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| 2. |
- Namkoong, H, et al.
(author)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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Journal article (peer-reviewed)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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| 3. |
- Wang, QBS, et al.
(author)
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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
- 2022
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4830-
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Journal article (peer-reviewed)abstract
- Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.
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| 4. |
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| 5. |
- Ehara, Masahiro, et al.
(author)
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Vibrationally resolved nitrogen K-shell photoelectron spectra of the dinitrogen oxide molecule : Experiment and theory
- 2007
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In: Chemical Physics Letters. - : Elsevier BV. - 0009-2614 .- 1873-4448. ; 438:1-3, s. 14-19
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Journal article (peer-reviewed)abstract
- Vibrationally resolved Nc and Nt K-shell photoelectron spectra of the dinitrogen oxide have been studied experimentally and theoretically. Vibrational frequencies for the Nc and Nt 1s ionized states obtained from the 2D potential surfaces computed by the CCSD(T) method within the equivalent core approximation reasonably agree with the experimental values. Experimental relative intensities of the vibrational structure are reasonably reproduced by the multi-channel Schwinger configuration interaction method (MCSCI) with the computed 2D potential surfaces. Improved relaxed geometries of these core–hole states are obtained from fitting the experimental spectra using the MCSCI calculations and regarding the bond lengths as fitting parameters.
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| 6. |
- Lucchese, Robert, et al.
(author)
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Vibrationally resolved partial cross sections and asymmetry parameters for nitrogen K-shell photoionization of the N2O molecule
- 2007
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In: Physical Review A. Atomic, Molecular, and Optical Physics. - 1050-2947 .- 1094-1622. ; 76:1, s. 012506-
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Journal article (peer-reviewed)abstract
- We have measured the vibrationally resolved partial cross sections σ(v1′,v2′,v3′) and asymmetry parameters β(v1′,v2′,v3′) for Nc and Nt K-shell photoionization of the N2O molecule in the σ* shape resonance region above the Nt and Nc K-shell ionization thresholds. Nc K-shell photoionization of the N2O molecule predominantly causes the excitation of the quasisymmetric vibrations (v1′), whereas Nt K-shell photoionization causes both quasisymmetric and quasiantisymmetric vibrations (v1′ and v3′) to be excited. The shape resonance energy in the Nc K-shell photoionization increases with an increase in v1′. The β(v1′,0,0) curves for the Nc K-shell photoionization exhibit maxima at energies close to the shape resonance energies for the individual values of v1′. The shape resonance energy in the Nt K-shell photoionization decreases with an increase in v1′ and slightly increases with an increase in v3′. The β(v1′,0,0) curves show a significant state dependence in the region of the shape resonance, with the curves shifting to lower energy as v1′ increases. The vibrational state dependence of the cross sections σ(v1′,v2′,v3′) and asymmetry parameters β(v1′,v2′,v3′) are well reproduced by the theoretical calculations using the multichannel Schwinger configuration interaction (MCSCI) method, including both the Nc and Nt ion states.
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| 7. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 8. |
- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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| 9. |
- Egawa-Tsuzuki, Tomoko, et al.
(author)
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The PDGF B-chain is involved in the ontogenic susceptibility of the developing rat brain to NMDA toxicity.
- 2004
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In: Experimental neurology. - : Elsevier BV. - 0014-4886. ; 186:1, s. 89-98
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Journal article (peer-reviewed)abstract
- Hypoxic-ischemic (H-I) injury to neonatal brains can cause a life-long neuronal deficit because of increased susceptibility in the neonatal period. Excitotoxicity due to overstimulation of the N-methyl-d-aspartate receptor (NMDAR) is assumed to be the basis of the injury. However, the ontogenic profile of the susceptibility does not directly correlate with the levels of NMDAR expression. Platelet-derived growth factor B-chain (PDGF-B) has been reported to protect neurons by suppressing the NMDA-evoked current and translocating the glutamate transporter to the cell membrane. Thus, we assessed the relationship between the susceptibility to H-I injury and the expression of PDGF-B in neonatal rat brain. PDGF-B infusion before and after an intrastriatal NMDA injection significantly reduced the size of the lesions in 7-day-old rats, when they are most susceptible and the neuronal expression of PDGF-B is low. Fourteen-day-old neonatal rats were found to be resistant to NMDA injury, even though NMDARs are expressed at high levels in the brain at this age. Inhibition of PDGF-B protein synthesis by antisense oligodeoxynucleotides increased the size of the NMDA-induced lesions up to 6-fold at postnatal day 14, when PDGF-B is expressed at high levels in neurons. These data suggest that PDGF-B is an important physiological modulator of NMDAR excitability in the developing brain, and that the balance between the expression of NMDAR and PDGF-B partly determines the ontogenic susceptibility to brain injury. Enhancement of the PDGF-B/receptor signal pathway might rescue neonatal brains at risk of H-I injury.
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| 11. |
- Hosokawa, Hiroyuki, et al.
