| 1. |
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| 2. |
- Sliz, E., et al.
(författare)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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| 3. |
- Tabassum, R, et al.
(författare)
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Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
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Tidskriftsartikel (refereegranskat)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
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| 4. |
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| 5. |
- Kurki, MI, et al.
(författare)
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FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
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Tidskriftsartikel (refereegranskat)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
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| 6. |
- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 7. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 8. |
- Broman, K. K., et al.
(författare)
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Surveillance of Sentinel Node-Positive Melanoma Patients with Reasons for Exclusion from MSLT-II: Multi-Institutional Propensity Score Matched Analysis
- 2021
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Ingår i: Journal of the American College of Surgeons. - : Ovid Technologies (Wolters Kluwer Health). - 1072-7515. ; 232:4, s. 424-431
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In sentinel lymph node (SLN)-positive melanoma, two randomized trials demonstrated equivalent melanoma-specific survival with nodal surveillance vs completion lymph node dissection (CLND). Patients with microsatellites, extranodal extension (ENE) in the SLN, or >3 positive SLNs constitute a high-risk group largely excluded from the randomized trials, for whom appropriate management remains unknown. STUDY DESIGN: SLN-positive patients with any of the three high-risk features were identified from an international cohort. CLND patients were matched 1:1 with surveillance patients using propensity scores. Risk of any-site recurrence, SLN-basin-only recurrence, and melanoma specific mortality were compared. RESULTS: Among 1,154 SLN-positive patients, 166 had ENE, microsatellites, and/or >3 positive SLN. At 18.5 months median follow-up, 49% had recurrence (vs 26% in patients without high-risk features, p < 0.01). Among high-risk patients, 52 (31%) underwent CLND and 114 (69%) received surveillance. Fifty-one CLND patients were matched to 51 surveillance patients. The matched cohort was balanced on tumor, nodal, and adjuvant treatment factors. There were no significant differences in any-site recurrence (CLND 49%, surveillance 45%, p = 0.99), SLN-basin-only recurrence (CLND 6%, surveillance 14%, p = 0.20), or melanoma-specific mortality (CLND 14%, surveillance 12%, p = 0.86). CONCLUSIONS: SLN-positive patients with microsatellites, ENE, or >3 positive SLN constitute a high-risk group with a 2-fold greater recurrence risk. For those managed with nodal surveillance, SLN-basin recurrences were more frequent, but all-site recurrence and melanoma-specific mortality were comparable to patients treated with CLND. Most recurrences were outside the SLN-basin, supporting use of nodal surveillance for SLN-positive patients with microsatellites, ENE, and/or >3 positive SLN. Crown Copyright (C) 2020 Published by Elsevier Inc. on behalf of the American College of Surgeons. All rights reserved.
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| 9. |
- Broman, K. K., et al.
(författare)
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Active surveillance of patients who have sentinel node positive melanoma: An international, multi-institution evaluation of adoption and early outcomes after the Multicenter Selective Lymphadenectomy trial II (MSLT-2)
- 2021
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 127:13, s. 2251-2261
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Tidskriftsartikel (refereegranskat)abstract
- Background For patients with sentinel lymph node (SLN)-positive cutaneous melanoma, the Second Multicenter Selective Lymphadenectomy trial demonstrated equivalent disease-specific survival (DSS) with active surveillance using nodal ultrasound versus completion lymph node dissection (CLND). Adoption and outcomes of active surveillance in clinical practice and in adjuvant therapy recipients are unknown. Methods In a retrospective cohort of SLN-positive adults treated at 21 institutions in Australia, Europe, and the United States from June 2017 to November 2019, the authors evaluated the impact of active surveillance and adjuvant therapy on all-site recurrence-free survival (RFS), isolated nodal RFS, distant metastasis-free survival (DMFS), and DSS using Kaplan-Meier curves and Cox proportional hazard models. Results Among 6347 SLN biopsies, 1154 (18%) were positive and had initial negative distant staging. In total, 965 patients (84%) received active surveillance, 189 (16%) underwent CLND. Four hundred thirty-nine patients received adjuvant therapy (surveillance, 38%; CLND, 39%), with the majority (83%) receiving anti-PD-1 immunotherapy. After a median follow-up of 11 months, 220 patients developed recurrent disease (surveillance, 19%; CLND, 22%), and 24 died of melanoma (surveillance, 2%; CLND, 4%). Sixty-eight patients had an isolated nodal recurrence (surveillance, 6%; CLND, 4%). In patients who received adjuvant treatment without undergoing prior CLND, all isolated nodal recurrences were resectable. On risk-adjusted multivariable analyses, CLND was associated with improved isolated nodal RFS (hazard ratio [HR], 0.36; 95% CI, 0.15-0.88), but not all-site RFS (HR, 0.68; 95% CI, 0.45-1.02). Adjuvant therapy improved all-site RFS (HR, 0.52; 95% CI, 0.47-0.57). DSS and DMFS did not differ by nodal management or adjuvant treatment. Conclusions Active surveillance has been adopted for most SLN-positive patients. At initial assessment, real-world outcomes align with randomized trial findings, including in adjuvant therapy recipients. Lay Summary For patients with melanoma of the skin and microscopic spread to lymph nodes, monitoring with ultrasound is an alternative to surgically removing the remaining lymph nodes. The authors studied adoption and real-world outcomes of ultrasound monitoring in over 1000 patients treated at 21 centers worldwide, finding that most patients now have ultrasounds instead of surgery. Although slightly more patients have cancer return in the lymph nodes with this strategy, typically, it can be removed with delayed surgery. Compared with up-front surgery, ultrasound monitoring results in the same overall risk of melanoma coming back at any location or of dying from melanoma.
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| 10. |
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| 11. |
- Eroglu, Z., et al.
(författare)
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Outcomes with adjuvant anti-PD-1 therapy in patients with sentinel lymph node-positive melanoma without completion lymph node dissection
- 2022
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Ingår i: Journal for Immunotherapy of Cancer. - : BMJ. - 2051-1426. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients.
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| 12. |
- Jack, C. R., et al.
(författare)
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Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative 2
- 2015
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:7, s. 740-756
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Alzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders. Methods: We review the contributions of the MRI core from present and past cycles of ADNI (ADNI-1, -Grand Opportunity and -2). We also review plans for the future-ADNI-3. Results: Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials. Discussion: Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future. (C) 2015 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.
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| 13. |
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| 14. |
- Agrawal, K., et al.
(författare)
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Allergic sensitization impairs lung resident memory CD8 T-cell response and virus clearance
- 2022
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749. ; 150:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with asthma often suffer from frequent respiratory viral infections and reduced virus clearance. Lung resident memory T cells provide rapid protection against viral reinfections. Objective: Because the development of resident memory T cells relies on the lung microenvironment, we investigated the impact of allergen sensitization on the development of virus-specific lung resident memory T cells and viral clearance. Methods: Mice were sensitized with house dust mite extract followed by priming with X47 and a subsequent secondary influenza infection. Antiviral memory T-cell response and protection to viral infection was assessed before and after secondary influenza infection, respectively. Gene set variation analysis was performed on data sets from the U-BIOPRED asthma cohort using an IFN-γ–induced epithelial cell signature and a tissue resident memory T-cell signature. Results: Viral loads were higher in lungs of sensitized compared with nonsensitized mice after secondary infection, indicating reduced virus clearance. X47 priming induced fewer antiviral lung resident memory CD8 T cells and resulted in lower pulmonary IFN-γ levels in the lungs of sensitized as compared with nonsensitized mice. Using data from the U-BIOPRED cohort, we found that patients with enrichment of epithelial IFN-γ–induced genes in nasal brushings and bronchial biopsies were also enriched in resident memory T-cell–associated genes, had more epithelial CD8 T cells, and reported significantly fewer exacerbations. Conclusions: The allergen-sensitized lung microenvironment interferes with the formation of antiviral resident memory CD8 T cells in lungs and virus clearance. Defective antiviral memory response might contribute to increased susceptibility of patients with asthma to viral exacerbations.
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| 15. |
- Avetisyan, A., et al.
