| 11. |
- Berntsson, Ronnie P., et al.
(författare)
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Crystal Structures of Botulinum Neurotoxin DC in Complex with Its Protein Receptors Synaptotagmin I and II
- 2013
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Ingår i: Structure. - : Elsevier BV. - 0969-2126 .- 1878-4186. ; 21:9, s. 1602-1611
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Tidskriftsartikel (refereegranskat)abstract
- Botulinum neurotoxins (BoNTs) can cause paralysis at exceptionally low concentrations and include seven serotypes (BoNT/A-G). The chimeric BoNT/DC toxin has a receptor binding domain similar to the same region in BoNT/C. However, BoNT/DC does not share protein receptor with BoNT/C. Instead, it shares synaptotagmin (Syt) I and II as receptors with BoNT/B, despite their low sequence similarity. Here, we present the crystal structures of the binding domain of BoNT/DC in complex with the recognition domains of its protein receptors, Syt-I and Syt-II. The structures reveal that BoNT/DC possesses a Syt binding site, distinct from the established Syt-II binding site in BoNT/B. Structure-based mutagenesis further shows that hydrophobic interactions play a key role in Syt binding. The structures suggest that the BoNT/DC ganglioside binding sites are independent of the protein receptor binding site. Our results reveal the remarkable versatility in the receptor recognition of the BoNTs.
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| 12. |
- Blaauw, M., et al.
(författare)
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Were last glacial climate events simultaneous between Greenland and France?
- 2010
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Ingår i: Journal of Quaternary Science. - : Wiley. - 0267-8179 .- 1099-1417. ; 25:3, s. 387-394
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Tidskriftsartikel (refereegranskat)abstract
- Several large abrupt climate fluctuations during the last glacial have been recorded in Greenland ice cores and archives from other regions. Often these Dansgaard–Oeschger events are assumed to have been synchronous over wide areas, and then used as tie-points to link chronologies between the proxy archives. However, it has not yet been tested independently whether or not these events were indeed synchronous over large areas. Here, we compare Dansgaard–Oeschger-type events in a well-dated record from southeastern France with those in Greenland ice cores. Instead of assuming simultaneous climate events between both archives, we keep their age models independent. Even these well-dated archives possess large chronological uncertainties that prevent us from inferring synchronous climate events at decadal to multi-centennial time scales. If possible, comparisons between proxy archives should be based on independent, non-tuned time-scales.
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| 13. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 14. |
- Boström, Pontus, 1982, et al.
(författare)
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The SNARE protein SNAP23 and the SNARE-interacting protein Munc18c in human skeletal muscle are implicated in insulin resistance/type 2 diabetes.
- 2010
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 59:8, s. 1870-8
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Our previous studies suggest that the SNARE protein synaptosomal-associated protein of 23 kDa (SNAP23) is involved in the link between increased lipid levels and insulin resistance in cardiomyocytes. The objective was to determine whether SNAP23 may also be involved in the known association between lipid accumulation in skeletal muscle and insulin resistance/type 2 diabetes in humans, as well as to identify a potential regulator of SNAP23. RESEARCH DESIGN AND METHODS: We analyzed skeletal muscle biopsies from patients with type 2 diabetes and healthy, insulin-sensitive control subjects for expression (mRNA and protein) and intracellular localization (subcellular fractionation and immunohistochemistry) of SNAP23, and for expression of proteins known to interact with SNARE proteins. Insulin resistance was determined by a euglycemic hyperinsulinemic clamp. Potential mechanisms for regulation of SNAP23 were also investigated in the skeletal muscle cell line L6. RESULTS: We showed increased SNAP23 levels in skeletal muscle from patients with type 2 diabetes compared with that from lean control subjects. Moreover, SNAP23 was redistributed from the plasma membrane to the microsomal/cytosolic compartment in the patients with the type 2 diabetes. Expression of the SNARE-interacting protein Munc18c was higher in skeletal muscle from patients with type 2 diabetes. Studies in L6 cells showed that Munc18c promoted the expression of SNAP23. CONCLUSIONS: We have translated our previous in vitro results into humans by showing that there is a change in the distribution of SNAP23 to the interior of the cell in skeletal muscle from patients with type 2 diabetes. We also showed that Munc18c is a potential regulator of SNAP23.
