| 1. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
- Tobias, Deirdre K, et al.
(författare)
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
- 2023
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Ingår i: Nature Medicine. - 1546-170X. ; 29:10, s. 2438-2457
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Forskningsöversikt (refereegranskat)abstract
- Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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| 3. |
- Margulies, Elliott H, et al.
(författare)
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Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome
- 2007
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 17:6, s. 760-774
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Tidskriftsartikel (refereegranskat)abstract
- A key component of the ongoing ENCODE project involves rigorous comparative sequence analyses for the initially targeted 1% of the human genome. Here, we present orthologous sequence generation, alignment, and evolutionary constraint analyses of 23 mammalian species for all ENCODE targets. Alignments were generated using four different methods; comparisons of these methods reveal large-scale consistency but substantial differences in terms of small genomic rearrangements, sensitivity (sequence coverage), and specificity (alignment accuracy). We describe the quantitative and qualitative trade-offs concomitant with alignment method choice and the levels of technical error that need to be accounted for in applications that require multisequence alignments. Using the generated alignments, we identified constrained regions using three different methods. While the different constraint-detecting methods are in general agreement, there are important discrepancies relating to both the underlying alignments and the specific algorithms. However, by integrating the results across the alignments and constraint-detecting methods, we produced constraint annotations that were found to be robust based on multiple independent measures. Analyses of these annotations illustrate that most classes of experimentally annotated functional elements are enriched for constrained sequences; however, large portions of each class (with the exception of protein-coding sequences) do not overlap constrained regions. The latter elements might not be under primary sequence constraint, might not be constrained across all mammals, or might have expendable molecular functions. Conversely, 40% of the constrained sequences do not overlap any of the functional elements that have been experimentally identified. Together, these findings demonstrate and quantify how many genomic functional elements await basic molecular characterization.
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| 4. |
- Thomassen, Mads, et al.
(författare)
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Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants : Application of a points-based ACMG/AMP approach
- 2022
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 43:12, s. 1921-1944
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Tidskriftsartikel (refereegranskat)abstract
- Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength.
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| 5. |
- Ficker, M., et al.
(författare)
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Being two is better than one - Catalytic reductions with dendrimer encapsulated copper - And copper-cobalt-subnanoparticles
- 2015
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Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1364-548X .- 1359-7345. ; 51:49, s. 9957-9960
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Tidskriftsartikel (refereegranskat)abstract
- Copper and copper-cobalt subnanoparticles have been synthesized using 4-carbomethoxypyrrolidone terminated PAMAM-dendrimers as templates. The metal particles were applied in catalytic reduction reactions. While Cu subnanoparticles were only capable of reducing conjugated double bonds, enhancing the Cu particles with Co led to a surprising increase in catalytic activity, reducing also isolated carbon double and triple bonds.
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| 6. |
- Brors, Gunhild, et al.
(författare)
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Modes of e-Health delivery in secondary prevention programmes for patients with coronary artery disease : a systematic review
- 2019
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Ingår i: BMC Health Services Research. - : BioMed Central. - 1472-6963. ; 19, s. 1-24
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Forskningsöversikt (refereegranskat)abstract
- BackgroundElectronic health (e-Health) interventions are emerging as an effective alternative model for improving secondary prevention of coronary artery disease (CAD). The aim of this study was to describe the effectiveness of different modes of delivery and components in e-Health secondary prevention programmes on adherence to treatment, modifiable CAD risk factors and psychosocial outcomes for patients with CAD.MethodA systematic review was carried out based on articles found in MEDLINE, CINAHL, and Embase. Studies evaluating secondary prevention e-Health programmes provided through mobile-Health (m-Health), web-based technology or a combination of m-Health and web-based technology were eligible. The main outcomes measured were adherence to treatment, modifiable CAD risk factors and psychosocial outcomes. The quality appraisal of the studies included was conducted using the Joanna Briggs Institute critical appraisal tool for RCT. The results were synthesised narratively.ResultA total of 4834 titles were identified and 1350 were screened for eligibility. After reviewing 123 articles in full, 24 RCTs including 3654 participants with CAD were included. Eight studies delivered secondary prevention programmes through m-Health, nine through web-based technology, and seven studies used a combination of m-Health and web-based technology. The majority of studies employed two or three secondary prevention components, of which health education was employed in 21 studies. The m-Health programmes reported positive effects on adherence to medication. Most studies evaluating web-based technology programmes alone or in combination with m-Health also utilised traditional CR, and reported improved modifiable CAD risk factors. The quality appraisal showed a moderate methodological quality of the studies.ConclusionEvidence exists that supports the use of e-Health interventions for improving secondary prevention of CAD. However, a comparison across studies highlighted a wide variability of components and outcomes within the different modes of delivery. High quality trials are needed to define the most efficient mode of delivery and components capable of addressing a favourable outcome for patients.Trial registrationNot applicable.
