| 1. |
- Gorski, Mathias, et al.
(författare)
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Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
- 2022
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
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Tidskriftsartikel (refereegranskat)abstract
- Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
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| 2. |
- Ntalla, Ioanna, et al.
(författare)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 3. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 4. |
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| 5. |
- Björklund, Patrik, et al.
(författare)
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Västerås slott : Slott och borgar
- 2000
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Rapport (populärvet., debatt m.m.)abstract
- En majoritet av dagens byggnadsuppgifter gäller att hantera det redan byggda. När vi står inför situationen att restaurera en befintlig byggnad är det viktigt att förstå olika tidsperioders stilideal liksom byggnadsteknik och material. Först då kan vi göra en väl avvägd analys, som tar tillvara och utvecklar de kvaliteter som byggnaderna själva besitter. Därför är utbildningen upplagd som ett växelspel mellan föreläsningar, seminarier, exkursioner och en för året vald studieuppgift.Slott och borgar har varit läsårets tema. Vi har valt att arbeta med Västerås och Örebro slott - två ganska bortglömda Vasaslott som är väl värda att lyfta fram. Särskilt har vi studerat de senaste 300 årens förändringar, som inte tidigare ägnats lika stora forskarmöda som medelitden och Vasatiden. I dessa två exempel finns en provkarta på estetiska, praktiska och tekniska ingrepp från Carl Hårlemans tid och fram till idag.Studierna har således omfattat både gestaltning, funktion och byggnadsteknik. Avsikten är att visa på kvaliteter i de omvandlingar och restaureringar som skett, men också att peka på problem och analysera olika möjligheter inför framtiden. Arbetet har skett i samarbete med Statens fastighetsverk och är tänkt att utgöra ett underlag till vårdprogram och framtida restaureringsinsatser.
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| 6. |
- Ellingsen, Pal Gunnar, et al.
(författare)
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Spectral correlation analysis of Amyloid beta plaque inhomogeneity from double staining experiments
- 2013
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Ingår i: Journal of Biomedical Optics. - : Society of Photo-optical Instrumentation Engineers (SPIE). - 1083-3668 .- 1560-2281. ; 18:10
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Tidskriftsartikel (refereegranskat)abstract
- A spectral correlation algorithm for the analysis of hyperspectral fluorescence images is proposed by Ellingsen et al. [J. Biomed. Opt. 18, 020501 (2013)]. Here, it is applied to the analysis of double-stained A beta amyloid plaques being related to the Alzheimers disease (AD). Sections of APP/PS1 AD mice model brains are double stained with luminescent-conjugated oligothiophenes, known to bind to amyloid protein deposits. Hyperspectral fluorescence images of the brain sections are recorded and by applying the correlation algorithm the spectral inhomogeneity of the double-stained samples is mapped in terms of radial distribution and spectral content. To further investigate the progression of A beta amyloid plaque formation, 19 AD mice of different ages up to 23 months are characterized, enabling a statistical analysis of the plaque heterogeneity. In accordance with recent findings by Nystrom et al. [ACS Chem. Biol. 8, 1128-1133 (2013)], the spectral distribution within A beta plaques is found to vary with age throughout the lifespan of the mouse. With the new correlation algorithm, it is possible to quantify the spectral abundance of the two stains depending on the relative distance from the plaque center and mouse age. Thus, we demonstrate the use of the correlation analysis approach in double-staining experiments and how it is possible to relate these to structural/spectral changes in biological samples. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.
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| 7. |
- Fischl, Caroline, et al.