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| 15. |
- Carlsson, Lena M S, 1957, et al.
(författare)
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Long-term incidence of serious fall-related injuries after bariatric surgery in Swedish obese subjects.
- 2019
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Ingår i: International journal of obesity (2005). - : Springer Science and Business Media LLC. - 1476-5497 .- 0307-0565. ; 43:4, s. 933-937
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Tidskriftsartikel (refereegranskat)abstract
- Obesity increases risk of falling, but the effect of bariatric surgery on fall-related injuries is unknown. The aim of this study was therefore to study the association between bariatric surgery and long-term incidence of fall-related injuries in the prospective, controlled Swedish Obese Subjects study. At inclusion, body mass index was≥34kg/m2 in men and ≥38kg/m2 in women. The surgery per-protocol group (n=2007) underwent gastric bypass (n=266), banding (n=376), or vertical banded gastroplasty (n=1365), and controls (n=2040) received usual care. At the time of analysis (31 December 2013), median follow-up was 19 years (maximal 26 years). Fall-related injuries requiring hospital treatment were captured using data from the Swedish National Patient Register. During follow-up, there were 617 first-time fall-related injuries in the surgery group and 513 in the control group (adjusted hazard ratio 1.21, 95% CI, 1.07-1.36; P=0.002). The incidence differed between treatment groups (P<0.001, log-rank test) and was higher after gastric bypass than after usual care, banding and vertical banded gastroplasty (adjusted hazard ratio 0.50-0.52, P<0.001 for all three comparisons). In conclusion, gastric bypass surgery was associated with increased risk of serious fall-related injury requiring hospital treatment.
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| 16. |
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| 17. |
- Fossum, Mariann, et al.
(författare)
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Effects of a computerized decision support system on care planning for pressure ulcers and malnutrition in nursing homes : an intervention study
- 2013
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Ingår i: International Journal of Medical Informatics. - : Elsevier BV. - 1386-5056 .- 1872-8243. ; 82:10, s. 911-921
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Tidskriftsartikel (refereegranskat)abstract
- Background: Nursing documentation is essential for facilitating the flow of information to guarantee continuity, quality and safety in care. High-quality nursing documentation is frequently lacking; the implementation of computerized decision support systems is expected to improve clinical practice and nursing documentation.Aim: The present study aimed at investigate the effects of a computerized decision support system and an educational program as intervention strategies for improved nursing documentation practice on pressure ulcers and malnutrition in nursing homes.Design, setting and participants: An intervention study with two intervention groups and one control group was used. Fifteen nursing homes in southern Norway were included. A convenience sample of electronic healthcare records from 46 units was included. Inclusion criteria were records with presence of pressure ulcers and/or malnutrition. The residents were assessed before and after an intervention of a computerized decision support system in the electronic healthcare records. Data were collected through a review of 150 records before (2007) and 141 records after the intervention (2009).Methods: The nurses in intervention group 1 were offered educational sessions and were trained to use the computerized decision support system, which they used for eight months in 2008 and 2009. The nurses in intervention group 2 were offered the same educational program but did not use the computerized decision support system. The nurses in the control group were not subject to any intervention. The resident records were examined for the completeness and comprehensiveness of the documentation of pressure ulcers and malnutrition with three data collection forms and the data were analyzed with non-parametric statistics.Results: The implementation of the computerized decision support system and the educational program resulted in a more complete and comprehensive documentation of pressure ulcer- and malnutrition-related nursing assessments and nursing interventions.Conclusion: This study provides evidence that the computerized decision support system and an educational program as implementation strategies had a positive influence on nursing documentation practice.
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| 18. |
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| 19. |
- Hammerich, Linda, et al.
