| 1. |
- Beier, Björn-Axel, et al.
(författare)
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Framtidens nationalstadspark: handlingsprogram. Del 1, Vision och förutsättningar
- 2006
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- I arbetet med regeringsuppdraget har en övergripande vision för Nationalstadsparkens utveckling, skötsel och förvaltning tagits fram: »Nationalstadsparken med där verksamma kunskapsinstitutioner ska utvecklas utifrån sina unika kultur-, natur- och rekreationsvärden och vara ett upplevelserikt och lättillgängligt område.« Viktiga förutsättningar för att visionen ska kunna förverkligas är:" att Nationalstadsparken blir ett känt och positivt begrepp," att Nationalstadsparken ses som en resurs," att Nationalstadsparken förvaltas och utvecklas i samverkan och samsyn.För att skapa en plattform och en inriktning för det fortsatta arbetet med Nationalstadsparken har fem ledord formulerats. För varje ledord anges de viktigaste förutsättningarna för att värdena ska kunna bevaras och utvecklas. Ledorden ska i ett längre tidsperspektiv vara vägledande för beslut om utveckling, skötsel och markanvändning.Ledorden är:" Kungligt inflytande och Sveriges historia" Folknöje" Kunskap" Biologisk mångfald" Hälsa och motionLedorden har även bildat utgångspunkt för de förslag till utvecklingsidéer som presenteras i del I och till de åtgärder som föreslås i del II.Några av de utvecklingsidéer som förs fram är:" Fler markerade entréer." Bättre förbindelser mellan sevärdheterna inom parken." Ta fasta på Brunnsviken som ett sammanhållet landskap från Gustav III:s tid." Utvecklat maritimt centrum kring Skeppsholmen-Galärvarvet-Beckholmen." Tydliga promenadstråk." Ett etablerat kunskaps- och informationscentrum för helaNationalstadsparken." Förbättrad tillgänglighet till parken." Förstärkning av kärnområden och spridningszoner för biologisk mångfald.
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| 2. |
- Beier, Björn-Axel, et al.
(författare)
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Framtidens nationalstadspark: handlingsprogram. Del II , Åtgärder och utveckling
- 2006
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Länsstyrelsen i Stockholms län har på uppdrag av regeringen arbetat fram ett program för Nationalstadsparkens utveckling. Det är utarbetat i samarbete med berörda aktörer. Programmet består av två delar. I del I redovisas förutsättningar och utvecklingsidéer för att bevara och utveckla Nationalstadsparken. I del II, handlingsprogrammet, föreslås ett antal åtgärder som behöver genomföras de närmaste åren. I de följande avsnitten redovisas de aktuella förslagen indelade i åtta olika åtgärdsområden:" Resurser" Informationsinsatser" Tillgänglighet" Särskilda insatser för minskat buller" Förvaltning" Särskilda insatser för det historiska landskapet" Särskilda insatser för biologisk mångfald" SamverkanFörslagen innefattar dels direkta åtgärder för att utveckla parken, dels sådana åtgärder som utgör viktiga medel för att stärka detta arbete. De föreslagna åtgärdernaredovisas först i tabellform. I de olika avsnitten följer sedan en mer utförlig redovisning av varje åtgärd.
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| 3. |
- Freischmidt, Axel, et al.
(författare)
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Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
- 2015
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 18:5, s. 631-
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.
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| 4. |
- Karlberg, Tobias, et al.
(författare)
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14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Pseudomonas are a common cause of hospital-acquired infections that may be lethal. ADP-ribosyltransferase activities of Pseudomonas exotoxin-S and -T depend on 14-3-3 proteins inside the host cell. By binding in the 14-3-3 phosphopeptide binding groove, an amphipathic C-terminal helix of ExoS and ExoT has been thought to be crucial for their activation. However, crystal structures of the 14-3-3 beta: ExoS and -ExoT complexes presented here reveal an extensive hydrophobic interface that is sufficient for complex formation and toxin activation. We show that C-terminally truncated ExoS ADP-ribosyltransferase domain lacking the amphipathic binding motif is active when co-expressed with 14-3-3. Moreover, swapping the amphipathic C-terminus with a fragment from Vibrio Vis toxin creates a 14-3-3 independent toxin that ADP-ribosylates known ExoS targets. Finally, we show that 14-3-3 stabilizes ExoS against thermal aggregation. Together, this indicates that 14-3-3 proteins activate exotoxin ADP-ribosyltransferase domains by chaperoning their hydrophobic surfaces independently of the amphipathic C-terminal segment.
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| 5. |
- Lauper, Kim, et al.
