| 1. |
- Hammarström, Per, 1972-
(författare)
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BIOLUMINESCENCE IMAGING Photonic amyloids
- 2019
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Ingår i: Nature Photonics. - : Nature Publishing Group. - 1749-4885 .- 1749-4893. ; 13:7, s. 442-444
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Tidskriftsartikel (refereegranskat)abstract
- Emerging data reveal that amyloid fibrils possess intrinsic photonic activity, showing luminescence over a wide range of the electromagnetic spectrum from the ultraviolet to the near-infrared.
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| 2. |
- Hammarström, Per, 1960-
(författare)
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Den judiska frågan i kristen press runt sekelskiftet 1900
- 2019
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- I svensk kristen press fanns decennierna runt 1900 ett intresse för judarna och judarnas ställning i samhället, både som politisk och teologisk fråga. Diskussionen kunde handla om allt ifrån mission, sionism och apokalyptik till politisk antisemitism, kulturkamp och kristendom kontra judendom. I mitt paper kommer jag presentera några huvuddrag i den tidens kristna debatt, svenskkyrklig såväl som frikyrklig, och diskutera framväxten av den moderna antisemitismen i förhållandet till den traditionella antijudaismen.
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| 3. |
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| 4. |
- Hammarström, Sofia, et al.
(författare)
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Identifying young people exposed to or at risk of sexual ill health: pilot implementation of an evidence-informed toolkit (SEXIT) at Swedish youth clinics
- 2019
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Ingår i: European Journal of Contraception and Reproductive Health Care. - : Informa UK Limited. - 1362-5187 .- 1473-0782. ; 24:1, s. 45-53
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: We aimed to develop and pilot-implement an evidence-informed toolkit (SEXual health Identification Tool; SEXIT) for identifying young people exposed to or at risk of sexual ill health, at Swedish youth clinics, and to investigate SEXIT’s potential to identify young people in need of special care and monitoring. Methods: The SEXIT toolkit was developed, validated and pilot-implemented at three Swedish youth clinics. Pre-implementation staff readiness was assessed and youth clinic visitors’ responses to SEXIT were analysed. Results: All staff perceived a need for screening for sexual risk-taking and exposure. The response rate from 268 youth clinic visitors (aged 15–24 years) was 86%. Half of the visitors had one or no variable associated with sexual ill health, a third had two or three, and 15% reported between four and seven variables. The most common variables were alcohol use, three or more sexual partners in the past year and previous chlamydia. Visitors rated SEXIT as important and not uncomfortable or difficult to answer. Conclusions: The SEXIT toolkit was found to be feasible and highly acceptable in a clinical setting. The use of SEXIT may facilitate important questions on sexual risk-taking and sexual ill health to be raised with youth clinic visitors. © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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| 5. |
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| 6. |
- Michno, Wojciech, 1992, et al.
(författare)
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Pyroglutamation of amyloid-βx-42 (Aβx-42) followed by Aβ1–40 deposition underlies plaque polymorphism in progressing Alzheimer's disease pathology
- 2019
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Ingår i: Journal of Biological Chemistry. - : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. - 0021-9258 .- 1083-351X. ; 294:17, s. 6719-6732
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid- (A) pathology in Alzheimer's disease (AD) is characterized by the formation of polymorphic deposits comprising diffuse and cored plaques. Because diffuse plaques are predominantly observed in cognitively unaffected, amyloid-positive (CU-AP) individuals, pathogenic conversion into cored plaques appears to be critical to AD pathogenesis. Herein, we identified the distinct A species associated with amyloid polymorphism in brain tissue from individuals with sporadic AD (s-AD) and CU-AP. To this end, we interrogated A polymorphism with amyloid conformation-sensitive dyes and a novel in situ MS paradigm for chemical characterization of hyperspectrally delineated plaque morphotypes. We found that maturation of diffuse into cored plaques correlated with increased A1-40 deposition. Using spatial in situ delineation with imaging MS (IMS), we show that A1-40 aggregates at the core structure of mature plaques, whereas A1-42 localizes to diffuse amyloid aggregates. Moreover, we observed that diffuse plaques have increased pyroglutamated Ax-42 levels in s-AD but not CU-AP, suggesting an AD pathology-related, hydrophobic functionalization of diffuse plaques facilitating A1-40 deposition. Experiments in tgAPP(Swe) mice verified that, similar to what has been observed in human brain pathology, diffuse deposits display higher levels of A1-42 and that A plaque maturation over time is associated with increases in A1-40. Finally, we found that A1-40 deposition is characteristic for cerebral amyloid angiopathy deposition and maturation in both humans and mice. These results indicate that N-terminal Ax-42 pyroglutamation and A1-40 deposition are critical events in priming and maturation of pathogenic A from diffuse into cored plaques, underlying neurotoxic plaque development in AD.
