| 61. |
- Sekijima, Yoshiki, et al.
(författare)
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Pathological, biochemical, and biophysical characteristics of the transthyretin variant Y114H (p.Y134H) explain its very mild clinical phenotype
- 2015
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Ingår i: Journal of the peripheral nervous system. - : WILEY-BLACKWELL. - 1085-9489 .- 1529-8027. ; 20:4, s. 372-379
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Tidskriftsartikel (refereegranskat)abstract
- Transthyretin (TTR) is a homotetrameric protein that must misfold in order to form amyloid fibrils. Misfolding includes rate limiting tetramer dissociation, followed by fast tertiary structural changes of the monomer that enable aggregation. Hereditary ATTR amyloidosis is an autosomal dominant genetic disorder with systemic deposition of amyloid fibrils induced by TTR gene mutation. We identified a rare Y114H (p.Y134H) TTR variant in a Japanese patient presenting with late-onset, very mild clinical course. The patient had an extremely low serum variant TTR concentration (18% of total TTR), whereas the composition of variant TTR was 55% in amyloid fibrils in tenosynovial tissues obtained at carpal tunnel release surgery. The amyloid fibril deposits in the ATTR Y114H patient had an altered structure compared with that in wild-type ATTR patients, as determined by luminescent conjugated poly/oligo-thiophene fluorescence spectroscopy. Biophysical studies using recombinant protein showed that Y114H TTR was markedly destabilized both thermodynamically and kinetically and was highly amyloidogenic in vitro. These data suggest that extremely low serum variant Y114H TTR concentration, probably due to endoplasmic reticulum-associated degradation of unstable variant TTR protein, protected this patient from severe amyloidosis, as self-assembly of the amyloidogenic intermediate is a concentration-dependent process.
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| 62. |
- Sjölander, Daniel, et al.
(författare)
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Sensitive and rapid assessment of amyloid by oligothiophene fluorescence in subcutaneous fat tissue
- 2015
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Ingår i: Amyloid. - : Informa Healthcare. - 1350-6129 .- 1744-2818. ; 22:1, s. 19-25
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Tidskriftsartikel (refereegranskat)abstract
- Systemic amyloidosis (SA) is often diagnosed late. Combining clinical and biochemical biomarkers is necessary for raising suspicion of disease. Fine needle aspiration (FNA) of subcutaneous fat enables SA detection by Congo red staining. The luminescent conjugated probe heptameric formic thiophene acetic acid (h-FTAA) is a sensitive alternative to Congo red-staining of tissue samples. Our objective was to compare h-FTAA fluorescence with the Congo red stain for amyloid detection in FNA-obtained fat tissue. Herein, we studied samples from 57 patients with established SA (19 with AA, 20 with AL, and 18 with ATTR) and 17 age-matched controls (34–75 years). Positivity for h-FTAA was graded according to a Congo red-based grading scale ranging from 0 to 4+. Amyloid grading by both methods correlated strongly (r = 0.87). Here h-FTAA was positive in 53 of 54 Congo red-positive cases (sensitivity 98%) and h-FTAA was negative in 7 of 17 Congo red-negative controls (specificity 41%), but was also positive for 3 Congo red-negative SA cases. We conclude that h-FTAA fluorescence is more sensitive than Congo red staining in this small exploratory study of fat tissue samples, implicating potential sensitivity for prodromal amyloidosis, but is less specific for clinical amyloidosis defined by Congo red positivity. Given its simplicity h-FTAA staining may therefore be the most appropriate method for rapid screening of fat tissue samples but should presently treat grade 1+ as only suggestive, whereas 2+ or higher as positive for amyloidosis. Parallel assessment of h-FTAA and Congo red staining appears highly promising for clinical applications.
