| 1. |
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- 2019
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Journal article (peer-reviewed)
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| 2. |
- Kattge, Jens, et al.
(author)
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TRY plant trait database - enhanced coverage and open access
- 2020
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In: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Journal article (peer-reviewed)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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| 3. |
- Speliotes, Elizabeth K., et al.
(author)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Journal article (peer-reviewed)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 4. |
- Mavaddat, Nasim, et al.
(author)
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Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants
- 2015
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:5, s. 036-036
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Journal article (peer-reviewed)abstract
- Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
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| 5. |
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| 6. |
- Anselm, Jonas, et al.
(author)
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Bannlys alla politiska beslut som ger mer klimatutsläpp
- 2014
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In: Dagens Nyheter.
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Journal article (other academic/artistic)abstract
- Torftig valdebatt. Dagspolitiken klarar inte att hantera ödesfrågan om klimatet, vilket oroar oss. Vi föreslår därför ett ”utsläppsmoratorium”: inga beslut får tas som ökar utsläppen av växthusgaser. Principen måste kopplas till mål om exempelvis förnybar energi och grön infrastruktur, skriver 23 forskare och debattörer.
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| 7. |
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| 8. |
- Elmendorf, Sarah C., et al.
(author)
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Global assessment of experimental climate warming on tundra vegetation : heterogeneity over space and time
- 2012
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In: Ecology Letters. - : Wiley. - 1461-023X .- 1461-0248. ; 15:2, s. 164-175
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Research review (peer-reviewed)abstract
- Understanding the sensitivity of tundra vegetation to climate warming is critical to forecasting future biodiversity and vegetation feedbacks to climate. In situ warming experiments accelerate climate change on a small scale to forecast responses of local plant communities. Limitations of this approach include the apparent site-specificity of results and uncertainty about the power of short-term studies to anticipate longer term change. We address these issues with a synthesis of 61 experimental warming studies, of up to 20 years duration, in tundra sites worldwide. The response of plant groups to warming often differed with ambient summer temperature, soil moisture and experimental duration. Shrubs increased with warming only where ambient temperature was high, whereas graminoids increased primarily in the coldest study sites. Linear increases in effect size over time were frequently observed. There was little indication of saturating or accelerating effects, as would be predicted if negative or positive vegetation feedbacks were common. These results indicate that tundra vegetation exhibits strong regional variation in response to warming, and that in vulnerable regions, cumulative effects of long-term warming on tundra vegetation and associated ecosystem consequences have the potential to be much greater than we have observed to date.
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| 9. |
- Elmendorf, Sarah C., et al.
(author)
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Plot-scale evidence of tundra vegetation change and links to recent summer warming
- 2012
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In: Nature Climate Change. - : Nature Publishing Group. - 1758-678X .- 1758-6798. ; 2:6, s. 453-457
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Journal article (peer-reviewed)abstract
- Temperature is increasing at unprecedented rates across most of the tundra biome. Remote-sensing data indicate that contemporary climate warming has already resulted in increased productivity over much of the Arctic, but plot-based evidence for vegetation transformation is not widespread. We analysed change in tundra vegetation surveyed between 1980 and 2010 in 158 plant communities spread across 46 locations.We found biome-wide trends of increased height of the plant canopy and maximum observed plant height for most vascular growth forms; increased abundance of litter; increased abundance of evergreen, low-growing and tall shrubs; and decreased abundance of bare ground. Intersite comparisons indicated an association between the degree of summer warming and change in vascular plant abundance, with shrubs, forbs and rushes increasing with warming. However, the association was dependent on the climate zone, the moisture regime and the presence of permafrost. Our data provide plot-scale evidence linking changes in vascular plant abundance to local summer warming in widely dispersed tundra locations across the globe.
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| 10. |
- Kuepper, Jochen, et al.
(author)
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X-Ray Diffraction from Isolated and Strongly Aligned Gas-Phase Molecules with a Free-Electron Laser
- 2014
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In: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 112:8, s. 083002-
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Journal article (peer-reviewed)abstract
- We report experimental results on x-ray diffraction of quantum-state-selected and strongly aligned ensembles of the prototypical asymmetric rotor molecule 2,5-diiodobenzonitrile using the Linac Coherent Light Source. The experiments demonstrate first steps toward a new approach to diffractive imaging of distinct structures of individual, isolated gas-phase molecules. We confirm several key ingredients of single molecule diffraction experiments: the abilities to detect and count individual scattered x-ray photons in single shot diffraction data, to deliver state-selected, e.g., structural-isomer-selected, ensembles of molecules to the x-ray interaction volume, and to strongly align the scattering molecules. Our approach, using ultrashort x-ray pulses, is suitable to study ultrafast dynamics of isolated molecules.
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| 11. |
- Lawrenson, Kate, et al.
(author)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 12. |
- Ling Lundström, Maria, et al.
