| 1. |
- Sønderby, Ida E., et al.
(författare)
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1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans
- 2021
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Ingår i: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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| 2. |
- van der Meer, Dennis, et al.
(författare)
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Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition
- 2020
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 77:4, s. 420-430
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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| 3. |
- Addazi, A., et al.
(författare)
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New high-sensitivity searches for neutrons converting into antineutrons and/or sterile neutrons at the HIBEAM/NNBAR experiment at the European Spallation Source
- 2021
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Ingår i: Journal of Physics G. - : Institute of Physics Publishing (IOPP). - 0954-3899 .- 1361-6471. ; 48:7
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Tidskriftsartikel (refereegranskat)abstract
- The violation of baryon number, , is an essential ingredient for the preferential creation of matter over antimatter needed to account for the observed baryon asymmetry in the Universe. However, such a process has yet to be experimentally observed. The HIBEAM/NNBAR program is a proposed two-stage experiment at the European Spallation Source to search for baryon number violation. The program will include high-sensitivity searches for processes that violate baryon number by one or two units: free neutron–antineutron oscillation () via mixing, neutron–antineutron oscillation via regeneration from a sterile neutron state (), and neutron disappearance (n → n'); the effective process of neutron regeneration () is also possible. The program can be used to discover and characterize mixing in the neutron, antineutron and sterile neutron sectors. The experiment addresses topical open questions such as the origins of baryogenesis and the nature of dark matter, and is sensitive to scales of new physics substantially in excess of those available at colliders. A goal of the program is to open a discovery window to neutron conversion probabilities (sensitivities) by up to three orders of magnitude compared with previous searches. The opportunity to make such a leap in sensitivity tests should not be squandered. The experiment pulls together a diverse international team of physicists from the particle (collider and low energy) and nuclear physics communities, while also including specialists in neutronics and magnetics.
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| 4. |
- Geisler, D., et al.
(författare)
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CAPOS : The bulge Cluster APOgee Survey I. Overview and initial ASPCAP results
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 652
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Tidskriftsartikel (refereegranskat)abstract
- Context. Bulge globular clusters (BGCs) are exceptional tracers of the formation and chemodynamical evolution of this oldest Galactic component. However, until now, observational difficulties have prevented us from taking full advantage of these powerful Galactic archeological tools. Aims. CAPOS, the bulge Cluster APOgee Survey, addresses this key topic by observing a large number of BGCs, most of which have only been poorly studied previously. Even their most basic parameters, such as metallicity, [alpha/Fe], and radial velocity, are generally very uncertain. We aim to obtain accurate mean values for these parameters, as well as abundances for a number of other elements, and explore multiple populations. In this first paper, we describe the CAPOS project and present initial results for seven BGCs. Methods. CAPOS uses the APOGEE-2S spectrograph observing in the H band to penetrate obscuring dust toward the bulge. For this initial paper, we use abundances derived from ASPCAP, the APOGEE pipeline. Results. We derive mean [Fe/H] values of -0.85 +/- 0.04 (Terzan 2), -1.40 +/- 0.05 (Terzan 4), -1.20 +/- 0.10 (HP 1), -1.40 +/- 0.07 (Terzan 9), -1.07 +/- 0.09 (Djorg 2), -1.06 +/- 0.06 (NGC 6540), and -1.11 +/- 0.04 (NGC 6642) from three to ten stars per cluster. We determine mean abundances for eleven other elements plus the mean [alpha/Fe] and radial velocity. CAPOS clusters significantly increase the sample of well-studied Main Bulge globular clusters (GCs) and also extend them to lower metallicity. We reinforce the finding that Main Bulge and Main Disk GCs, formed in situ, have [Si/Fe] abundances slightly higher than their accreted counterparts at the same metallicity. We investigate multiple populations and find our clusters generally follow the light-element (anti)correlation trends of previous studies of GCs of similar metallicity. We finally explore the abundances of the iron-peak elements Mn and Ni and compare their trends with field populations. Conclusions. CAPOS is proving to be an unprecedented resource for greatly improving our knowledge of the formation and evolution of BGCs and the bulge itself.
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| 5. |
- Anand, Vibha, et al.