(författare)
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Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination
- 2019
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Ingår i: Nature Medicine. - : Nature Publishing Group. - 1078-8956 .- 1546-170X. ; 25:5, s. 814-824
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Tidskriftsartikel (refereegranskat)abstract
- Indolent non-Hodgkin’s lymphomas (iNHLs) are incurable with standard therapy and are poorly responsive to checkpoint blockade. Although lymphoma cells are efficiently killed by primed T cells, in vivo priming of anti-lymphoma T cells has been elusive. Here, we demonstrate that lymphoma cells can directly prime T cells, but in vivo immunity still requires cross-presentation. To address this, we developed an in situ vaccine (ISV), combining Flt3L, radiotherapy, and a TLR3 agonist, which recruited, antigen-loaded and activated intratumoral, cross-presenting dendritic cells (DCs). ISV induced anti-tumor CD8+ T cell responses and systemic (abscopal) cancer remission in patients with advanced stage iNHL in an ongoing trial (NCT01976585). Non-responding patients developed a population of PD1+CD8+ T cells after ISV, and murine tumors became newly responsive to PD1 blockade, prompting a follow-up trial of the combined therapy. Our data substantiate that recruiting and activating intratumoral, cross-priming DCs is achievable and critical to anti-tumor T cell responses and PD1-blockade efficacy.
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| 20. |
- Herstad-Svärd, S., et al.
(författare)
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Ramprogram – Åtgärder för samtidig minimering av alkalirelaterade driftproblem, Etapp 2
- 2007
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Combustion of an increasing amount of biofuel and waste woods has resulted in certainenvironmental advantages, including decreased emissions of fossil CO2, SO2 andmetals. On the other hand, a number of chloride and alkali related operational problemshave occurred which are related to combustion of these fuels.Alkali related operational problems have been studied in a project consisting of twoparts. The overall scope has been to characterise the operational problems and to studymeasures to minimise them. The first part was reported in Värmeforsk report 997 wherethe results were summarised in a table of different measures. In part two, additionalmeasures have been included in the test plan and initial corrosion has been studiedlinked to the different measures. The tests have also in part two been carried out at the12 MW CFB boiler at Chalmers. The effect of the selected measures has beeninvestigated concerning both deposit formation and bed agglomeration, and at the sametime emissions and other operational conditions were characterised.The second part of the project has among other things focused on:• To investigate measures which decrease the content of alkali and chloride in thedeposits, and consequently decrease the risk for corrosion (by investigating theinitial corrosion). Focus was also on trying to explain favourable effects.• To investigate if it is possible to combine a rather low dosage of kaolin and injectionof ammonium sulphate. This was done in order to reduce both bed agglomerationand problems from deposits during combustion of fuels rich in chlorine.• To investigate if co-combustion with sewage sludge, de-inking sludge or peat withhigh ash content, could give similar advantages as conventional additives.• Investigate if ash from PFBC is possible to use as an alternative bed material.By comparing the different measures in part two, it could be concluded that cocombustionof sewage sludge gave the best overall effect. The judgement was based onthe effects concerning bed agglomeration, level of alkali chloride in the flue gas,deposits and initial corrosion. Simultaneous addition of kaolin and ammonia sulphatealso had a favourable impact both in the bed and on the alkali chlorides in the gas phase.Dosage of kaolin did not reduce the effect of injected ammonium sulphate. Cocombustionof peat could also be a very attractive alternative, but it is critical to select asuitable peat type. It is of special concern to avoid peat with a high content of calcium,since it can increase the level of alkali chlorides by reacting with available sulphur.Change of bed material to ash from PFBC can decrease problems with bedagglomeration, but there is a risk of increased deposit formation and corrosion. A boileroperated with high steam data should consequently combine the change of bed materialwith injection of ammonium sulphate or another source of sulphur.Co-combustion of de-inking sludge from pulp and paper production can reduceproblems with bed agglomeration. There is, however, an increased chance of corrosiondue to the high content of calcium. Injection of sulphates may improve the situationconcerning corrosion. The results also showed that low potassium chlorine content in the flue gas decreasesthe risk of corrosion. Increased amount of potassium chlorine content in the flue gaswill not necessary give a high amount of chlorine content in the deposits if there is sulphur in the system.Key words: agglomeration, deposits, corrosion, alkali, kaolin, ammonium sulphate,sludge
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