| 1. |
- Diehl, Carl, et al.
(författare)
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Protein Flexibility and Conformational Entropy in Ligand Design Targeting the Carbohydrate Recognition Domain of Galectin-3.
- 2010
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 132, s. 14577-14589
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Tidskriftsartikel (refereegranskat)abstract
- Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. (15)N and (2)H spin relaxation measurements showed that the protein backbone and side chains respond to ligand binding by increased conformational fluctuations, on average, that differ among the three ligand-bound states. Variability in the response to ligand binding is prominent in the hydrophobic core, where a distal cluster of methyl groups becomes more rigid, whereas methyl groups closer to the binding site become more flexible. The results reveal an intricate interplay between structure and conformational fluctuations in the different complexes that fine-tunes the affinity. The estimated change in conformational entropy is comparable in magnitude to the binding enthalpy, demonstrating that it contributes favorably and significantly to ligand binding. We speculate that the relatively weak inherent protein-carbohydrate interactions and limited hydrophobic effect associated with oligosaccharide binding might have exerted evolutionary pressure on carbohydrate-binding proteins to increase the affinity by means of conformational entropy.
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| 2. |
- Kadhirvel, Saraboji, et al.
(författare)
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The Carbohydrate-Binding Site in Galectin-3 Is Preorganized To Recognize a Sugarlike Framework of Oxygens: Ultra-High-Resolution Structures and Water Dynamics
- 2012
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 51:1, s. 296-306
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Tidskriftsartikel (refereegranskat)abstract
- The recognition of carbohydrates by proteins is a fundamental aspect of communication within and between living cells. Understanding the molecular basis of carbohydrate-protein interactions is a prerequisite for the rational design of synthetic ligands. Here we report the high- to ultrahigh-resolution crystal structures of the carbohydrate recognition domain of galectin-3 (Gal3C) in the ligand-free state (1.08 angstrom at 100 K, 1.25 angstrom at 298 K) and in complex with lactose (0.86 angstrom) or glycerol (0.9 angstrom). These structures reveal striking similarities in the positions of water and carbohydrate oxygen atoms in all three states, indicating that the binding site of Gal3C is preorganized to coordinate oxygen atoms in an arrangement that is nearly optimal for the recognition of beta-galactosides. Deuterium nuclear magnetic resonance (NMR) relaxation dispersion experiments and molecular dynamics simulations demonstrate that all water molecules in the lactose-binding site exchange with bulk water on a time scale of nanoseconds or shorter. Nevertheless, molecular dynamics simulations identify transient water binding at sites that agree well with those observed by crystallography, indicating that the energy landscape of the binding site is maintained in solution. All heavy atoms of glycerol are positioned like the corresponding atoms of lactose in the Gal3C complexes. However, binding of glycerol to Gal3C is insignificant in solution at room temperature, as monitored by NMR spectroscopy or isothermal titration calorimetry under conditions where lactose binding is readily detected. These observations make a case for protein cryo-crystallography as a valuable screening method in fragment-based drug discovery and further suggest that identification of water sites might inform inhibitor design.
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| 3. |
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| 4. |
- Merlo, Juan, et al.
(författare)
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God vård på lika villkor vid hjärtinfarkt i dagens Sverige. Geografiska skillnader i dödlighet utan betyd
- 2005
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Ingår i: Läkartidningen. - 0023-7205. ; 102:1-2, s. 20-23
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Tidskriftsartikel (refereegranskat)abstract
- It is a known fact that the 1990s brought a decrease in mortality after myocardial infarction in Sweden but that differences in mortality rates following myocardial infarction still remain between the Swedish counties. Unresolved, however, are questions as to what these inter-county differences mean for the individual patient and what role hospital care plays in this context. We analysed all patients aged 64-85 years who were hospitalised following diagnosis of myocardial infarction in Sweden during the period 1993-1996. To gain an understanding of the relevance of geographical differences in mortality after myocardial infarction for the individual patient we applied multi-level regression analysis and calculated county and hospital median odds ratios (MORs) in relation to 28-day mortality. For hospitalised patients with myocardial infarction, being cared for in another hospital with higher mortality would increase the risk of dying by 9% (MOR=1.09) in men and 12% in women. If these patients moved to another county with higher mortality the risk would increase by 7% and 3%, respectively. The small geographical differences in 28-day mortality after myocardial infarction found in Sweden suggest a high degree of equality across the country; however, further improvement could be achieved in hospital care, especially for women - an issue that deserves further analysis.
