κ-carbide in a high-Mn light-weight steel : precipitation, off-stoichiometry and deformation

Nanometer-sized κ-carbides are efficient strengtheners making light-weight austenitic ($\gamma$) Fe-Mn-Al-C steels ultra-strong yet highly ductile. However, they lack fundamental understanding. Not only their interaction with dislocation during deformation, but also their atomistic structure, off-stoichiometry and effect of elemental partitioning on those, are not fully clear. These, however, are essential to instruct alloy design and optimization. This work aims at clarifying these pending questions by an atomistic-scale investigation of aged or deformed κ/$\gamma$ microstructure. A quaternary model Fe-29.8Mn-7.7Al-1.3C (wt.%) steel aged at 600 °C for 0-2016 hours was chosen for this study. The 24h-aged sample with well-precipitated grain interior (GI) κ-carbides was thoroughly investigated in terms of particle morphology and arrangement, elemental partitioning and off-stoichiometry, κ/$\gamma$ interface and particle-dislocation interaction upon deformation; whereas more attention was paid to the phase evolution in the 4- or 12-weeks-aged samples. The microstructural characterization was carried out by exploiting various cutting-edge techniques, including synchrotron x-ray diffraction (SXRD), high-resolution scanning electron microscopy (HR-SEM), (scanning) transmission electron microscopy ((S)TEM), atom probe tomography (APT) and correlative TEM and APT. Density functional theory (DFT) was employed to elucidate the atomistic site-occupancy of κ-carbide and understand its off-stoichiometry. The results reveal that particle shearing is the predominant co-deformation mechanism in the studied κ/$\gamma$ alloy and ordering strengthening is the primary contribution to the precipitation strengthening. Though rough and not atomically sharp, the κ/$\gamma$ interface is fully coherent, causing an elastic strain around κ-carbide precipitates and an elastic interaction between them. As a result, in comparison to the ideal bulk L’12 perovskite, the measured κ-carbide is off-stoichiometric with a depletion in C and Al compositions due to the formation of C vacancies and Mn$\gamma$Al anti-sites. The elastic stress not only results in their nanometer-scale size, stack alignment, thermal stability upon prolonged ageing, but also leads to a limited elemental partitioning. In comparison to the thermodynamic stable grain boundary (GB) κ0-carbide, the elemental partitioning of solutes for the grain interior (GI) precipitation are all restricted, giving rise to the different chemical compositions and morphologies between GI κ-carbide and GB κ0-carbide

Upregulation of HBV transcription by sodium taurocholate cotransporting polypeptide at the postentry step is inhibited by the entry inhibitor Myrcludex B

Abstract Sodium taurocholate cotransporting polypeptide (NTCP) is a functional receptor for hepatitis B virus (HBV) entry. However, little is known regarding whether NTCP is involved in regulating the postentry steps of the HBV life cycle. Here, we found that NTCP expression upregulated HBV transcription at the postentry step and that the NTCP-targeting entry inhibitor Myrcludex B (MyrB) effectively suppressed HBV transcription both in an HBV in vitro infection system and in mice hydrodynamically injected with an HBV expression plasmid. Mechanistically, NTCP upregulated HBV transcription via farnesoid X receptor α (FxRα)-mediated activation of the HBV EN2/core promoter at the postentry step in a manner that was dependent on the bile acid (BA)-transport function of NTCP, which was blocked by MyrB. Our findings uncover a novel role for NTCP in the HBV life cycle and provide a reference for the use of novel NTCP-targeting entry inhibitors to suppress HBV infection and replication

Combination of an Antiviral Drug and Immunomodulation against Hepadnaviral Infection in the Woodchuck Model▿

The essential role of multispecific immune responses for the control of hepatitis B virus (HBV) infection implies the need of multimodal therapeutic strategies for chronic HBV infection, including antiviral chemotherapy and immunomodulation. This hypothesis was tested in the woodchuck model by a combination of lamivudine pretreatment and subsequent immunizations of woodchucks chronically infected with woodchuck hepatitis virus. The immunizations were performed with DNA vaccines or antigen-antibody immune complexes (IC)/DNA vaccines. Immunizations with IC/DNA vaccines led to an anti-woodchuck hepatitis virus surface antibody response and significant reductions of viral load and antigenemia, suggesting that such a strategy may be effective against chronic HBV infection

RNA binding protein 24 regulates the translation and replication of hepatitis C virus

Abstract The secondary structures of hepatitis C virus (HCV) RNA and the cellular proteins that bind to them are important for modulating both translation and RNA replication. However, the sets of RNA-binding proteins involved in the regulation of HCV translation, replication and encapsidation remain unknown. Here, we identified RNA binding motif protein 24 (RBM24) as a host factor participated in HCV translation and replication. Knockdown of RBM24 reduced HCV propagation in Huh7.5.1 cells. An enhanced translation and delayed RNA synthesis during the early phase of infection was observed in RBM24 silencing cells. However, both overexpression of RBM24 and recombinant human RBM24 protein suppressed HCV IRES-mediated translation. Further analysis revealed that the assembly of the 80S ribosome on the HCV IRES was interrupted by RBM24 protein through binding to the 5′-UTR. RBM24 could also interact with HCV Core and enhance the interaction of Core and 5′-UTR, which suppresses the expression of HCV. Moreover, RBM24 enhanced the interaction between the 5′- and 3′-UTRs in the HCV genome, which probably explained its requirement in HCV genome replication. Therefore, RBM24 is a novel host factor involved in HCV replication and may function at the switch from translation to replication

Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients

BACKGROUND: The dynamic changes of lymphocyte subsets and cytokines profiles of patients with novel coronavirus disease (COVID-19) and their correlation with the disease severity remain unclear. METHODS: Peripheral blood samples were longitudinally collected from 40 confirmed COVID-19 patients and examined for lymphocyte subsets by flow cytometry and cytokine profiles by specific immunoassays. FINDINGS: Of the 40 COVID-19 patients enrolled, 13 severe cases showed significant and sustained decreases in lymphocyte counts [0•6 (0•6-0•8)] but increases in neutrophil counts [4•7 (3•6-5•8)] than 27 mild cases [1.1 (0•8-1•4); 2•0 (1•5-2•9)]. Further analysis demonstrated significant decreases in the counts of T cells, especially CD8+ T cells, as well as increases in IL-6, IL-10, IL-2 and IFN-γ levels in the peripheral blood in the severe cases compared to those in the mild cases. T cell counts and cytokine levels in severe COVID-19 patients who survived the disease gradually recovered at later time points to levels that were comparable to those of the mild cases. Moreover, the neutrophil-to-lymphocyte ratio (NLR) (AUC=0•93) and neutrophil-to-CD8+ T cell ratio (N8R) (AUC =0•94) were identified as powerful prognostic factors affecting the prognosis for severe COVID-19. INTERPRETATION: The degree of lymphopenia and a proinflammatory cytokine storm is higher in severe COVID-19 patients than in mild cases, and is associated with the disease severity. N8R and NLR may serve as a useful prognostic factor for early identification of severe COVID-19 cases