(författare)
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Preface
- 2019
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Ingår i: APSSE 2019 Actual Problems of System and Software Engineering. - : CEUR-WS. ; , s. 1-2
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Konferensbidrag (refereegranskat)
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| 16. |
- Chatzikonstantinou, T, et al.
(författare)
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COVID-19 severity and mortality in patients with CLL: an update of the international ERIC and Campus CLL study
- 2021
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 35:12, s. 3444-3454
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Tidskriftsartikel (refereegranskat)abstract
- Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated.
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| 17. |
- Divakar, Pradeep K., et al.
(författare)
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Evolution of complex symbiotic relationships in a morphologically derived family of lichen-forming fungi
- 2015
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Ingår i: New Phytologist. - : Wiley. - 0028-646X .- 1469-8137. ; 208:4, s. 1217-1226
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Tidskriftsartikel (refereegranskat)abstract
- We studied the evolutionary history of the Parmeliaceae (Lecanoromycetes, Ascomycota), one of the largest families of lichen-forming fungi with complex and variable morphologies, also including several lichenicolous fungi. We assembled a six-locus data set including nuclear, mitochondrial and low-copy protein-coding genes from 293 operational taxonomic units (OTUs). The lichenicolous lifestyle originated independently three times in lichenized ancestors within Parmeliaceae, and a new generic name is introduced for one of these fungi. In all cases, the independent origins occurred c. 24 million yr ago. Further, we show that the Paleocene, Eocene and Oligocene were key periods when diversification of major lineages within Parmeliaceae occurred, with subsequent radiations occurring primarily during the Oligocene and Miocene. Our phylogenetic hypothesis supports the independent origin of lichenicolous fungi associated with climatic shifts at the Oligocene-Miocene boundary. Moreover, diversification bursts at different times may be crucial factors driving the diversification of Parmeliaceae. Additionally, our study provides novel insight into evolutionary relationships in this large and diverse family of lichen-forming ascomycetes.
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| 18. |
- Frisoni, G. B., et al.
(författare)
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Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers
- 2017
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Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 16:8, s. 661-676
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Tidskriftsartikel (refereegranskat)abstract
- The diagnosis of Alzheimer's disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimer's disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimer's disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics.
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| 19. |
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| 20. |
- Mansouri, L, et al.
(författare)
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Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY
- 2023
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 37:2, s. 339-347
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Tidskriftsartikel (refereegranskat)abstract
- Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3–9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.
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| 21. |
- Sutton, M. A., et al.
(författare)
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Dynamics of ammonia exchange with cut grassland : Strategy and implementation of the GRAMINAE Integrated Experiment
- 2009
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Ingår i: Biogeosciences. - : Copernicus Publications (on behalf of the European Geosciences Union). - 1726-4170 .- 1726-4189. ; 6:3, s. 309-331
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Tidskriftsartikel (refereegranskat)abstract
- A major international experiment on ammonia (NH3) biosphere-atmosphere exchange was conducted over intensively managed grassland at Braunschweig, Germany. The experimental strategy was developed to allow an integrated analysis of different features of NH3 exchange including: a) quantification of nearby emissions and advection effects, b) estimation of net NH3 fluxes with the canopy by a range of micrometeorological measurements, c) analysis of the sources and sinks of NH3 within the plant canopy, including soils and bioassay measurements, d) comparison of the effects of grassland management options on NH3 fluxes and e) assessment of the interactions of NH3 fluxes with aerosol exchange processes. Additional technical objectives included the inter-comparison of different estimates of sensible and latent heat fluxes, as well as continuous-gradient and Relaxed Eddy Accumulation (REA) systems for NH3 fluxes. The prior analysis established the spatial and temporal design of the experiment, allowing significant synergy between these objectives. The measurements were made at 7 measurement locations, thereby quantifying horizontal and vertical profiles, and covered three phases: a) tall grass canopy prior to cutting (7 days), b) short grass after cutting (7 days) and c) re-growing sward following fertilization with ammonium nitrate (10 days). The sequential management treatments allowed comparison of sources-sinks, advection and aerosol interactions under a wide range of NH3 fluxes. This paper describes the experimental strategy and reports the grassland management history, soils, environmental conditions and air chemistry during the experiment, finally summarizing how the results are coordinated in the accompanying series of papers.
