| 1. |
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| 2. |
- Sonderby, Ida E., et al.
(författare)
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Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:3, s. 584-602
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Tidskriftsartikel (refereegranskat)abstract
- Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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| 3. |
- 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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| 4. |
- 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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| 5. |
- Yordanov, Deyan T., et al.
(författare)
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Structural trends in atomic nuclei from laser spectroscopy of tin
- 2020
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Ingår i: Communications Physics. - : Springer Nature. - 2399-3650. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Tin is the chemical element with the largest number of stable isotopes. Its complete proton shell, comparable with the closed electron shells in the chemically inert noble gases, is not a mere precursor to extended stability; since the protons carry the nuclear charge, their spatial arrangement also drives the nuclear electromagnetism. We report high-precision measurements of the electromagnetic moments and isomeric differences in charge radii between the lowest 1/2(+), 3/2(+), and 11/2(-) states in Sn117-131, obtained by collinear laser spectroscopy. Supported by state-of-the-art atomic-structure calculations, the data accurately show a considerable attenuation of the quadrupole moments in the closed-shell tin isotopes relative to those of cadmium, with two protons less. Linear and quadratic mass-dependent trends are observed. While microscopic density functional theory explains the global behaviour of the measured quantities, interpretation of the local patterns demands higher-fidelity modelling. Measurements of the hyperfine structure of chemical elements isotopes provide unique insight into the atomic nucleus in a nuclear model-independent way. The authors present collinear laser spectroscopy data obtained at the CERN ISOLDE and measure hyperfine splitting along a long chain of odd-mass tin isotopes.
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| 6. |
- Abeysekara, A. U., et al.
(författare)
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VERITAS and Fermi-LAT Observations of TeV Gamma-Ray Sources Discovered by HAWC in the 2HWC Catalog
- 2018
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Ingår i: Astrophysical Journal. - : Institute of Physics Publishing. - 0004-637X .- 1538-4357. ; 866:1
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Tidskriftsartikel (refereegranskat)abstract
- The High Altitude Water Cherenkov (HAWC) collaboration recently published their 2HWC catalog, listing 39 very high energy (VHE; >100 GeV) gamma-ray sources based on 507 days of observation. Among these, 19 sources are not associated with previously known teraelectronvolt (TeV) gamma-ray sources. We have studied 14 of these sources without known counterparts with VERITAS and Fermi-LAT. VERITAS detected weak gamma-ray emission in the 1 TeV-30 TeV band in the region of DA 495, a pulsar wind nebula coinciding with 2HWC J1953+294, confirming the discovery of the source by HAWC. We did not find any counterpart for the selected 14 new HAWC sources from our analysis of Fermi-LAT data for energies higher than 10 GeV. During the search, we detected gigaelectronvolt (GeV) gamma-ray emission coincident with a known TeV pulsar wind nebula, SNR G54.1+0.3 (VER J1930+188), and a 2HWC source, 2HWC J1930+188. The fluxes for isolated, steady sources in the 2HWC catalog are generally in good agreement with those measured by imaging atmospheric Cherenkov telescopes. However, the VERITAS fluxes for SNR G54.1+0.3, DA 495, and TeV J2032+4130 are lower than those measured by HAWC, and several new HAWC sources are not detected by VERITAS. This is likely due to a change in spectral shape, source extension, or the influence of diffuse emission in the source region.
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| 7. |
- Arama, Charles, et al.
