| 1. |
- Bartels, M., et al.
(författare)
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Childhood aggression and the co-occurrence of behavioural and emotional problems: results across ages 3-16years from multiple raters in six cohorts in the EU-ACTION project
- 2018
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Ingår i: European Child & Adolescent Psychiatry. - : Springer Science and Business Media LLC. - 1018-8827 .- 1435-165X. ; 27:9, s. 1105-1121
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Tidskriftsartikel (refereegranskat)abstract
- Childhood aggression and its resulting consequences inflict a huge burden on affected children, their relatives, teachers, peers and society as a whole. Aggression during childhood rarely occurs in isolation and is correlated with other symptoms of childhood psychopathology. In this paper, we aim to describe and improve the understanding of the co-occurrence of aggression with other forms of childhood psychopathology. We focus on the co-occurrence of aggression and other childhood behavioural and emotional problems, including other externalising problems, attention problems and anxiety-depression. The data were brought together within the EU-ACTION (Aggression in Children: unravelling gene-environment interplay to inform Treatment and InterventiON strategies) project. We analysed the co-occurrence of aggression and other childhood behavioural and emotional problems as a function of the child's age (ages 3 through 16years), gender, the person rating the behaviour (father, mother or self) and assessment instrument. The data came from six large population-based European cohort studies from the Netherlands (2x), the UK, Finland and Sweden (2x). Multiple assessment instruments, including the Child Behaviour Checklist (CBCL), the Strengths and Difficulties Questionnaire (SDQ) and Multidimensional Peer Nomination Inventory (MPNI), were used. There was a good representation of boys and girls in each age category, with data for 30,523 3- to 4-year-olds (49.5% boys), 20,958 5- to 6-year-olds (49.6% boys), 18,291 7- to 8-year-olds (49.0% boys), 27,218 9- to 10-year-olds (49.4% boys), 18,543 12- to 13-year-olds (48.9% boys) and 10,088 15- to 16-year-olds (46.6% boys). We replicated the well-established gender differences in average aggression scores at most ages for parental ratings. The gender differences decreased with age and were not present for self-reports. Aggression co-occurred with the majority of other behavioural and social problems, from both externalising and internalising domains. At each age, the co-occurrence was particularly prevalent for aggression and oppositional and ADHD-related problems, with correlations of around 0.5 in general. Aggression also showed substantial associations with anxiety-depression and other internalizing symptoms (correlations around 0.4). Co-occurrence for self-reported problems was somewhat higher than for parental reports, but we found neither rater differences, nor differences across assessment instruments in co-occurrence patterns. There were large similarities in co-occurrence patterns across the different European countries. Finally, co-occurrence was generally stable across age and sex, and if any change was observed, it indicated stronger correlations when children grew older. We present an online tool to visualise these associations as a function of rater, gender, instrument and cohort. In addition, we present a description of the full EU-ACTION projects, its first results and the future perspectives.
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| 2. |
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| 3. |
- Czamara, D, et al.
(författare)
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Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2548-
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.
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| 4. |
- 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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| 5. |
- Sundén, Henrik, 1978, et al.
(författare)
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Synthesis and Biological Evaluation of Second-Generation Tropanol-Based Androgen Receptor Modulators
- 2015
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 58:3, s. 1569-1574
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Tidskriftsartikel (refereegranskat)abstract
- To circumvent antiandrogen resistance in prostate cancer, antiandrogens effective for both the androgen receptor (AR) and AR mutants are required. The AR antagonists in this study originate from previous findings, which showed that subtle differences in substitution pattern lead to a conformational change that alters the ligand activity, rendering an agonist to an antagonist. We have identified small yet potent tropanol-based ligands possessing significant antiandrogenic activity with both wild-type AR and the two most common AR ligand binding domain (LBD) mutants.
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| 6. |
- Alho, Markku, et al.
(författare)
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Hybrid modeling of cometary plasma environments : II. Remote-sensing of a cometary bow shock
- 2019
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 630
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Tidskriftsartikel (refereegranskat)abstract
- Context. The ESA Rosetta probe has not seen direct evidence of a fully formed bow shock at comet 67P/Churyumov–Gerasimenko (67P). Ion spectrometer measurements of cometary pickup ions measured in the vicinity of the nucleus of 67P are available and may contain signatures of the large-scale plasma environment.Aims. The aim is to investigate the possibility of using pickup ion signatures to infer the existence or nonexistence of a bow shock-like structure and possibly other large-scale plasma environment features.Methods. A numerical plasma model in the hybrid plasma description was used to model the plasma environment of a comet. Simulated pickup ion spectra were generated for different interplanetary magnetic field conditions. The results were interpreted through test particle tracing in the hybrid simulation solutions.Results. Features of the observed pickup ion energy spectrum were reproduced, and the model was used to interpret the observation to be consistent with a shock-like structure. We identify (1) a spectral break related to the bow shock, (2) a mechanism for generating the spectral break, and (3) a dependency of the energy of the spectral break on the interplanetary magnetic field magnitude and bow shock standoff distance.
