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1.	Heid, Iris M, et al. (author) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution 2010 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960 Journal article (peer-reviewed)abstract Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
2.	Hillier, Ladeana W, et al. (author) Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution 2004 In: Nature. - 0028-0836 .- 1476-4687. ; 432:7018, s. 695-716 Journal article (peer-reviewed)abstract We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.
3.	Lango Allen, Hana, et al. (author) Hundreds of variants clustered in genomic loci and biological pathways affect human height. 2010 In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8 Journal article (peer-reviewed)abstract Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
4.	Speliotes, Elizabeth K., et al. (author) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index 2010 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948 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.
5.	Chen, Weena J Y, et al. (author) Association of plasma osteoprotegerin and adiponectin with arterial function, cardiac function and metabolism in asymptomatic type 2 diabetic men 2011 In: Cardiovascular Diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 10, s. 67- Journal article (peer-reviewed)abstract BACKGROUND:Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, is linked to cardiovascular disease. Negative associations exist between circulating OPG and cardiac function. The adipocytokine adiponectin (ADPN) is downregulated in type 2 diabetes mellitus (T2DM) and coronary artery disease and shows an inverse correlation with insulin sensitivity and cardiovascular disease risk. We assessed the relationship of plasma OPG and ADPN and arterial function, cardiac function and myocardial glucose metabolism in T2DM.METHODS:We included 78 asymptomatic men with uncomplicated, well-controlled T2DM, without inducible ischemia, assessed by dobutamine-stress echocardiography, and 14 age-matched controls. Cardiac function was measured by magnetic resonance imaging, myocardial glucose metabolism (MMRglu) by 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography. OPG and ADPN levels were measured in plasma.RESULTS:T2DM patients vs. controls showed lower aortic distensibility, left ventricular (LV) volumes, impaired LV diastolic function and MMRglu (all P < 0.05). In T2DM men vs. controls, OPG levels were higher (P = 0.02), whereas ADPN concentrations were decreased (P = 0.04). OPG correlated inversely with aortic distensibility, LV volumes and E/A ratio (diastolic function), and positively with LV mass/volume ratio (all P < 0.05). Regression analyses showed the associations with aortic distensibility and LV mass/volume ratio to be independent of age-, blood pressure- and glycated hemoglobin (HbA1c). However, the associations with LV volumes and E/A ratio were dependent of these parameters. ADPN correlated positively with MMRglu (P < 0.05), which, in multiple regression analysis, was dependent of whole-body insulin sensitivity, HbA1c and waist.CONCLUSIONS:OPG was inversely associated with aortic distensibility, LV volumes and LV diastolic function, while ADPN was positively associated with MMRglu. These findings indicate that in asymptomatic men with uncomplicated T2DM, OPG and ADPN may be markers of underlying mechanisms linking the diabetic state to cardiac abnormalities.TRIAL REGISTRATION:Current Controlled Trials ISRCTN53177482.
6.	Estrada, Karol, et al. (author) A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation. 2009 In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 18:18, s. 3516-24 Journal article (peer-reviewed)abstract Northwestern Europeans are among the tallest of human populations. The increase in body height in these people appears to have reached a plateau, suggesting the ubiquitous presence of an optimal environment in which genetic factors may have exerted a particularly strong influence on human growth. Therefore, we performed a genome-wide association study (GWAS) of body height using 2.2 million markers in 10 074 individuals from three Dutch and one German population-based cohorts. Upon genotyping, the 12 most significantly height-associated single nucleotide polymorphisms (SNPs) from this GWAS in 6912 additional individuals of Dutch and Swedish origin, a genetic variant (rs6717918) on chromosome 2q37.1 was found to be associated with height at a genome-wide significance level (P(combined) = 3.4 x 10(-9)). Notably, a second SNP (rs6718438) located approximately 450 bp away and in strong LD (r(2) = 0.77) with rs6717918 was previously found to be suggestive of a height association in 29 820 individuals of mainly northwestern European ancestry, and the over-expression of a nearby natriuretic peptide precursor type C (NPPC) gene, has been associated with overgrowth and skeletal anomalies. We also found a SNP (rs10472828) located on 5p14 near the natriuretic peptide receptor 3 (NPR3) gene, encoding a receptor of the NPPC ligand, to be associated with body height (P(combined) = 2.1 x 10(-7)). Taken together, these results suggest that variation in the C-type natriuretic peptide signaling pathway, involving the NPPC and NPR3 genes, plays an important role in determining human body height.
7.	Fall, Tove, et al. (author) The Role of Adiposity in Cardiometabolic Traits : A Mendelian Randomization Analysis 2013 In: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 10:6, s. e1001474- Journal article (peer-reviewed)abstract Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
8.	In ’t Veld, Sjors G.J.G., et al. (author) Detection and localization of early- and late-stage cancers using platelet RNA 2022 In: Cancer Cell. - : Elsevier. - 1535-6108 .- 1878-3686. ; 40:9, s. 999-1009.e6 Journal article (peer-reviewed)abstract Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.