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| 63. |
- Svensson, Harry R:son, 1976-
(författare)
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Fabian Philip, familjen Ruben och örlogsstaden : Entreprenörsfamiljen som grundade Mosaiska församlingen i Karlskrona 1780–1945
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The purpose of the dissertation is to investigate Jewish integration in the naval city of Karlskrona in the period 1780–1945. This was done by the investigation of the economic, social and cultural strategies that the Jewish Philip/Ruben family used in their family business in Karlskrona during the 19th century. This has made it possible to understand how a Jewish family and congregation interacted with and became integrated in a Swedish naval-city environment. The study gives also new information about and a better understanding of the Swedish naval environment and naval production capacity. The study provides new knowledge on different fields of studies as Swedish Jewish history, urban history, naval history (the history of the Swedish Royal Navy), history of migration and integration, and the history of Karlskrona. The dissertation studies the history of the Philip/Ruben family in three distinct perspectives: economic, social and cultural. Moreover, the study pays attention to the process of the family’s integration and adaptation of different Jewish groups in Karlskrona.Fabian Philip obtained an exception from the Swedish legislation forbidding Jews to live in other towns than Stockholm, Göteborg and Norrköping, and settled in the naval city of Karlskrona. His family came to constitute the Jewish congregation in Karlskrona in the period 1782–1862. Karlskrona therefore became the fourth city in Sweden where Jews were allowed to settle. Fabian Philip and his family originated from Bützow in northern Germany. Fabian Philip’s establishment in Karlskrona depended upon his role as contractor, supplying sailcloth to the Swedish Royal Navy. After the Vienna Congress of 1815 Sweden adopted a Doctrine of Central defense and The Swedish Royal Navy lost its importance for the defense of Sweden. With a minimum of funding the Swedish Royal Navy went into a state of despair and so did Karlskrona’s local economy.By 1830 agriculture was the only viable economic niche in the economically neglected Karlskrona but Jews were prohibited to own landed property until 1860. Fabian Philip was able, with the help of Karlskrona’s officer staff, to circumnavigate the legislation and became a landowner of big Afvelsgärde estate. Of all the Jewish-owned estates in Sweden in the mid-century 10 percent were to be owned by the Philip/Ruben family. When Sweden was industrialized in 1870–1890, the local economy of Karlskrona managed to compensate for the decline in activities of the Swedish Royal Navy. The family succeeded to take part in the program of local modernization that was launched from the 1880s. The Philip/Ruben family contributed to the economic modernization of Karlskrona as bankers and factory owners. The family thrived in the city’s surprisingly open and cosmopolitan environment. Until now, no research has been undertaken about the Jewish congregation or the Jewish life in Karlskrona. The results of this dissertation contribute to the understanding of Jewish life in Sweden.
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| 64. |
- Wennberg, Maria, et al.
(författare)
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Irregular eating of meals in adolescence and the metabolic syndrome in adulthood : results from a 27-year prospective cohort
- 2016
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Ingår i: Public Health Nutrition. - : Cambridge University Press. - 1368-9800 .- 1475-2727. ; 19:3, s. 667-673
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The objective was to investigate whether irregular eating of meals in adolescence predicts the metabolic syndrome and its components in adulthood, and if any specific meal is of particular importance. Design: Prospective cohort study with 27 years of follow-up. Information on meals (breakfast, school lunch and dinner with family), lifestyle (alcohol consumption, smoking habits, physical activity, consumption of sweets and pastries) at age 16 years was assessed from questionnaires, and presence or not of the metabolic syndrome and its components were defined at age 43 years in 889 participants (82.1 % of total cohort). Logistic regression was used to calculate odds ratios and confidence intervals. Setting: The Northern Swedish Cohort; all school-leavers of the 9th grade in the town Lulea in 1981. Subjects: Adolescents (age 16 years). Results: Irregular eating of meals at age 16 years was associated with higher prevalence of the metabolic syndrome at age 43 years (OR=1.74; 95 % CI 1.12, 2.71), but this was explained by concurrent unhealthy lifestyle at age 16 years. Poor breakfast at age 16 years was the only meal associated with the metabolic syndrome at age 43 years, independent of other meals, BMI (kg/m2) and lifestyle at age 16 years (OR = 1.67; 95 % CI 1.00, 2.80). Conclusions: Irregular eating of meals in adolescence predicted the metabolic syndrome in adulthood, but not independently of BMI and lifestyle in adolescence. Poor breakfast in adolescence was the only specific meal associated with future metabolic syndrome, even after adjustments. Breakfast eating should be encouraged in adolescence.
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| 65. |
- Wennberg, Maria, et al.