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| 5. |
- Almehed, Sverker, et al.
(författare)
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A Silicon-Tungsten Electromagnetic Calorimeter for LEP
- 1991
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Ingår i: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - : Elsevier BV. - 0167-5087 .- 0168-9002. ; 305:2, s. 320-330
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Tidskriftsartikel (refereegranskat)abstract
- This report describes a silicon-tungsten electromagnetic calorimeter used to determine some beam properties and luminosity in the DELPHI experiment at LEP. The polar angular range covered by this detector is 5–8 mrad, which allows the detection of a Bhabha rate about 10 times the rate of produced Z particles at the peak cross section.
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| 6. |
- Andréasson, Sven, et al.
(författare)
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Behandling av alkohol- och narkotikaproblem : En evidensbaserad kunskapssammanställning
- 2001
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Utvärderingens syfteMissbruk och beroende av alkohol är ett av de största folkhälsoproblemen. Narkotikamissbruk är mindre vanligt men har stora medicinska konsekvenser för de berörda. De sociala och juridiska aspekterna är betydande. En kritisk genomgång av litteraturen vad avser behandling av abstinens, protraherad abstinens, behandling i syfte att förhindra återfall, psykologiska och sociala behandlingar för att minska återfallsrisken, behandlingsprogram och institutionsvårdens roll, samt behandling av missbruk under graviditet. Dessutom en granskning av mini-intervention i primärvård och annan vård vars syfte är att minska konsumtionen hos högkonsumenter av alkohol. Nyligen gjorda meta-analyser inom området värderas och särskild vikt fästs vid interventioner som finns eller lätt kan introduceras i den svenska vårdorganisationen. Behandlingsprogram för patienter med samtidig annan psykisk störning värderas.Så kallat lågdosberoende av bensodiazepiner och andra lugnande medel eller sömnmedel behandlas inte. Inte heller belyses effekten av behandlingar vars primära mål är kroppsliga komplikationer av missbruket, och inte heller granskas metoder att minska tillgänglighet.TillvägagångssättStrukturerad översikt, kostnadsanalyser.Insamling av primärdataSystematisk sökning i relevanta databaser, litteraturlistor i påträffade studier samt i aktuella monografier. Ingen bakre tidsbegränsning och sökning i databaser till och med februari 1999.Utgångspunkt för urval av dataHuvudsakligen randomiserade, kontrollerade, dubbelblinda studier, samt metaanalyser som baseras på sådana studier. Vad gäller långtidsförlopp och ekonomiska analyser även kohortstudier och andra naturalistiska studier.Genomgång av publikationenSamtliga studier värderas med hjälp av en i gruppen utarbetad, och med övriga psykiatriprojekt gemensam, kvalitetsmall. Alla centrala studier läses av minst två i gruppen.Färdiga manuskript värderas av styrelse, expertgrupp samt externa granskare.
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| 7. |
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| 8. |
- Arvidsson, Inger, et al.