9.	Prokopenko, Inga, et al. (author) Variants in MTNR1B influence fasting glucose levels 2009 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 77-81 Journal article (peer-reviewed)abstract To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
10.	Reverté, Sara, et al. (author) National records of 3000 European bee and hoverfly species : A contribution to pollinator conservation 2023 In: Insect Conservation and Diversity. - 1752-458X. ; 16:6, s. 758-775 Journal article (peer-reviewed)abstract Pollinators play a crucial role in ecosystems globally, ensuring the seed production of most flowering plants. They are threatened by global changes and knowledge of their distribution at the national and continental levels is needed to implement efficient conservation actions, but this knowledge is still fragmented and/or difficult to access. As a step forward, we provide an updated list of around 3000 European bee and hoverfly species, reflecting their current distributional status at the national level (in the form of present, absent, regionally extinct, possibly extinct or non-native). This work was attainable by incorporating both published and unpublished data, as well as knowledge from a large set of taxonomists and ecologists in both groups. After providing the first National species lists for bees and hoverflies for many countries, we examine the current distributional patterns of these species and designate the countries with highest levels of species richness. We also show that many species are recorded in a single European country, highlighting the importance of articulating European and national conservation strategies. Finally, we discuss how the data provided here can be combined with future trait and Red List data to implement research that will further advance pollinator conservation.
11.	Ried, Janina S., et al. (author) A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape 2016 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7 Journal article (peer-reviewed)abstract Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
12.	Surakka, Ida, et al. (author) The impact of low-frequency and rare variants on lipid levels. 2015 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:6, s. 589-597 Journal article (peer-reviewed)abstract Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.
13.	van der Harst, Pim, et al. (author) Seventy-five genetic loci influencing the human red blood cell 2012 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7429, s. 369-375 Journal article (peer-reviewed)abstract Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
14.	Aulchenko, Yurii S, et al. (author) Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts 2009 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41:1, s. 47-55 Journal article (peer-reviewed)abstract Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 x 10(-11); LDL, P = 2.6 x 10(-10)), TMEM57 (TC, P = 5.4 x 10(-10)), CTCF-PRMT8 region (HDL, P = 8.3 x 10(-16)), DNAH11 (LDL, P = 6.1 x 10(-9)), FADS3-FADS2 (TC, P = 1.5 x 10(-10); LDL, P = 4.4 x 10(-13)) and MADD-FOLH1 region (HDL, P = 6 x 10(-11)). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.
15.	Barban, N, et al. (author) Genome-wide analysis identifies 12 loci influencing human reproductive behavior 2016 In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 48:12, s. 1462-1472 Journal article (peer-reviewed)
16.	Best, Myron G., et al. (author) RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics 2015 In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 28:5, s. 666-676 Journal article (peer-reviewed)abstract Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based "liquid biopsies".
17.	Best, Myron G., et al. (author) Swarm Intelligence-Enhanced Detection of Non-Small-Cell Lung Cancer Using Tumor-Educated Platelets 2017 In: Cancer Cell. - : Elsevier. - 1535-6108 .- 1878-3686. ; 32:2, s. 238-252 Journal article (peer-reviewed)abstract Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92-0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83-0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources.
18.	de Langen, Adrianus J, et al. (author) Monitoring response to antiangiogenic therapy in non-small cell lung cancer using imaging markers derived from PET and dynamic contrast-enhanced MRI 2011 In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 52:1, s. 48-55 Journal article (peer-reviewed)abstract With antiangiogenic agents, tumor shrinkage may be absent, despite survival benefit. The present study assessed the predictive value of molecular imaging for the identification of survival benefit during antiangiogenic treatment with bevacizumab and erlotinib in patients with advanced non–small cell lung cancer.Methods:Patients were evaluated using an imaging protocol including CT, 18F-FDG PET, H215O PET, and dynamic contrast-enhanced MRI to derive measurements on tumor size, glucose metabolism, perfusion, and microvascular permeability. The percentage change in imaging parameters after 3 wk of treatment as compared with baseline was calculated and correlated with progression-free survival (PFS).Results:Forty-four patients were included, and 40 underwent CT and 18F-FDG PET at both time points. Complete datasets, containing all imaging modalities, were available for 14 patients. Bevacizumab and erlotinib treatment resulted in decreased metabolism, perfusion, and tumor size. A decrease in standardized uptake value or tumor perfusion of more than 20% at week 3 was associated with longer PFS (9.7 vs. 2.8 mo, P = 0.01, and 12.5 vs. 2.9 mo, P = 0.009, respectively). Whole-tumor Ktrans (the endothelial transfer constant) was not associated with PFS, but patients with an increase of more than 15% in the SD of tumor Ktrans values—that is, an increase in regions with low or high Ktrans values—after 3 wk had shorter PFS (2.3 vs. 7.0 mo, P = 0.008). A partial response, according to the response evaluation criteria in solid tumors (RECIST), at week 3 was also associated with prolonged PFS (4.6 vs. 2.9 mo, P = 0.017). However, 40% of patients with a partial response as their best RECIST response still had stable disease at week 3. In these cases tumor perfusion was already decreased and Ktrans heterogeneity showed no increase, indicating that the latter parameters seem to be more discriminative than RECIST at the 3-wk time point.Conclusion:PET and dynamic contrast-enhanced MRI were able to identify patients who benefit from bevacizumab and erlotinib treatment. Molecular imaging seems to allow earlier response evaluation than CT.