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| 22. |
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| 23. |
- Vas de Almeida, M D., et al.
(författare)
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Alcohol consumption in elderly people across European countries : Results from the food in later life project
- 2005
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Ingår i: Ageing International. - : Springer Science and Business Media LLC. - 0163-5158 .- 1936-606X. ; 30:4, s. 377-395
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this paper is to identify social and cultural aspects of alcohol consumption in a sample of older people living in their own homes, in eight different European countries. We explore several aspects of alcohol consumption, establishing comparisons between genders, age groups and living circumstances. The phenomenon of alcohol consumption within these countries and cultures is compared in order to gain a better understanding of similarities and differences.
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| 24. |
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| 25. |
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| 26. |
- Bjornstad, T., et al.
(författare)
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The Doubly Closed Shell Nucleus Sn-132(50)82
- 1986
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Ingår i: Nuclear Physics A. - : Elsevier BV. - 0375-9474. ; 453:3, s. 463-485
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Tidskriftsartikel (refereegranskat)abstract
- The structure of excited states in 132Sn, fed in the β-decay of 132In, has been investigated. Absolute intensities were deduced from γ-singles measurements. From multi-spectrum analysis of γ-lines the half-life of 132In was determined to be 186 ± 22 ms. A level scheme based on γγ and βγ coincidences is presented. The conversion electron spectrum has been studied and internal conversion coefficients deduced for two low-energy transitions. The total decay energy of 132In was determined, from γ-gated β-spectra, to be Qβ = 13.6 ± 0.4 MeV. A lower limit of 6.968 MeV for the neutron separation energy in 132Sn was deduced from the β-delayed neutron spectrum. The experimental results on the level structure of the doubly closed shell nucleus 132Sn show that the shell model is applicable even far from the valley of stability.
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| 27. |
- Bridel, Claire, et al.
(författare)
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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
- 2019
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
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Forskningsöversikt (refereegranskat)abstract
- Importance Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure The cNfL levels adjusted for age and sex across diagnoses.Results Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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| 28. |
- Crespo, Ana, et al.
(författare)
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Phylogenetic generic classification of parmelioid lichens (Parmeliaceae,Ascomycota) based on molecular, morphological and chemical evidence.
- 2010
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Ingår i: Taxon. - : John Wiley & Sons. - 0040-0262 .- 1996-8175. ; 59:6, s. 1735-1753
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Tidskriftsartikel (refereegranskat)abstract
- Parmelioid lichens are a diverse and ubiquitous group of foliose lichens. Generic delimitation in parmelioid lichens has been in a state of flux since the late 1960s with the segregation of the large, heterogeneous genus Parmelia into numerous smaller genera. Recent molecular phylogenetic studies have demonstrated that some of these new genera were monophyletic, some were not, and others, previously believed to be unrelated, fell within single monophyletic groups, indicating the need for a revision of the generic delimitations. This study aims to give an overview of current knowledge of the major clades of all parmelioid lichens. For this, we assembled a dataset of 762 specimens, including 31 of 33 currently accepted parmelioid genera (and 63 of 84 accepted genera of Parmeliaceae). We performed maximum likelihood and Bayesian analyses of combined datasets including two, three and four loci. Based on these phylogenies and the correlation of morphological and chemical characters that characterize monophyletic groups, we accept 27 genera within nine main clades. We re-circumscribe several genera and reduce Parmelaria to synonymy with Parmotrema. Emodomelanelia Divakar & A. Crespo is described as a new genus (type: E. masonii). Nipponoparmelia (Kurok.) K.H. Moon, Y. Ohmura & Kashiw. ex A. Crespo & al. is elevated to generic rank and 15 new combinations are proposed (in the genera Flavoparmelia, Parmotrema, Myelochroa, Melanelixia and Nipponoparmelia). A short discussion of the accepted genera is provided and remaining challenges and areas requiring additional taxon sampling are identified.