(författare)
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Poor breakfast habits in adolescence predict the metabolic syndrome in adulthood
- 2015
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Ingår i: Public Health Nutrition. - 1368-9800 .- 1475-2727. ; 18:1, s. 122-129
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To analyse whether poor breakfast habits in adolescence predict the metabolic syndrome and its components in adulthood. Previous studies suggest that regular breakfast consumption improves metabolic parameters. Design: Prospective. Breakfast habits and other lifestyle variables at age 16 years were assessed from questionnaires. Poor breakfast habits were defined as skipping breakfast or only drinking or eating something sweet. At age 43 years, the effective sample consisted of 889 participants defined as having the metabolic syndrome or not, using the International Diabetes Federation criteria. Logistic regression was used to calculate odds ratios and confidence intervals. Setting: The Northern Swedish Cohort, a longitudinal population-based cohort with 27-year follow-up. Subjects: Adolescents (age 16 years). Results: Prevalence of the metabolic syndrome at age 43 years was 27.0%. Of the participants, 9.9% were classified with poor breakfast habits at age 16 years. Adjusted odds for the metabolic syndrome at age 43 years was OR = 1.68 (95% CI 1.01, 2.78) for those with poor breakfast habits at age 16 years compared with breakfast eaters. Looking at the metabolic syndrome components, poor breakfast habits at age 16 years were associated with central obesity (OR = 1.71; 95% CI 1.00, 2.92) and high fasting glucose (OR = 1.75; 95% CI 1.01, 3.02) at age 43 years, even after multivariate adjustments. Conclusions: Poor breakfast habits in adolescence predicted the metabolic syndrome in adulthood. Of the metabolic syndrome components, poor breakfast habits in adolescence predicted central obesity and high fasting glucose in adulthood. Further research is needed to fully understand the relationship between early breakfast habits and adult metabolic syndrome.
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| 66. |
- Westerlund, Hugo, et al.
(författare)
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Parental academic involvement in adolescence as predictor of mental health trajectories over the life course : a prospective population-based cohort study
- 2015
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Ingår i: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mental health problems are rising, especially among younger people, indicating a need to identify determinants of the development of mental health over the life course. Parental involvement in their children's studies, particularly in terms of academic socialisation, has been shown to predict better mental health in adulthood, as well as other more favourable health outcomes, but no study published so far has examined its impact on trajectories of mental health. We therefore sought to elucidate the role of parental involvement at age 16 on the life course development of internalised mental health symptoms. Methods: In a population-based cohort (452 women and 488 men, 87 % of the eligible participants), we examined the association between parental involvement in their offspring's studies, measured by teacher and pupil ratings at age 16, and an index of internalised mental health symptoms at the ages of 16, 18, 21, 30, and 43. Using latent class trajectory analysis, 5 different trajectories were derived from these indices: Very low stable (least symptoms), Low stable, Increasing, Moderate stable, and High decreasing (most symptoms). Multinomial logistic regression was used to regress trajectory membership on the parental involvement variables. Results: Teacher-rated parental interest in their offspring's studies during the last year of compulsory school was associated with a lower risk of entering the Moderate stable (OR = 0.54; 95 % CI 0.30 to 0.98) and High decreasing (OR = 0.41; 0.18 to 0.91) trajectories, compared with the Low stable, also after adjustment for sex, parental social class and mental health, family unemployment and own school grades. Both these associations were present only in children with grades above the national average. Student-rated availability of assistance with homework was associated with a higher chance of entering the Very low stable trajectory in the whole sample (OR = 1.24; 1.07 to 1.43), in men (OR = 1.25; 1.05 to 1.48) and in those with above average grades (OR = 1.39; 1.13 to 1.72), and with a lower risk of entering the Moderate stable in women (OR = 0.74; 0.55 to 0.99), also after the same adjustments. Conclusions: Parental involvement in their offspring's studies may buffer against poor mental health in adolescence which may track into adulthood.
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| 67. |
- Zhang, Jun, et al.
(författare)
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Detection and Imaging of A beta 1-42 and Tau Fibrils by Redesigned Fluorescent X-34 Analogues
- 2018
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Ingår i: Chemistry - A European Journal. - : WILEY-V C H VERLAG GMBH. - 0947-6539 .- 1521-3765. ; 24:28, s. 7210-7216
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Tidskriftsartikel (refereegranskat)abstract
- We revisited the Congo red analogue 2,5-bis(4-hydroxy-3-carboxy-styryl)benzene (X-34) to develop this highly fluorescent amyloid dye for imaging Alzheimers disease (AD) pathology comprising A beta and Tau fibrils. A selection of ligands with distinct optical properties were synthesized by replacing the central benzene unit of X-34, with other heterocyclic moieties. Full photophysical characterization was performed, including recording absorbance and fluorescence spectra, Stokes shift, quantum yield and fluorescence lifetimes. All ligands displayed high affinity towards recombinant amyloid fibrils of A beta 1-42 (13-300nmK(d)) and Tau (16-200nmK(d)) as well as selectivity towards the corresponding disease-associated protein aggregates in AD tissue. We observed that these ligands efficiently displaced X-34, but not Pittsburgh compound B (PiB) from recombinant A beta 1-42 amyloid fibrils, arguing for retained targeting of the Congo red type binding site. We foresee that the X-34 scaffold offers the possibility to develop novel high-affinity ligands for A pathology found in human AD brain in a different mode compared with PiB, potentially recognizing different polymorphs of A fibrils.