19.	During, Melanie A. D., et al. (author) The Mesozoic terminated in boreal spring 2022 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 603:7899, s. 91-94 Journal article (peer-reviewed)abstract The Cretaceous–Palaeogene mass extinction around 66 million years ago was triggered by the Chicxulub asteroid impact on the present-day Yucatán Peninsula. This event caused the highly selective extinction that eliminated about 76% of species, including all non-avian dinosaurs, pterosaurs, ammonites, rudists and most marine reptiles. The timing of the impact and its aftermath have been studied mainly on millennial timescales, leaving the season of the impact unconstrained. Here, by studying fishes that died on the day the Mesozoic era ended, we demonstrate that the impact that caused the Cretaceous–Palaeogene mass extinction took place during boreal spring. Osteohistology together with stable isotope records of exceptionally preserved perichondral and dermal bones in acipenseriform fishes from the Tanis impact-induced seiche deposits reveal annual cyclicity across the final years of the Cretaceous period. Annual life cycles, including seasonal timing and duration of reproduction, feeding, hibernation and aestivation, vary strongly across latest Cretaceous biotic clades. We postulate that the timing of the Chicxulub impact in boreal spring and austral autumn was a major influence on selective biotic survival across the Cretaceous–Palaeogene boundary.
20.	Goderis, Steven, et al. (author) Globally distributed iridium layer preserved within the Chicxulub impact structure 2021 In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:9 Journal article (peer-reviewed)abstract The Cretaceous-Paleogene (K-Pg) mass extinction is marked globally by elevated concentrations of iridium, emplaced by a hypervelocity impact event 66 million years ago. Here, we report new data from four independent laboratories that reveal a positive iridium anomaly within the peak-ring sequence of the Chicxulub impact structure, in drill core recovered by IODP-ICDP Expedition 364. The highest concentration of ultrafine meteoritic matter occurs in the post-impact sediments that cover the crater peak ring, just below the lowermost Danian pelagic limestone. Within years to decades after the impact event, this part of the Chicxulub impact basin returned to a relatively low-energy depositional environment, recording in unprecedented detail the recovery of life during the succeeding millennia. The iridium layer provides a key temporal horizon precisely linking Chicxulub to K-Pg boundary sections worldwide.
21.	Gulick, Sean, P.S., et al. (author) The first day of the Cenozoic 2019 In: Proceedings of the National Academy of Sciences of the United States of America. - : US National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116, s. 19342-19351 Journal article (peer-reviewed)abstract Highly expanded Cretaceous–Paleogene (K-Pg) boundary section from the Chicxulub peak ring, recovered by International Ocean Discovery Program (IODP) –International Continental Scientific Drilling Program (ICDP) Expedition 364, provides an unprecedented window into the immediate aftermath of the impact. Site M0077 includes ∼130 m of impact melt rock and suevite deposited the first day of the Cenozoic covered by <1 m of micrite-rich carbonate deposite over subsequent weeks to years. We present an interpreted series of events based on analyses of these drill cores. Within minutes of the impact, centrally uplifted basement rock collapsed outward to forma peak ring capped in melt rock. Within tens of minutes, the peak ring was covered in ∼40 m of brecciated impact melt rock and coarsegrained suevite, including clasts possibly generated by melt–water interactions during ocean resurge. Within an hour, resurge crested the peak ring, depositing a 10-m-thick layer of suevite with increased particle roundness and sorting. Within hours, the full resurge deposit formed through settling and seiches, resulting in an 80-m-thick fining-upward, sorted suevite in the flooded crater. Within a day, the reflected rim-wave tsunami reached the crater, depositing a cross-bedded sand-to-fine gravel layer enriched in polycyclic aromatic hydrocarbons overlain by charcoal fragments. Generation of a deep crater open to the ocean allowed rapid flooding and sediment accumulation rates among the highest known in the geologic record. The high-resolution section provides insight into the impact environmental effects, including charcoal as evidence for impactinduced wildfires and a paucity of sulfur-rich evaporites from the target supporting rapid global cooling and darkness as extinction mechanisms.
22.	Harrison, Seamus C., et al. (author) A gene-centric study of common carotid artery remodelling 2013 In: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 226:2, s. 440-446 Journal article (peer-reviewed)abstract Background: Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. Methods: Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). Results: rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08-0.18 mm, P = 8.2 x 10(-8)). A proxy SNP (rs4916251, R-2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case-control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03-1.17, p = 2.8 x 10(-3), I-2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. Conclusions: Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.
23.	Helgadottir, Anna, et al. (author) Apolipoprotein(a) Genetic Sequence Variants Associated With Systemic Atherosclerosis and Coronary Atherosclerotic Burden But Not With Venous Thromboembolism 2012 In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 60:8, s. 722-729 Journal article (peer-reviewed)abstract Objectives The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. Background It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. Methods The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n(e)] = 9,396); peripheral arterial disease (n(e) = 5,215); abdominal aortic aneurysm (ne = 4,572); venous thromboembolism (ne = 4,607); intracranial aneurysm (ne = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). Results LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 X 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 x 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 x 10(-5)), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 x 10(-12)). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (-1.58 years/allele; p = 8.2 x 10(-8)) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). Conclusions LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes. (J Am Coll Cardiol 2012; 60: 722-9) (C) 2012 by the American College of Cardiology Foundation
24.	Horikoshi, Momoko, et al. (author) Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation. 2015 In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 11:7 Journal article (peer-reviewed)abstract Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
25.	Koettgen, Anna, et al. (author) Genome-wide association analyses identify 18 new loci associated with serum urate concentrations 2013 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:2, s. 145-154 Journal article (peer-reviewed)abstract Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SEMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
26.	Lenters, Virissa, et al. (author) Phthalates, perfluoroalkyl acids, metals and organochlorines and reproductive function: a multipollutant assessment in Greenlandic, Polish and Ukrainian men. 2015 In: Occupational and Environmental Medicine. - : BMJ. - 1470-7926 .- 1351-0711. ; 72:6, s. 385-393 Journal article (peer-reviewed)abstract Numerous environmental contaminants have been linked to adverse reproductive health outcomes. However, the complex correlation structure of exposures and multiple testing issues limit the interpretation of existing evidence. Our objective was to identify, from a large set of contaminant exposures, exposure profiles associated with biomarkers of male reproductive function.
