| 1. |
- Folke, Carl, et al.
(author)
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Reconnecting to the biosphere
- 2011
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In: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 40:7, s. 719-738
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Journal article (peer-reviewed)abstract
- Humanity has emerged as a major force in the operation of the biosphere, with a significant imprint on the Earth System, challenging social-ecological resilience. This new situation calls for a fundamental shift in perspectives, world views, and institutions. Human development and progress must be reconnected to the capacity of the biosphere and essential ecosystem services to be sustained. Governance challenges include a highly interconnected and faster world, cascading social-ecological interactions and planetary boundaries that create vulnerabilities but also opportunities for social-ecological change and transformation. Tipping points and thresholds highlight the importance of understanding and managing resilience. New modes of flexible governance are emerging. A central challenge is to reconnect these efforts to the changing preconditions for societal development as active stewards of the Earth System. We suggest that the Millennium Development Goals need to be reframed in such a planetary stewardship context combined with a call for a new social contract on global sustainability. The ongoing mind shift in human relations with Earth and its boundaries provides exciting opportunities for societal development in collaboration with the biosphere-a global sustainability agenda for humanity.
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| 2. |
- Sarwar, Nadeem, et al.
(author)
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Interleukin-6 receptor pathways in coronary heart disease : a collaborative meta-analysis of 82 studies
- 2012
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In: The Lancet. - New York, NY, USA : Elsevier. - 0140-6736 .- 1474-547X. ; 379:9822, s. 1205-1213
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Journal article (peer-reviewed)abstract
- Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele >= 0.04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% (95% CI 30.4-38.2) and of interleukin 6 by 14.6% (10.7-18.4), and mean concentration of C-reactive protein was reduced by 7.5% (5.9-9.1) and of fibrinogen by 1.0% (0.7-1.3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3.4% (1.8-5.0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.
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| 3. |
- Adrian Meredith, Jenny, 1971-, et al.
(author)
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P2 '-truncated BACE-1 inhibitors with a novel hydroxethylene-like core
- 2010
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 45:2, s. 542-554
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Journal article (peer-reviewed)abstract
- Highly potent BACE-1 protease inhibitors derived from a novel hydroxyethylene-like core structure were recently developed by our group using X-ray crystal structure data and molecular modelling. In a continuation of this work guided by molecular modelling we have explored a truncated core motif where the P2' amide group is replaced by an ether linkage resulting in a set of alkoxy, aryloxy and alkylaryl groups, with the overall aim to reduce molecular weight and the number of amide bonds to increase permeability and bestow the inhibitors with drug-like features. The most potent of these inhibitors displayed a BACE-I IC50 value of 140 nM. The synthesis of these BACE-I inhibitors utilizes readily available starting materials, furnishing the target compounds in good overall yields.
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| 4. |
- Albrectsen, Benedicte R., 1960-, et al.
(author)
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Endophytic fungi in European aspen (Populus tremula) leaves - diversity, detection, and a suggested correlation with herbivory resistance
- 2010
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In: Fungal diversity. - : Springer Science and Business Media LLC. - 1560-2745 .- 1878-9129. ; 41:1, s. 17-28
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Journal article (peer-reviewed)abstract
- According to the geographic mosaic theory of coevolution (GMTC), clines of traits reflecting local co-adaptation (including resistance genes) should be common between a host and its parasite and should persist across time. To test the GMTC-assumption of persistent clinal patterns we compared the natural prevalence of two parasites on aspen Populus tremula trees: mining moths of the genus Phyllocnistis and leaf rust Melampsora spp. Damage data were collated from the Swedish National Forest Damage Inventory (2004–2006). In addition, occurrence of the parasites was scored in field conditions in two common gardens in the north and south of Sweden over five growing seasons (2004–2008), then related to biomass (stem height and diameter) and to concentrations of eleven leaf phenolics. Phyllocnistis mainly occurred in the northern garden, a distribution range which was confirmed by the countrywide inventory, although Phyllocnistis was more abundant on southern clones, providing evidence for possible local maladaptation. Melampsora occurred all over the country and in both gardens, but built up more quickly on northern clones, which suggests a centre of local clone maladaptation in the north. Stem growth also followed a clinal pattern as did the concentration of three phenolic compounds: benzoic acid, catechin and cinnamic acid. However, only benzoic acid was related to parasite presence: negatively to Phyllocnistis and positively to Melampsora and it could thus be a potential trait under selection. In conclusion, clines of Phyllocnistis were stronger and more persistent compared to Melampsora, which showed contrasting clines of varying strength. Our data thus support the assumption of the GMTC model that clines exist in the border between hot and cold spots and that they may be less persistent for parasites with an elevated gene flow, and/or for parasites which cover relatively larger hot spots surrounded by fewer cold spots.
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| 5. |
- Barbu, Andreea, et al.
