ankylosing spondylitis (AS), and both conditions are strongly associated with human leukocyte antigen (HLA)-B 27 , implying a shared etiology. This study aims to apply genomewide association study (GWAS) to characterize the genetic associations of AAU and their relationship to the genetics of AS. METHODS. We undertook the GWAS analyses in 2752 patients with AS with AAU (cases) and 3836 patients with AS without AAU (controls). There were 7,436,415 single-nucleotide polymorphisms (SNPs) available alter SNP microarray genotyping, imputation, and quality-control filtering. RESULTS. We identified one locus associated with AAU at genomewide significance: rs9378248 (P = 2.69 x 10(-8), odds ratio [OR] = 0.78), lying close to HLA-B. Suggestive association was observed at 11 additional loci, including previously reported AS loci ERAP1 (rs27529, P = 2.19 x 10(-7), OR = 1.22) and NOS2 (rs2274894, P = 8.22 x 10(-7), OR = 0.83). Multiple novel suggestive associations were also identified, including MERTK (rsl0171979, P = 2.56 x 10(-6), OR = 1.20), KIFAP3 (rs508063, P = 5.64 x 10(-7), OR = 1.20), CLCN7 (rs67412457, P = 1.33 x 10(-6), OR = 1.25), ACAA2 (rs9947182, P = 9.70 x 10(-7), OR = 1.37), and 5 intergenic loci. The SNP-based heritability is approximately 0.5 for AS alone, and is much higher (approximately 0.7) for AS with AAU. Consistent with the high heritability, a genomewide polygenic risk score shows strong power in identifying individuals at high risk of either AS with AAU or AS alone. CONCLUSIONS. We report here the first GWAS for AAU and identify new susceptibility loci. Our findings confirm the strong overlap in etiopathogenesis of AAU with AS, and also provide new insights into the genetic basis of AAU.
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| 4. |
- Couthouis, Julien, et al.
(författare)
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A yeast functional screen predicts new candidate ALS disease genes
- 2011
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:52, s. 20881-20890
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of the segenes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having amore severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.
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| 5. |
- Gallagher, Michael D., et al.
(författare)
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TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions
- 2014
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 127:3, s. 407-418
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Tidskriftsartikel (refereegranskat)abstract
- Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
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| 6. |
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| 7. |
- Garner, J., et al.
(författare)
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Identification of Aminopyrimidine Regioisomers via Line Broadening Effects in 1H and 13C NMR Spectroscopy
- 2004
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Ingår i: Australian Journal of Chemistry. ; 57:11, s. 1079-1083
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Tidskriftsartikel (refereegranskat)abstract
- Substituted mono- and diamino-pyrimidines were synthesized as part of our medicinal chemistry programmes. Primary amines substituted at the 4-position exhibited room-temperature line broadening effects in both 1H and 13C NMR spectroscopy due to the presence of rotamers, but these effects were not observed for substituents in the 2-position. This provided a simple diagnostic tool for the identification of regioisomers, a determination which would otherwise have required two-dimensional experiments.
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| 8. |
- Hill, Timothy A., et al.
(författare)
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Iminochromene Inhibitors of Dynamins I and II GTPase Activity and Endocytosis
- 2010
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:10, s. 4094-4102
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Tidskriftsartikel (refereegranskat)abstract
- Herein we report the synthesis of discrete iminochromene (“iminodyn”) libraries (14−38) as potential inhibitors of dynamin GTPase. Thirteen iminodyns were active (IC50 values of 260 nM to 100 μM), with N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (17), N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (22), and N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (23) (IC50 values of 330 ± 70, 450 ± 50, and 260 ± 80 nM, respectively) being the most potent. Five of the most potent iminodyns all inhibited dynamins I and II approximately equally. Iminodyn-22 displayed uncompetitive inhibition with respect to GTP. Selected iminodyns were evaluated for their ability to block receptor mediated endocytosis (RME, mediated by dynamin II) and synaptic vesicle endocytosis (SVE, mediated by dynamin I), with 17 showing no activity while 22 returned RME and SVE IC50 values of 10.7 ± 4.5 and 99.5 ± 1.7 μM, respectively. The iminodyns reported herein represent a new chemical class of the first nanomolar potent dynamin inhibitors that are also effective endocytosis inhibitors.
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| 9. |
- Hill, Timothy A, et al.