(författare)
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A recombinant Bacille Calmette-Guerin construct expressing the Plasmodium falciparum circumsporozoite protein enhances dendritic cell activation and primes for circumsporozoite-specific memory cells in BALB/c mice
- 2012
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Ingår i: Vaccine. - : Elsevier. - 0264-410X .- 1873-2518. ; 30:37, s. 5578-5584
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Tidskriftsartikel (refereegranskat)abstract
- A protective malaria vaccine may induce both high levels of neutralising antibodies and strong T-cell responses. The Plasmodium falciparum circumsporozoite protein (CSp) is a leading pre-erythrocytic vaccine candidate. CSp is a week immunogen per se, but Mycobacterium bovis Bacille Calmette-Guérin (BCG) has excellent adjuvant activity and has been utilized as a vector to deliver heterologous vaccine candidate antigens. It is safe in immunocompetent individuals and inexpensive to produce. We assessed in vitro and in vivo a recombinant BCG-expressing CSp (BCG-CS) as malaria vaccine candidate. Immunisation of BALB/c mice with BCG-CS augmented numbers of dendritic cells (DCs) in draining lymph nodes and in the spleen. The activation markers MHC-class-II, CD40, CD80 and CD86 on DCs were significantly upregulated by BCG-CS as compared to wild-type BCG (wt-BCG). In vitro stimulation of bone marrow-derived DCs and macrophages with BCG-CS induced IL-12 and TNF-α production. BCG-CS induced higher phagocytic activity in macrophages as compared to wt-BCG. Immunogenicity studies show that BCG-CS induced CS-specific antibodies and IFN-γ-producing memory cells. In conclusion, BCG-CS is highly efficient in activating antigen-presenting cells (APCs) for priming of adaptive immunity. Implications for the rational design of novel vaccines against malaria and TB, the two major devastating poverty-related diseases, are discussed.
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| 8. |
- Arama, Charles, et al.
(författare)
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Heterologous prime-boost regimen adenovector 35-circumsporozoite protein vaccine/recombinant Bacillus Calmette-Guerin expressing the Plasmodium falciparum circumsporozoite induces enhanced long-term memory immunity in BALB/c mice
- 2012
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 30:27, s. 4040-4045
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sustained antibody levels are a hallmark of immunity against many pathogens, and induction of long-term durable antibody titers is an essential feature of effective vaccines. Heterologous prime-boost approaches with vectors are optimal strategies to improve a broad and prolonged immunogenicity of malaria vaccines. Results: In this study, we demonstrate that the heterologous prime-boost regimen Ad35-CS/BCG-CS induces stronger immune responses by enhancing type 1 cellular producing-cells with high levels of CSp-specific IFN-gamma and cytophilic IgG2a antibodies as compared to a homologous BCG-CS and a heterologous BCG-CS/CSp prime-boost regimen. Moreover, the heterologous prime-boost regimen elicits the highest level of LLPC-mediated immune responses. Conclusion: The increased IFN-gamma-producing cell responses induced by the combination of Ad35-CS/BCG-CS and sustained type 1 antibody profile together with high levels of LLPCs may be essential for the development of long-term protective immunity against liver-stage parasites.
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| 9. |
- Boen, Rune, et al.
(författare)
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Beyond the global brain differences : intraindividual variability differences in 1q21.1 distal and 15q11.2 bp1-bp2 deletion carriers
- 2024
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Ingår i: Biological Psychiatry. - 0006-3223 .- 1873-2402. ; 95:2, s. 147-160
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Tidskriftsartikel (refereegranskat)abstract
- Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference.Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness.Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.
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| 10. |
- Darmoise, Alexandre, et al.
(författare)
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Lysosomal alpha-galactosidase controls the generation of self lipid antigens for natural killer T cells.
- 2010
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Ingår i: Immunity. - : Elsevier BV. - 1097-4180 .- 1074-7613. ; 33:2, s. 216-28
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Tidskriftsartikel (refereegranskat)abstract
- Natural Killer T (NKT) cells are lipid-reactive, CD1d-restricted T lymphocytes important in infection, cancer, and autoimmunity. In addition to foreign antigens, NKT cells react with endogenous self lipids. However, in the face of stimulating self antigen, it remains unclear how overstimulation of NKT cells is avoided. We hypothesized that constantly degraded endogenous antigen only accumulates upon inhibition of alpha-galactosidase A (alpha-Gal-A) in lysosomes. Here, we show that alpha-Gal-A deficiency caused vigorous activation of NKT cells. Moreover, microbes induced inhibition of alpha-Gal-A activity in antigen-presenting cells. This temporary enzyme block depended on Toll-like receptor (TLR) signaling and ultimately triggered lysosomal lipid accumulation. Thus, we present TLR-dependent negative regulation of alpha-Gal-A as a mechanistic link between pathogen recognition and self lipid antigen induction for NKT cells.
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