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| 2. |
- Vogel, Jacob W., et al.
(författare)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 3. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 5. |
- Sclafani, F., et al.
(författare)
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PAN-EX : a pooled analysis of two trials of neoadjuvant chemotherapy followed by chemoradiotherapy in MRI-defined, locally advanced rectal cancer
- 2016
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 27:8, s. 1557-1565
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Tidskriftsartikel (refereegranskat)abstract
- This analysis confirms that administering neoadjuvant chemotherapy (NACT) before chemoradiotherapy (CRT) could be a potential option for high-risk, locally advanced rectal cancer. In this setting, MRI tumour regression grade is an independent prognostic factor and, when assessed after NACT, may predict the probability and magnitude of incremental benefit from sequential CRT.EXPERT and EXPERT-C were phase II clinical trials of neoadjuvant chemotherapy (NACT) followed by chemoradiotherapy (CRT) in high-risk, locally advanced rectal cancer (LARC). We pooled individual patient data from these trials. The primary objective was overall survival (OS) in the intention-to-treat (ITT) population. Prognostic factors were also analysed. A total of 269 patients were included. Of these, 91.1% completed NACT, 88.1% completed CRT and 240 (89.2%) underwent curative surgery (R0/R1). After a median follow-up of 71.9 months, 5-year progression-free survival (PFS) and OS were 66.4% and 73.3%, respectively. In the group of R0/R1 resection patients, 5-year relapse-free survival (RFS) and OS were 71.6% and 77.2%, respectively, with local recurrence occurring in 5.5% and distant metastases in 20.6% of cases. Significant prognostic factors after multivariate analyses included age, tumour grade and MRI extramural venous invasion (mrEMVI) at baseline, MRI tumour regression grade (mrTRG) after CRT, ypT stage after surgery and adherence to study treatment. mrTRG after NACT was associated with PFS (P = 0.002) and OS (P = 0.018) and appeared to stratify patients based on the incremental benefit from sequential CRT. Among the outcome measures considered, in the subgroup of R0/R1 resection patients, ypT and ypStage had the highest predictive accuracy for RFS (concordance index: 0.6238 and 0.6252, respectively) and OS (concordance index: 0.6094 and 0.6132, respectively). Administering NACT before CRT could be a potential strategy for high-risk LARC. In this setting, mrTRG after CRT is an independent prognostic factor, while mrTRG after NACT should be tested as a parameter for treatment selection in trials of NACT +/- CRT. ypT stage may be a valuable surrogate end point for future phase II trials investigating intensified neoadjuvant treatments in similar patient populations.
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| 6. |
- Aamer, Aysha, et al.
(författare)
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A precursor plateau and pre-maximum [O ii] emission in the superluminous SN2019szu : a pulsational pair-instability candidate
- 2023
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Ingår i: Monthly notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 527:4, s. 11970-11995
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Tidskriftsartikel (refereegranskat)abstract
- We present a detailed study on SN2019szu, a Type I superluminous supernova at z = 0.213 that displayed unique photometric and spectroscopic properties. Pan-STARRS and ZTF forced photometry show a pre-explosion plateau lasting ∼40 d. Unlike other SLSNe that show decreasing photospheric temperatures with time, the optical colours show an apparent temperature increase from ∼15 000 to ∼20 000 K over the first 70 d, likely caused by an additional pseudo-continuum in the spectrum. Remarkably, the spectrum displays a forbidden emission line (likely attributed to λλ7320,7330) visible 16 d before maximum light, inconsistent with an apparently compact photosphere. This identification is further strengthened by the appearances of [O III] λλ4959, 5007, and [O III] λ4363 seen in the spectrum. Comparing with nebular spectral models, we find that the oxygen line fluxes and ratios can be reproduced with ∼0.25 M⊙ of oxygen-rich material with a density of ∼10−15 g cm−3. The low density suggests a circumstellar origin, but the early onset of the emission lines requires that this material was ejected within the final months before the terminal explosion, consistent with the timing of the precursor plateau. Interaction with denser material closer to the explosion likely produced the pseudo-continuum bluewards of ∼5500 Å. We suggest that this event is one of the best candidates to date for a pulsational pair-instability ejection, with early pulses providing the low density material needed for the formation of the forbidden emission line, and collisions between the final shells of ejected material producing the pre-explosion plateau.
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| 7. |
- Spillmann, Dorothe, et al.
(författare)
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Characterization of a novel pyruvylated carbohydrate unit implicated in the cell aggregation of the marine sponge Microciona prolifera
- 1993
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 268:18, s. 13378-13387
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Tidskriftsartikel (refereegranskat)abstract
- The species-specific Ca(2+)-dependent reaggregation of dissociated cells of the marine sponge Microciona prolifera is mediated by a large extracellular adhesion proteoglycan. The glycans of this molecule are involved in the interactions of the proteoglycan with itself and with the sponge cells. Monoclonal antibodies against the glycans block the aggregation of sponge cells (Misevic, G. N., Finne, J., and Burger, M. M. (1987) J. Biol. Chem. 262, 5870-5877). Proteoglycan oligosaccharides were prepared by partial acid hydrolysis of the isolated glycans, and their reactivity with the monoclonal antibodies was monitored after linkage to phospholipid and immunostaining of thin layer chromatograms. One major antibody-reactive oligosaccharide was detected and purified by ion-exchange chromatography and high performance liquid chromatography. 1H NMR spectroscopy, fast atom bombardment-mass spectrometry, methylation analysis, and sequential chemical and enzymatic degradation studies indicated the structure [formula: see text] for the oligosaccharide. The depyruvylated derivative of the oligosaccharide did not react with the aggregation-blocking antibody, which indicates that the pyruvate acetal is an essential part of the epitope.