(författare)
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Islet Autoimmunity and HLA Markers of Presymptomatic and Clinical Type 1 Diabetes : Joint Analyses of Prospective Cohort Studies in Finland, Germany, Sweden, and the U.S
- 2021
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 44, s. 2269-2276
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and estimate risk of islet autoimmunity and progression to clinical diabetes.RESEARCH DESIGN AND METHODS: For prospective cohorts in Finland, Germany, Sweden, and the U.S., 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes have been followed. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years.RESULTS: In the infant-toddler cohort, 1,413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two, or three autoantibodies at seroconversion: 45% (95% CI 40-52), 85% (78-90), and 92% (85-97), respectively. Among those with a single autoantibody, status 2 years after seroconversion predicted diabetes risk: 12% (10-25) if reverting to autoantibody negative, 30% (20-40) if retaining a single autoantibody, and 82% (80-95) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single-autoantibody status. Their 15-year diabetes incidence for higher- versus lower-risk genotypes was 40% (28-50) vs. 12% (5-38). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies, ranging from 20% per year to 6% per year in children developing multipositivity in ≤2 years or >7.4 years, respectively.CONCLUSIONS: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining a single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.
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| 6. |
- Carlsson, Leo S., et al.
(författare)
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Modeling the Effect of Scrap on the Electrical Energy Consumption of an Electric Arc Furnace
- 2020
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Ingår i: Processes. - : MDPI. - 2227-9717. ; 8:9
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Tidskriftsartikel (refereegranskat)abstract
- The melting time of scrap is a factor that affects the Electrical Energy (EE) consumption of the Electric Arc Furnace (EAF) process. The EE consumption itself stands for most of the total energy consumption during the process. Three distinct representations of scrap, based partly on the apparent density and shape of scrap, were created to investigate the effect of scrap on the accuracy of a statistical model predicting the EE consumption of an EAF. Shapley Additive Explanations (SHAP) was used as a tool to investigate the effects by each scrap category on each prediction of a selected model. The scrap representation based on the shape of scrap consistently resulted in the best performing models while all models using any of the scrap representations performed better than the ones without any scrap representation. These results were consistent for all four distinct and separately used cleaning strategies on the data set governing the models. In addition, some of the main scrap categories contributed to the model prediction of EE in accordance with the expectations and experience of the plant engineers. The results provide significant evidence that a well-chosen scrap categorization is important to improve a statistical model predicting the EE and that experience on the specific EAF under study is essential to evaluate the practical usefulness of the model.
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| 7. |
- Córdova-Palomera, Aldo, et al.
(författare)
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Genetic control of variability in subcortical and intracranial volumes
- 2021
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 26:8, s. 3876-3883
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Tidskriftsartikel (refereegranskat)abstract
- Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in ten key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume, cortical surface area, and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n = 25,575 individuals; 8-89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in thalamus volume and cortical thickness. The variance-controlling loci involved genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.
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| 8. |
- Fritzell, P., et al.
(författare)
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Antibiotics should not be used to treat patients with back/leg pain
- 2020
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Ingår i: Läkartidningen. - 1652-7518. ; 117
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Tidskriftsartikel (refereegranskat)abstract
- This report is based on results from three research groups in Sweden (Fritzell et al), Denmark (Udby et al), and Norway (Bråten et al). The groups have conducted studies published in international journals in 2019 [8-10]. The results complement each other and strongly suggest that antibiotics, in the absence of clear signs of a clinically relevant infection (discitis/spondylitis), should not be used for back pain with or without leg pain. The Swedish study showed that bacteria found in the disc/vertebra during surgery are very likely due to contamination [8], the Danish study showed that patients with Modic Changes (MC) on MR in the long term were not associated with more back pain or functional impairment than in patients without MC [9], and the Norwegian study showed that antibiotics for residual back pain after previous disc herniation had no better clinical effect than placebo [10]. Antibiotic resistance is one of the biggest threats to public health today and in the future.
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| 9. |
- Garg, Manik, et al.
(författare)
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Tumour gene expression signature in primary melanoma predicts long-term outcomes
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10−5) and overall survival (HR = 1.61, p = 1.67 × 10−4), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (pAUROC = 7.03 × 10−4), or published prognostic signatures (pAUROC < 0.05). The signature score negatively correlated with measures of immune cell infiltration (ρ = −0.75, p < 2.2 × 10−16), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.
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| 10. |
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