(author)
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Blood flow in endogenous and transplanted pancreatic islets in anesthetized rats : Effects of lactate and pyruvate
- 2012
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In: Pancreas. - 0885-3177 .- 1536-4828. ; 41:8, s. 1263-1271
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The objective of this study was to evaluate the effects of exogenously administered lactate and pyruvate on blood perfusion in endogenous and transplanted islets. METHODS: Anesthetized Wistar-Furth rats were given lactate or pyruvate intravenously, and regional blood perfusion was studied 3 or 30 minutes later with a microsphere technique. Separate rats received a 30-minute infusion of pyruvate or lactate into the portal vein before blood flow measurements. We also administered these substances to islet-implanted rats 4 weeks after transplantation and measured graft blood flow with laser Doppler flowmetry. The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was analyzed. RESULTS: The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was markedly up-regulated in transplanted as compared with endogenous islets. Administration of pyruvate, but not lactate, increased mesenteric blood flow after 3 minutes. Pyruvate decreased mesenteric blood flow after 30 minutes, whereas lactate decreased only islet blood flow. These responses were absent in transplanted animals. A continuous intraportal infusion of lactate or pyruvate increased selectively islet blood flow but did not affect blood perfusion of transplanted islets. CONCLUSIONS: Lactate and pyruvate affect islet blood flow through effects mediated by interactions between the liver and the nervous system. Such a response can help adjust the release of islet hormones during excess substrate concentrations.
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| 6. |
- Berndt, Sonja I., et al.
(author)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Journal article (peer-reviewed)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 7. |
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| 8. |
- Björklund, Catarina, 1981-, et al.
(author)
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Design and synthesis of potent and selective BACE-1 inhibitors
- 2010
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In: Journal of Medicinal Chemistry. - : American Chemical Society. - 0022-2623 .- 1520-4804. ; 53:4, s. 1458-1464
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Journal article (peer-reviewed)abstract
- Several highly potent BACE-1 protease inhibitors have been developed from an inhibitor series containing a novel hydroxyethylene (HE) core structure displaying aryloxymethyl or benzyloxymethyl P1 side chains and a methoxy P1’ side chain. The target molecules were readily synthesized from chiral carbohydrate starting materials, furnishing the inhibitor compounds in good overall yields. The inhibitors show both high BACE-1 potency and good selectivity against cathepsin D, where the most potent inhibitor furnish a BACE-1 IC50 value of 0.32 nM and displays > 3000 fold selectivity over cathepsin D.
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| 9. |
- Björklund, Catarina, 1981-, et al.
(author)
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Discovery of Potent BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold : Exploration of P1’ Alkoxy Residues and an Aminoethylene (AE) Central Core
- 2010
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In: Bioorganic & Medicinal Chemistry. - : Elsevier Ltd.. - 0968-0896 .- 1464-3391. ; 18:4, s. 1711-1723
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Journal article (peer-reviewed)abstract
- In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1’ methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1’ pocket by introducing a set of P1’ alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1’ positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1’ positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed IC50 values in the range of 4-45 nM, where the most potent compounds featured small P1’ groups. The cathepsin D selectivity which was high for the smallest P1’ sustituents (P1’=ethoxy, fold selectively >600) dropped for larger groups (P1’=benzyloxy, fold selectivity of 1.6). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.
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| 10. |
- Bäck, Maria, 1978, et al.
(author)
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The impact on kinesiophobia (fear of movement) by clinical variables for patients with coronary artery disease
- 2013
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In: International Journal of Cardiology. - : Elsevier Ireland Ltd. - 0167-5273 .- 1874-1754. ; 167:2, s. 391-397
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Journal article (peer-reviewed)abstract
- Background: The impact on kinesiophobia (fear of movement) for patients with coronary artery disease (CAD) is not known. The aims were to describe the occurrence of kinesiophobia in patients with CAD, and to investigate the influence on kinesiophobia by clinical variables. Material and methods: In total, 332 patients, mean age, 65±9.1 years diagnosed with CAD at a university hospital were included in the study. The Tampa Scale for Kinesiophobia Heart (TSK-SV Heart) was used to assess kinesiophobia. Comparisons between high versus low levels of kinesiophobia were measured for each variable. Binary logistic regression analyses were performed with a high level of kinesiophobia (TSK-SV Heart >37) as dependent variable, and with the observed variables as independent. The study had an exploratory, cross-sectional design. Results: A high level of kinesiophobia was found in 20% of the patients. The following variables decreased the odds ratio (OR) for a high level of kinesiophobia: Attending cardiac rehabilitation (yes vs no; -56.7%), level of physical activity (medium vs high; -80.2%), Short Form-36: general health (-4,3%), physical functioning (-1.8%). Two variables increased the OR for a high level of kinesiophobia: heart failure as complication at hospital (yes vs no; 418.7%), anxiety (19.2%). Previous heart failure (yes vs no) was unexpectedly found to reduce kinesiophobia (-88.3%) due to suppression. Conclusions: Several important clinical findings with impact on rehabilitation and prognosis for patients with CAD were found to be associated with a high level of kinesiophobia. Therefore, kinesiophobia needs to be considered in secondary prevention for patients with CAD.
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