(författare)
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Inhibition of dynamin mediated endocytosis by the dynoles : synthesis and functional activity of a family of indoles
- 2009
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 52:12, s. 3762-3773
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Tidskriftsartikel (refereegranskat)abstract
- Screening identified two bisindolylmaleimides as 100 microM inhibitors of the GTPase activity of dynamin I. Focused library approaches allowed development of indole-based dynamin inhibitors called dynoles. 100-Fold in vitro enhancement of potency was noted with the best inhibitor, 2-cyano-3-(1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-N-octylacrylamide (dynole 34-2), a 1.3 +/- 0.3 microM dynamin I inhibitor. Dynole 34-2 potently inhibited receptor mediated endocytosis (RME) internalization of Texas red-transferrin. The rank order of potency for a variety of dynole analogues on RME in U2OS cells matched their rank order for dynamin inhibition, suggesting that the mechanism of inhibition is via dynamin. Dynoles are the most active dynamin I inhibitors reported for in vitro or RME evaluations. Dynole 34-2 is 15-fold more active than dynasore against dynamin I and 6-fold more active against dynamin mediated RME (IC(50) approximately 15 microM; RME IC(50) approximately 80 microM). The dynoles represent a new series of tools to better probe endocytosis and dynamin-mediated trafficking events in a variety of cells.
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| 10. |
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| 11. |
- Majounie, Elisa, et al.
(författare)
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Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
- 2012
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Ingår i: Lancet Neurology. - 1474-4465. ; 11:4, s. 323-330
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Tidskriftsartikel (refereegranskat)abstract
- Background We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. Findings In patients with sporadic ALS, we identified the repeat expansion in 236 (7.0%) of 3377 white individuals from the USA, Europe, and Australia, two (4.1%) of 49 black individuals from the USA, and six (8.3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39.3%) of 552 white individuals with familial MS from Europe and the USA. 59 (6.0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24.8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic MS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. Interpretation A common Mendelian genetic lesion in C9472 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.
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| 12. |
- Odell, Luke R, et al.
(författare)
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The Pthaladyns : GTP Competitive Inhibitors of Dynamin I and II GTPase Derived from Virtual Screening
- 2010
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:14, s. 5267-5280
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Tidskriftsartikel (refereegranskat)abstract
- We report the development of a homology model for the GTP binding domain of human dynamin I based on the corresponding crystal structure of Dictyostelium discoidum dynamin A. Virtual screening identified 2-[(2-biphenyl-2-yl-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonyl)amino]-4-chlorobenzoic acid (1) as a 170 μM potent inhibitor. Homology modeling- and focused library-led synthesis resulted in development of a series of active compounds (the “pthaladyns”) with 4-chloro-2-(2-(4-(hydroxymethyl)phenyl)-1,3-dioxoisoindoline-5-carboxamido)benzoic acid (29), a 4.58 ± 0.06 μM dynamin I GTPase inhibitor. Pthaladyn-29 displays borderline selectivity for dynamin I relative to dynamin II (5−10 fold). Only pthaladyn-23 (dynamin I IC50 17.4 ± 5.8 μM) was an effective inhibitor of dynamin I mediated synaptic vesicle endocytosis in brain synaptosomes with an IC50 of 12.9 ± 5.9 μM. This compound was also competitive with respect to Mg2+·GTP. Thus the pthaladyns are the first GTP competitive inhibitors of dynamin I and II GTPase and may be effective new tools for the study of neuronal endocytosis.
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| 13. |
- Olsson, B, et al.
(författare)
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Association of Cerebrospinal Fluid Neurofilament Light Protein Levels With Cognition in Patients With Dementia, Motor Neuron Disease, and Movement Disorders.