(author)
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Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by repressing Id2 and Zbtb16
- 2018
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In: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 19:12, s. 1427-1440
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Journal article (peer-reviewed)abstract
- Multipotent progenitor cells confirm their T cell–lineage identity in the CD4–CD8– double-negative (DN) pro-T cell DN2 stages, when expression of the essential transcription factor Bcl11b begins. In vivo and in vitro stage-specific deletions globally identified Bcl11b-controlled target genes in pro-T cells. Proteomics analysis revealed that Bcl11b associated with multiple cofactors and that its direct action was needed to recruit those cofactors to selective target sites. Regions near functionally regulated target genes showed enrichment for those sites of Bcl11b-dependent recruitment of cofactors, and deletion of individual cofactors relieved the repression of many genes normally repressed by Bcl11b. Runx1 collaborated with Bcl11b most frequently for both activation and repression. In parallel, Bcl11b indirectly regulated a subset of target genes by a gene network circuit via the transcription inhibitor Id2 (encoded by Id2) and transcription factor PLZF (encoded by Zbtb16); Id2 and Zbtb16 were directly repressed by Bcl11b, and Id2 and PLZF controlled distinct alternative programs. Thus, our study defines the molecular basis of direct and indirect Bcl11b actions that promote T cell identity and block alternative potentials.
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| 12. |
- Hosokawa, Hiroyuki, et al.
(author)
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Transcription Factor PU.1 Represses and Activates Gene Expression in Early T Cells by Redirecting Partner Transcription Factor Binding
- 2018
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In: Immunity. - : Elsevier BV. - 1074-7613. ; 48:6, s. 7-1134
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Journal article (peer-reviewed)abstract
- Transcription factors normally regulate gene expression through their action at sites where they bind to DNA. However, the balance of activating and repressive functions that a transcription factor can mediate is not completely understood. Here, we showed that the transcription factor PU.1 regulated gene expression in early T cell development both by recruiting partner transcription factors to its own binding sites and by depleting them from the binding sites that they preferred when PU.1 was absent. The removal of partner factors Satb1 and Runx1 occurred primarily from sites where PU.1 itself did not bind. Genes linked to sites of partner factor “theft” were enriched for genes that PU.1 represses despite lack of binding, both in a model cell line system and in normal T cell development. Thus, system-level competitive recruitment dynamics permit PU.1 to affect gene expression both through its own target sites and through action at a distance. Transcription factors regulate target genes via sequence-specific DNA binding. They may collaborate when bound together, but are assumed to be independent at sites where they bind alone. Hosokawa, Ungerbäck et al. show that PU.1 broadly shifts the genome-wide site choice of Runx1 DNA binding, enabling PU.1 to repress some target genes at a distance.
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| 13. |
- Ito, Komei, et al.
(author)
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The usefulness of casein-specific IgE and IgG4 antibodies in cow's milk allergic children
- 2012
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In: Clinical and Molecular Allergy. - : Springer Science and Business Media LLC. - 1476-7961. ; 10:1, s. 1-
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Journal article (peer-reviewed)abstract
- BackgroundCow's milk allergy is one of the most common food allergies among younger children. We investigated IgE antibodies to milk, and IgE and IgG4 antibodies to casein, α-lactalbumin and β-lactoglobulin in cow's milk allergic (CMA) and non-allergic (non-CMA) children in order to study their clinical usefulness.MethodsEighty-three children with suspected milk allergy (median age: 3.5 years, range: 0.8-15.8 years) were diagnosed as CMA (n = 61) or non-CMA (n = 22) based on an open milk challenge or convincing clinical history. Their serum concentrations of allergen-specific (s) IgE and IgG4 antibodies were measured using ImmunoCAP®. For the sIgG4 analysis, 28 atopic and 31 non-atopic control children were additionally included (all non-milk sensitized).ResultsThe CMA group had significantly higher levels of milk-, casein- and β-lactoglobulin-sIgE antibodies as compared to the non-CMA group. The casein test showed the best discriminating performance with a clinical decision point of 6.6 kUA/L corresponding to 100% specificity. All but one of the CMA children aged > 5 years had casein-sIgE levels > 6.6 kUA/L. The non-CMA group had significantly higher sIgG4 levels against all three milk allergens compared to the CMA group. This was most pronounced for casein-sIgG4 in non-CMA children without history of previous milk allergy. These children had significantly higher casein-sIgG4 levels compared to any other group, including the non-milk sensitized control children.ConclusionsHigh levels of casein-sIgE antibodies are strongly associated with milk allergy in children and might be associated with prolonged allergy. Elevated casein-sIgG4 levels in milk-sensitized individuals on normal diet indicate a modified Th2 response. However, the protective role of IgG4 antibodies in milk allergy is unclear.
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| 18. |
- Yabuta, Hikaru, et al.
(author)
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Macromolecular organic matter in samples of the asteroid (162173) Ryugu
- 2023
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In: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 379:6634
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Journal article (peer-reviewed)abstract
- Samples of the carbonaceous asteroid (162173) Ryugu were collected and brought to Earth by the Hayabusa2 spacecraft. We investigated the macromolecular organic matter in Ryugu samples and found that it contains aromatic and aliphatic carbon, ketone, and carboxyl functional groups. The spectroscopic features of the organic matter are consistent with those in chemically primitive carbonaceous chondrite meteorites that experienced parent-body aqueous alteration (reactions with liquid water). The morphology of the organic carbon includes nanoglobules and diffuse carbon associated with phyllosilicate and carbonate minerals. Deuterium and/or nitrogen-15 enrichments indicate that the organic matter formed in a cold molecular cloud or the presolar nebula. The diversity of the organic matter indicates variable levels of aqueous alteration on Ryugus parent body.
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