(author)
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Fecal Biomarkers of Neutrophil and Eosinophil Origin Reflect the Response to Biological Therapy and Corticosteroids in Patients With Inflammatory Bowel Disease
- 2023
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In: Clinical and Translational Gastroenterology. - : Nature Publishing Group. - 2155-384X. ; 14:8
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Journal article (peer-reviewed)abstract
- Introduction: Fecal calprotectin (FC) is anoninvasive tool for examining response to biologics in inflammatory boweldisease (IBD), but its performance in relation to other novel fecal markers of various cellular origins is unknown.Methods: We performed a prospective multicenter cohort study and included patients with active IBD who provided a fecal sample at initiation of biological therapy. Levels of FC, myeloperoxidase (MPO), human neutrophil lipocalin (HNL), and eosinophil-derived neurotoxin (EDN) were analyzed and related to clinical remission status at 3 months. Changes in levels of markers at 3 months were calculated, and the impact of concomitant use of corticosteroids at baseline was estimated.Results: In patients achieving clinical remission (n = 27), a decrease in levels of FC (P = 0.005), MPO (P < 0.001), HNL (P < 0.001), and EDN (P < 0.001) was observed, whereas no significant decrease was seen in patients not achieving remission (n = 39). There was a significant difference in the change in the level of MPO (P = 0.01) and HNL (P = 0.02) between patients achieving clinical remission and those who did not, but changes in FC and EDN could not differentiate between these groups. Patients with concomitant systemic corticosteroids at inclusion had lower levels of HNL (P = 0.01) and EDN (P < 0.001) at baseline, compared with patients without corticosteroids.Discussion: Fecal MPO, HNL, and EDN are all promising biomarkers for assessing the treatment outcome of biologics in patients with IBD. Fecal levels of EDN and HNL are significantly affected by corticosteroids indicating a greater sensitivity to the effects of corticosteroids compared with levels of FC and MPO.
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| 13. |
- Ludvigsson, Johnny, et al.
(author)
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GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus
- 2012
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In: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 366:5, s. 433-442
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Journal article (peer-reviewed)abstract
- BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences.CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period.
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| 14. |
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| 15. |
- Shu, Xiang, et al.
(author)
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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
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In: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
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Journal article (peer-reviewed)abstract
- Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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| 16. |
- Sumaila, U. Rashid, et al.
(author)
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WTO must ban harmful fisheries subsidies
- 2021
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 374:6567, s. 544-544
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Journal article (other academic/artistic)
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| 17. |
- Zeng, Chenjie, et al.
(author)
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
- 2016
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18
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Journal article (peer-reviewed)abstract
- Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
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| 18. |
- Blasiak, Robert, et al.
(author)
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Evolving Perspectives of Stewardship in the Seafood Industry
- 2021
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In: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 8
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Journal article (peer-reviewed)abstract
- Humanity has never benefited more from the ocean as a source of food, livelihoods, and well-being, yet on a global scale this has been accompanied by trajectories of degradation and persistent inequity. Awareness of this has spurred policymakers to develop an expanding network of ocean governance instruments, catalyzed civil society pressure on the public and private sector, and motivated engagement by the general public as consumers and constituents. Among local communities, diverse examples of stewardship have rested on the foundation of care, knowledge and agency. But does an analog for stewardship exist in the context of globally active multinational corporations? Here, we consider the seafood industry and its efforts to navigate this new reality through private governance. We examine paradigmatic events in the history of the sustainable seafood movement, from seafood boycotts in the 1970s through to the emergence of certification measures, benchmarks, and diverse voluntary environmental programs. We note four dimensions of stewardship in which efforts by actors within the seafood industry have aligned with theoretical concepts of stewardship, which we describe as (1) moving beyond compliance, (2) taking a systems perspective, (3) living with uncertainty, and (4) understanding humans as embedded elements of the biosphere. In conclusion, we identify emerging stewardship challenges for the seafood industry and suggest the urgent need to embrace a broader notion of ocean stewardship that extends beyond seafood.
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| 19. |
- Bokhorst, Stef Frederik, et al.
(author)
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Variable temperature effects of Open Top Chambers at polar and alpine sites explained by irradiance and snow depth
- 2013
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In: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 19:1, s. 64-74
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Research review (peer-reviewed)abstract
- Environmental manipulation studies are integral to determining biological consequences of climate warming. Open Top Chambers (OTCs) have been widely used to assess summer warming effects on terrestrial biota, with their effects during other seasons normally being given less attention even though chambers are often deployed year-round. In addition, their effects on temperature extremes and freeze-thaw events are poorly documented. To provide robust documentation of the microclimatic influences of OTCs throughout the year, we analysed temperature data from 20 studies distributed across polar and alpine regions. The effects of OTCs on mean temperature showed a large range (-0.9 to 2.1 degrees C) throughout the year, but did not differ significantly between studies. Increases in mean monthly and diurnal temperature were strongly related (R-2 = 0.70) with irradiance, indicating that PAR can be used to predict the mean warming effect of OTCs. Deeper snow trapped in OTCs also induced higher temperatures at soil/vegetation level. OTC-induced changes in the frequency of freeze-thaw events included an increase in autumn and decreases in spring and summer. Frequency of high-temperature events in OTCs increased in spring, summer and autumn compared with non-manipulated control plots. Frequency of low-temperature events was reduced by deeper snow accumulation and higher mean temperatures. The strong interactions identified between aspects of ambient environmental conditions and effects of OTCs suggest that a detailed knowledge of snow depth, temperature and irradiance levels enables us to predict how OTCs will modify the microclimate at a particular site and season. Such predictive power allows a better mechanistic understanding of observed biotic response to experimental warming studies and for more informed design of future experiments. However, a need remains to quantify OTC effects on water availability and wind speed (affecting, for example, drying rates and water stress) in combination with microclimate measurements at organism level.