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| 8. |
- Spillmann, Dorothe, et al.
(författare)
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Characterization of a Novel Sulfated Carbohydrate Unit Implicated in the CarbohydrateCarbohydrate-mediated Cell Aggregation of the Marine Sponge Microciona prolifera
- 1995
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 270, s. 5089-5097
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Tidskriftsartikel (refereegranskat)abstract
- Species-specific cell reaggregation in the marine sponge Microciona prolifera is mediated by an adhesion proteoglycan. Two interactions are involved in the process: a Ca(2+)-dependent homophilic binding between proteoglycan molecules and a Ca(2+)-independent binding between the molecule and cells. Both interactions are mediated by the glycan moieties of the proteoglycan. The interaction of the proteoglycan with itself has been characterized as a carbohydrate-carbohydrate interaction of multiple low affinity sites. The monoclonal antibodies Block 1 and Block 2 raised against the purified aggregation proteoglycan and selected for inhibition of aggregation bind to these glycans. In a previous report the structure, [formula: see text] was assigned to the oligosaccharide reacting with Block 1 antibody (Spillmann, D., Hård, K., Thomas-Oates, J., Vliegenthart, J. F. G., Misevic, G., Burger, M. M., and Finne, J. (1993) J. Biol. Chem. 268, 13378-13387). By the technique of attaching the water-soluble acid-degraded fragments to a lipid carrier for immunochemical detection and by chemical, enzymatic and spectroscopic methods the structure, [formula: see text] was assigned to the oligosaccharide reacting with the aggregation-blocking monoclonal antibody Block 2. The structure, [formula: see text] was assigned to a major nonreactive oligosaccharide, which outlined the molecular requirements of antibody binding of the two aggregation-associated epitopes. These data demonstrate that two different functional sites with distinct structural characteristics and antibody reactivities are involved in the reaggregation of sponge cells, a model of carbohydrate-carbohydrate-mediated cell interactions.
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| 9. |
- Buckley, Michael, et al.
(författare)
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Comparing the survival of osteocalcin and mtDNA in archaeological bone from four European sites
- 2008
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Ingår i: Journal of Archaeological Science. - : Elsevier BV. - 0305-4403 .- 1095-9238. ; 35:6, s. 1756-1764
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Tidskriftsartikel (refereegranskat)abstract
- The small mineral-binding bone protein, osteocalcin, has been applied in a number of studies on ancient bone due to predictions of its long-term stability. However, the intact protein has not been shown to survive in ancient bone devoid of DNA, which is a much more phylogenetically informative biomolecule. In this investigation, the survival of osteocalcin is directly compared to the amplification of mtDNA in a set of 34 archaeological samples from four sites throughout Europe. We also present unpublished osteocalcin sequences of seven mammalian species in addition to the 19 published sequences to highlight phylogenetic limitations of this protein. The results indicate that the intact osteocalcin molecule survives less in archaeological samples than mtDNA and is more subject to the temperature of the archaeological site. Amino acid analyses show the persistence of the dominant protein collagen in samples that failed both osteocalcin and mtDNA analyses. The implications these findings present for biomolecular species identification in archaeological and palaeontological material are that, although proteins do survive beyond ancient DNA, osteocalcin does not appear to be the most ideal target
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| 10. |
- Bulone, Vincent, et al.
(författare)
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Characterisation of horse dander allergen glycoproteins using amino acid and glycan structure analyses - A mass spectrometric method for glycan chain analysis of glycoproteins separated by two-dimensional electrophoresis
- 2000
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Ingår i: International Archives of Allergy and Immunology. - : S. Karger AG. - 1018-2438 .- 1423-0097. ; 123:3, s. 220-227
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Tidskriftsartikel (refereegranskat)abstract
- Separation of horse dander allergens using two-dimensional PAGE resulted in the identification of 16 proteins that react with allergic patient sera. A sensitive method has been developed for analysing the structures of the glycan chains of individual glycoprotein allergens transferred to blots following two-dimensional PAGE, and has allowed the structural identification of the glycan chains of the most abundant isoforms of Equ c 1, a glycosylated horse dander major allergen. The method involves separation of the allergens by two-dimensional PAGE, transfer to polyvinylidene difluoride membranes, release of the glycan chains using peptide N-glycosidase F, permethylation and mass spectrometric analysis of the derivatised glycans. The amino acid compositions of the 16 horse dander allergens separated by two-dimensional PAGE have been determined, allowing the identification of the various isoforms of Equ c 1. These results also confirmed that the two non-glycosylated major allergens, Equ c 2.0101 and Equ c 2.0102, belong to the lipocalin family, and support the idea that these two allergens are most probably isoforms of the same protein. The glycan structures identified using the mass spectrometric method are common biantennary and triantennary glycan chains. These carbohydrate moieties may have a role in the binding of IgE; however, it is more likely that the overall glycoprotein structure involving both the glycan and protein moieties, rather than the structure of the glycan chains alone, is responsible for eliciting allergic responses.
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