(författare)
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Older adults’ perceptions of contexts surrounding their social participation in a digitalized society—an exploration in rural communities in Northern Sweden
- 2020
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Ingår i: European Journal of Ageing. - : Springer. - 1613-9372 .- 1613-9380. ; 17:3, s. 281-290
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Tidskriftsartikel (refereegranskat)abstract
- Social participation and digital engagement can contribute to health and well-being among older adults. Because of older adults’ decline in abilities, coupled with complex technology and its perceived insufficient relevance to daily life, there is a need to create and tailor social opportunities and services that are supported by digital technologies for older adults to continue participating in society. Thus, it becomes relevant to explore older adults’ perceptions about contexts surrounding their social participation in a digital society. This exploration used a qualitative research design with focus group interviews and qualitative content analysis. Eighteen older adults, aged 66–81 years, from rural communities in Northern Sweden, participated in this study. The analysis resulted in three categories: experiencing conditions for social participation in a state of flux, perceiving drawbacks of urbanization on social participation, and welcoming digital technology that facilitates daily and community living. These categories were encapsulated in the theme—the juxtaposition of narrowing offline social networks and expanding digital opportunities for social participation. The findings suggested that co-creating usable digitalized services and facilitating satisfactory use of digital technologies could support older adults’ social participation through activities that they find relevant in their lives, and subsequently, might enable them to live longer at home.
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| 8. |
- Jin, Yuesheng, et al.
(författare)
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Distinct mitotic segregation errors mediate chromosomal instability in aggressive urothelial cancers.
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:6, s. 1703-1712
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Chromosomal instability (CIN) is believed to have an important role in the pathogenesis of urothelial cancer (UC). The aim of this study was to evaluate whether disturbances of mitotic segregation contribute to CIN in UC, if these processes have any effect on the course of disease, and how deregulation of these mechanisms affects tumor cell growth. Experimental Design: We developed molecular cytogenetic methods to classify mitotic segregation abnormalities in a panel of UC cell lines. Mitotic instabilities were then scored in biopsies from 52 UC patients and compared with the outcome of tumor disease. Finally, UC cells were exposed in vitro to a telomerase inhibitor to assess how this affects mitotic stability and cell proliferation. Results: Three distinct chromosome segregation abnormalities were identified: (a) telomere dysfunction, which triggers structural rearrangements and loss of chromosomes through anaphase bridging; (b) sister chromatid nondisjunction, which generates discrete chromosomal copy number variations; and (c) supernumerary centrosomes, which cause dramatic shifts in chromosome copy number through multipolar cell division. Chromosome segregation errors were already present in preinvasive tumors and a high rate mitotic instability was an independent predictor of poor survival. However, induction of even higher levels of the same segregation abnormalities in UC cells by telomerase inhibition in vitro led to reduced tumor cell proliferation and clonogenic survival. Conclusion: Several distinct chromosome segregation errors contribute to CIN in UC, and the rate of such mitotic errors has a significant effect on the clinical course. Efficient tumor cell proliferation may depend on the tight endogenous control of these processes.
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| 9. |
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| 10. |
- Knutsson, Sofie, et al.
(författare)
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Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency
- 2018
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:23, s. 10545-10557
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Tidskriftsartikel (refereegranskat)abstract
- Resistance development in insects significantly threatens the important benefits obtained by insecticide usage in vector control of disease-transmitting insects. Discovery of new chemical entities with insecticidal activity is highly desired in order to develop new insecticide candidates. Here, we present the design, synthesis, and biological evaluation of phenoxyacetamide-based inhibitors of the essential enzyme acetylcholinesterase 1 (AChE1). AChE1 is a validated insecticide target to control mosquito vectors of, e.g., malaria, dengue, and Zika virus infections. The inhibitors combine a mosquito versus human AChE selectivity with a high potency also for the resistance-conferring mutation G122S; two properties that have proven challenging to combine in a single compound. Structure activity relationship analyses and molecular dynamics simulations of inhibitor protein complexes have provided insights that elucidate the molecular basis for these properties. We also show that the inhibitors demonstrate in vivo insecticidal activity on disease-transmitting mosquitoes. Our findings support the concept of noncovalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development.
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| 11. |
- Lindgren, Cecilia, et al.
(författare)
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Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase
- 2022
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Ingår i: Chemistry - A European Journal. - : John Wiley & Sons. - 0947-6539 .- 1521-3765. ; 28:40
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Tidskriftsartikel (refereegranskat)abstract
- Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and pre-reactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNA-inhibited AChE.