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| 20. |
- Crona, Beatrice, et al.
(author)
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Sharing the seas : a review and analysis of ocean sector interactions
- 2021
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In: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 16:6
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Research review (peer-reviewed)abstract
- Ocean activities are rapidly expanding as Blue Economy discussions gain traction, creating new potential synergies and conflicts between sectors. To better manage ocean sectors and their development, we need to understand how they interact and the respective outcomes of these interactions. To provide a first comprehensive picture of the situation, we review 3187 articles to map and analyze interactions between economically important ocean sectors and find 93 unique direct and 61 indirect interactions, often mediated via the ocean ecosystem. Analysis of interaction outcomes reveals that some sectors coexist synergistically (e.g. renewable energy, tourism), but many interactions are antagonistic, and negative effects on other sectors are often incurred via degradation of marine ecosystems. The analysis also shows that ocean ecosystems are fundamental for supporting many ocean sectors, yet 13 out of 14 ocean sectors have interactions resulting in unidirectional negative ecosystem impact. Fishing, drilling, and shipping are hubs in the network of ocean sector interactions, and are involved in many of the antagonistic interactions. Antagonistic interactions signal trade-offs between sectors. Qualitative analysis of the literature shows that these tradeoffs relate to the cumulative nature of many ecosystem impacts incurred by some sectors, and the differential power of ocean sectors to exert their rights or demands in the development of the ocean domain. There are also often time lags in how impacts manifest. The ocean governance landscape is not currently well-equipped to deal with the full range of trade-offs, and opportunities, likely to arise in the pursuit of a Blue Economy in a rapidly changing ocean context. Based on our analysis, we therefore propose a set principles that can begin to guide strategic decision-making, by identifying both tradeoffs and opportunities for sustainable and equitable development of ocean sectors.
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| 21. |
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| 22. |
- Dvorak, Dominik, et al.
(author)
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Curriculum Making and Subject Traditions : Curriculum Reforms in Social Studies and Physics and the Concept of Knowledge
- 2019
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In: Presented at ECER 2019.
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Conference paper (peer-reviewed)abstract
- In Sweden, a knowledge debate was initiated in the early 1990s through the official report School for Bildung (SOU 1992:94). The purpose of the report was two-fold: to widen the concept of knowledge from a one-sided cognitive meaning and to offer ‘new’ concepts of knowledge adapted to a performance model (Bernstein 2000) of school curriculum. Since this official investigation in the early 1990s, a new grading system and a standards-based and subject-based model of curriculum with prescribed ‘knowledge requirements’, have been implemented, but the knowledge base in the first part of the curriculum has remained the same. Two overarching issues are addressed in this paper: i) The transnational influence on educational knowledge concepts and ii) the transnational influence on curriculum structure resulting in standards-based curriculum. Both aspects are explored in relation to the implications for the subject of social science (civics). Thus, we especially examine what education is for (Biesta 2011) in social science, as it is expressed within the Swedish framework of curriculum. The purpose of this paper is to analyse the Swedish ‘hybrid’ curriculum, composed of a content- and subject based idea on the one hand and an idea of a result-focused, ability-centered curriculum on the other hand, in relation to social science. In the study, the following research questions, focused on curriculum making, are explored: How is knowledge in civics expressed in the Swedish curricula for compulsory and upper secondary school? What are the implications of transnational influences of the concepts of standards and competences for the subject of civics? Theoretical framework and method In the theoretical framework, we draw on Bernstein’s (2000) two pedagogical models, as well as his understanding of horizontal and vertical knowledge in order to relate the Swedish curricula Lgr 11 (compulsory school) and Lgy 11 (upper secondary school) to a theoretical model of curriculum. Following Deng & Luke (2008), we explore the character of the knowledge concept in the school subject of civics. The dominating knowledge discourse is related to a typology of civics (Barr; Barth & Shermis 1977; Englund 1997; Wahlström 2014). We specifically discuss the assessment practice and its consequences for how the knowledge in the subject is understood (Adolfsson 2018, Vogt 2017). In the analysis, we illustrate the subject tradition of social sciences in Sweden, as representative for the Nordic countries, as well as the subject’s current dilemmas in a standards-based curriculum.