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| 31. |
- DiJulio, Douglas, et al.
(författare)
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Electromagnetic properties of vibrational bands in Er-170
- 2011
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Ingår i: European Physical Journal A. - : Springer Science and Business Media LLC. - 1434-6001 .- 1434-601X. ; 47:2, s. 25-
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Tidskriftsartikel (refereegranskat)abstract
- Excited states of the nucleus Er-170 have been studied by Coulomb excitation using the GASP gamma-ray detector system at the Laboratori Nazionali di Legnaro. The ground-state band along with a low-lying K-pi = 0(+) band and gamma-vibrational band were populated during the experiment. Based on the measured gamma-ray yields, a set of interband and intraband matrix elements has been extracted using the Coulomb excitation code GOSIA. The resulting E2 matrix elements are compared to collective model predictions.
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| 32. |
- Drevinge, Christina, 1983, et al.
(författare)
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Perilipin 5 is protective in the ischemic heart
- 2016
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 219, s. 446-454
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Tidskriftsartikel (refereegranskat)abstract
- Background: Myocardial ischemia is associated with alterations in cardiac metabolism, resulting in decreased fatty acid oxidation and increased lipid accumulation. Here we investigate how myocardial lipid content and dynamics affect the function of the ischemic heart, and focus on the role of the lipid droplet protein perilipin 5 (Plin5) in the pathophysiology of myocardial ischemia. Methods and results: We generated Plin5(-/-) mice and found that Plin5 deficiency dramatically reduced the triglyceride content in the heart. Under normal conditions, Plin5(-/-) mice maintained a close to normal heart function by decreasing fatty acid uptake and increasing glucose uptake, thus preserving the energy balance. However, during stress or myocardial ischemia, Plin5 deficiency resulted in myocardial reduced substrate availability, severely reduced heart function and increased mortality. Importantly, analysis of a human cohort with suspected coronary artery disease showed that a common noncoding polymorphism, rs884164, decreases the cardiac expression of PLIN5 and is associated with reduced heart function following myocardial ischemia, indicating a role for Plin5 in cardiac dysfunction. Conclusion: Our findings indicate that Plin5 deficiency alters cardiac lipid metabolism and associates with reduced survival following myocardial ischemia, suggesting that Plin5 plays a beneficial role in the heart following ischemia. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.
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| 33. |
- Ekman, Stina, et al.
(författare)
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Effect of circadian rhythm, age, training and acute lameness on serum concentrations of cartilage oligomeric matrix protein (COMP) neo-epitope in horses
- 2019
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Ingår i: Equine Veterinary Journal. - : Wiley. - 0425-1644 .- 2042-3306. ; 51:5, s. 674-680
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Tidskriftsartikel (refereegranskat)abstract
- Background Molecular serum markers that can identify early reversible osteoarthritis (OA) in horses are lacking. Objectives We studied serum concentrations of a novel cartilage oligomeric matrix protein (COMP) neo-epitope in horses subjected to short-term exercise and with acute lameness. The effects of circadian rhythm and age were also evaluated. Study design Longitudinal studies in healthy horses and cross-sectional comparison of lame and non-lame horses. Methods Sera were collected from five horses before and after short-term interval exercise and during full-day box rest. Sera from 32 acutely lame horses were used to evaluate age-related effects. Independent samples from control horses (n = 41) and horses with acute lameness (n = 71) were included. COMP neo-epitope concentrations were analysed using custom-developed inhibition ELISAs validated for equine serum. The presence of COMP neo-epitope was delineated in healthy and osteoarthritic articular cartilage with immunohistochemistry. Results COMP neo-epitope concentrations decreased after speed training but returned to baseline levels post-exercise. No correlations between age and serum COMP neo-epitope concentrations were found (r = 0.0013). The mean (+/- s.d.) serum concentration of COMP neo-epitope in independent samples from non-lame horses was 0.84 +/- 0.38 mu g/mL, and for lame horses was 5.24 +/- 1.83 mu g/mL (P<0.001). Antibodies against COMP neo-epitope did not stain normal articular cartilage, but intracytoplasmic staining was found in superficial chondrocytes of mild OA cartilage and in the extracellular matrix of moderately osteoarthritic cartilage. Main limitations ELISA was based on polyclonal antisera rather than a monoclonal antibody. There is a sex and breed bias within the groups of horses, also it could have been of value to include horses with septic arthritis and tendonitis and investigated joint differences. Conclusions This COMP neo-epitope can be measured in sera, and results indicate that it could be a biomarker for pathologic fragmentation of cartilage in connection with acute joint lameness.