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| 12. |
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| 13. |
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| 14. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 15. |
- Middeldorp, Christel M., et al.
(författare)
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The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects
- 2019
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 34:3, s. 279-300
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Tidskriftsartikel (refereegranskat)abstract
- The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
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| 16. |
- Muxamuud, Xabiibo, et al.
(författare)
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A collaborative development initiative to strengthen Midwifery Education in Somalia
- 2024
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Ingår i: Somali Health Action Journal. - 2004-1985. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- Galkayo University, in an ongoing partnership with Benadir University and the Karolinska Institutet, reports on the co-creation of a mentorship program for midwifery educators at Galkayo University. This program was initiated in Spring 2023 with the aim of sharing experiences on midwifery education between educators from Sweden and Somalia—both countries with long traditions of midwifery care. By leveraging the expertise of Swedish and Somali midwifery educators, the mentorship program seeks to bridge gaps in knowledge and skills, ultimately contributing to better midwifery education and care in both Somalia and Sweden. This commentary describes the significance of the program and its potential for impact if scaled up after contextualization.
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| 17. |
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| 18. |
- Nyström, Sofie, et al.
(författare)
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Evidence for Age-Dependent in Vivo Conformational Rearrangement within A beta Amyloid Deposits
- 2013
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Ingår i: ACS Chemical Biology. - : American Chemical Society. - 1554-8929 .- 1554-8937. ; 8:6, s. 1128-1133
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Tidskriftsartikel (refereegranskat)abstract
- Deposition of aggregated A beta peptide in the brain is one of the major hallmarks of Alzheimers disease. Using a combination of two structurally different, but related, hypersensitive fluorescent amyloid markers, LCOs, reporting on separate ultrastructural elements, we show that conformational rearrangement occurs within A beta plaques of transgenic mouse models as the animals age. This important mechanistic insight should aid the design and evaluation of experiments currently using plaque load as readout.
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| 19. |
- Pernrud, Björn
(författare)
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Explorations of a Sex Therapy Question in Feminism : Feminist Interventions in Sex Therapy
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This study aims to investigate the consequences for feminist sex therapy that it is promoted as an alternative to a mainstream approach. Analytically I focus on the relation between normativity, claims to knowledge and professional legitimacy. I study sex therapeutic academic texts, and the material is approached through a framework developed by combining Donna Haraway’s concept of situated knowledges with elements from Karen Barad’s agential realismMy analysis starts in feminist sex therapists’ criticism of how masculine norms in mainstream sex therapy lead to a flawed theory of sexual matters. Feminist sex therapists, however, allege that it is specifically feminist norms that grant a more complete theory of sex and sexual problems within feminist alternatives in sex therapy. To that effect, feminists discern sexual problems in relation to the impact a patriarchal society has on particularly women’s sexualities, and treatment is articulated as seeking to liberate women from constraints associated with gendered social positions.In mainstream sex therapy, allegedly value-neutral insights into human physiology are called upon for the establishment of professional legitimacy. Nevertheless, normative investments are relied upon implicitly to discern sexual problems and sexual well-being with the consequence that sexual problems are understood as conditions that interfere with the ability to have sex, largely equated with coitus, and with the motivation to form coupled sexual relations. By alleviating sexual problems, these abilities and motivations are allegedly restored in the form of natural, already present, capacities for sexual functioning. Comparing my analysis to feminist critiques, I argue that the latter have not fully theorized the significance of normative investments, and have left unchallenged assumptions in mainstream therapy that enable a restorative and liberationist construal of sex therapy’s objective.Although feminist alternatives contain a markedly different theorization of sexual problems, they have retained, from the mainstream approach, the notion that sex therapy seeks to liberate its clients. This notion stands in conflict with feminist theorizations of sexual problems, and in my conclusion I argue that feminist sex therapy would benefit from abandoning its liberationist element.