(författare)
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Oral glucocorticoid use in patients with rheumatoid arthritis initiating TNF-inhibitors, tocilizumab or abatacept : Results from the international TOCERRA and PANABA observational collaborative studies
- 2024
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Ingår i: Joint Bone Spine. - 1297-319X. ; 91:2
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate and compare the use of oral glucocorticoids with three classes of bDMARDs in patients with rheumatoid arthritis (RA). Methods: We included patients from 13 observational registries treated with a TNF-inhibitor, abatacept or tocilizumab and with available information on the use of oral glucocorticoids. The main outcome was oral glucocorticoid withdrawal. A McNemar test was used to analyse the change in the use of glucocorticoids after 1 year. Kaplan-Meier estimates and Cox regressions, adjusted for patient, treatment, and disease characteristics, were used to evaluate glucocorticoid discontinuation in patients with glucocorticoids at baseline. Because of heterogeneity, analyses were done by registers and pooled using random-effects meta-analysis. Results: A total of 12,334 participants treated with TNF-inhibitors, 2100 with tocilizumab and 3229 with abatacept were included. At one-year, oral glucocorticoid use decreased in all treatment groups (odds ratio for stopping vs. starting of 2.19 [95% CI 1.58; 3.04] for TNF-inhibitors, 2.46 [1.39; 4.35] for tocilizumab; 1.73 [1.25; 2.21] for abatacept). Median time to glucocorticoid withdrawal was ≈2 years or more in most countries, with a gradual decrease over time. Compared to TNF-inhibitors, crude hazard ratios of glucocorticoid discontinuation were 0.65[0.48–0.87] for abatacept, and 1.04 [0.76–1.43] for tocilizumab, and adjusted hazard ratios were 1.1 [0.83–1.47] for abatacept, and 1.30 [0.96–1.78] for tocilizumab. Conclusion: After initiation of a bDMARD, glucocorticoid use decreased similarly in all treatment groups. However, glucocorticoid withdrawal was much slower than advocated by current international guidelines. More effort should be devoted to glucocorticoid tapering when low disease activity is achieved.
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| 6. |
- Lizárraga Jurado, Raquel, 1974-
(författare)
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Non-collinear Magnetism in d- and f-electron Systems
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, non-collinear magnetism has been studied by using density functional theory and the augmented plane wave method with local orbitals (APW+lo). Two conditions for non-collinear instabilities have been identified in this thesis. First, the Fermi energy should cut through both spin up and down states. Secondly, strong nesting between the spin up and spin down Fermi surfaces is needed. The two criteria described here can be fulfilled by tuning the exchange-splitting and/or by modifying the volume. Calculations on several elements; bcc V, bcc and fcc Mn, bcc Fe, bcc and fcc Co, and bcc and fcc Ni show that a non-collinear state can be stabilized provided that the criteria discussed above are met. More complex materials have also been analyzed in terms of these two criteria. The substitutional alloys TlCo2Se2-xSx are found in experiments to possess spin spiral structures for x = {0-1.5} and at a concentration x = 1.75 the alloys become ferromagnetic. As S takes the place of Se in the crystal structure the distance between the Co layers is reduced and the turn angle of the spin spiral becomes smaller until it totally vanishes at x = 1.75. This thesis show that the evolution of the magnetic structure in these alloys is the consequence of a modification of the distance between Co layers, which induces a change in the interlayer exchange coupling. Fermi surfaces have been analyzed in TbNi5 in order to determine nesting features which would be responsible for the magnetic spin spiral observed in this material. The electronic structure of CeRhIn5 is also reported in this thesis. Furthermore, the 3-k magnetic structure of UO2 was investigated and the crystal field levels were calculated. Transition metal systems such as Fe in the superconducting high-pressure hcp phase and in the fcc crystal structure were also studied. The results obtained for fcc Fe are in accordance with previous reports. However the paramagnetic state in hcp Fe is found to be more stable than the antiferromagnetic configurations discussed earlier in the literature as being favored in the volume range where the hcp phase is stable and superconductivity appears (~ 15 GPa). The complex non-collinear magnetic structure in Mn3IrSi was calculated and the results are found to be in good agreement with experiments.
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| 7. |
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| 8. |
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| 9. |
- Nordström, Axel, et al.