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| 7. |
- Mishra, Rajesh, et al.
(författare)
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Impact of N-glycosylation site variants during human PrP aggregation and fibril nucleation
- 2019
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Ingår i: Biochimica et Biophysica Acta - Proteins and Proteomics. - : ELSEVIER. - 1570-9639 .- 1878-1454. ; 1867:10, s. 909-921
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Tidskriftsartikel (refereegranskat)abstract
- Misfolding and aggregation of the human prion protein (PrP) cause neurodegenerative transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease. Mature native PrP is composed of 209 residues and is folded into a C-terminal globular domain (residues 125-209) comprising a small two-stranded beta-sheet and three alpha-helices. The N-terminal domain (residues 23-124) is intrinsically disordered. Expression of truncated PrP (residues 90-231) is sufficient to cause prion disease and residues 90/100-231 is comprising the amyloid-like fibril core of misfolded infectious PrP. During PrP fibril formation under native conditions in vitro, the disordered N-terminal domain slows down fibril formation likely due to a mechanism of initial aggregation forming morphologically disordered aggregates. The morphological disordered aggregate is a transient phase. Nucleation of fibrils occurs from this initial aggregate. The aggregate phase is largely circumvented by seeding with preformed PrP fibrils. In vivo PrP is N-glycosylated at positions Asn181 and Asn197. Little is known about the importance of these positions and their glycans for PrP stability, aggregation and fibril formation. We have in this study taken a step towards that goal by mutating residues 181 and 197 for cysteines to study the positional impact on these processes. We have further by organic synthetic chemistry and chemical modification generated synthetic glycosylations in these positions. Our data shows that residue 181 when mutated to a cysteine is a key residue for self -chaperoning, rendering a trap in the initial aggregate preventing conformational changes towards amyloid fibril formation. Position 197 is less involved in the aggregate trapping and is more geared towards beta-sheet structure conversion within amyloid fibrils. As expected, synthetic glycosylated 197 is less affected towards fibril formation compared to glycosylated 181. Our data are rather compatible with the parallel in-register intermolecular beta-sheet model structure of the PrP90-231 fibril and sheds light on the misfolding transitions of PrP in vitro. We hypothesize that glycosylation of position 181 is a key site for prion strain differentiation in vivo.