27.	Lenters, Virissa, et al. (author) Serum concentrations of polybrominated diphenyl ethers (PBDEs) and a polybrominated biphenyl (PBB) in men from Greenland, Poland and Ukraine 2013 In: Environment International. - : Elsevier BV. - 1873-6750 .- 0160-4120. ; 61, s. 8-16 Journal article (peer-reviewed)abstract Many brominated flame retardants (BFRs)-including polybrominated diphenyl ethers (PBDEs)-have been shown to persist in the environment, and some have been associated with adverse health effects. The aim of the present study was to quantify serum concentrations of common brominated flame retardants in Inuit men from across Greenland, and in men from Warsaw, Poland and Kharkiv, Ukraine. Serum was sampled between 2002 and 2004 from men 19 to 50 years of age. 299 samples were analyzed for BDE-28, 47, 99, 100, 153, 154 and 183 and the brominated biphenyl BB-153 using gas chromatography-high resolution mass spectrometry. BDE-47 and BDE-153 were detected in more than 95% of samples from all three populations. All other congeners, except BDE-154, were detected in more than 70% of samples from Greenland; lower detection frequencies were observed in Polish and Ukrainian samples. Concentrations of individual congeners were 2.7 to 15 fold higher in Greenlandic relative to Polish and Ukrainian men. Geometric mean concentrations of the sum of the most abundant PBDEs of the Penta-BDE commercial mixture (BDE-47, 99, 100, 153 and 154) were 6.1, 1.7 and 0.87 ng/g lipids in the Greenlandic, Polish and Ukrainian men, respectively. Furthermore, significant geographical differences in BFR concentrations were observed within Greenland. Principal component analysis revealed distinct clustering of samples by country of origin. The associations between Sigma PBDEs and age were inconsistent, varying from no association in Greenlandic and Polish study populations to a U-shaped relationship in Ukrainians. We report BFR levels for three populations for which sparse biomonitoring data exists. (C) 2013 Elsevier Ltd. All rights reserved.
28.	Marschall, Tobias, et al. (author) Computational pan-genomics : status, promises and challenges 2018 In: Briefings in Bioinformatics. - : Oxford University Press (OUP). - 1467-5463 .- 1477-4054. ; 19:1, s. 118-135 Journal article (peer-reviewed)abstract Many disciplines, from human genetics and oncology to plant breeding, microbiology and virology, commonly face the challenge of analyzing rapidly increasing numbers of genomes. In case of Homo sapiens, the number of sequenced genomes will approach hundreds of thousands in the next few years. Simply scaling up established bioinformatics pipelines will not be sufficient for leveraging the full potential of such rich genomic data sets. Instead, novel, qualitatively different computational methods and paradigms are needed. We will witness the rapid extension of computational pan-genomics, a new sub-area of research in computational biology. In this article, we generalize existing definitions and understand a pan-genome as any collection of genomic sequences to be analyzed jointly or to be used as a reference. We examine already available approaches to construct and use pan-genomes, discuss the potential benefits of future technologies and methodologies and review open challenges from the vantage point of the above-mentioned biological disciplines. As a prominent example for a computational paradigm shift, we particularly highlight the transition from the representation of reference genomes as strings to representations as graphs. We outline how this and other challenges from different application domains translate into common computational problems, point out relevant bioinformatics techniques and identify open problems in computer science. With this review, we aim to increase awareness that a joint approach to computational pan-genomics can help address many of the problems currently faced in various domains.
29.	McLeod, Olga, et al. (author) Plasma autoantibodies against apolipoprotein B-100 peptide 210 in subclinical atherosclerosis. 2014 In: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 232:1, s. 242-248 Journal article (peer-reviewed)abstract Experimental studies have suggested that autoimmunity is involved in atherosclerosis and provided evidence that both protective and pro-atherogenic immune responses exist. This concept has received support from small clinical studies implicating autoantibodies directed against apolipoprotein B-100 (apoB-100) in human atherosclerosis. We examined circulating autoantibodies directed against native and malondialdehyde (MDA)-modified epitope p210 of apoB-100 (IgG-p210nat and IgM-p210MDA) in relation to early atherosclerosis in a large, European longitudinal cohort study of healthy high-risk individuals.
30.	Merckx, Vincent S. F. T., et al. (author) Evolution of endemismon a young tropical mountain 2015 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 524:7565, s. 347- Journal article (peer-reviewed)abstract Tropical mountains are hot spots of biodiversity and endemism(1-3), but the evolutionary origins of their unique biotas are poorly understood(4). In varying degrees, local and regional extinction, long-distance colonization, and local recruitment may all contribute to the exceptional character of these communities(5). Also, it is debated whether mountain endemics mostly originate from local lowland taxa, or from lineages that reach the mountain by long-range dispersal from cool localities elsewhere(6). Here we investigate the evolutionary routes to endemism by sampling an entire tropical mountain biota on the 4,095-metre-high Mount Kinabalu in Sabah, East Malaysia. We discover that most of its unique biodiversity is younger than the mountain itself (6 million years), and comprises a mix of immigrant pre-adapted lineages and descendants from local lowland ancestors, although substantial shifts from lower to higher vegetation zones in this latter group were rare. These insights could improve forecasts of the likelihood of extinction and 'evolutionary rescue'(7) in montane biodiversity hot spots under climate change scenarios.