(författare)
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Distinct eicosanoid patterns in severe recalcitrant nasal polyposis
- 2023
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Ingår i: International Forum of Allergy & Rhinology. - 2042-6984. ; 13:11, s. 2043-2054
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although altered eicosanoid levels are related to disease severity in chronic rhinosinusitis with nasal polyps (CRSwNP), identifying patients prone to recurrent NPs is still difficult. We investigated levels of nasally secreted eicosanoids before and after NP surgery in patients with or without NP recurrence and explored potential endotypes based on pre-surgical eicosanoid levels.METHODS: Levels of leukotriene (LT) E4 , LTB4 , prostaglandin (PG) D2 , PGE2 and 15(S) hydroxyeicosatetraenoic acid (15(S)-HETE) were measured in nasal secretions with specific immunoassays at pre-surgery (n = 38) and six- and 12-months post-surgery (n = 35) where NP recurrence was identified endoscopically. Pre- and post-surgical levels were compared between patients with and without NP recurrence. Eicosanoid patterns among patients were explored with cluster analysis and evaluated with clinical parameters.RESULTS: Patients with recurrent NPs had pronounced pre-surgical levels of nasal 15(S)-HETE, PGD2 and LTE4 . From pre-surgery to 12-months after, NP recurrence was associated with significant decrease of 15(S)-HETE and PGD2 relative to non-recurrence whereas levels of LTE4 decreased at six-months but increased again at 12-months. Clustering revealed three potential endotypes. Cluster 1 and 3 featured high and low eicosanoid levels, respectively. Cluster 2 had higher levels of LTE4 and PGD2 , lower levels of PGE2 and LTB4 , and more cases of recurrent NPs and previous NP surgeries.CONCLUSION: Elevated nasal LTE4 , 12-month post-surgery, in NP recurrent subjects suggests that postoperative LTE4 measurements may indicate rapid NP regrowth. A distinct nasal eicosanoid profile may be used for the identification of the most severe recalcitrant patients in need of targeted immunomodulatory therapies. This article is protected by copyright. All rights reserved.
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| 10. |
- Nordström, Axel
(författare)
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Exploring eicosanoids as biomarkers in severe chronic rhinosinusitis with nasal polyps
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic rhinosinusitis (CRS) is one of the most common inflammatory chronic conditions, leading to a persistent nasal congestion, nasal discharge, and a loss of smell. Despite sinus surgery and frequent use of oral corticosteroids, a large proportion of individuals with CRS are difficult to treat and have recurrent inflammation. They are usually referred to as individuals with recalcitrant disease and having recurrent nasal polyps (NPs; CRSwNP). The disease poses a significant impact on the patients' health-related quality of life (HrQoL), mainly because of a complete loss of smell. Pharmacological treatment with biological therapies has recently been developed, targeting mediators of the type 2 inflammatory response. However, not everyone benefits from the biological therapy, and it has proven difficult to identify and characterise patients that are responsive to these new medications. Eicosanoids, being arachidonic acid derived bioactive lipid mediators, has been shown to be implicated in CRSwNP. Although there is a clear link between an imbalanced biosynthesis of pro- and anti-inflammatory eicosanoids and type 2 inflammation, to date research has not focused on them as biomarkers in CRSwNP.The overall aim of this thesis was to explore the potential role of eicosanoids as biomarkers and characterise changes over time in HrQoL as well as the degree of smell loss in patients with severe recalcitrant CRSwNP. The project involved immunoassay analysis of levels of various inflammatory mediators, including a selection of eicosanoids, in nasal tissue, nasal secretions and urine from patients with CRSwNP as well as gene expression analyses regarding biosynthetic enzymes and receptors for eicosanoids in nasal tissues. HrQoL was assessed with SNOT-22 and RAND-36, along with point-of-care tests as eosinophil blood count, fractional exhaled nitric oxide (FeNO) and smell tests with Burghart Sniffin’ Sticks.Levels of eicosanoids in nasal secretions were found to associate with the disease severity, defined as the extent of NP growth (paper I). One of the eicosanoids, leukotriene E4 (LTE4), were correlated to the degree of smell loss (paper I). An increase in LTE4 between six and 12 months after surgery was demonstrated in patients with recurrent NPs (paper II). Recurrent NPs were identified endoscopically 12 months after surgery and a distinct eicosanoid profile involving LTE4, prostaglandin D2 and 15(S) hydroxyeicosatetraenoic acid was found to be more common in those with recurrence (paper II). A similar eicosanoid profile, based on measurements from nasal tissue samples instead, was also associated with NP recurrence (paper III).Levels of eicosanoids in nasal tissue and nasal secretions were correlated suggesting that analysis of biomarkers in nasal secretions reflects release from the nasal tissue (paper III). Patients with recurrent NPs had elevated blood eosinophil counts before their surgery, and their sense of smell was significantly impaired both before and after (paper IV). This finding suggests that loss of smell may be the first symptom during recurrence. Although measures of HrQoL could not distinguish patients with recurrent NPs, there was a strong correlation to the degree of smell loss suggesting that loss of smell has a significant impact on the HrQoL (paper IV).In summary, the results from this thesis contribute to an extended knowledge regarding characteristics relevant for identifying severe recalcitrant CRSwNP. Characteristics of interest included a distinct eicosanoid profile, severe loss of smell and eosinophil involvement, all of which may be possible prognostic markers for severe recalcitrant CRSwNP with rapid NP growth. It may be concluded that such biomarkers can guide the choice of treatment for these severely ill patients – repeated surgery or pharmacological treatment with the newly developed biological therapies.
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