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| 23. |
- Elmsjö, Albert, et al.
(author)
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Postmortem Metabolomics Reveal Acylcarnitines as Potential Biomarkers for Fatal Oxycodone-Related Intoxication
- 2022
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In: Metabolites. - : MDPI. - 2218-1989 .- 2218-1989. ; 12:2
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Journal article (peer-reviewed)abstract
- Postmortem metabolomics has recently been suggested as a potential tool for discovering new biological markers able to assist in death investigations. Interpretation of oxycodone concentrations in postmortem cases is complicated, as oxycodone tolerance leads to overlapping concentrations for oxycodone intoxications versus non-intoxications. The primary aim of this study was to use postmortem metabolomics to identify potential endogenous biomarkers that discriminate between oxycodone-related intoxications and non-intoxications. Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry data from 934 postmortem femoral blood samples, including oxycodone intoxications and controls positive and negative for oxycodone, were used in this study. Data were processed and evaluated with XCMS and SIMCA. A clear trend in group separation was observed between intoxications and controls, with a model sensitivity and specificity of 80% and 76%. Approximately halved levels of short-, medium-, and long-chain acylcarnitines were observed for oxycodone intoxications in comparison with controls (p < 0.001). These biochemical changes seem to relate to the toxicological effects of oxycodone and potentially acylcarnitines constituting a biologically relevant biomarker for opioid poisonings. More studies are needed in order to elucidate the potential of acylcarnitines as biomarker for oxycodone toxicity and their relation to CNS-depressant effects.
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| 24. |
- Escala-Garcia, Maria, et al.
(author)
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A network analysis to identify mediators of germline-driven differences in breast cancer prognosis
- 2020
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
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| 25. |
- Florén, Carl-Robert, 1988, et al.
(author)
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Modelling complete methane oxidation over palladium oxide in a porous catalyst using first-principles surface kinetics
- 2018
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In: Catalysis Science and Technology. - : Royal Society of Chemistry (RSC). - 2044-4753 .- 2044-4761. ; 8:2, s. 508-520
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Journal article (peer-reviewed)abstract
- A comprehensive model is developed for complete methane oxidation over supported palladium. The model is based on first-principles microkinetics and accounts for mass and heat transport in a porous catalytic layer. The turnover frequency (TOF) is simulated for wet exhaust gas compositions, exploring the effects of temperature and total pressure on the TOF. Three different temperature regimes are identified each with different dependency on the total pressure. The regimes originate from temperature and pressure dependent coverages of carbon dioxide and water, which are the most abundant surface species hindering methane dissociation at low temperatures. The TOF is controlled by surface kinetics below 400 °C whereas above 500 °C and up to 8 atm, internal mass transport is controlling. A combination of kinetics, external and internal mass transport controls the TOF at other reaction conditions. The physically meaningful model paves the way for extrapolation and optimization of catalyst design parameters for high catalytic efficiency.
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| 26. |
- Florén, Carl-Robert, 1988, et al.
(author)
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Multiscale reactor modelling of total pressure effects on complete methane oxidation over Pd/Al2O3
- 2019
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In: Catalysis Science and Technology. - : Royal Society of Chemistry (RSC). - 2044-4753 .- 2044-4761. ; 9:12, s. 3055-3065
-
Journal article (peer-reviewed)abstract
- A two-dimensional multiscale model is developed for complete methane oxidation in a continuous flow reactor. The model considers mass and heat transfer for a porous alumina supported palladium catalyst coated on a ceramic monolith substrate and the surface kinetics are described by a first-principles microkinetic model for complete methane oxidation over PdO(101). The temperature dependent conversion for a synthetic exhaust gas composition shows a delayed ignition but a higher conversion at elevated temperatures when the total pressure is increased from 1 to 10 atm. The simulations reveal a temperature and total pressure dependent operating point where the methane conversion is maximized. Analysis of the kinetics shows that the reaction is suppressed by bicarbonates, hydroxyl species and water originating from adsorbed carbon dioxide and water from the gas phase. The reaction order with respect to water and carbon dioxide at 1 atm is -0.94 and -0.99, respectively, and decreases with increasing total pressure. The developed model paves the way for exploring how design parameters and reaction conditions influence the complete methane oxidation reaction.
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| 27. |
- Haycock, Philip C., et al.
(author)
-
Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study
- 2017
-
In: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 3:5, s. 636-651
-
Journal article (peer-reviewed)abstract
- IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [ 95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [ 95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [ 95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [ 95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [ 95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
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| 28. |
- Jiao, Xiang, et al.
(author)
-
PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1
- 2017
-
In: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:61, s. 102769-102782
-
Journal article (peer-reviewed)abstract
- Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
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| 29. |
- Juzenas, Simonas, et al.