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| 7. |
- Dimmock, Andrew P., et al.
(författare)
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Direct evidence of nonstationary collisionless shocks in space plasmas
- 2019
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Ingår i: Science Advances. - : AMER ASSOC ADVANCEMENT SCIENCE. - 2375-2548. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- Collisionless shocks are ubiquitous throughout the universe: around stars, supernova remnants, active galactic nuclei, binary systems, comets, and planets. Key information is carried by electromagnetic emissions from particles accelerated by high Mach number collisionless shocks. These shocks are intrinsically nonstationary, and the characteristic physical scales responsible for particle acceleration remain unknown. Quantifying these scales is crucial, as it affects the fundamental process of redistributing upstream plasma kinetic energy into other degrees of freedom-particularly electron thermalization. Direct in situ measurements of nonstationary shock dynamics have not been reported. Thus, the model that best describes this process has remained unknown. Here, we present direct evidence demonstrating that the transition to nonstationarity is associated with electron-scale field structures inside the shock ramp.
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| 8. |
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| 9. |
- Kumar, Anmol, et al.
(författare)
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GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function
- 2015
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Ingår i: PLOS Genetics. - : PLoS. - 1553-7390 .- 1553-7404. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson's disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of GDNF has been attempted for Parkinson's disease treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role of endogenous GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowledge is scarce. Here, we report that prevention of transcription of Gdnf 3'UTR in Gdnf endogenous locus yields GDNF hypermorphic mice with increased, but spatially unchanged GDNF expression, enabling analysis of postnatal GDNF function. We found that increased level of GDNF in the central nervous system increases the number of adult dopamine neurons in the substantia nigra pars compacta and the number of dopaminergic terminals in the dorsal striatum. At the functional level, GDNF levels increased striatal tissue dopamine levels and augmented striatal dopamine release and re-uptake. In a proteasome inhibitor lactacystin-induced model of Parkinson's disease GDNF hypermorphic mice were protected from the reduction in striatal dopamine and failure of dopaminergic system function. Importantly, adverse phenotypic effects associated with spatially unregulated GDNF applications were not observed. Enhanced GDNF levels up-regulated striatal dopamine transporter activity by at least five fold resulting in enhanced susceptibility to 6-OHDA, a toxin transported into dopamine neurons by DAT. Further, we report how GDNF levels regulate kidney development and identify microRNAs miR-9, miR-96, miR-133, and miR-146a as negative regulators of GDNF expression via interaction with Gdnf 3'UTR in vitro. Our results reveal the role of GDNF in nigrostriatal dopamine system postnatal development and adult function, and highlight the importance of correct spatial expression of GDNF. Furthermore, our results suggest that 3'UTR targeting may constitute a useful tool in analyzing gene function.
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| 10. |
- Lakka, A., et al.
(författare)
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The Cross-Polar Cap Saturation in GUMICS-4 During High Solar Wind Driving
- 2018
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Ingår i: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 123:5, s. 3320-3332
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Tidskriftsartikel (refereegranskat)abstract
- It is well known that the Earth's ionospheric cross‐polar cap potential (CPCP) saturates as a response to the solar wind (SW) driver especially when the level of driving is high and the interplanetary magnetic field is oriented southward. Moreover, previous studies have shown that the upstream Alfvén Mach number may be an important factor in the saturation effect. While the CPCP is often viewed as a measure of the SW‐magnetosphere‐ionosphere coupling, the processes associated with the nonlinearity of the coupling remain an open issue. We use fourth edition of the Grand Unified Magnetosphere‐Ionosphere Coupling Simulation (GUMICS‐4) and artificial SW data to mimic weak and strong driving in order to study the CPCP response to a wide range of interplanetary magnetic field magnitudes (3.5–30 nT) and upstream Alfvén Mach number values (1.2–22). The results provide the first overview of the CPCP saturation in GUMICS‐4 and show that the onset of saturation is strongly dependent on the upstream Alfvén Mach number and the physical processes responsible for the saturation effect might take place both in the Earth's magnetosheath and in the upstream SW.
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