(författare)
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Burnout among school teachers : quantitative and qualitative results from a follow-up study in southern Sweden
- 2019
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Ingår i: BMC Public Health. - : BioMed Central. - 1471-2458. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background: Teachers are at high risk of stress-related disorders. This longitudinal study aimed to (a) identify which occupational, sociodemographic and life-style factors and self-efficacy at baseline that were of importance for burnout, (b) explore associations between changes in the studied factors versus changes in burnout, and (c) by interviews increase the understanding of perceived job demands among teachers.Methods: A cohort of 310 Swedish teachers in school-years 4–9 responded to a questionnaire of occupational, sociodemographic and life-style factors, self-efficacy and burnout, at baseline and at follow-up (mean 30 months later). A combined measure with four levels of burnout was crafted, based on exhaustion, cynicism and professional efficacy (Maslach Burnout Inventory-General Survey). Quantitative data were analysed with multiple ordinal regression, and qualitative data were analysed with content analysis of interview responses from a subgroup of the teachers (n = 81).Results: The occurrence of high burnout (level 2 and 3 combined) were similar at baseline and follow-up (14% vs. 15%). However, many teachers fluctuated between the levels of burnout (28% increased and 24% decreased). Burnout at baseline was of importance for change of work or being off duty at follow up. In the multi-exposure model, low self-efficacy [OR 0.42; CI 0.26–0.68] and high job demands [OR 1.97; CI 1.02–3.8] were the strongest explanatory variables. Low self-efficacy remained as the strongest explanatory factor after adjustment for burnout at baseline. Increased job demands during follow-up was associated with an increased level of burnout [OR 3.41; CI 1.73–6.69], whereas increased decision latitude was associated with a decreased level of burnout [OR 0.51; CI 0.30–0.87]. Two major categories of demands emerged in the qualitative analysis; i.e. too high workload and a sense of inadequacy.Conclusions: A substantial proportion of teachers showed signs of burnout at both occasions. Low self-efficacy and high job demands was of importance for burnout, and changes in burnout was further associated with changes in decision latitude. The results points to the need of actions on individual, organizational and a societal levels.
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| 9. |
- Arvidsson, Inger, et al.
(författare)
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Should I stay or should I go? Associations between occupational factors, signs of exhaustion and the intention to change workplace among swedish principals
- 2021
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1661-7827 .- 1660-4601. ; 18:10, s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- A high turnover among principals may disrupt the continuity of leadership and negatively affect teachers and, by extension, the students. The aim was to investigate to what extent various work environment factors and signs of exhaustion were associated with reported intentions to change workplace among principals working in compulsory schools. A web-based questionnaire was administered twice, in 2018 and in 2019. Part I of the study involved cross-sectional analyses of the associations 2018 (n = 984) and 2019 (n = 884) between occupational factors, signs of exhaustion, and the intention to change workplace, using Generalized Estimating Equations models. Part II involved 631 principals who participated in both surveys. The patterns of intended and actual changes of workplace across two years were described, together with associated changes of occupational factors and signs of exhaustion. Supportive management was associated with an intention to stay, while demanding role conflicts and the feeling of being squeezed between management and co-workers (buffer-function) were associated with the intention to change workplace. The principals who intended to change their workplace reported more signs of exhaustion. To increase retention among principals, systematic efforts are probably needed at the national, municipal, and local level, in order to improve their working conditions.
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| 10. |
- Arvidsson, Inger, et al.
(författare)
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Should I stay or should I go? Associations between occupational factors, signs of exhaustion and the intention to change workplace among swedish principals
- 2021
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI Multidisciplinary Digital Publishing Institute. - 1661-7827 .- 1660-4601. ; 18:10, s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- A high turnover among principals may disrupt the continuity of leadership and negatively affect teachers and, by extension, the students. The aim was to investigate to what extent various work environment factors and signs of exhaustion were associated with reported intentions to change workplace among principals working in compulsory schools. A web-based questionnaire was administered twice, in 2018 and in 2019. Part I of the study involved cross-sectional analyses of the associations 2018 (n = 984) and 2019 (n = 884) between occupational factors, signs of exhaustion, and the intention to change workplace, using Generalized Estimating Equations models. Part II involved 631 principals who participated in both surveys. The patterns of intended and actual changes of workplace across two years were described, together with associated changes of occupational factors and signs of exhaustion. Supportive management was associated with an intention to stay, while demanding role conflicts and the feeling of being squeezed between management and co-workers (buffer-function) were associated with the intention to change workplace. The principals who intended to change their workplace reported more signs of exhaustion. To increase retention among principals, systematic efforts are probably needed at the national, municipal, and local level, in order to improve their working conditions.
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