(author)
-
Detailed transcriptional landscape of peripheral blood points to increased neutrophil activation in treatment-naïve inflammatory bowel disease
- 2022
-
In: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 16:7, s. 1097-1109
-
Journal article (peer-reviewed)abstract
- BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohn's disease (CD) or ulcerative colitis (UC). These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and thus, common immune regulatory pathways.METHODS: Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naïve (n=110) and treatment-exposed (n=177) IBD patients as well as symptomatic- (n=65) and healthy controls (n=95).RESULTS: Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naïve IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, the IL1B was identified as the central gene. The co-expression levels among IL1B and chemosensing receptor (CXCR1/2 and FPR1/2) genes were reduced in the blood of IBD patients when compared with healthy controls.CONCLUSIONS: Immune dysregulation seen in peripheral blood transcriptomes of treatment-naïve IBD patients is mainly driven by neutrophil activation.
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| 30. |
- Krampert, Monika, et al.
(author)
-
Smad7 Regulates the Adult Neural Stem/Progenitor Cell Pool in a Transforming Growth Factor β- and Bone Morphogenetic Protein-Independent Manner
- 2010
-
In: Molecular and Cellular Biology. - : American Society for Microbiology. - 0270-7306 .- 1098-5549. ; 30:14, s. 3685-3694
-
Journal article (peer-reviewed)abstract
- Members of the transforming growth factor beta (TGF-beta) family of proteins modulate the proliferation, differentiation, and survival of many different cell types. Neural stem and progenitor cells (NPCs) in the adult brain are inhibited in their proliferation by TGF-beta and by bone morphogenetic proteins (BMPs). Here, we investigated neurogenesis in a hypomorphic mouse model for the TGF-beta and BMP inhibitor Smad7, with the hypothesis that NPC proliferation might be reduced due to increased TGF-beta and BMP signaling. Unexpectedly, we found enhanced NPC proliferation as well as an increased number of label-retaining cells in vivo. The enhanced proliferation potential of mutant cells was retained in vitro in neurosphere cultures. We observed a higher sphere-forming capacity as well as faster growth and cell cycle progression. Use of specific inhibitors revealed that these effects were independent of TGF-beta and BMP signaling. The enhanced proliferation might be at least partially mediated by elevated signaling via epidermal growth factor (EGF) receptor, as mutant cells showed higher expression and activation levels of the EGF receptor. Conversely, an EGF receptor inhibitor reduced the proliferation of these cells. Our data indicate that endogenous Smad7 regulates neural stem/progenitor cell proliferation in a TGF-beta- and BMP-independent manner.
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| 31. |
- Ling Lundström, Maria, et al.
(author)
-
Faecal biomarkers for diagnosis and prediction of disease course in treatment-naïve patients with IBD.
- 2024
-
In: Alimentary Pharmacology and Therapeutics. - 0269-2813 .- 1365-2036.
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Faecal biomarkers can be used to assess inflammatory bowel disease (IBD).AIM: To explore the performance of some promising biomarkers in diagnosing and predicting disease course in IBD.METHODS: We included 65 patients with treatment-naïve, new-onset Crohn's disease (CD), 90 with ulcerative colitis (UC), 67 symptomatic controls (SC) and 41 healthy controls (HC) in this prospective observational study. We analysed faecal samples for calprotectin (FC), myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein ECP and eosinophil-derived neurotoxin (EDN) and compared markers among groups. We assessed the diagnostic capability of biomarkers with receiver operating characteristic curves. Clinical disease course was determined for each patient with IBD and analysed the association with biomarkers by logistic regression.RESULTS: All markers were elevated at inclusion in patients with IBD compared with HC (p < 0.001) and SC (p < 0.001). FC (AUC 0.85, 95% CI: 0.79-0.89) and MPO (AUC 0.85, 95% CI: 0.80-0.89) showed the highest diagnostic accuracy in distinguishing IBD from SC. The diagnostic ability of biomarkers differed between IBD subtypes with the highest performance for FC and MPO in CD. The diagnostic accuracy was further improved by combining FC and MPO (p = 0.02). Levels of FC, MPO and HNL at inclusion were predictive of an aggressive disease course with MPO showing the strongest association (p = 0.006).CONCLUSIONS: This study provides new insight into the diagnostic and prognostic capability of neutrophil and eosinophil biomarkers in IBD and suggests that MPO, alone or in combination with FC, may add to the diagnostic power of faecal biomarkers.
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| 32. |
- Marouli, Eirini, et al.
(author)
-
Rare and low-frequency coding variants alter human adult height
- 2017
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
-
Journal article (peer-reviewed)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 33. |
- Moraes Holst, Luiza, et al.