31.	Petzold, Max, 1973, et al. (author) Introducing Innovative Indicators to Track Sweden's Open Research Data Objective: How to Measure Progress? Defining Indicators to Track Open Research Data Across Swedish Universities 2023 In: Research Data Alliance 20th Plenary Meeting (RDA P20), March 21-23, Gothenburg, Sweden. Conference paper (other academic/artistic)abstract Sweden has set an ambitious objective to make all their research data open by 2026. In order to achieve this, there needs to be individual and institutional behavior changes and a framework to track these changes and progress. The Swedish National Data Service, together with Stockholm University, Karolinska Institutet, University of Gothenburg, and Elsevier have started initial discussions to identify the right indicators to track progress. In this workshop we will present the early results from the pilot project, including a framework of indicators that can be used to track progress. The pilot indicator data have been extracted from open metadata sources as well as from Elsevier's publication indexing. We will also demonstrate how these indicators can be used to identify gaps and challenges in the current data sharing practices. In addition, practical insights arising from the project will be discussed, as well as opportunities and challenges that this effort presents. Participants will have the opportunity to join the discussion and share their own experiences with similar initiatives. By means of sharing these insights, we hope to inspire others and stimulate a global dialogue on the topic and leverage existing efforts rather than reinventing the wheel. Results and conclusions will be distributed under the EOSC association umbrella. We hope to to receive feedback from attendees/RDA Community on the proposed framework of indicators and learn about existing best practices.
32.	Saliba-Gustafsson, P., et al. (author) Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy 2019 In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 660-675 Journal article (peer-reviewed)abstract Background Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. Objective We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. Methods A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central. Results The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. Conclusions For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.
33.	Sauri, Ana, et al. (author) The Bam (Omp85) complex is involved in secretion of the autotransporter haemoglobin protease. 2009 In: Microbiology (Reading, England). - : Microbiology Society. - 1465-2080 .- 1350-0872. ; 155:Pt 12, s. 3982-91 Journal article (peer-reviewed)abstract Autotransporters are large virulence factors secreted by Gram-negative bacteria. They are synthesized with a C-terminal domain that forms a beta-barrel pore in the outer membrane implicated in translocation of the upstream 'passenger' domain across the outer membrane. However, recent structural data suggest that the diameter of the beta-barrel pore is not sufficient to allow the passage of partly folded structures observed for several autotransporters. Here, we have used a stalled translocation intermediate of the autotransporter Hbp to identify components involved in insertion and translocation of the protein across the outer membrane. At this intermediate stage the beta-domain was not inserted and folded as an integral beta-barrel in the outer membrane whereas part of the passenger was surface exposed. The intermediate was copurified with the periplasmic chaperone SurA and subunits of the Bam (Omp85) complex that catalyse the insertion and assembly of outer-membrane proteins. The data suggest a critical role for this general machinery in the translocation of autotransporters across the outer membrane.
34.	Schmitz, Birger, et al. (author) Meteorite flux to Earth in the Early Cretaceous as reconstructed from sediment-dispersed extraterrestrial spinels 2017 In: Geology. - 0091-7613. ; 45:9, s. 807-810 Journal article (peer-reviewed)abstract We show that Earth’s sedimentary strata can provide a record of the collisional evolution of the asteroid belt. From 1652 kg of pelagic Maiolica limestone of Berriasian–Hauterivian age from Italy, we recovered 108 extraterrestrial spinel grains (32–250 μm) representing relict minerals from coarse micrometeorites. Elemental and three oxygen isotope analyses were used to characterize the grains, providing a first-order estimate of the major types of asteroids delivering material at the time. Comparisons were made with meteorite-flux time “windows” in the Ordovician before and after the L-chondrite parent-body breakup. In the Early Cretaceous, ∼80% of the extraterrestrial spinels originated from ordinary chondrites. The ratios between the three groups of ordinary chondrites, H, L, LL, appear similar to the present, ∼1:1:0.2, but differ significantly from Ordovician ratios. We found no signs of a hypothesized Baptistina LL-chondrite breakup event. About 10% of the grains in the Maiolica originate from achondritic meteorite types that are very rare (<1%) on Earth today, but that were even more common in the Ordovician. Because most meteorite groups have lower spinel content than the ordinary chondrites, our data indicate that the latter did not dominate the flux during the Early Cretaceous to the same extent as today. Based on studies of three windows in deep time, we argue that there may have been a gradual long-term (a few hundred million years) turnover in the meteorite flux from dominance of achondrites in the early Phanerozoic to ordinary chondrites in the late Phanerozoic, interrupted by short-term (a few million years) meteorite cascades from single asteroid breakup events.
35.	Schumann, Gunter, et al. (author) Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption 2011 In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:17, s. 7119-7124 Journal article (peer-reviewed)abstract Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of similar to 2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 x 10(-8) to P = 4 x 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Downregulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.
