| 1. |
- Santini, Marina, 1960-, et al.
(författare)
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Can We quantify domainhood? : Exploring measures to assess domain-specificity in web corpora
- 2018
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Ingår i: Commun. Comput. Info. Sci.. - Cham : Springer International Publishing. - 9783319991320 - 9783319991337 ; , s. 207-217
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Konferensbidrag (refereegranskat)abstract
- Web corpora are a cornerstone of modern Language Technology. Corpora built from the web are convenient because their creation is fast and inexpensive. Several studies have been carried out to assess the representativeness of general-purpose web corpora by comparing them to traditional corpora. Less attention has been paid to assess the representativeness of specialized or domain-specific web corpora. In this paper, we focus on the assessment of domain representativeness of web corpora and we claim that it is possible to assess the degree of domain-specificity, or domainhood, of web corpora. We present a case study where we explore the effectiveness of different measures - namely the Mann-Withney-Wilcoxon Test, Kendall correlation coefficient, Kullback–Leibler divergence, log-likelihood and burstiness - to gauge domainhood. Our findings indicate that burstiness is the most suitable measure to single out domain-specific words from a specialized corpus and to allow for the quantification of domainhood.
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| 2. |
- Alirezaie, Marjan, et al.
(författare)
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SmartEnv ontology in E-care@home (Short paper)
- 2018
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Ingår i: CEUR Workshop Proceedings. - : CEUR-WS. ; , s. 72-79, s. 72-79
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Konferensbidrag (refereegranskat)abstract
- In this position paper we briey introduce SmartEnv ontology which relies on SEmantic Sensor Network (SSN) ontology and is used to represent different aspects of smart and sensorized environments. We will also talk about E-carehome project aiming at providing an IoT-based health-care system for elderly people at their homes. Furthermore, we refer to the role of SmartEnv in Ecarehome and how it needs to be further extended to achieve semantic interoperability as one of the challenges in development of autonomous health care systems at home.
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| 3. |
- Hanzén, Sarah, et al.
(författare)
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Lifespan Control by Redox-Dependent Recruitment of Chaperones to Misfolded Proteins
- 2016
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Ingår i: Cell. - : Elsevier BV. - 0092-8674. ; 166:1, s. 140-151
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Tidskriftsartikel (refereegranskat)abstract
- Caloric restriction (CR) extends the lifespan of flies, worms, and yeast by counteracting age-related oxidation of H2O2-scavenging peroxiredoxins (Prxs). Here, we show that increased dosage of the major cytosolic Prx in yeast, Tsa1, extends lifespan in an Hsp70 chaperone-dependent and CR-independent manner without increasing H2O2 scavenging or genome stability. We found that Tsa1 and Hsp70 physically interact and that hyperoxidation of Tsa1 by H2O2 is required for the recruitment of the Hsp70 chaperones and the Hsp104 disaggregase to misfolded and aggregated proteins during aging, but not heat stress. Tsa1 counteracted the accumulation of ubiquitinated aggregates during aging and the reduction of hyperoxidized Tsa1 by sulfiredoxin facilitated clearance of H2O2-generated aggregates. The data reveal a conceptually new role for H2O2 signaling in proteostasis and lifespan control and shed new light on the selective benefits endowed to eukaryotic peroxiredoxins by their reversible hyperoxidation.
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| 4. |
- Hägglund, Maria, Lektor, 1975-, et al.
(författare)
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Världsbäst på eHälsa kräver internationellt samarbete
- 2017
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Ingår i: Svenska dagbladet. - Stockholm, Sweden : Svenska Dagbladet AB & Co.. - 1101-2412.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Det är glädjande att myndigheter nu äntligen tittar mer på internationellt delade detaljerade dokumentationsmodeller för innehåll i journaler. Vi hoppas att de ger tillräckligt kraftfulla och tydliga budskap så att de upphandlande vårdgivarna också ser vikten av detta. Om vi ska bli världsbäst på eHälsa krävs internationellt samarbete, skriver flera forskare i medicinsk informatik.
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| 5. |
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| 6. |
- Johansson, Roger, et al.