(author)
-
Downregulated Mucosal Autophagy, Alpha Kinase-1 and IL-17 Signaling Pathways in Active and Quiescent Ulcerative Colitis
- 2022
-
In: Clinical and Experimental Gastroenterology. - : DOVE MEDICAL PRESS LTD. - 1178-7023. ; 15, s. 129-144
-
Journal article (peer-reviewed)abstract
- Background: Improved mucosal immune profiling in active and quiescent colonic inflammatory bowel disease (IBD) is needed to develop therapeutic options for treating and preventing flares. This study therefore aimed to provide a comprehensive mucosal characterization with emphasis on immunological host response of patients with active ulcerative colitis (UC active), UC during remission (UC remission) and active colonic Crohn's disease (CD active).Methods: Colonic biopsies from 47 study subjects were collected for gene expression and pathway analyses using the NanoString host-response panel, including 776 genes and 56 immune-related pathways.Results: The majority of mucosal gene expression and signaling pathway scores were increased in active IBD (n=27) compared to healthy subjects (n=10). However, both active IBD and UC remission (n=10) demonstrated decreased gene expression and signaling pathway scores related to autophagy, alpha kinase-1 and IL-17 signaling pathways compared to healthy subjects. Further, UC remission was characterized by decreased scores of several signaling pathways linked to homeostasis along with increased mononuclear cell migration pathway score as compared to healthy subjects. No major differences in the colonic mucosal gene expression between CD active (n=7) and UC (n=20) active were observed.Conclusion: This study indicates that autophagy, alpha kinase-1 and IL-17 signaling pathways are persistently downregulated in UC irrespective of disease activity. Further, UC patients in remission present a unique mucosal environment, potentially preventing patients from reaching and sustaining true homeostasis. These findings may enable better comprehension of the remitting and relapsing pattern of colonic IBD and guide future treatment and prevention of flares.
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| 34. |
- Mueller, Stefanie H., et al.
(author)
-
Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
- 2023
-
In: Genome Medicine. - : BioMed Central (BMC). - 1756-994X. ; 15
-
Journal article (peer-reviewed)abstract
- Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.
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| 35. |
- Norström, Albert, et al.
(author)
-
Principles for knowledge co-production in sustainability research
- 2020
-
In: Nature Sustainability. - : Springer Science and Business Media LLC. - 2398-9629. ; 3:3, s. 182-190
-
Journal article (peer-reviewed)abstract
- Research practice, funding agencies and global science organizations suggest that research aimed at addressing sustainability challenges is most effective when 'co-produced' by academics and non-academics. Co-production promises to address the complex nature of contemporary sustainability challenges better than more traditional scientific approaches. But definitions of knowledge co-production are diverse and often contradictory. We propose a set of four general principles that underlie high-quality knowledge co-production for sustainability research. Using these principles, we offer practical guidance on how to engage in meaningful co-productive practices, and how to evaluate their quality and success. Research addressing sustainability issues is more effective if 'co-produced' by academics and non-academics, but definitions of co-production vary. This Perspective presents four knowledge co-production principles for sustainability research and guides on how to engage in co-productive practices.
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| 36. |
- Nyström, Magnus, et al.
(author)
-
Steering feedbacks toward healthier marine ecosystems
-
Other publication (other academic/artistic)abstract
- Marine ecosystem decline is accelerating. At some point degradation may pass a tipping point beyond which ecosystems become trapped in alternative degraded states, as a result of changes in critical feedbacks. Self-reinforcing feedbacks pose a major challenge for managers and policy-makers seeking remedial actions to curb the marine crisis. Here we synthesize the dynamics of critical feedbacks of the degraded states in five socio-economically important marine ecosystems; coral reefs, kelp forests, seagrass beds, shallow unvegetated soft-bottom habitats, and coastal pelagic food webs. A better understanding of the way human actions influence the strength and direction of feedbacks, how different feedbacks interact and at what scales they operate, is crucial for successful implementation of marine ecosystem management. We advocate a critical-feedback management approach that ventures beyond traditionally discipline boundaries, as an essential element of marine ecosystem management.
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| 37. |
- Pettersson, Carl Henrik, 1971-
(author)
-
The tectonic evolution of northwest Svalbard
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- Svalbard represents the uplifted and exhumed northwest corner of the Barents Sea Shelf. Pre-Carboniferous rocks of Svalbard are divided into the Eastern, Northwestern and Southwestern Terranes, were amalgamated during the Caledonian Orogen and are separated by north-south-trending strike-slip faults. Even though our knowledge of Svalbard’s pre-Carboniferous history has increased dramatically during the last two decades, a major issue remains: Where did the different tectonostratigraphic terranes of Svalbard originate? The answer to this question has profound significance for the entire eastern Laurentian margin, which spans two supercontinent cycles, from the amalgamation and breakup of Rodinia to the amalgamation of Pangea. This thesis constrains the tectonothermal evolution of Svalbard’s Northwestern Terrane (NWT) using ion microprobe and LA-ICP-MS U-Pb zircon geochronology and electron microprobe thermobarometry on metasediments, clastic rocks and granitoids. Detrital zircon age populations of metasediments from the NWT suggests that they (e.g. the Krossfjorden Group) were deposited at c. 1000 Ma in a remnant ocean basin setting outboard the Eastern Grenville Province and were subsequently deformed and intruded by Late Grenvillian granitoids during the final suturing of Rodinia. Thus, a northern branch of the Grenvillian/Sveconorwegian orogeny is not present. This older history of the NWT is extensively overprinted by Late Caledonian deformation and metamorphism, with peak metamorphic conditions of 850 °C at >6 kbars, and subsequent migmatization of the Krossfjorden Group at c. 420 Ma. Based on these data, together with the detrital zircon age population from overlying Late Silurian-Early Devonian clastic rocks, a unifying model is proposed involving fragments from the Grampian orogen and Avalonian crust originally accreted to the Laurentian margin, subsequently transported northwards along sinistral strike-slip faults during Scandian deformation.