36.	Scott, Robert A., et al. (author) Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways 2012 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005 Journal article (peer-reviewed)abstract Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
37.	Simon, David, 1957, et al. (author) Cities coping with COVID-19: Comparative perspectives 2021 In: City. - : Informa UK Limited. - 1470-3629 .- 1360-4813. ; 25:1-2, s. 129-170 Journal article (peer-reviewed)
38.	Simon, David, 1957, et al. (author) The challenges of transdisciplinary knowledge production: from unilocal to comparative research 2018 In: Environment and Urbanization. - : SAGE Publications. - 0956-2478 .- 1746-0301. ; 30:2, s. 481-500 Journal article (peer-reviewed)abstract This reflective paper surveys the lessons learnt and challenges faced by the Mistra Urban Futures (MUF) research centre and its research platforms in Sweden, the UK, South Africa and Kenya in developing and deploying different forms of transdisciplinary co-production of knowledge. Considerable experience with a distinctive portfolio of such methods has been gained and reflective evaluation is now under way. While it is important to understand the local context within which each method has evolved, we seek to explain the potential for adaptation in diverse contexts so that such knowledge co-production methods can be more widely utilized. Furthermore, the current phase of MUF’s work is undertaking innovative comparative transdisciplinary co-production research across its research platforms. Since the specific local projects differ, systematic thematic comparison requires great care and methodological rigour. Transdisciplinary co-production is inherently complex, time consuming and often unpredictable in terms of outcomes, and these challenges are intensified when it is undertaken comparatively.
39.	Smit, Jeroen M., et al. (author) The Nasolabial Fold as Potential Vascular Receptor Site : An Anatomic Study 2009 In: Journal of reconstructive microsurgery. - : Georg Thieme Verlag KG. - 0743-684X .- 1098-8947. ; 25:9, s. 539-543 Journal article (peer-reviewed)abstract Free and pedicled flaps are frequently used in reconstruction of the lower two-thirds of the face. For these reconstructions, the submandibular facial vessels are extensively used as a receptor site. In this anatomic study, we investigate if the facial vessels in the nasolabial fold can be used as a receptor site as well. In 13 human cadavers, the facial artery and vein were dissected in the nasolabial fold in the same way as would be done during surgery. The case of dissection and length, diameter, and location of the vessels were analyzed. The average length of the dissected artery was 28 mm (+/- 11 standard deviations [SD]) and of the dissected vein, 19 mm (+/- 6 SD). The mean diameter of the artery was 1.5 mm (+/- 0.4 SD) and 2.5 mm (+/- 0.8 SD) for the vein. In 85% of the sides, both vessels were suitable to use as a microsurgical receptor site. The easy access and the measured diameter of the facial vessels in the nasolabial fold make it a potential site for microsurgical anastomosis.
40.	Smit, Warren, et al. (author) Replicating projects for comparative research: Mistra Urban Futures’ experiences with comparative work on knowledge exchange, food and transport 2020 In: Simon, D., Palmer, H. and Riise, J. (eds.), "Comparative urban research from theory to practice: Co-production for sustainability". - Bristol : Policy Press. - 9781447353126 - 9781447354093 ; , s. 63-88 Book chapter (peer-reviewed)abstract This chapter discusses three comparative projects that were all, at least partially, created through the replication of research across the Mistra Urban Futures cities. A typology of six possible models was developed, illustrating how comparative transdisciplinary knowledge co-production could take place across multiple cities, and the second of these approaches was identified as “local projects replicated”. This is where particular successful projects initiated in individual cities had been, or were intended to be, replicated in other cities, thus opening up possibilities for cross-city comparison. As it turned out, three Mistra Urban Futures comparative projects were partially or entirely based on projects that had been replicated in other cities: the knowledge exchange project, the suite of linked food comparative projects, and transport and sustainable urban development comparative project. This chapter draws on our practical experience in developing and implementing these comparative projects. First, we discuss the issue of “replication” and the different ways that this can occur. Second, we discuss the initial work on these themes (knowledge exchange, food, transport) which formed the basis for the development of these particular comparative projects. Third, we discuss the complex processes through which this work assembled into comparative projects. Finally, we reflect on the challenges and benefits of “replicating” projects for comparative research.
41.	Smit, Warren, et al. (author) The challenge of conflicting rationalities about urban development : Experiences from Mistra Urban Futures’ transdisciplinary urban research 2019 In: Trialog – A Journal for Planning and Building in a Global Context. ; 2:137, s. 31-37 Journal article (peer-reviewed)abstract This paper reflects on ten years of transdisciplinary urban research by Mistra Urban Futures, a global centre focusing on the co-production of knowledge for more just and sustainable cities across the Global South and Global North. The paper focuses on one of the key challenges that Mistra Urban Futures has faced in its work: in addition to the competing interests and agendas of participants in co-production processes, there are also often deeper underlying conflicting rationalities about many of the key concepts and substantive issues relating to making cities more just and sustainable, driven by ideological, educational, contextual and personal factors. These differences can be even more polarised between different cities and countries, including deep divisions regarding the fundamental nature of the problem, the ultimate goals and objectives of urban development interventions, and the key underlying concepts. This paper explores these challenges and reflects on the various approaches adopted by Mistra Urban Futures to facilitate the understanding of these differences and identify commonalities and overlaps of interest. Ultimately, understanding and engaging with the different rationalities of participants in co-production processes is essential for different actors to work together to co-produce and operationalise knowledge for cities that are more just and sustainable.