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| 34. |
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| 35. |
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| 36. |
- Grdic, D, et al.
(författare)
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Splenic marginal zone dendritic cells mediate the cholera toxin adjuvant effect : Dependence on the ADP-ribosyltransferase activity of the holotoxin
- 2005
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Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 175:8, s. 5192-5202
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Tidskriftsartikel (refereegranskat)abstract
- The in vivo mechanisms of action of most vaccine adjuvants are poorly understood. In this study, we present data in mice that reveal a series of critical interactions between the cholera toxin (CT) adjuvant and the dendritic cells (DC) of the splenic marginal zone (MZ) that lead to effective priming of an immune response. For the first time, we have followed adjuvant targeting of MZ DC in vivo. We used CT-conjugated OVA and found that the Ag selectively accumulated in MZ DC following i.v. injections. The uptake of Ag into DC was GM1 ganglioside receptor dependent and mediated by the B subunit of CT (CTB). The targeted MZ DC were quite unique in their phenotype: CD11c(+), CD8 alpha(-), CD11b(-), B220(-), and expressing intermediate or low levels of MHC class II and DEC205. Whereas CTB only delivered the Ag to MZ DC, the ADP-ribosyltransferase activity of CT was required for the maturation and migration of DC to the T cell zone, where these cells distinctly up-regulated CD86, but not CD80. This interaction appeared to instruct Ag-specific CD4(+) T cells to move into the B cell follicle and strongly support germinal center formations. These events may explain why CT-conjugated Ag is substantially more immunogenic than Ag admixed with soluble CT and why CTB-conjugated Ag can tolerize immune responses when given orally or at other mucosal sites.
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| 37. |
- Grinberg, Marianna, et al.
(författare)
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Reaching the limits of prognostication in non-small cell lung cancer : an optimized biomarker panel fails to outperform clinical parameters.
- 2017
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 30:7, s. 964-977
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Tidskriftsartikel (refereegranskat)abstract
- Numerous protein biomarkers have been analyzed to improve prognostication in non-small cell lung cancer, but have not yet demonstrated sufficient value to be introduced into clinical practice. Here, we aimed to develop and validate a prognostic model for surgically resected non-small cell lung cancer. A biomarker panel was selected based on (1) prognostic association in published literature, (2) prognostic association in gene expression data sets, (3) availability of reliable antibodies, and (4) representation of diverse biological processes. The five selected proteins (MKI67, EZH2, SLC2A1, CADM1, and NKX2-1 alias TTF1) were analyzed by immunohistochemistry on tissue microarrays including tissue from 326 non-small cell lung cancer patients. One score was obtained for each tumor and each protein. The scores were combined, with or without the inclusion of clinical parameters, and the best prognostic model was defined according to the corresponding concordance index (C-index). The best-performing model was subsequently validated in an independent cohort consisting of tissue from 345 non-small cell lung cancer patients. The model based only on protein expression did not perform better compared to clinicopathological parameters, whereas combining protein expression with clinicopathological data resulted in a slightly better prognostic performance (C-index: all non-small cell lung cancer 0.63 vs 0.64; adenocarcinoma: 0.66 vs 0.70, squamous cell carcinoma: 0.57 vs 0.56). However, this modest effect did not translate into a significantly improved accuracy of survival prediction. The combination of a prognostic biomarker panel with clinicopathological parameters did not improve survival prediction in non-small cell lung cancer, questioning the potential of immunohistochemistry-based assessment of protein biomarkers for prognostication in clinical practice.Modern Pathology advance online publication, 10 March 2017; doi:10.1038/modpathol.2017.14.
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| 38. |
- Gulda, K, et al.
