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  • 1
    Online Resource
    Online Resource
    DOCK2 is involved in the host genetics and biology of severe COVID-19
    Springer Science and Business Media LLC ; 2022
    In:  Nature Vol. 609, No. 7928 ( 2022-09-22), p. 754-760
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 609, No. 7928 ( 2022-09-22), p. 754-760
    Abstract: Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1–5 . 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.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-022-05163-5
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
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    Wnt3a stimulates maturation of impaired neutrophils developed from severe congenital neutropenia patient-derived pluripotent stem cells
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 8 ( 2013-02-19), p. 3023-3028
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 8 ( 2013-02-19), p. 3023-3028
    Abstract: The derivation of induced pluripotent stem (iPS) cells from individuals of genetic disorders offers new opportunities for basic research into these diseases and the development of therapeutic compounds. Severe congenital neutropenia (SCN) is a serious disorder characterized by severe neutropenia at birth. SCN is associated with heterozygous mutations in the neutrophil elastase [elastase, neutrophil-expressed (ELANE)] gene, but the mechanisms that disrupt neutrophil development have not yet been clarified because of the current lack of an appropriate disease model. Here, we generated iPS cells from an individual with SCN (SCN-iPS cells). Granulopoiesis from SCN-iPS cells revealed neutrophil maturation arrest and little sensitivity to granulocyte-colony stimulating factor, reflecting a disease status of SCN. Molecular analysis of the granulopoiesis from the SCN-iPS cells vs. control iPS cells showed reduced expression of genes related to the wingless-type mmtv integration site family, member 3a (Wnt3a)/β-catenin pathway [e.g., lymphoid enhancer-binding factor 1] , whereas Wnt3a administration induced elevation lymphoid enhancer-binding factor 1-expression and the maturation of SCN-iPS cell-derived neutrophils. These results indicate that SCN-iPS cells provide a useful disease model for SCN, and the activation of the Wnt3a/β-catenin pathway may offer a novel therapy for SCN with ELANE mutation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1217039110
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
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  • 3
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    Preferential mutation of paternally derived RB gene as the initial event in sporadic osteosarcoma
    Springer Science and Business Media LLC ; 1989
    In:  Nature Vol. 338, No. 6211 ( 1989-3), p. 156-158
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 338, No. 6211 ( 1989-3), p. 156-158
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/338156a0
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1989
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
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  • 4
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    The genome sequence and structure of rice chromosome 1
    Springer Science and Business Media LLC ; 2002
    In:  Nature Vol. 420, No. 6913 ( 2002-11), p. 312-316
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 420, No. 6913 ( 2002-11), p. 312-316
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/nature01184
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2002
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
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  • 5
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    Defect tolerant zero-bias topological photocurrent in a ferroelectric semiconductor
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 34 ( 2020-08-25), p. 20411-20415
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 34 ( 2020-08-25), p. 20411-20415
    Abstract: Lattice defect is a major cause of energy dissipation in conventional electric current due to the drift and diffusion motions of electrons. Different nature of current emerges when noncentrosymmetric materials are excited by light. This current, called the shift current, originates from the change in the Berry connection of electrons’ wave functions during the interband optical transition. Here, we demonstrate the defect tolerance of shift current using single crystals of ferroelectric semiconductor antimony sulfoiodide (SbSI). Although the dark conductance spreads over several orders of magnitude in each crystal due to the difference in the density of defect levels, the observed shift current converges to an identical value. We also reveal that the shift current is scarcely disturbed by the surface defects while they drastically suppress the conventional photocurrent. The defect tolerance is a manifestation of the topological nature of shift current, which will be a crucial advantage in optoelectronic applications.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2007002117
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
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  • 6
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    Triplet repeat polymorphism in the transmembrane region of the MICA gene: A strong association of six GCT repetitions with Behçet disease
    Proceedings of the National Academy of Sciences ; 1997
    In:  Proceedings of the National Academy of Sciences Vol. 94, No. 4 ( 1997-02-18), p. 1298-1303
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 94, No. 4 ( 1997-02-18), p. 1298-1303
    Abstract: A member of a novel family of the human major histocompatibility complex (MHC) class I genes termed MIC (MHC class I chain-related genes), MICA, has been recently identified near the HLA-B gene on the short arm of human chromosome 6. The predicted amino acid sequence of the MICA chain suggests that it folds similarly to typical class I chains and may have the capacity to bind peptides or other short ligands. Therefore, MICA is predicted to have a specialized function in antigen presentation or T cell recognition. During nucleotide sequence analyses of the MICA genomic clone, we found a triplet repeat microsatellite polymorphism of (GCT/AGC) n in the transmembrane (TM) region of the MICA gene. In 68 HLA homozygous B cell lines, 5 distinct alleles of this microsatellite sequence were detected. One of them contained an additional one base insertion that created a frameshift mutation resulting in a premature termination codon in the TM region. This particular allele may encode a soluble, secreted form of the MICA molecule. In addition, we have investigated this microsatellite polymorphism in 77 Japanese patients with Behçet disease, which is known to be associated with HLA-B51. The microsatellite allele consisting of 6 repetitions of GCT/AGC was present at significantly higher frequency in the patient group ( Pc = 0.00055) than in a control population. Furthermore, the (GCT/AGC) 6 allele was present in all B51 positive patients and in an additional 13 B51 negative patients. These results suggest the possibility of a primary association of Behçet disease with MICA rather than HLA-B.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.94.4.1298
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1997
    detail.hit.zdb_id: 209104-5
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  • 7