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| 20. |
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| 21. |
- Rosendahl, Erik, et al.
(författare)
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High-intensity functional exercise program and protein-enriched energy supplement for older persons dependent in activities of daily living : a randomised controlled trial
- 2006
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Ingår i: Australian Journal of Physiotherapy. - 0004-9514. ; 52:2, s. 105-113
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Tidskriftsartikel (refereegranskat)abstract
- The aims of this randomised controlled trial were to determine if a high-intensity functional exercise program improves balance, gait ability, and lower-limb strength in older persons dependent in activities of daily living and if an intake of protein-enriched energy supplement immediately after the exercises increases the effects of the training. One hundred and ninety-one older persons dependent in activities of daily living, living in residential care facilities, and with a Mini-Mental State Examination (MMSE) score of ? 10 participated. They were randomised to a high-intensity functional exercise program or a control activity, which included 29 sessions over 3 months, as well as to protein-enriched energy supplement or placebo. Berg Balance Scale, self-paced and maximum gait speed, and one-repetition maximum in lower-limb strength were followed-up at three and six months and analysed by 2 x 2 factorial ANCOVA, using the intention-to-treat principle. At three months, the exercise group had improved significantly in self-paced gait speed compared with the control group (mean difference 0.04 m/s, p = 0.02). At six months, there were significant improvements favouring the exercise group for Berg Balance Scale (1.9 points, p = 0.05), self-paced gait speed (0.05 m/s, p = 0.009), and lower-limb strength (10.8 kg, p = 0.03). No interaction effects were seen between the exercise and nutrition interventions. In conclusion, a high-intensity functional exercise program has positive long-term effects in balance, gait ability, and lower-limb strength for older persons dependent in activities of daily living. An intake of protein-enriched energy supplement immediately after the exercises does not appear to increase the effects of the training.
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- Sole, Marina, et al.
(författare)
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Inter- and intra-breed genome-wide copy number diversity in a large cohort of European equine breeds
- 2019
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Ingår i: BMC Genomics. - : BMC. - 1471-2164. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Copy Number Variation (CNV) is a common form of genetic variation underlying animal evolution and phenotypic diversity across a wide range of species. In the mammalian genome, high frequency of CNV differentiation between breeds may be candidates for population-specific selection. However, CNV differentiation, selection and its population genetics have been poorly explored in horses. Results We investigated the patterns, population variation and gene annotation of CNV using the Axiom (R) Equine Genotyping Array (670,796 SNPs) from a large cohort of individuals (N = 1755) belonging to eight European horse breeds, varying from draught horses to several warmblood populations. After quality control, 152,640 SNP CNVs (individual markers), 18,800 segment CNVs (consecutive SNP CNVs of same gain/loss state or both) and 939 CNV regions (CNVRs; overlapping segment CNVs by at least 1 bp) compared to the average signal of the reference (Belgian draught horse) were identified. Our analyses showed that Equus caballus chromosome 12 (ECA12) was the most enriched in segment CNV gains and losses (similar to 3% average proportion of the genome covered), but the highest number of segment CNVs were detected on ECA1 and ECA20 (regardless of size). The Friesian horses showed private SNP CNV gains (> 20% of the samples) on ECA1 and Exmoor ponies displayed private SNP CNV losses on ECA25 (> 20% of the samples). The Warmblood cluster showed private SNP CNV gains located in ECA9 and Draught cluster showed private SNP CNV losses located in ECA7. The length of the CNVRs ranged from 1 kb to 21.3 Mb. A total of 10,612 genes were annotated within the CNVRs. The PANTHER annotation of these genes showed significantly under- and overrepresented gene ontology biological terms related to cellular processes and immunity (Bonferroni P-value < 0.05). We identified 80 CNVRs overlapping with known QTL for fertility, coat colour, conformation and temperament. We also report 67 novel CNVRs. Conclusions This work revealed that CNV patterns, in the genome of some European horse breeds, occurred in specific genomic regions. The results provide support to the hypothesis that high frequency private CNVs residing in genes may potentially be responsible for the diverse phenotypes seen between horse breeds.