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| 38. |
- Roggen, Heidi, et al.
(author)
-
2-Substituted agelasine analogs : Synthesis and biological activity, and structure and reactivity of synthetic intermediates
- 2011
-
In: Pure and Applied Chemistry. - 0033-4545 .- 1365-3075. ; 83:3, s. 645-653
-
Journal article (peer-reviewed)abstract
- 2-Substituted N-methoxy-9-methyl-9H-purin-6-amines were synthesized either from their corresponding 6-chloro-9-methyl-9H-purines or 2-chloro-N-methoxy-9-methyl-9H-purin-6-amine. Great diversity in the amino/imino tautomeric ratios was observed and calculated based on H-1 NMR. The tautomers were identified by 1D and 2D H-1, C-13, and N-15 NMR techniques, and showed significant variation both in C-13 and N-15 shift values. Comparison of the tautomeric ratios with Hammett F values revealed that as the field/inductive withdrawing abilities of the 2-substituent increased, the ratio of amino: imino tautomers was shifted toward the amino tautomer. Computational chemistry exposed the significance of hydrogen bonding between solvent and the compound in question to reach accurate predictions for tautomeric ratios. B3LYP/def2-TZVP density functional theory (DFT) calculations resulted in quantitatively more accurate predictions than when employing the less expensive BP86 functional. N-7-Alkylation of the 2-substituted N-methoxy-9-methyl-9H-purin-6-amines showed that when the field/inductive withdrawing ability of the 2-substituent reached a certain point the reactivity drastically dropped. This correlated with the atomic charges on N-7 calculated using a natural bond orbital (NBO) analysis. Biological screening of the final 2-substituted agelasine analogs indicated that the introduction of a methyl group in the 2-position is advantageous for antimycobacterial and antiprotozoal activity, and that an amino function may improve activity against several cancer cell lines.
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| 39. |
- Shah, Carl-Henrik, et al.
(author)
-
Vascular endothelial growth factor receptor 2, but not S100A4 or S100A6, correlates with prolonged survival in advanced urothelial carcinoma
- 2014
-
In: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 32:8, s. 1215-1224
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: A major challenge in muscle-invasive urothelial carcinoma (UC) is to identify biomarkers that can predict disease prognosis and treatment response after cystectomy. Therefore, we analyzed the potential prognostic value of the proteins vascular endothelial growth factor receptor 2 (VEGFR2), S100A4, and S100A6 in UC.METHODS: Retrospective outcome data and tumor specimens from 83 cystectomy patients with histologically confirmed invasive UC were included. Expression levels of VEGFR2 (also called flk-1 and KDR), S100A4, and S100A6 were analyzed in primary tumor tissue by immunohistochemistry.RESULTS: Immunohistochemical staining and analysis of VEGFR2, S100A4, and S100A6 showed localization mainly in tumor cell cytoplasm. High VEGFR2 expression and low tumor category were independent variables associated with longer overall survival (OS) and disease-free survival, revealed by a bivariate Cox proportional hazards regression model (both P<0.001). In addition, the univariate log-rank test and the Cox model demonstrated that OS beyond 2 years was significantly greater among patients with low S100A6 expression than in those with high S100A6 expression (P = 0.017 and 0.022, respectively). Differences in tumor expression of S100A4 were not significantly associated with outcome.CONCLUSION: In this study, VEGFR2 expression was significantly correlated with risk of disease relapse and OS in a defined cohort of patients with UC of the bladder treated by cystectomy.
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| 40. |
- Stevens, Kristen N, et al.
(author)
-
19p13.1 is a triple negative-specific breast cancer susceptibility locus
- 2012
-
In: Cancer Research. - 0008-5472 .- 1538-7445. ; 72, s. 1795-
-
Journal article (peer-reviewed)abstract
- The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with risk of ovarian cancer. Here we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 Odds Ratio (OR)=1.10, 95% Confidence Interval (CI) 1.05 - 1.15, p=3.49 x 10-5] and triple negative (TN) (ER, PR and HER2 negative) breast cancer [rs8170 OR=1.22, 95% CI 1.13 - 1.31, p=2.22 x 10-7]. However, rs8170 was no longer associated with ER-negative breast cancer risk when TN cases were excluded [OR=0.98, 95% CI 0.89 - 1.07, p=0.62]. In addition, a combined analysis of TN cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC) (n=3,566) identified a genome-wide significant association between rs8170 and TN breast cancer risk [OR=1.25, 95% CI 1.18 - 1.33, p=3.31 x 10-13]. Thus, 19p13.1 is the first triple negative-specific breast cancer risk locus and the first locus specific to a histological subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple negative tumors and other subtypes likely arise through distinct etiologic pathways.