(författare)
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Scanpath components reveal how eye movement reinstatements differentially contribute to episodic remembering
- 2019
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Konferensbidrag (refereegranskat)abstract
- An extensive body of research has shown that episodic remembering involves spontaneous eye movements that largely reproduce the gaze patterns that were present during encoding (e.g., Brandt & Stark, 1997; Johansson et al., 2012). Recent work has further shown that fixation locations that overlap between encoding and recall promote cortical episodic reconstruction (Bone et al., 2018; Johansson et al., 2018) and successful remembering (Johansson & Johansson, 2014). While such findings indicate that gaze location plays an active role during episodic reconstruction, the unfolding scanpaths also encompass more complex information over and above simple gaze locations, such as order, direction, shape, length and duration. Virtually nothing is known about how such spatio-temporal components contribute to episodic reconstruction. The present study investigated the encoding-retrieval overlap in scanpaths for 60 participants who encoded and recalled 36 visuospatial stimuli of two types: scenes and object arrangements. Results replicate and extend previous findings, by analyzing scanpath reinstatement over a multitude of spatio-temporal components. Critically, by combining subjective ratings of memory quality with a surprise test of forced-choice recognition, we demonstrate how such components contribute to successful remembering to different extents, and in different ways depending on the stimulus type. Results indicate that scanpath shape contributes to reconstructing the global scene structure whereas scanpath position, order and direction contribute to reconstructing the arrangement of individual objects in a spatial context. To our knowledge, this is the first systematic demonstration of how eye movement reinstatements contribute to episodic remembering in a multifaceted way.
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| 7. |
- Lundgren, Lena, et al.
(författare)
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Immigration Status and Substance Use Disorder-related Mortality in Sweden : A National Longitudinal Registry Study
- 2019
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Ingår i: Journal of addiction medicine. - : Wolters Kluwer. - 1932-0620 .- 1935-3227. ; 13:6, s. 483-492
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: First-generation immigrants, in many countries, are healthier than their native counterparts. This study examined the association between first- and second-generation immigrant status and alcohol- or drugs other than alcohol-related (primarily opioids) mortality for those with risky substance use.Methods: A Swedish longitudinal, 2003 to 2017, registry study combined Addiction Severity Index (ASI) assessment data with mortality data (n = 15 601). Due to missing data, the analysis sample for this study was 15 012. Multivariate models tested the relationship between immigration status and drugs other than alcohol or alcohol-related mortality, controlling for demographics and the 7 ASI composite scores (CS).Results: Age, a higher ASI CS for alcohol, a lower ASI CS family and social relationship, a lower ASI CS for drug use and a higher ASI CS for health significantly predicted mortality because of alcohol-related causes. Higher ASI CS for drugs other than alcohol, employment, and health, age, male sex, and immigration status predicted drugs other than alcohol, related mortality. Individuals born in Nordic countries, excluding Sweden, were 1.76 times more likely to die of drugs other than alcohol compared with their Swedish counterparts. Individuals born outside a Nordic country (most common countries: Iran, Somalia, Iraq, Chile) were 61% less likely to die of drugs other than alcohol compared with their Swedish counterparts. Those with parents born outside Nordic countries were 54% less likely to die of drugs other than alcohol.Discussion: Research is needed on why people with risky substance use from Nordic countries (not Sweden) residing in Sweden, have higher mortality rates because of drugs other than alcohol (primarily opioids drugs other than alcohol compared with the other population groups in our study). Findings indicate that ASI CSs are strong predictors of future health problems including mortality due to alcohol and other drug-related causes.
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| 8. |
- Noichri, Y., et al.
(författare)
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In vivo parameters influencing 2-Cys Prx oligomerization: The role of enzyme sulfinylation
- 2015
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Ingår i: Redox Biology. - : Elsevier. - 2213-2317. ; 6, s. 326-333
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Tidskriftsartikel (refereegranskat)abstract
- 2-Cys Prxs are H2O2-specific antioxidants that become inactivated by enzyme hyperoxidation at elevated H2O2 levels. Although hyperoxidation restricts the antioxidant physiological role of these enzymes, it also allows the enzyme to become an efficient chaperone holdase. The critical molecular event allowing the peroxidase to chaperone switch is thought to be the enzyme assembly into high molecular weight (HMW) structures brought about by enzyme hyperoxidation. How hyperoxidation promotes HMW assembly is not well understood and Prx mutants allowing disentangling its peroxidase and chaperone functions are lacking. To begin addressing the link between enzyme hyperoxidation and HMW structures formation, we have evaluated the in vivo 2-Cys Prxs quaternary structure changes induced by H2O2 by size exclusion chromatography (SEC) on crude lysates, using wild type (Wt) untagged and Myc-tagged S. cerevisiae 2-Cys Prx Tsa1 and derivative Tsa1 mutants or genetic conditions known to inactivate peroxidase or chaperone activity or altering the enzyme sensitivity to hyperoxidation. Our data confirm the strict causative link between H2O2-induced hyperoxidation and HMW formation/stabilization, also raising the question of whether CP hyperoxidation triggers the assembly of HMW structures by the stacking of decamers, which is the prevalent view of the literature, or rather, the stabilization of preassembled stacked decamers. © 2015 Published by Elsevier B.V.