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| 8. |
- Sandberg, Alexander, 1986-
(författare)
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Polymorphic protein aggregation in tauopathies
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease(s) comprises one of the most common and costly neurodegenerative diseases. With a larger population and an increasing life expectancy, amyloid diseases (with age as one of the most prominent risk factors) will generate an even larger burden on healthcare. We know that protein misfolding is involved in the disease process but lack a complete understanding of the mechanism behind these diseases, both the sporadic and hereditary variants. It is not always known whether it is a gain-of-toxic function or loss‐of‐function that causes the neurodegeneration. To determine the correct diagnosis is a major challenge. If diagnosed, only a few amyloid diseases can be treated today.Amyloids are highly ordered filamentous protein aggregates with a β‐sheet structure. From identical or similar amino acid sequences, a large variety of structures can be formed by different secondary and tertiary structures and by different packing of the individual filaments. This is known as fibril polymorphism.This work focuses on characterization on two proteins involved in Alzheimer’s disease and other neurodegenerative diseases, namely Amyloid‐β (Aβ) and microtubule associated protein tau (tau). In order to investigate the properties of these proteins in vitro it is important to have protocols for production of recombinant protein that enables characterization of these aggregation prone proteins. We present protocols for recombinant expression, purification and non‐denaturing fibrillation assays used in our lab to produce and analyze Aβ, tau and the prion protein.Development of new ligands for characterization of fibrils is an important way of investigating different fibrillary structures and characterizing and distinguishing between the different polymorphs of aggregates. We showed that the central benzene ring of the amyloid ligand X‐34 can be exchanged for other heterocyclic motifs and still retain targeting of the “Congo red” binding site. The compounds do not compete with the Pittsburgh compound B (PiB) binding site on recombinant Aβ fibrils.We also characterized tau fibrils formed from seeding with tau aggregates from patients diagnosed with different neurodegenerative tauopathies. We use aggregation kinetics to test the seeding activity on two different sequence isoforms of tau, 0N3R and 0N4R. Fibrillation kinetics, an array of recently developed ligands (including the X‐34 analogs) and electron microscopy were used to characterize different polymorphs of the tau aggregates formed by seeded templating from patient derived seeds. Our data showed that brains contain seeds with different morphologies even with in patients diagnosed with the same disease.Investigations of the rare tau mutant G273R found in a patient with a presumed tauopathy also highlights the problem with proper diagnostics. Our results reveal that in vitro this mutation change the binding properties of 0N4R tau to the cytoskeletal proteins microtubule and F‐actin. Furthermore, we could show that when seeded, the fibril formation seeding activity followed a sequence similarity dependent manner. In fibrils formed during heparin-induced aggregation we can be distinguished between wild type and mutant tau as they form fibrils with different thickness. Our in vitro biophysical data support that the G237R mutant is causing a 4R tauopathy.The work in this thesis increase our knowledge in the field of tau aggregation and tau fibril polymorphism.
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| 9. |
- Zhang, Jun, et al.
(författare)
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Phenolic Bis-styrylbenzo[c]-1,2,5-thiadiazoles as Probes for Fluorescence Microscopy Mapping of A beta Plaque Heterogeneity
- 2019
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Ingår i: Journal of Medicinal Chemistry. - : AMER CHEMICAL SOC. - 0022-2623 .- 1520-4804. ; 62:4, s. 2038-2048
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Tidskriftsartikel (refereegranskat)abstract
- A fluorescent bis-styryl-benzothiadiazole (BTD) with carboxylic acid functional groups (X-34/Congo red analogue) showed lower binding affinity toward A beta 1-42 and A beta 1-40 fibrils than its neutral analogue. Hence, variable patterns of neutral OH-substituted bis-styryl-BTDs were generated. All bis-styryl-BTDs showed higher binding affinity to A beta 1-42 fibrils than to A beta 1-40 fibrils. The para-OH on the phenyl rings was beneficial for binding affinity while a meta-OH decreased the affinity. Differential staining of transgenic mouse A beta amyloid plaque cores compared to peripheral coronas using neutral compared to anionic bis-styryl ligands indicate differential recognition of amyloid polymorphs. Hyperspectral imaging of transgenic mouse A beta plaque stained with uncharged para-hydroxyl substituted bis-styryl-BTD implicated differences in binding site polarity of polymorphic amyloid plaque. Most properties of the corresponding bis-styryl-BTD were retained with a rigid alkyne linker rendering a probe insensitive to cis trans isomerization. These new BTDbased ligands are promising probes for spectral imaging of different A beta fibril polymorphs.
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