(författare)
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Quadrupole deformed and octupole collective bands in Ra-228
- 1998
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Ingår i: NUCLEAR PHYSICS A. - : ELSEVIER SCIENCE BV. - 0375-9474. ; 636:1, s. 28-46
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Tidskriftsartikel (refereegranskat)abstract
- Spins and parities for collective states in Ra-228 have been determined from conversion electron measurements with a mini-orange beta spectrometer. The fast-timing beta gamma gamma(t) method has been used to measure lifetimes of T-1/2 = 550(20) ps and 181
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| 39. |
- Herrmann, B., et al.
(författare)
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Vertical structure and diurnal variability of ammonia exchange potential within an intensively managed grass canopy
- 2009
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Ingår i: Biogeosciences. - Kaltenburg-Lindau : Copernicus on behalf of the European Geosciences Union. - 1726-4170 .- 1726-4189. ; 6:1, s. 15-23
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Tidskriftsartikel (refereegranskat)abstract
- Stomatal ammonia compensation points (χs) of grass species on a mixed fertilized grassland were determined by measurements of apoplastic [NH4+] and [H>+] in the field. Calculated χs values were compared with in-canopy atmospheric NH3 concentration (χa) measurements.Leaf apoplastic [NH4+] increased by a factor of two from the lowest level in the canopy to the top level. Bulk leaf [NH4+] and especially [NO3−] slightly increased at the bottom of the canopy and these concentrations were very high in senescent plant litter. Calculated χs values were below atmospheric χs at all canopy levels measured, indicating that the grassland was characterized by NH3 deposition before cutting. This was confirmed by the χa profile, showing the lowest χa close to the ground (15 cm above soil surface) and an increase in χa with canopy height. Neither χs nor χa could be measured close to the soil surface, however, the [NH4+] in the litter material indicated a high potential for NH3 emission.A diurnal course in apoplastic [NH4+] was seen in the regrowing grass growing after cutting, with highest concentration around noon. Both apoplastic and tissue [NH4+] increased in young grass compared to tall grass. Following cutting, in-canopy gradients of atmospheric χa showed NH3 emission but since calculated χs values of the cut grass were still lower than atmospheric NH3 concentrations, the emissions could not entirely be explained by stomatal NH3 loss. High tissue [NH4+] in the senescent plant material indicated that this fraction constituted an NH3 source. After fertilization, [NH4+] increased both in apoplast and leaf tissue with the most pronounced increase in the former compared to the latter. The diurnal pattern in apoplastic [NH4+] was even more pronounced after fertilization and calculated χs values were generally higher, but remained below atmospheric [NH3].
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| 40. |
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| 41. |
- Klaric, Lucija, et al.
(författare)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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| 42. |
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| 43. |
- Lagergren, K, et al.
(författare)
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Haemochromatosis and gastrointestinal cancer
- 2016
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Ingår i: International journal of cancer. - : Wiley. - 1097-0215 .- 0020-7136. ; 139:8, s. 1740-1743
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Tidskriftsartikel (refereegranskat)
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| 44. |
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| 45. |
- Lång, K., et al.
(författare)
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14C bomb-pulse dating and stable isotope analysis for growth rate and dietary information in breast cancer?
- 2016
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Ingår i: Radiation Protection Dosimetry. - : Oxford University Press (OUP). - 0144-8420 .- 1742-3406. ; 169:1, s. 158-164
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to perform an initial investigation of the possibility to determine breast cancer growth rate with 14C bomb-pulse dating. Tissues from 11 breast cancers, diagnosed in 1983, were retrieved from a regional biobank. The estimated average age of the majority of the samples overlapped the year of collection (1983) within 3σ. Thus, this first study of tumour tissue has not yet demonstrated that 14C bomb-pulse dating can obtain information on the growth of breast cancer. However, with further refinement, involving extraction of cell types and components, there is a possibility that fundamental knowledge of tumour biology might still be gained by the bomb-pulse technique. Additionally, δ13C and δ15N analyses were performed to obtain dietary and metabolic information, and to serve as a base for improvement of the age determination.
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| 47. |
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