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| 9. |
- Nyström, Dennis, et al.
(författare)
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Inventering av barkkvastmossa Dicranum viride på Gotland 2016 : samtlistning och noteringar av övriga naturvårdsintressanta och skyddsvärda mossoroch lavar på besökta lokaler
- 2016
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- På uppdrag av Länsstyrelsen i Gotlands län genomfördes en översiktlig inventering av barkkvastmossa Dicranum viride på Gotland under februari 2016. Inventeringen syftade till att eftersöka arten på potentiella lokaler med lämpliga förhållanden. Inventeringsansträngningen kom att koncentreras till bland- eller lövdominerade skogar med hög luftfuktighet och långvarig skoglig kontinuitet av lämpliga substratträd, främst rikbarksträd med högt bark-PH, till exempel ask, ek, alm och asp. Arten påträffas oftast på lutande, senvuxna och knotiga stammar på lokaler med hög luftfuktighet, till exempel i närheten av vattendrag och sjöar. Arten är sedan tidigare känd från en lokal på Gotland i Natura 2000-området Brunnsrar i Etelhem socken.Barkkvastmossa omfattas av ett åtgärdsprogram för hotade arter som löper ut 2016. Arten ingår i Art- och habitatdirektivets bilaga 2 och är fridlyst enligt 8 § Artskyddsförordningen (2007:845) vilket innebär att det är förbjudet att i den omfattning som framgår av bilaga 2 plocka, gräva upp eller på annat sätt ta bort eller skada hela eller delar av exemplar. Arten är upptagen som starkt hotad (EN) i den svenska rödlistan 2015.På grund av tidsbrist inventerades ett 10-tal lokaler som vid en första anblick ansågs mer eller mindre lämpliga med avseende på arten levnadspreferenser. Den närstående arten nålkvastmossa D. tauricum är relativt vanlig på Gotland vilket avsevärt försvårar identifieringen. Det faktum av båda arterna sannolikt finns på lokaler med förekomst av D. viride gör arten mycket svårinventerad.Vid inventering belades därför varje fynd och mikroskoperades för att studera bl.a. cellängden i nedre halvan av bladet som morfologiskt skiljer arterna åt. Trots studier av många belägg i mikroskop hittades bara D. tauricum på de inventerade lokalerna. Även om barkkvastmossa är mycket sällsynt på Gotland är den med största sannolikhet förbisedd.
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| 10. |
- Nyström, Mikael, 1977-, et al.
(författare)
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Det krävs en riktad satsning på e-hälsa
- 2016
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Ingår i: Dagens medicin. - Stockholm. - 1104-7488. ; :18, s. 22-
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Tidskriftsartikel (populärvet., debatt m.m.)
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| 11. |
- Olsson, Linda, et al.
(författare)
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Improved cytogenetic characterization and risk stratification of pediatric acute lymphoblastic leukemia using single nucleotide polymorphism array analysis : A single center experience of 296 cases
- 2018
-
Ingår i: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 57:11, s. 604-607
-
Tidskriftsartikel (refereegranskat)abstract
- Single nucleotide polymorphism array (SNP-A) analyses are increasingly being introduced in routine genetic diagnostics of acute lymphoblastic leukemia (ALL). Despite this, only few studies that have compared the diagnostic value of SNP-A with conventional chromosome banding have been published. We here report such a comparison of 296 ALL cases, the largest series to date. Only genomic imbalances >5 Mb and microdeletions targeting the BTG1, CDKN2A/B, EBF1, ERG, ETV6, IKZF1, PAX5, and RB1 genes and the pseudoautosomal region 1 (PAR1) were ascertained, in agreement with recent guidelines. Of 36 T-cell ALL cases, the karyotypes of 24 cases (67%) were revised by SNP-A analyses that either revealed additional imbalances >5 Mb or better characterized the changes found by G-banding. Of 260 B-cell precursor (BCP) ALL cases, SNP-A analyses identified additional copy number alterations, including the above-mentioned microdeletions, or better characterized the imbalances found by G-banding in 236 (91%) cases. Furthermore, the cytogenetic subtype classification of 41/260 (16%) BCP ALL cases was revised based on the SNP-A findings. Of the subtype revisions, 12/41 (29%) had clinical implications as regards risk stratifying cytogenetic groups or genotype-specific minimal residual disease stratification. We conclude that SNP-A analyses dramatically improve the cytogenetic characterization of both T-cell and BCP ALL and also provide important information pertinent to risk stratification of BCP ALL.