- 2019
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 76:3, s. 318-325
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal and axonal destruction are hallmarks of neurodegenerative diseases, but it is difficult to estimate the extent and progress of the damage in the disease process.To investigate cerebrospinal fluid (CSF) levels of neurofilament light (NFL) protein, a marker of neuroaxonal degeneration, in control participants and patients with dementia, motor neuron disease, and parkinsonian disorders (determined by clinical criteria and autopsy), and determine its association with longitudinal cognitive decline.In this case-control study, we investigated NFL levels in CSF obtained from controls and patients with several neurodegenerative diseases. Collection of samples occurred between 1996 and 2014, patients were followed up longitudinally for cognitive testing, and a portion were autopsied in a single center (University of Pennsylvania). Data were analyzed throughout 2016.Concentrations of NFL in CSF.Levels of CSF NFL and correlations with cognition scores.A total of 913 participants (mean [SD] age, 68.7 [10.0] years; 456 [49.9%] women) were included: 75 control participants plus 114 patients with mild cognitive impairment (MCI), 397 with Alzheimer disease, 96 with frontotemporal dementia, 68 with amyotrophic lateral sclerosis, 41 with Parkinson disease (PD), 19 with PD with MCI, 29 with PD dementia, 33 with dementia with Lewy bodies, 21 with corticobasal syndrome, and 20 with progressive supranuclear palsy. Cognitive testing follow-up occurred for 1 to 18 years (mean [SD], 0.98 [2.25] years); autopsy-verified diagnoses were available for 120 of 845 participants with diseases (14.2%). There was a stepwise increase in CSF NFL levels between control participants (median [range] score, 536 [398-777] pg/mL), participants with MCI (831 [526-1075] pg/mL), and those with Alzheimer disease (951 [758-1261] pg/mL), indicating that NFL levels increase with increasing cognitive impairment. Levels of NFL correlated inversely with baseline Mini-Mental State Examination scores (ρ, -0.19; P<.001) in the full cohort (n=822) and annual score decline in the full cohort (ρ, 0.36, P<.001), participants with AD (ρ, 0.25; P<.001), and participants with FTD (ρ, 0.46; P=.003). Concentrations of NFL were highest in participants with amyotrophic lateral sclerosis (median [range], 4185 [2207-7453] pg/mL) and frontotemporal dementia (2094 [230-7744] pg/mL). In individuals with parkinsonian disorders, NFL concentrations were highest in those with progressive supranuclear palsy (median [range], 1578 [1287-3104] pg/mL) and corticobasal degeneration (1281 [828-2713] pg/mL). The NFL concentrations in CSF correlated with TDP-43 load in 13 of 17 brain regions in the full cohort. Adding NFL to β-amyloid 42, total tau, and phosphorylated tau increased accuracy of discrimination of diseases.Levels of CSF NFL are associated with cognitive impairments in patients with Alzheimer disease and frontotemporal dementia. In other neurodegenerative disorders, NFL levels appear to reflect the intensity of the neurodegenerative processes.
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| 14. |
- Portelius, Erik, 1977, et al.
(författare)
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Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology.
- 2018
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 136:3, s. 363-376
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Tidskriftsartikel (refereegranskat)abstract
- Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer's disease dementia (ADD),and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson's disease (p<0.0001), frontotemporal dementia (p<0.0001), and amyotrophic lateral sclerosis (p=0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque score, p=0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p=0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p=0.0006 and p<0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology.
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| 15. |
- Sandelius, Åsa P, et al.
(författare)
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Elevated CSF GAP-43 is Alzheimer's disease specific and associated with tau and amyloid pathology.
- 2019
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 15:1, s. 55-64
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Tidskriftsartikel (refereegranskat)abstract
- The level of the presynaptic protein growth-associated protein 43 (GAP-43) in cerebrospinal fluid (CSF) has previously been shown to be increased in Alzheimer's disease (AD) and thus may serve as an outcome measure in clinical trials and facilitate earlier disease detection.We developed an enzyme-linked immunosorbent assay for CSF GAP-43 and measured healthy controls (n=43), patients with AD (n=275), or patients with other neurodegenerative diseases (n=344). In a subpopulation (n=93), CSF GAP-43 concentrations from neuropathologically confirmed cases were related to Aβ plaques, tau, α-synuclein, and TDP-43 pathologies.GAP-43 was significantly increased in AD compared to controls and most neurodegenerative diseases and correlated with the magnitude of neurofibrillary tangles and Aβ plaques in the hippocampus, amygdala, and cortex. GAP-43 was not associated to α-synuclein or TDP-43 pathology.The presynaptic marker GAP-43 is associated with both diagnosis and neuropathology of AD and thus may be useful as a sensitive and specific biomarker for clinical research.
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| 16. |
- Wu, L., et al.
(författare)
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The global catalogue of microorganisms 10K type strain sequencing project: closing the genomic gaps for the validly published prokaryotic and fungi species
- 2018
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Ingår i: GigaScience. - : Oxford University Press (OUP). - 2047-217X. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- Genomic information is essential for taxonomic, phylogenetic, and functional studies to comprehensively decipher the characteristics of microorganisms, to explore microbiomes through metagenomics, and to answer fundamental questions of nature and human life. However, large gaps remain in the available genomic sequencing information published for bacterial and archaeal species, and the gaps are even larger for fungal type strains. The Global Catalogue of Microorganisms (GCM) leads an internationally coordinated effort to sequence type strains and close gaps in the genomic maps of microorganisms. Hence, the GCM aims to promote research by deep-mining genomic data.
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