42.	Smit, Warren, et al. (author) The challenge of conflicting rationalities about urban development: Experiences from Mistra Urban Futures’ transdisciplinary urban research 2019 In: Trialog 2019 Conference: “Whose knowledge counts? The meaning of co-productive processes for urban development and urban research”, Institute of Urban Planning and Design (Städtebau Institut) at the University of Stuttgart, 7–9 November 2019, Stuttgart, Germany. Conference paper (peer-reviewed)abstract This paper reflects on ten years of transdisciplinary urban research by Mistra Urban Futures. Mistra Urban Futures was established in 2010 as a global centre focusing on the co-production of knowledge for more just and sustainable cities. The core partners in Mistra Urban Futures are from four countries (Sweden, the United Kingdom, Kenya and South Africa), and the centre also works in two other countries (India and Argentina). In addition to undertaking local knowledge co-production work in each partner city, Mistra Urban Futures has also linked up local work into international transdisciplinary projects. The paper focuses on one of the key challenges that Mistra Urban Futures has faced in its work: in addition to the competing interests and agendas of participants in co-production processes, there are also often deeper underlying conflicting (or diverging) rationalities about urban development. Many of the key concepts and substantive issues relating to making cities more just and sustainable are highly contested. Within cities, people and organisations from different sectors and different disciplines often have very different understandings of what the problems and solutions are, driven by ideological, educational, contextual and personal factors. These differences can be even more polarised between different cities and countries, for example between cities in the global North and global South and between cities in countries with different political cultures. For example, there can be deep divisions about the fundamental nature of the problem (poverty, inequity, lack of economic growth, lack of political empowerment, unsustainability, lack of government capacity, etc.) and the ultimate goals and objectives of urban development interventions (such as equity, economic growth, maintaining the status quo or radical change). In addition, concepts such as such as “fairness”, “justice” and “resilience”, and substantive issues such as “public transport”, “sustainable urban food systems” and “tackling climate change”, can mean very different things to different people and in different places. This paper explores these challenges and reflects on the various approaches adopted by Mistra Urban Futures to facilitate the understanding of these differences and identify commonalities and overlaps of interest. For example, most of the Mistra Urban Futures projects had initial phases to identify and understand the different views of participants in order to be able to identify common ground for collaboration. In some cases, the different terminologies and concepts used by people from different sectors or disciplines required developing a common conceptual vocabulary during this initial phase. In one particular project in Cape Town, the research method included the mapping of the different rationalities of key stakeholders as a basis for identifying opportunities for further collaboration. Having a diversity of rationalities and approaches often stimulates creativity, resulting in the development of innovative methodologies, policies and practices. Ultimately, understanding and engaging with the different rationalities of participants in co-production processes is essential for different actors to successfully work together to co-produce and operationalise knowledge for more just and sustainable cities.
43.	Smit, Warren, et al. (author) The challenge of conflicting rationalities about urban development – Experiences from Mistra Urban Futures’ transdisciplinary urban research : Die Herausforderung widersprüchlicher Rationalitäten in der Stadtentwicklung: Erfahrungen aus der transdisziplinären Stadtforschung von ‘Mistra Urban Futures‘ 2021 In: Trialog – A Journal for Planning and Building in a Global Context. - 0724-6234. ; 137:2, s. 31-37 Journal article (peer-reviewed)abstract This paper reflects on ten years of transdisciplinary urban research by Mistra Urban Futures, a global centre focusing on the co-production of knowledge for more just and sustainable cities across the Global South and Global North. The paper focuses on one of the key challenges that Mistra Urban Futures has faced in its work: in addition to the competing interests and agendas of participants in co-production processes, there are also often deeper underlying conflicting rationalities about many of the key concepts and substantive issues relating to making cities more just and sustainable, driven by ideological, educational, contextual and personal factors. These differences can be even more polarised between different cities and countries, including deep divisions regarding the fundamental nature of the problem, the ultimate goals and objectives of urban development interventions, and the key underlying concepts. This paper explores these challenges and reflects on the various approaches adopted by Mistra Urban Futures to facilitate the understanding of these differences and identify commonalities and overlaps of interest. Ultimately, understanding and engaging with the different rationalities of participants in co-production processes is essential for different actors to work together to co-produce and operationalise knowledge for cities that are more just and sustainable. ........................................................................................................................................................................................................ Der vorliegende Artikel reflektiert zehn Jahre transdisziplinäre Stadtforschung von Mistra Urban Futures, einem globalen Zentrum mit Schwerpunkt auf Koproduktion von Wissen für gerechtere und nachhaltigere Städte im globalen Norden und Süden. Der Artikel konzentriert sich auf eine der Kernherausforderungen, mit der sich Mistra Urban Futures in seiner Arbeit konfrontiert sah: Zusätzlich zu den konkurrieren-den Interessen und Agenden der an Koproduktion Beteiligten liegen häufig gegensätzliche Denkweisen zugrunde. Schlüsselkonzepte und substanzielle Fragen in Bezug darauf, wie Städte gerechter und nachhaltiger gemacht werden können, unterscheiden sich je nach Einfluss von ideologischen, bildungs- und kontextbezogenen sowie persönlichen Faktoren mitunter deutlich. Diese Unterschiede können zwischen verschiedenen Städten und Ländern noch stärker hervortreten, bis hin zu einer tiefen Spaltung in Bezug auf die Natur des zugrundeliegenden Problems, die übergeordneten Ziele sowie den Zweck urbaner Entwicklungsmaßnahmen. Dieser Artikel untersucht die Herausforderungen und reflektiert über die verschiedenen Ansätze, die Mistra Urban Futures verfolgte, um das Verständnis dieser Unterschiede zu fördern und Gemeinsamkeiten und geteilte Interessen zu identifizieren. Letztlich erweist es sich für die verschiedenen an Koproduktion beteiligten Ak-teure als unerlässlich, die unterschiedlichen Denkweisen zu verstehen und sich auf sie einzustellen, um produktiv zusammenzuarbeiten und Wissen für gerechtere und nachhaltigere Städte zu operationalisieren.