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| 12. |
- Psonka-Antonczyk, Katarzyna M., et al.
(författare)
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Nanoscale Structure and Spectroscopic Probing of A beta 1-40 Fibril Bundle Formation
- 2016
-
Ingår i: Frontiers in Chemistry. - : Frontiers Research Foundation. - 2296-2646. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid plaques composed of fibrillar Amyloid-beta (A beta) are hallmarks of Alzheimers disease. However, A beta fibrils are morphologically heterogeneous. Conformation sensitive luminescent conjugated oligothiophenes (LCOs) are versatile tools for monitoring such fibril polymorphism in vivo and in vitro. Biophysical methods applied on in vitro generated A beta fibrils, stained with LCOs with different binding and fluorescence properties, can be used to characterize the A beta fibrillation in depth, far beyond that possible for in vivo generated amyloid plaques. In this study, in vitro fibrillation of the A beta 1-40 peptide was monitored by time-lapse transmission electron microscopy, LCO fluorescence, and atomic force microscopy. Differences in the LCO binding in combination with nanoscale imaging revealed that spectral variation correlated with fibrils transforming from solitary filaments (empty set similar to 2.5 nm) into higher order bundled structures (empty set similar to 5 nm). These detailed in vitro experiments can be used to derive data that reflects the heterogeneity of in vivo generated A beta plaques observed by LCO fluorescence. Our work provides new structural basis for targeted drug design and molecular probe development for amyloid imaging.
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| 13. |
- Romu, Thobias, et al.
(författare)
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A randomized trial of cold-exposure on energy expenditure and supraclavicular brown adipose tissue volume in humans
- 2016
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Ingår i: Metabolism-Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 65:6, s. 926-934
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To study if repeated cold-exposure increases metabolic rate and/or brown adipose tissue (BAT) volume in humans when compared with avoiding to freeze. Design. Randomized, open, parallel-group trial. Methods. Healthy non-selected participants were randomized to achieve cold-exposure 1 hour/day, or to avoid any sense of feeling cold, for 6 weeks. Metabolic rate (MR) was measured by indirect calorimetry before and after acute cold-exposure with cold vests and ingestion of cold water. The BAT volumes in the supraclavicular region were measured with magnetic resonance imaging (MRI). Results. Twenty-eight participants were recruited, 12 were allocated to controls and 16 to cold-exposure. Two participants in the cold group dropped out and one was excluded. Both the non-stimulated and the cold-stimulated MR were lowered within the group randomized to avoid cold (MR at room temperature from 1841 +/- 199 kCal/24 h to 1795 +/- 213 kCal/24 h, p = 0.047 cold-activated MR from 1900 +/- 150 kCal/24 h to 1793 +/- 215 kCal/24 h, p = 0.028). There was a trend towards increased MR at room temperature following the intervention in the cold-group (p = 0.052). The difference between MR changes by the interventions between groups was statistically significant (p = 0.008 at room temperature, p = 0.032 after cold-activation). In an on-treatment analysis after exclusion of two participants that reported >= 8 days without cold-exposure, supraclavicular BAT volume had increased in the cold-exposure group (from 0.0175 +/- 0.015 1 to 0.0216 +/- 0.014 1, p = 0.049). Conclusions. We found evidence for plasticity in metabolic rate by avoiding to freeze compared with cold-exposure in a randomized setting in non-selected humans.
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| 14. |
- Santini, Marina, 1960-, et al.
