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- Klaric, Lucija, et al.
(författare)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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| 2. |
- Czeszumski, Artur, et al.
(författare)
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#EEGManyLabs: Investigating the Replicability of Influential EEG Experiments
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- There is growing awareness across the neuroscience community that the replicability of findings on the relationship between brain activity and cognitive phenomena can be improved by conducting studies with high statistical power that adhere to well-defined and standardized analysis pipelines. Inspired by efforts from the psychological sciences, and with the desire to examine some of the foundational findings using electroencephalography (EEG), we have launched #EEGManyLabs, a large-scale international collaborative replication effort. Since its discovery in the early 20th century, EEG has had a profound influence on our understanding of human cognition, but there is limited evidence on the replicability of some of the most highly cited discoveries. After a systematic search and selection process, we have identified 27 of the most influential and continually cited studies in the field. We plan to directly test the replicability of key findings from 20 of these studies in teams of at least three independent laboratories. The design and protocol of each replication effort will be submitted as a Registered Report and peer-reviewed prior to data collection. Prediction markets, open to all EEG researchers, will be used as a forecasting tool to examine which findings the community expects to replicate. This project will update our confidence in some of the most influential EEG findings and generate a large open access database that can be used to inform future research practices. Finally, through this international effort, we hope to create a cultural shift towards inclusive, high-powered multi-laboratory collaborations.
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| 3. |
- Herrera-Rivero, Marisol, et al.
(författare)
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Exploring the genetics of lithium response in bipolar disorders.
- 2023
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Ingår i: Research square.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II.We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism.Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.
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| 4. |
- Andersen, Jeppe R., et al.
(författare)
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Les Houches 2017: Physics at TeV Colliders Standard Model Working Group Report
- 2018. - 07977
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- This Report summarizes the proceedings of the 2017 Les Houches workshop on Physics at TeV Colliders. Session 1 dealt with (I) new developments relevant for high precision Standard Model calculations, (II) theoretical uncertainties and dataset dependence of parton distribution functions, (III) new developments in jet substructure techniques, (IV) issues in the theoretical description of the production of Standard Model Higgs bosons and how to relate experimental measurements, (V) phenomenological studies essential for comparing LHC data from Run II with theoretical predictions and projections for future measurements, and (VI) new developments in Monte Carlo event generators.
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| 8. |
- Kaufmann, Philipp, 1991-, et al.
(författare)
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Assembly of polymorphic Y chromosomes reveals molecular basis of variation in male body size
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The Y chromosome of males is theorized to facilitate the evolution of sexual dimorphism by accumulating sexually antagonistic loci, but empirical support is limited. In the seed beetle Callosobruchus maculatus, variation in sexually antagonistic body size is linked to at least two segregating Y haplotypes in males that facilitated rapid laboratory evolution of sexual size dimorphism. Here we assemble previously uncharacterized C. maculatus sex chromosome sequences and identify molecular differences between the two predicted Y haplotypes. The Y chromosome of C. maculatus shows typical hallmarks of degeneration: it is ampliconic and approximately 80% smaller than the X. Nevertheless, the Y harbors over 400 genes with a mixed autosomal and X chromosome ancestry that are enriched with metabolic, developmental and gene regulatory functions. Crucially, we find that besides an autosomal copy of the gene target of rapamycin (TOR), males carry an additional TOR copy on the Y chromosome. TOR is a conserved regulator of growth across taxa, and a Y-linked copy of TOR thus provides a male specific opportunity to alter body size. The two identified Y haplotypes show fixed single nucleotide differences in or in close proximity to over 100 genes, but also copy number variation for TOR, where the more frequent (~95%) Y haplotype that causes increased sexual size dimorphism has two additional TOR copies. These results suggest that part of the sexual conflict over body size has been mitigated by autosome to Y translocation of TOR followed by gene duplications that further increased sexual dimorphism.
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| 9. |
- Schröder, Henning, et al.
(författare)
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Varying photo-dissociation mechanisms in Fe(CO)5 and Cr(CO)6 from femtosecond valence photoemission and excited-state moleculardynamics simulations
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We present measured and calculated time-resolved photoelectron spectra of photoexcited gas-phase Fe(CO)5 and Cr(CO)6. Upon electronic excitation with 266 nm pump pulses and by probing with 23 eV photons from a femtosecond high-order har-monic generation source, we observe differences between Fe(CO)5 and Cr(CO)6 that indicate that the excited-state and dissociation dynamics are slower in Fe(CO)5 than in Cr(CO)6. Changing photoelectron intensities and binding energies combined with excited-state molecular dynamics simulations indicate repopulations of excited states from bound excited to dissociative excited states and to the dissociated species. We find that the more open and flexible structure of Fe(CO)5 with larger metal-carbonyl angles enables the photoexcited states of Fe(CO)5 to dissipate energy by angular distortions as observed in longer populations of bound excited states. The more compactand closed structure of Cr(CO)6 does not enable this relaxation resulting in fasterdissociation.
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