44.	Smit, Warren, et al. (author) The challenge of conflicting rationalities about urban development – Experiences from Mistra Urban Futures’ transdisciplinary urban research 2021 In: Trialog. - 0724-6234. ; 137:2, s. 31-37 Journal article (peer-reviewed)abstract This paper reflects on ten years of transdisciplinary urban research by Mistra Urban Futures, a global centre focusing on the co-production of knowledge for more just and sustainable cities across the Global South and Global North. The paper focuses on one of the key challenges that Mistra Urban Futures has faced in its work: in addition to the competing interests and agendas of participants in co-production processes, there are also often deeper underlying conflicting rationalities about many of the key concepts and substantive issues relating to making cities more just and sustainable, driven by ideological, educational, contextual and personal factors. These differences can be even more polarised between different cities and countries, including deep divisions regarding the fundamental nature of the problem, the ultimate goals and objectives of urban development interventions, and the key underlying concepts. This paper explores these challenges and reflects on the various approaches adopted by Mistra Urban Futures to facilitate the understanding of these differences and identify commonalities and overlaps of interest. Ultimately, understanding and engaging with the different rationalities of participants in co-production processes is essential for different actors to work together to co-produce and operationalise knowledge for cities that are more just and sustainable.
45.	Stevens, Jan, 1955, et al. (author) Wiskundig onderzoek per computer? 2009 In: Nieuw Archief voor Wiskunde. - 0028-9825. ; (5) 10:3, s. 197-200 Journal article (other academic/artistic)
46.	Strom, Nora I., et al. (author) Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population 2024 In: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. Journal article (peer-reviewed)abstract While 1-2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13-38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed = 3.06 × 10-5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33-43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.
47.	Strom, Nora I., et al. (author) Meta-analysis of genome-wide association studies of hoarding symptoms in 27,537 individuals 2022 In: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 12:1 Journal article (peer-reviewed)abstract Hoarding Disorder (HD) is a mental disorder characterized by persistent difficulties discarding or parting with possessions, often resulting in cluttered living spaces, distress, and impairment. Its etiology is largely unknown, but twin studies suggest that it is moderately heritable. In this study, we pooled phenotypic and genomic data from seven international cohorts (N = 27,537 individuals) and conducted a genome wide association study (GWAS) meta-analysis of parent- or self-reported hoarding symptoms (HS). We followed up the results with gene-based and gene-set analyses, as well as leave-one-out HS polygenic risk score (PRS) analyses. To examine a possible genetic association between hoarding symptoms and other phenotypes we conducted cross-trait PRS analyses. Though we did not report any genome-wide significant SNPs, we report heritability estimates for the twin-cohorts between 26-48%, and a SNP-heritability of 11% for an unrelated sub-cohort. Cross-trait PRS analyses showed that the genetic risk for schizophrenia and autism spectrum disorder were significantly associated with hoarding symptoms. We also found suggestive evidence for an association with educational attainment. There were no significant associations with other phenotypes previously linked to HD, such as obsessive-compulsive disorder, depression, anxiety, or attention-deficit hyperactivity disorder. To conclude, we found that HS are heritable, confirming and extending previous twin studies but we had limited power to detect any genome-wide significant loci. Much larger samples will be needed to further extend these findings and reach a "gene discovery zone". To move the field forward, future research should not only include genetic analyses of quantitative hoarding traits in larger samples, but also in samples of individuals meeting strict diagnostic criteria for HD, and more ethnically diverse samples.
48.	Teslovich, Tanya M., et al. (author) Biological, clinical and population relevance of 95 loci for blood lipids 2010 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7307, s. 707-713 Journal article (peer-reviewed)abstract Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
49.	van Ballegooijen, Wouter, et al. (author) Adherence to Internet-based and face-to-face cognitive behavioural therapy for depression : a meta-analysis 2014 In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 9:7, s. e100674- Journal article (peer-reviewed)abstract BACKGROUND: Internet-based cognitive behavioural therapy (iCBT) is an effective and acceptable treatment for depression, especially when it includes guidance, but its treatment adherence has not yet been systematically studied. We conducted a meta-analysis, comparing the adherence to guided iCBT with the adherence to individual face-to-face CBT.METHODS: Studies were selected from a database of trials that investigate treatment for adult depression (see www.evidencebasedpsychotherapies.org), updated to January 2013. We identified 24 studies describing 26 treatment conditions (14 face-to-face CBT, 12 guided iCBT), by means of these inclusion criteria: targeting depressed adults, no comorbid somatic disorder or substance abuse, community recruitment, published in the year 2000 or later. The main outcome measure was the percentage of completed sessions. We also coded the percentage of treatment completers (separately coding for 100% or at least 80% of treatment completed).RESULTS: We did not find studies that compared guided iCBT and face-to-face CBT in a single trial that met our inclusion criteria. Face-to-face CBT treatments ranged from 12 to 28 sessions, guided iCBT interventions consisted of 5 to 9 sessions. Participants in face-to-face CBT completed on average 83.9% of their treatment, which did not differ significantly from participants in guided iCBT (80.8%, P = .59). The percentage of completers (total intervention) was significantly higher in face-to-face CBT (84.7%) than in guided iCBT (65.1%, P < .001), as was the percentage of completers of 80% or more of the intervention (face-to-face CBT: 85.2%, guided iCBT: 67.5%, P = .003). Non-completers of face-to-face CBT completed on average 24.5% of their treatment, while non-completers of guided iCBT completed on average 42.1% of their treatment.CONCLUSION: We did not find studies that compared guided iCBT and face-to-face CBT in a single trial. Adherence to guided iCBT appears to be adequate and could be equal to adherence to face-to-face CBT.

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