(författare)
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A Web Corpus for eCare : Collection, Lay Annotation and Learning - First Results
- 2017
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Konferensbidrag (refereegranskat)abstract
- In this position paper, we put forward two claims: 1) it is possible to design a dynamic and extensible corpus without running the risk of getting into scalability problems; 2) it is possible to devise noise-resistant Language Technology applications without affecting performance. To support our claims, we describe the design, construction and limitations of a very specialized medical web corpus, called eCare_Sv_01, and we present two experiments on lay-specialized text classification. eCare_Sv_01 is a small corpus of web documents written in Swedish. The corpus contains documents about chronic diseases. The sublanguage used in each document has been labelled as “lay” or “specialized” by a lay annotator. The corpus is designed as a flexible text resource, where additional medical documents will be appended over time. Experiments show that the lay-specialized labels assigned by the lay annotator are reliably learned by standard classifiers. More specifically, Experiment 1 shows that scalability is not an issue when increasing the size of the datasets to be learned from 156 up to 801 documents. Experiment 2 shows that lay-specialized labels can be learned regardless of the large amount of disturbing factors, such as machine translated documents or low-quality texts that are numerous in the corpus.
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| 15. |
- Santini, Marina, 1960-, et al.
(författare)
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Designing an Extensible Domain-Specific Web Corpus for “Layfication” : A Case Study in eCare at Home : Chapter 6
- 2019
-
Ingår i: Cyber-Physical Systemsfor Social Applications. - Hershey PA, USA 17033 : Engineering Science Reference. - 9781522578796 - 9781522578802 ; , s. 98-155
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- In the era of data-driven science, corpus-based language technology is an essential part of cyber physicalsystems. In this chapter, the authors describe the design and the development of an extensible domainspecificweb corpus to be used in a distributed social application for the care of the elderly at home.The domain of interest is the medical field of chronic diseases. The corpus is conceived as a flexible andextensible textual resource, where additional documents and additional languages will be appendedover time. The main purpose of the corpus is to be used for building and training language technologyapplications for the “layfication” of the specialized medical jargon. “Layfication” refers to the automaticidentification of more intuitive linguistic expressions that can help laypeople (e.g., patients, familycaregivers, and home care aides) understand medical terms, which often appear opaque. Exploratoryexperiments are presented and discussed.
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| 16. |
- Santini, Marina, et al.
(författare)
-
Designing an Extensible Domain-Specific Web Corpus for “Layfication” : A Case Study in eCare at Home
- 2019
-
Ingår i: Cyber-Physical Systems for Social Applications. - Hershey, PA, USA : IGI Global. - 9781522593454 - 9781522578802 ; , s. 98-155
-
Bokkapitel (refereegranskat)abstract
- In the era of data-driven science, corpus-based language technology is an essential part of cyber physical systems. In this chapter, the authors describe the design and the development of an extensible domain-specific web corpus to be used in a distributed social application for the care of the elderly at home. The domain of interest is the medical field of chronic diseases. The corpus is conceived as a flexible and extensible textual resource, where additional documents and additional languages will be appended over time. The main purpose of the corpus is to be used for building and training language technology applications for the “layfication” of the specialized medical jargon. “Layfication” refers to the automatic identification of more intuitive linguistic expressions that can help laypeople (e.g., patients, family caregivers, and home care aides) understand medical terms, which often appear opaque. Exploratory experiments are presented and discussed.
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| 17. |
- Törring, Ove, et al.
(författare)
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Impaired Quality of Life After Radioiodine Therapy Compared to Antithyroid Drugs or Surgical Treatment for Graves’ Hyperthyroidism : A Long-Term Follow-Up with the Thyroid-Related Patient-Reported Outcome Questionnaire and 36-Item Short Form Health Status Survey
- 2019
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Ingår i: Thyroid. - : Mary Ann Liebert. - 1050-7256 .- 1557-9077. ; 29:3, s. 322-331
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hyperthyroidism is known to have a significant impact on the quality of life (QoL) at least in the short term. The purpose of the present study was to assess QoL in patients at 6-10 years after treatment for Graves' disease (GD) with radioiodine (RAI) to those treated with thyroidectomy or antithyroid drugs (ATD) as assessed with both a thyroid-specific (ThyPRO) and general (SF-36) QoL surveys.METHODS: We evaluated 1186 GD patients in a sub-cohort from an incidence study 2003-2005 which had been treated according to routine clinical practice at seven participating centers. Patients were included if they had returned the ThyPRO (n=975) and/or the SF-36 questionnaire (n=964) and informed consent at follow-up. Scores from ThyPRO were compared with scores from a general population sample (n=712), using multiple linear regression adjusting for age and gender as well as multiple testing. Treatment related QoL outcome for ATD, RAI and surgery were compared including adjustment for the number of treatments received, sex, age and co-morbidity.RESULTS: Regardless of treatment modality, patients with GD had worse thyroid-related QoL 6-10 years after diagnosis compared with the general population. Patients treated with RAI had worse thyroid-related and general QoL than patients treated with ATD or thyroidectomy on the majority of QoL-scales. Sensitivity analyses supported the relative negative comparative effects of RAI treatment on QoL in patients with hyperthyroidism.CONCLUSIONS: Graves' disease is associated with a lower QoL many years after treatment compared to the general population. In a previous, small RCT we did not show any difference in patient satisfaction years after ATD, RAI or surgery. We now report that in a large non-randomized cohort, patients who received RAI had adverse scores on ThyPRO and SF-36. These findings in a Swedish population are limited by comparison to normative data from Denmark, by older age and possibly a more prolonged course in those patients who received radioiodine, and a lack of information regarding thyroid status at the time of evaluation. The way RAI may adversely affect QoL is unknown but since the results may be important for future considerations regarding treatment options for GD they need to be substantiated in further studies.