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    Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 25 ( 2022-06-21)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 25 ( 2022-06-21)
    Abstract: The epidermis is the outermost layer of the skin and the body’s primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2116027119
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
    detail.hit.zdb_id: 209104-5
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  • 8
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    Integration of Shaker-type K + channel, KAT1, into the endoplasmic reticulum membrane: Synergistic insertion of voltage-sensing segments, S3–S4, and independent insertion of pore-forming segments, S5–P–S6
    Proceedings of the National Academy of Sciences ; 2002
    In:  Proceedings of the National Academy of Sciences Vol. 99, No. 1 ( 2002-01-08), p. 60-65
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 99, No. 1 ( 2002-01-08), p. 60-65
    Abstract: KAT1 is a member of the Shaker family of voltage-dependent K + channels, which has six transmembrane segments (called S1–S6), including an amphipathic S4 with several positively charged residues and a hydrophobic pore-forming region (called P) between S5 and S6. In this study, we systematically evaluated the function of individual and combined transmembrane segments of KAT1 to direct the final topology in the endoplasmic reticulum membrane by in vitro translation and translocation experiments. The assay with single-transmembrane constructs showed that S1 possesses the type II signal-anchor function, whereas S2 has the stop-transfer function. The properties fit well with the results derived from combined insertion of S1 and S2. S3 and S4 failed to integrate into the membrane by themselves. The inserted glycosylation sequence at the S3–S4 loop neither prevented the translocation of S3 and S4 nor impaired the function of voltage-dependent K + transport regardless of the changed length of the S3–S4 loop. S3 and S4 are likely to be posttranslationally integrated into the membrane only when somewhat specific interaction occurs between them. S5 had the ability of translocation reinitiation, and S6 had a strong preference for N exo /C cyt orientation. The pore region resided outside because of its lack of its transmembrane-spanning property. According to their own topogenic function, combined constructs of S5–P–S6 conferred the membrane-pore-membrane topology. This finding supports the notion that a set of S5–P–S6 can be independently integrated into the membrane. The results in this study provide the fundamental topogenesis mechanism of transmembrane segments involving voltage sensor and pore region in KAT1.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.012399799
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2002
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  • 9
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    Evidence in support of a four transmembrane-pore-transmembrane topology model for the Arabidopsis thaliana Na + /K + translocating AtHKT1 protein, a member of the superfamily of K + transporters
    Proceedings of the National Academy of Sciences ; 2001
    In:  Proceedings of the National Academy of Sciences Vol. 98, No. 11 ( 2001-05-22), p. 6488-6493
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 11 ( 2001-05-22), p. 6488-6493
    Abstract: The Arabidopsis thaliana AtHKT1 protein, a Na + /K + transporter, is capable of mediating inward Na + currents in Xenopus laevis oocytes and K + uptake in Escherichia coli . HKT1 proteins are members of a superfamily of K + transporters. These proteins have been proposed to contain eight transmembrane segments and four pore-forming regions arranged in a mode similar to that of a K + channel tetramer. However, computer analysis of the AtHKT1 sequence identified eleven potential transmembrane segments. We have investigated the membrane topology of AtHKT1 with three different techniques. First, a gene fusion alkaline phosphatase study in E. coli clearly defined the topology of the N-terminal and middle region of AtHKT1, but the model for membrane folding of the C-terminal region had to be refined. Second, with a reticulocyte-lysate supplemented with dog-pancreas microsomes, we demonstrated that N -glycosylation occurs at position 429 of AtHKT1. An engineered unglycosylated protein variant, N429Q, mediated Na + currents in X. laevis oocytes with the same characteristics as the wild-type protein, indicating that N -glycosylation is not essential for the functional expression and membrane targeting of AtHKT1. Five potential glycosylation sites were introduced into the N429Q. Their pattern of glycosylation supported the model based on the E. coli -alkaline phosphatase data. Third, immunocytochemical experiments with FLAG-tagged AtHKT1 in HEK293 cells revealed that the N and C termini of AtHKT1, and the regions containing residues 135–142 and 377–384, face the cytosol, whereas the region of residues 55–62 is exposed to the outside. Taken together, our results show that AtHKT1 contains eight transmembrane-spanning segments.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.101556598
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2001
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    detail.hit.zdb_id: 1461794-8
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  • 10
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    Photovoltaic effect by soft phonon excitation
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 14 ( 2022-04-05)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 14 ( 2022-04-05)
    Abstract: Photodetection is an indispensable function of optoelectronic devices in modern communication and sensing systems. Contrary to the near-infrared/visible regions, the fast and sensitive photodetectors operated at room temperature for the far-infrared/terahertz regions are not well developed despite a possibly vast range of applications. The bulk photovoltaic effect (BPVE) in single-phase, noncentrosymmetric materials based on the shift current mechanism enables less-dissipative energy conversion endowed with instantaneous responsivity owing to the quantum-mechanical geometric phase of electronic states. Nevertheless, the small–band-gap material for the low-energy BPVE inevitably suffers from the thermal noise due to the intrinsically high conductivity. Here, we demonstrate the shift current induced by soft-phonon excitations without creation of electron-hole pairs in the archetypal ferroelectric BaTiO 3 by using the terahertz light, whose energy scale is three orders of magnitude smaller than the electronic band gap. At and above room temperature, we observe appreciable photocurrents caused by the soft-phonon excitation as large as that for electronic excitation and their strong phonon-mode dependence. The observed phonon-driven BPVE can be well accounted for by the shift current model, considering the electron–phonon coupling in the displacement-type ferroelectrics, as supported by the first-principles calculation. Our findings establish the efficient quantum BPVE arising from low-energy elementary excitations, suggesting the principle for the high-performance terahertz photodetectors.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2122313119
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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