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  • 1
    Abstract: Quiescent long-term hematopoietic stem cells (LT-HSCs) are efficiently activated by type I interferon (IFN-I). However, this effect remains poorly investigated in the context of IFN-I-inducing virus infections. Here we report that both vesicular stomatitis virus (VSV) and murine cytomegalovirus (MCMV) infection induce LT-HSC activation that substantially differs from the effects triggered upon injection of synthetic IFN-I-inducing agents. In both infections, inflammatory responses had to exceed local thresholds within the bone marrow to confer LT-HSC cell cycle entry, and IFN-I receptor triggering was not critical for this activation. After resolution of acute MCMV infection, LT-HSCs returned to phenotypic quiescence. However, non-acute MCMV infection induced a sustained inflammatory milieu within the bone marrow that was associated with long-lasting impairment of LT-HSC function. In conclusion, our results show that systemic virus infections fundamentally affect LT-HSCs and that also non-acute inflammatory stimuli in bone marrow donors can affect the reconstitution potential of bone marrow transplants.
    Type of Publication: Journal article published
    PubMed ID: 28614719
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  • 2
    Abstract: BACKGROUND & AIM: Virus-induced fulminant hepatitis is a major cause of acute liver failure. During acute viral hepatitis the impact of type I interferon (IFN-I) on myeloid cells, including liver-resident Kupffer cells (KC), is only partially understood. Herein, we dissected the impact of locally induced IFN-I responses on myeloid cell function and hepatocytes during acute liver inflammation. METHODS: Two different DNA-encoded viruses, vaccinia virus (VACV) and murine cytomegalovirus (MCMV), were studied. In vivo imaging was applied to visualize local IFN-beta induction and IFN-I receptor (IFNAR) triggering in VACV-infected reporter mice. Furthermore, mice with a cell type-selective IFNAR ablation were analyzed to dissect the role of IFNAR signaling in myeloid cells and hepatocytes. Experiments with Cx3cr1(+/gfp) mice revealed the origin of reconstituted KC. Finally, mixed bone marrow chimeric mice were studied to specifically analyze the effect of IFNAR triggering on liver infiltrating monocytes. RESULTS: VACV infection induced local IFN-beta responses, which lead to IFNAR signaling primarily within the liver. IFNAR triggering was needed to control the infection and prevent fulminant hepatitis. The severity of liver inflammation was independent of IFNAR triggering of hepatocytes, whereas IFNAR triggering of myeloid cells protected from excessive inflammation. Upon VACV or MCMV infection KC disappeared, whereas infiltrating monocytes differentiated to KC afterwards. During IFNAR triggering such replenished monocyte-derived KC comprised more IFNAR-deficient than -competent cells in mixed bone marrow chimeric mice, whereas after the decline of IFNAR triggering both subsets showed an even distribution. CONCLUSION: Upon VACV infection IFNAR triggering of myeloid cells, but not of hepatocytes, critically modulates acute viral hepatitis. During infection with DNA-encoded viruses IFNAR triggering of liver-infiltrating blood monocytes delays the development of monocyte-derived KC, pointing towards new therapeutic strategies for acute viral hepatitis. LAY SUMMARY: Viral infection can cause fulminant hepatitis, which in turn is a major cause of acute liver failure. Herein, we aimed to study the role of type 1 interferon responses in acute viral hepatitis. We identified that during infection with DNA-encoded viruses, type 1 interferon receptor triggering of blood monocytes delays the development of monocyte-derived Kupffer cells. This points to new therapeutic strategies for acute viral hepatitis.
    Type of Publication: Journal article published
    PubMed ID: 29274730
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  • 3
    ISSN: 1089-7550
    Source: AIP Digital Archive
    Topics: Physics
    Notes: One goal of this work was to develop a reproducible method of preparing high quality Y-Ba-Cu-O superconducting films and to study their properties versus thickness. This was accomplished by rf diode sputtering from a single target. Twenty-seven depositions were made using a target containing 8.9-at. % Y, 37.3-at. % Ba, and 53.8-at. % Cu. Film thicknesses ranged from 0.09 to 2.4 μm. The film compositions obtained were 15.6±1.0-at. % Y, 35.8±1.0-at. % Ba, and 48.7±1.7-at. % Cu for the mean and standard deviation. The films were amorphous as-deposited and crystallized by annealing in O2 at 915 °C. X-ray diffraction, transmission electron microscopy, and scanning electron microscopy indicated that, on (100)SrTiO3 substrates, films with thickness less than ∼0.25 μm were epitaxially oriented with their c axis perpendicular to the substrate. Films on (110)SrTiO3 were oriented with their c axis parallel to the substrate. On (100)SrTiO3, zero resistance was achieved in 30 samples from 27 runs at 85.6±1.4 K with a transition width (10%–90%) of 1.8±1.1 K independent of thickness. Results for deposition on a variety of other substrates were more variable. Diamagnetic shielding of up to 38% was calculated from the initial slope of M vs H. This low value was attributed to the presence of second phases and a significant diffusion layer thickness, both observed by transmission electron microscopy. Critical currents, measured by transport using a four-point probe, reached 8.1×105 A/cm2 at 77.35 K for a 0.2-μm film deposited on (100)SrTiO3 . Comparable values were obtained by calculation from the M-H hysteresis loop, from which we infer that there are either continuous epitaxial sheets of c axis oriented 123 or, if there are grain boundaries, the coupling across them is strong.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1089-7550
    Source: AIP Digital Archive
    Topics: Physics
    Notes: One goal of this work was to develop a reproducible method of preparing high quality Y-Ba-Cu-O superconducting films and to study their properties versus thickness. This was accomplished by rf diode sputtering from a single target. Twenty-seven depositions were made using a target containing 8.9-at. % Y, 37.3-at. % Ba, and 53.8-at. % Cu. Film thicknesses ranged from 0.09 to 2.4 μm. The film compositions obtained were 15.6±1.0-at. % Y, 35.8±1.0-at. % Ba, and 48.7±1.7-at. % Cu for the mean and standard deviation. The films were amorphous as deposited and crystallized by annealing in O2 at 915 °C. X-ray diffraction, transmission electron microscopy, and scanning electron microscopy indicated that, on (100)SrTiO3 substrates, films with thickness less than ∼0.25 μm were epitaxially oriented with their c axis perpendicular to the substrate. Films on (110)SrTiO3 were oriented with their c axis parallel to the substrate. On (100)SrTiO3, zero resistance was achieved in 30 samples from 27 runs at 85.6±1.4 K with a transition width (10%–90%) of 1.8±1.1 K independent of thickness. Results for deposition on a variety of other substrates were more variable. Diamagnetic shielding of up to 38% was calculated from the initial slope of M vs H. This low value was attributed to the presence of second phases and a significant diffusion layer thickness, both observed by transmission electron microscopy. Critical currents, measured by transport using a four-point probe, reached 8.1×105 A/cm2 at 77.35 K for a 0.2-μm film deposited on (100)SrTiO3 . Comparable values were obtained by calculation from the M-H hysteresis loop, from which we infer that there are either continuous epitaxial sheets of c axis oriented 123 or, if there are grain boundaries, the coupling across them is strong.
    Type of Medium: Electronic Resource
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