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| 41. |
- Stray-Pedersen, Asbjorg, et al.
(author)
-
Primary immunodeficiency diseases : Genomic approaches delineate heterogeneous Mendelian disorders
- 2017
-
In: Journal of Allergy and Clinical Immunology. - : MOSBY-ELSEVIER. - 0091-6749 .- 1097-6825. ; 139:1, s. 232-245
-
Journal article (peer-reviewed)abstract
- Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/ 110) and management was directly altered in nearly a quarter (26/ 110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
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| 42. |
- Söderberg, Carl, et al.
(author)
-
Antipsychotics - Postmortem fatal and non-fatal reference concentrations
- 2016
-
In: Forensic Science International. - : Elsevier BV. - 0379-0738 .- 1872-6283. ; 266, s. 91-101
-
Journal article (peer-reviewed)abstract
- Making the diagnosis fatal intoxication is a challenging task for the forensic pathologist and toxicologist, particularly when the cases involve substances where reference information is scarce or not at all available. This study presents postmortem femoral blood concentrations for 24 antipsychotic substances, based on samples collected and analyzed from 4949 autopsy cases in Sweden during 1992-2010. In addition our study provides information about the prevalence of different antipsychotics in accidental, suicidal, homicidal and uncertain deaths.The data have been selected and evaluated according to strict inclusion and exclusion criteria as well as a manual, multi-reviewer, case-by-case evaluation. The reference information is subdivided into intoxications by one specific substance only (group A, n = 259), multi-substance intoxications (group B, n = 614) and postmortem controls, consisting of deaths not involving incapacitation by substances (group C, n = 507). Moreover, the results are compared with data based on therapeutic drug monitoring, and data collected from driving under the influence cases.Median concentrations in group A were significantly higher than in group C for all substances evaluated. For 17 of 24 substances, the median concentrations in group B were significantly higher than in group C. In general, the therapeutic drug monitoring and driving under the influence concentrations were similar to, or lower than, the concentrations in group C.
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| 43. |
- Thompson, Paul M., et al.
(author)
-
The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
-
In: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
-
Journal article (peer-reviewed)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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| 44. |
- Österblom, Henrik, et al.
(author)
-
Scientific mobilization of keystone actors for biosphere stewardship
- 2022
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12
-
Journal article (peer-reviewed)abstract
- The biosphere crisis requires changes to existing business practices. We ask how corporations can become sustainability leaders, when constrained by multiple barriers to collaboration for biosphere stewardship. We describe how scientists motivated, inspired and engaged with ten of the world’s largest seafood companies, in a collaborative process aimed to enable science-based and systemic transformations (2015–2021). CEOs faced multiple industry crises in 2015 that incentivized novel approaches. New scientific insights, an invitation to collaborate, and a bold vision of transformative change towards ocean stewardship, created new opportunities and direction. Co-creation of solutions resulted in new knowledge and trust, a joint agenda for action, new capacities, international recognition, formalization of an organization, increased policy influence, time-bound goals, and convergence of corporate change. Independently funded scientists helped remove barriers to cooperation, provided means for reflection, and guided corporate strategies and actions toward ocean stewardship. By 2021, multiple individuals exercised leadership and the initiative had transitioned from preliminary and uncomfortable conversations, to a dynamic, operational organization, with capacity to perform global leadership in the seafood industry. Mobilizing transformational agency through learning, collaboration, and innovation represents a cultural evolution with potential to redirect and accelerate corporate action, to the benefit of business, people and the planet.
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| 45. |
- Österblom, Henrik, et al.
(author)
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Transnational Corporations, Biosphere Stewardship, and Sustainable Futures
- 2022
-
In: Annual Review Environment and Resources. - : Annual Reviews. - 1543-5938 .- 1545-2050. ; 47, s. 609-635
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Research review (peer-reviewed)abstract
- Corporations are perceived as increasingly powerful and critically important to ensuring that irreversible climatological or ecological tipping points on Earth are not crossed. Environmental impacts of corporate activities include pollution of soils, freshwater and the ocean, depletion of ecosystems and species, unsustainable use of resources, changes to air quality, and alteration of the global climate. Negative social impacts include unacceptable working conditions, erosion of traditional practices, and increased inequalities. Multiple formal and informal mechanisms have been developed, and innovative examples of corporate biosphere stewardship have resulted in progress. However, the biosphere crisis underscores that such efforts have been insufficient and that transformative change is urgently needed. We provide suggestions for aligning corporate activities with the biosphere and argue that such corporate biosphere stewardship requires more ambitious approaches taken by corporations, combined with new and formalized public governance approaches by governments.
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