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| 7. |
- Elholm Madsen, Esben, et al.
(författare)
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Can psychological characteristics, football experience, and player status predict state anxiety before important matches in Danish elite-level female football players?
- 2022
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - West Sussex : John Wiley & Sons. - 0905-7188 .- 1600-0838. ; 32:S1, s. 150-160
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Tidskriftsartikel (refereegranskat)abstract
- Elite football can make players feel nervous, and personality characteristics, as well as experience, affect how well pressure is handled before important games. Studying the psychological characteristics of female football players can provide information on how well psychological pressure is handled and generate knowledge on how to support players in order to improve performance. Based on a sample of 128 female elite football players from 8 top-level teams, the present study investigates whether psychological characteristics and football experience/player stus in elite female football players can predict state anxiety before important matches. Our results outline that high age and national team experience negatively predicted most of the trait anxiety subscales. In line with previous research, no psychological differences were found between goalkeepers, defenders, midfielders, and strikers while starting players revealed to have significantly lower trait anxiety. When measuring before important matches, we found that somatic state anxiety was negatively associated with senior national team experience and positively associated with worry trait anxiety and fear of failure. Cognitive state anxiety was negatively associated with hope for success and positively associated with somatic and worry trait anxiety. Self-confidence was positively associated with youth national team experience and negatively associated with worry trait anxiety. It can be concluded that psychological characteristics and national team experience are both important for optimal state anxiety before important matches in elite-level women's football. Implications for practice and future research are discussed. © 2020 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.
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| 8. |
- Thuesen, Anne Cathrine Baun, et al.
(författare)
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Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment
- 2023
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Ingår i: Molecular Genetics and Metabolism Reports. - : Elsevier BV. - 2214-4269. ; 35
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Tidskriftsartikel (refereegranskat)abstract
- Background: Functionally disruptive variants in the glucokinase gene (GCK) cause a form of mild non-progressive hyperglycemia, which does not require pharmacological treatment. A substantial proportion of patients with type 2 diabetes (T2D) carry GCK variants. We aimed to investigate whether carriers of rare GCK variants diagnosed with T2D have a glycemic phenotype and treatment response consistent with GCK-diabetes. Methods: Eight patients diagnosed with T2D from the Danish DD2 cohort who had previously undergone sequencing of GCK participated. Clinical examinations at baseline included an oral glucose tolerance test and continuous glucose monitoring. Carriers with a glycemic phenotype consistent with GCK-diabetes took part in a three-month treatment withdrawal. Results: Carriers of pathogenic and likely pathogenic variants had lower median fasting glucose and C-peptide levels compared to carriers of variants of uncertain significance and benign variants (median fasting glucose: 7.3 (interquartile range: 0.4) mmol/l vs. 9.5 (1.6) mmol/l, p = 0.04; median fasting C-peptide 902 (85) pmol/l vs. 1535 (295) pmol/l, p = 0.03). Four participants who discontinued metformin treatment and one diet-treated participant were reevaluated after three months. There was no deterioration of HbA1c or fasting glucose (median baseline HbA1c: 49 (3) vs. 51 (6) mmol/mol after three months, p = 0.4; median baseline fasting glucose: 7.3 (0.4) mmol/l vs. 7.0 (0.6) mmol/l after three months, p = 0.5). Participants did not consistently fulfill best practice guidelines for GCK screening nor clinical criteria for monogenic diabetes. Discussion: Carriers of pathogenic or likely pathogenic GCK variants identified by unselected screening in T2D should be reported, as they have a glycemic phenotype and treatment response consistent with GCK-diabetes. Variants of uncertain significance should be interpreted with care. Systematic genetic screening of patients with common T2D receiving routine care can lead to the identification and precise care of patients with misclassified GCK-diabetes who are not identifiable through common genetic screening criteria.
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