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| 18. |
- Wolthers, Benjamin Ole, et al.
(författare)
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Insulin-dependent diabetes : a chronic complication to acute pancreatitis in childhood acute lymphoblastic leukemia
- 2019
-
Ingår i: Pediatric Blood & Cancer. - : Wiley-Blackwell. - 1545-5009 .- 1545-5017. ; 66:1
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatitis is a frequent toxicity to acute lymphoblastic leukemia (ALL) treatment, significantly associated with asparaginase use, and may be followed by severe complications such as acute hyperglycaemia, need for mechanical ventilation, pseudocysts, and death. Here, we provide novel data on seven patients diagnosed with diabetes after pancreatitis and still requiring insulin treatment after a median follow-up of 4.2 years (range: 1.7-9.2). We describe the clinical course of pancreatitis and illustrate the association between pancreatic pseudocysts, older age, and development of insulin-dependent diabetes. Together, this study documents the persisting burden of pancreatitis in childhood ALL and underlines the need for plasma glucose level monitoring.
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| 19. |
- 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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| 20. |
- 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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| 21. |
- 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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| 22. |
- Zhang, Jun, Dr. 1987-, et al.
(författare)
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trans-Stilbenoids with Extended Fluorescence Lifetimes for the Characterization of Amyloid Fibrils
- 2017
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 2:8, s. 4693-4704
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Tidskriftsartikel (refereegranskat)abstract
- It was previously reported that two naphthyl-based trans-stilbene probes, (E)-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol (1) and (E)-4-(2-(naphthalen-2-yl)vinyl)benzene-1,2-diol (3), can bind to both native transthyretin (TTR) and misfolded protofibrillar TTR at physiological concentrations, displaying distinct emission maxima bound to the different conformational states (>100 nm difference). To further explore this amyloid probe scaffold to obtain extended fluorescence lifetimes, two new analogues with expanded aromatic ring systems (anthracene and pyrene), (E)-4-(2-(anthracen-2-yl)vinyl)benzene-1,2-diol (4) and (E)-4-(2-(pyren-2-yl)vinyl)benzene-1,2-diol (5), were synthesized employing the palladium-catalyzed Mizoroki–Heck reaction. (E)-4-Styrylbenzene-1,2-diol (2), 3, 4, and 5 were investigated with respect to their photophysical properties in methanol and when bound to insulin, lysozyme, and Aβ1-42 fibrils, including time-resolved fluorescence measurements. In conclusion, 4 and 5 can bind to both native and fibrillar TTR, becoming highly fluorescent. Compounds 2–5 bind specifically to insulin, lysozyme, and Aβ1-42 fibrils with an apparent fluorescence intensity increase and moderate binding affinities. The average fluorescence lifetimes of the probes bound to Aβ1-42 fibrils are 1.3 ns (2), 1.5 ns (3), 5.7 ns (4), and 29.8 ns (5). In summary, the variable aromatic moieties of the para-positioned trans-stilbenoid vinyl-benzene-1,2-diol with benzene, naphthalene, anthracene, and pyrene showed that the extended conjugated systems retained the amyloid targeting properties of the probes. Furthermore, both the anthracene and pyrene moieties extensively enhanced the fluorescence intensity and prolonged lifetimes. These attractive probe properties should improve amyloid detection and characterization by fluorescence-based techniques.
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