| 1. |
- Blokland, G. A. M., et al.
(author)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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In: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Journal article (peer-reviewed)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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| 2. |
- Fremling, C., et al.
(author)
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The Zwicky Transient Facility Bright Transient Survey. I. Spectroscopic Classification and the Redshift Completeness of Local Galaxy Catalogs
- 2020
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 895:1
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Journal article (peer-reviewed)abstract
- The Zwicky Transient Facility (ZTF) is performing a three-day cadence survey of the visible northern sky (similar to 3 pi) with newly found transient candidates announced via public alerts. The ZTF Bright Transient Survey (BTS) is a large spectroscopic campaign to complement the photometric survey. BTS endeavors to spectroscopically classify all extragalactic transients with m(peak) <= 18.5 mag in either the g(ZTF) or r(ZTF) filters, and publicly announce said classifications. BTS discoveries are predominantly supernovae (SNe), making this the largest flux-limited SN survey to date. Here we present a catalog of 761 SNe, classified during the first nine months of ZTF (2018 April 1-2018 December 31). We report BTS SN redshifts from SN template matching and spectroscopic host-galaxy redshifts when available. We analyze the redshift completeness of local galaxy catalogs, the redshift completeness fraction (RCF; the ratio of SN host galaxies with known spectroscopic redshift prior to SN discovery to the total number of SN hosts). Of the 512 host galaxies with SNe Ia, 227 had previously known spectroscopic redshifts, yielding an RCF estimate of 44% 4%. The RCF decreases with increasing distance and decreasing galaxy luminosity (for z < 0.05, or similar to 200 Mpc, RCF 0.6). Prospects for dramatically increasing the RCF are limited to new multifiber spectroscopic instruments or wide-field narrowband surveys. Existing galaxy redshift catalogs are only similar to 50% complete at r 16.9 mag. Pushing this limit several magnitudes deeper will pay huge dividends when searching for electromagnetic counterparts to gravitational wave events or sources of ultra-high-energy cosmic rays or neutrinos.
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| 3. |
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| 4. |
- van Rheenen, W, et al.
(author)
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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
- 2021
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 53:12, s. 1636-
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Journal article (peer-reviewed)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
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| 5. |
- Kool, Erik C., et al.
(author)
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SN 2020bqj : A Type Ibn supernova with a long-lasting peak plateau
- 2021
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 652
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Journal article (peer-reviewed)abstract
- Context. Type Ibn supernovae (SNe Ibn) are a rare class of stripped envelope supernovae interacting with a helium-rich circumstellar medium (CSM). The majority of the SNe Ibn reported in the literature display a surprising homogeneity in their fast-evolving lightcurves and are typically found in actively starforming spiral galaxies.Aims. We present the discovery and the study of SN 2020bqj (ZTF20aalrqbu), a SN Ibn with a long-duration peak plateau lasting 40 days and hosted by a faint low-mass galaxy. We aim to explain its peculiar properties using an extensive photometric and spectroscopic data set.Methods. We compare the photometric and spectral evolution of SN 2020bqj with regular SNe Ibn from the literature, as well as with other outliers in the SN Ibn subclass. We fit the bolometric and multi-band lightcurves with powering mechanism models such as radioactive decay and CSM interaction. We also model the host galaxy of SN 2020bqj.Results. The risetime, peak magnitude and spectral features of SN 2020bqj are consistent with those of most SNe Ibn, but the SN is a clear outlier in the subclass based on its bright, long-lasting peak plateau and the low mass of its faint host galaxy. We show through modeling that the lightcurve of SN 2020bqj can be powered predominantly by shock heating from the interaction of the SN ejecta and a dense CSM, combined with radioactive decay. The peculiar Type Ibn SN 2011hw is a close analog to SN 2020bqj in terms of lightcurve and spectral evolution, suggesting a similar progenitor and CSM scenario. In this scenario a very massive progenitor star in the transitional phase between a luminous blue variable and a compact Wolf-Rayet star undergoes core-collapse, embedded in a dense helium-rich CSM with an elevated opacity compared to normal SNe Ibn, due to the presence of residual hydrogen. This scenario is consistent with the observed properties of SN 2020bqj and the modeling results.Conclusions. SN 2020bqj is a compelling example of a transitional SN Ibn/IIn based on not only its spectral features, but also its lightcurve, host galaxy properties and the inferred progenitor properties. The strong similarity with SN 2011hw suggests this subclass may be the result of a progenitor in a stellar evolution phase that is distinct from those of progenitors of regular SNe Ibn.
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| 6. |
- Gupta, Dhanu, et al.
(author)
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Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles
- 2021
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In: Nature Biomedical Engineering. - Stockholm : Karolinska Institutet, Dept of Laboratory Medicine. - 2157-846X.
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Journal article (peer-reviewed)abstract
- Extracellular vesicles (EVs) can be functionalized to display specific protein receptors on their surface. However, surface-display technology typically labels only a small fraction of the EV population. Here, we show that the joint display of two different therapeutically relevant protein receptors on EVs can be optimized by systematically screening EV-loading protein moieties. We used cytokine-binding domains derived from tumour necrosis factor receptor 1 (TNFR1) and interleukin-6 signal transducer (IL-6ST), which can act as decoy receptors for the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and IL-6, respectively. We found that the genetic engineering of EV-producing cells to express oligomerized exosomal sorting domains and the N-terminal fragment of syntenin (a cytosolic adaptor of the single transmembrane domain protein syndecan) increased the display efficiency and inhibitory activity of TNFR1 and IL-6ST and facilitated their joint display on EVs. In mouse models of systemic inflammation, neuroinflammation and intestinal inflammation, EVs displaying the cytokine decoys ameliorated the disease phenotypes with higher efficacy as compared with clinically approved biopharmaceutical agents targeting the TNF-α and IL-6 pathways.
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