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| 68. |
- Zhang, Jun, Dr. 1987-, et al.
(författare)
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Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.
- 2018
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Ingår i: ChemPhysChem. - Weinheim, Germany : Wiley-VCH Verlag. - 1439-4235 .- 1439-7641. ; 19:22, s. 3001-3009
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Tidskriftsartikel (refereegranskat)abstract
- Two analogues to the fluorescent amyloid probe 2,5-bis(4'-hydroxy-3'-carboxy-styryl)benzene (X-34) were synthesized based on the trans-stilbene pyrene scaffold (Py1SA and Py2SA). The compounds show strikingly different emission spectra when bound to preformed Aβ1-42 fibrils. This remarkable emission difference is retained when bound to amyloid fibrils of four distinct proteins, suggesting a common binding configuration for each molecule. Density functional theory calculations show that Py1SA is twisted, while Py2SA is more planar. Still, an analysis of the highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LUMOs) of the two compounds indicates that the degree of electronic coupling between the pyrene and salicylic acid (SA) moieties is larger in Py1SA than in Py2SA. Excited state intramolecular proton transfer (ESIPT) coupled-charge transfer (ICT) was observed for the anionic form in polar solvents. We conclude that ICT properties of trans-stilbene derivatives can be utilized for amyloid probe design with large changes in emission spectra and decay times from analogous chemical structures depending on the detailed physical nature of the binding site.less thanbr /greater than (© 2018 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim.)
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| 69. |
- 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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| 70. |
- Zhang, Jun, Dr. 1987-
(författare)
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Synthesis and characterization of fluorescent stilbene-based probes targeting amyloid fibrils
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) is characterized by two main protein aggregate hallmarks in the brain: extracellular deposition of the amyloid-β (Aβ) in senile plaques and intracellular neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau protein. The past decade has seen great progress in the development of imaging probes for the non-invasive detection of Aβ and tau aggregates. Here positron emission tomography (PET), single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI), are highly promising technologies for clinical diagnostics. However, as a research tool, optical imaging is superior because it is real-time, sensitive, inexpensive, not radioactive and that it in particular affords high-resolution studies both in vitro and in vivo. Fluorescent probes are especially useful for designing novel binding scaffolds for structure investigations of protein aggregates. This thesis describes design, synthesis and evaluation of a series of fluorescent probes for detection of amyloid fibrils, especially Aβ or tau aggregates in vitro.Firstly, trans-stilbenoid vinylbenzene-1,2-diol with benzene, naphthalene, anthracene, and pyrene are investigated with respect to their photophysical properties free in solution and when bound to amyloid fibrils, including time-resolved fluorescence measurements. It is noted that the extended conjugated systems retained the amyloid targeting properties of the probes and both the anthracene and pyrene moieties extensively enhanced the fluorescence intensity and prolonged lifetimes.Secondly, the synthesis of two molecules, Py1SA and Py2SA, based on pyrene linked to salicylic acid via a trans-stilbene C = C bond is presented. The compounds show strikingly different emission spectra when bound to preformed Aβ1-42 fibrils as well as to fibrils from four other distinct proteins. Additionally, excited state intramolecular proton transfer (ESIPT) coupled-charge transfer (ICT) is observed for the anionic form of the probes in polar solvents. This is likely the reason for the spectral differences of the probes when bound to amyloid fibrils.Moreover, the synthesis of a further development of the Congo red analogue X-34 [2,5-bis(4’-hydroxy-3’-carboxy-styryl) benzene] by rational design and synthesis is described. Full photophysical characterization was performed, including recording absorbance and fluorescence spectra, Stokes shift, quantum yield and fluorescence lifetimes. All ligands displayed high affinity towards recombinant amyloid fibrils of Aβ1-42 and tau as well as selectivity towards the corresponding disease-associated protein aggregates in human post mortem AD tissue.Lastly, the synthesis of a set of 2,1,3-benzothiadiazole (BTD)-based ligands with different conjugated spacers and variable patterns of OH substitutions of bis-styryl-BTD prototypes were developed. Aβ binding affinities (Aβ1-42 and Aβ1-40 fibrils) and the specificity towards Aβ plaques of all ligands were determined. These findings extend the structure to activity relationships of BTD-based ligands for Aβ fibril binding.Throughout the studies in this dissertation, new interesting properties of small molecule fluorescence probes have been discovered and analyzed. This knowledge should facilitate the development of noninvasive probes for early detection of Alzheimer's disease and to distinguish different Aβ fibril polymorphs.
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