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| 26. |
- van de Vegte, Yordi, et al.
(författare)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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| 27. |
- Vandermeulen, Nina, et al.
(författare)
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Getting a grip on the writing process : (Effective) approaches to write argumentative and narrative texts in L1 and L2
- 2024
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Ingår i: Journal of second language writing. - : Elsevier. - 1060-3743 .- 1873-1422. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- This study explored writing processes in two languages (L1-Swedish and L2-English) and in two text types (argumentative and narrative) of 158 upper-secondary students by analysing keystroke logging data. The main aim of this study was to identify effective writing processes of argumentative and narrative tasks in L1 and L2. First, results of the mixed effects model analysis showed that students' typical writing processes displayed differences in timing, higher and lower order pauses, production speed, and revision depending on the language in which they wrote and the type of text they wrote. Secondly, using regression model analyses we explored which writing process patterns were positively related to text quality. By combining a reduced set of process measures, we identified effective writing process patterns. These patterns explained a rather substantial part of the variance in text quality, more precisely, between 56.1 % and 69.3 %. This study contributes to the current field of writing process studies by expanding our knowledge of typical and effective writing processes in argumentative and narrative writing in upper-secondary students' L1 and L2. These insights can be used to further shape writing education to support students’ writing across languages and text types.
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| 28. |
- Vandermeulen, Nina, et al.
(författare)
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Getting a grip on the writing process : (Effective) approaches to write argumentative and narrative texts in L1 and L2
- 2024
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Ingår i: Journal of second language writing. - : Elsevier. - 1060-3743 .- 1873-1422. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- This study explored writing processes in two languages (L1-Swedish and L2-English) and in twotext types (argumentative and narrative) of 158 upper-secondary students by analysing keystrokelogging data. The main aim of this study was to identify effective writing processes of argumentativeand narrative tasks in L1 and L2. First, results of the mixed effects model analysisshowed that students’ typical writing processes displayed differences in timing, higher and lowerorder pauses, production speed, and revision depending on the language in which they wrote andthe type of text they wrote. Secondly, using regression model analyses we explored which writingprocess patterns were positively related to text quality. By combining a reduced set of processmeasures, we identified effective writing process patterns. These patterns explained a rathersubstantial part of the variance in text quality, more precisely, between 56.1 % and 69.3 %. Thisstudy contributes to the current field of writing process studies by expanding our knowledge oftypical and effective writing processes in argumentative and narrative writing in upper-secondarystudents’ L1 and L2. These insights can be used to further shape writing education to supportstudents’ writing across languages and text types.
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| 29. |
- Vidal-Albalat, Andreu, et al.
(författare)
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Structure-activity relationships reveal beneficial selectivity profiles of inhibitors targeting acetylcholinesterase of disease-transmitting mosquitoes
- 2023
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:9, s. 6333-6353
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Tidskriftsartikel (refereegranskat)abstract
- Insecticide resistance jeopardizes the prevention of infectious diseases such as malaria and dengue fever by vector control of disease-transmitting mosquitoes. Effective new insecticidal compounds with minimal adverse effects on humans and the environment are therefore urgently needed. Here, we explore noncovalent inhibitors of the well-validated insecticidal target acetylcholinesterase (AChE) based on a 4-thiazolidinone scaffold. The 4-thiazolidinones inhibit AChE1 from the mosquitoes Anopheles gambiae and Aedes aegypti at low micromolar concentrations. Their selectivity depends primarily on the substitution pattern of the phenyl ring; halogen substituents have complex effects. The compounds also feature a pendant aliphatic amine that was important for activity; little variation of this group is tolerated. Molecular docking studies suggested that the tight selectivity profiles of these compounds are due to competition between two binding sites. Three 4-thiazolidinones tested for in vivo insecticidal activity had similar effects on disease-transmitting mosquitoes despite a 10-fold difference in their in vitro activity.
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