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- Michel, M., et al.
(author)
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Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
- 2022
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In: Science. - Stockholm : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 376:6600, s. 1471-1476
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Journal article (peer-reviewed)abstract
- Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging. © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
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| 3. |
- Bonomi, A, et al.
(author)
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Analysis of the genetic variants associated with circulating levels of sgp130. Results from the IMPROVE study
- 2020
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In: Genes and immunity. - : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 21:2, s. 100-108
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Journal article (peer-reviewed)abstract
- The genes regulating circulating levels of soluble gp130 (sgp130), the antagonist of the inflammatory response in atherosclerosis driven by interleukin 6, are largely unknown. Aims of the present study were to identify genetic loci associated with circulating sgp130 and to explore the potential association between variants associated with sgp130 and markers of subclinical atherosclerosis. The study is based on IMPROVE (n = 3703), a cardiovascular multicentre study designed to investigate the determinants of carotid intima media thickness, a measure of subclinical atherosclerosis. Genomic DNA was genotyped by the CardioMetaboChip and ImmunoChip. About 360,842 SNPs were tested for association with log-transformed sgp130, using linear regression adjusted for age, gender, and population stratification using PLINK v1.07. A p value of 1 × 10−5 was chosen as threshold for significance value. In an exploratory analysis, SNPs associated with sgp130 were tested for association with c-IMT measures. We identified two SNPs significantly associated with sgp130 levels and 24 showing suggestive association with sgp130 levels. One SNP (rs17688225) on chromosome 14 was positively associated with sgp130 serum levels (β = 0.03 SE = 0.007, p = 4.77 × 10−5) and inversely associated with c-IMT (c-IMTmean–maxβ = −0.001 SE = 0.005, p = 0.0342). Our data indicate that multiple loci regulate sgp130 levels and suggest a possible common pathway between sgp130 and c-IMT measures.
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| 5. |
- Biel, D., et al.
(author)
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sTREM2 is associated with amyloid-related p-tau increases and glucose hypermetabolism in Alzheimer's disease
- 2023
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In: Embo Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 15:2
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Journal article (peer-reviewed)abstract
- Microglial activation occurs early in Alzheimer's disease (AD) and previous studies reported both detrimental and protective effects of microglia on AD progression. Here, we used CSF sTREM2 to investigate disease stage-dependent drivers of microglial activation and to determine downstream consequences on AD progression. We included 402 patients with measures of earliest beta-amyloid (CSF A beta(1-42)) and late-stage fibrillary A beta pathology (amyloid-PET centiloid), as well as sTREM2, p-tau(181), and FDG-PET. To determine disease stage, we stratified participants into early A beta-accumulators (A beta CSF+/PET-; n = 70) or late A beta-accumulators (A beta CSF+/PET+; n = 201) plus 131 controls. In early A beta-accumulators, higher centiloid was associated with cross-sectional/longitudinal sTREM2 and p-tau(181) increases. Further, higher sTREM2 mediated the association between centiloid and cross-sectional/longitudinal p-tau(181) increases and higher sTREM2 was associated with FDG-PET hypermetabolism. In late A beta-accumulators, we found no association between centiloid and sTREM2 but a cross-sectional association between higher sTREM2, higher p-tau(181) and glucose hypometabolism. Our findings suggest that a TREM2-related microglial response follows earliest A beta fibrillization, manifests in inflammatory glucose hypermetabolism and may facilitate subsequent p-tau(181) increases in earliest AD.
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| 9. |
- Cheesman, Rosa, et al.
(author)
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How interactions between ADHD and schools affect educational achievement : a family-based genetically sensitive study.
- 2022
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In: Journal of Child Psychology and Psychiatry. - : Wiley-Blackwell Publishing Inc.. - 0021-9630 .- 1469-7610. ; 63:10, s. 1174-1185
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Journal article (peer-reviewed)abstract
- BACKGROUND: Children with ADHD tend to achieve less than their peers in school. It is unknown whether schools moderate this association. Nonrandom selection of children into schools related to variations in their ADHD risk poses a methodological problem.METHODS: We linked data on ADHD symptoms of inattention and hyperactivity and parent-child ADHD polygenic scores (PGS) from the Norwegian Mother, Father, and Child Cohort Study (MoBa) to achievement in standardised tests and school identifiers. We estimated interactions of schools with individual differences between students in inattention, hyperactivity, and ADHD-PGS using multilevel models with random slopes for ADHD effects on achievement over schools. In our PGS analyses, we adjust for parental selection of schools by adjusting for parental ADHD-PGS (a within-family PGS design). We then tested whether five school sociodemographic measures explained any interactions.RESULTS: Analysis of up to 23,598 students attending 2,579 schools revealed interactions between school and ADHD effects on achievement. The variability between schools in the effects of inattention, hyperactivity and within-family ADHD-PGS on achievement was 0.08, 0.07 and 0.05 SDs, respectively. For example, the average effect of inattention on achievement was β = -0.23 (SE = 0.009), but in 2.5% of schools with the weakest effects, the value was -0.07 or less. ADHD has a weaker effect on achievement in higher-performing schools. Schools make more of a difference to the achievements of students with higher levels of ADHD, explaining over four times as much variance in achievement for those with high versus average inattention symptoms. School sociodemographic measures could not explain the ADHD-by-school interactions.CONCLUSIONS: Although ADHD symptoms and genetic risk tend to hinder achievement, schools where their effects are weaker do exist. Differences between schools in support for children with ADHD should be evened out.
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| 10. |
- Goriaev, A., et al.
(author)
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The upgraded TOMAS device : A toroidal plasma facility for wall conditioning, plasma production, and plasma-surface interaction studies
- 2021
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In: Review of Scientific Instruments. - : AMER INST PHYSICS. - 0034-6748 .- 1089-7623. ; 92:2
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Journal article (peer-reviewed)abstract
- The Toroidal Magnetized System device has been significantly upgraded to enable development of various wall conditioning techniques, including methods based on ion and electron cyclotron (IC/EC) range of frequency plasmas, and to complement plasma-wall interaction research in tokamaks and stellarators. The toroidal magnetic field generated by 16 coils can reach its maximum of 125 mT on the toroidal axis. The EC system is operated at 2.45 GHz with up to 6 kW forward power. The IC system can couple up to 6 kW in the frequency range of 10 MHz-50 MHz. The direct current glow discharge system is based on a graphite anode with a maximum voltage of 1.5 kV and a current of 6 A. A load-lock system with a vertical manipulator allows exposure of material samples. A number of diagnostics have been installed: single- and triple-pin Langmuir probes for radial plasma profiles, a time-of-flight neutral particle analyzer capable of detecting neutrals in the energy range of 10 eV-1000 eV, and a quadrupole mass spectrometer and video systems for plasma imaging. The majority of systems and diagnostics are controlled by the Siemens SIMATIC S7 system, which also provides safety interlocks.
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