Tim-3 Negatively Regulates IL-12 Expression by Monocytes in HCV Infection

T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) is a newly identified negative immunomodulator that is up-regulated on dysfunctional T cells during viral infections. The expression and function of Tim-3 on human innate immune responses during HCV infection, however, remains poorly characterized. In this study, we report that Tim-3 is constitutively expressed on human resting CD14+ monocyte/macrophages (M/MØ) and functions as a cap to block IL-12, a key pro-inflammatory cytokine linking innate and adaptive immune responses. Tim-3 expression is significantly reduced and IL-12 expression increased upon stimulation with Toll-like receptor 4 (TLR4) ligand - lipopolysaccharide (LPS) and TLR7/8 ligand - R848. Notably, Tim-3 is over-expressed on un-stimulated as well as TLR-stimulated M/MØ, which is inversely associated with the diminished IL-12 expression in chronically HCV-infected individuals when compared to healthy subjects. Up-regulation of Tim-3 and inhibition of IL-12 are also observed in M/MØ incubated with HCV-expressing hepatocytes, as well as in primary M/MØ or monocytic THP-1 cells incubated with HCV core protein, an effect that mimics the function of complement C1q and is reversible by blocking the HCV core/gC1qR interaction. Importantly, blockade of Tim-3 signaling significantly rescues HCV-mediated inhibition of IL-12, which is primarily expressed by Tim-3 negative M/MØ. Tim-3 blockade reduces HCV core-mediated expression of the negative immunoregulators PD-1 and SOCS-1 and increases STAT-1 phosphorylation. Conversely, blocking PD-1 or silencing SOCS-1 gene expression also decreases Tim-3 expression and enhances IL-12 secretion and STAT-1 phosphorylation. These findings suggest that Tim-3 plays a crucial role in negative regulation of innate immune responses, through crosstalk with PD-1 and SOCS-1 and limiting STAT-1 phosphorylation, and may be a novel target for immunotherapy to HCV infection

Induction of p38- and gC1qR-dependent IL-8 expression in pulmonary fibroblasts by soluble hepatitis C core protein

BACKGROUND: Recent studies suggest that HCV infection is associated with progressive declines in pulmonary function in patients with underlying pulmonary diseases such as asthma and chronic obstructive pulmonary disease. Few molecular studies have addressed the inflammatory aspects of HCV-associated pulmonary disease. Because IL-8 plays a fundamental role in reactive airway diseases, we examined IL-8 signaling in normal human lung fibroblasts (NHLF) in response to the HCV nucleocapsid core protein, a viral antigen shown to modulate intracellular signaling pathways involved in cell proliferation, apoptosis and inflammation. METHODS: NHLF were treated with HCV core protein and assayed for IL-8 expression, phosphorylation of the p38 MAPK pathway, and for the effect of p38 inhibition. RESULTS: Our studies demonstrate that soluble HCV core protein induces significant increases in both IL-8 mRNA and protein expression in a dose- and time-dependent manner. Treatment with HCV core led to phosphorylation of p38 MAPK, and expression of IL-8 was dependent upon p38 activation. Using TNFα as a co-stimulant, we observed additive increases in IL-8 expression. HCV core-mediated expression of IL-8 was inhibited by blocking gC1qR, a known receptor for soluble HCV core linked to MAPK signaling. CONCLUSION: These studies suggest that HCV core protein can lead to enhanced p38- and gC1qR-dependent IL-8 expression. Such a pro-inflammatory role may contribute to the progressive deterioration in pulmonary function recently recognized in individuals chronically infected with HCV

On the Relation Between Jupiter's Aurora and the Dawnside Current Sheet

Jupiter's auroral emission is a spectacular phenomenon that provides insight into energy release processes related to the coupling of its magnetosphere and ionosphere. This energy release is influenced by solar wind conditions. Using joint observations from Juno and the Hubble Space Telescope (HST), we statistically investigate the relationship between auroral power and current sheet variations under different solar wind conditions. In this study, we reveal that during global main auroral brightening events that are closely connected to solar wind compressions, the dawn side current sheet is substantially thinner than during times when a quiet auroral morphology is present. Furthermore, the total current intensity in the current sheet is found to increase under solar wind compression conditions compared to the quiet period. These findings provide important observational evidence for how magnetospheric dynamics driven by solar wind behavior affect auroral activity, deepening our understanding of the coupling between Jupiter's magnetosphere and ionosphere

Segmentation of sales for a mobile phone service through CART classification tree algorithm

The work consisted of detailing the CRISP-DM method in order to identify optimal groups of customers who are more likely to migrate from a prepaid to postpaid option in order to formulate an improvement plan for in call management by sorting the database. Classification models were applied to analyze the characteristics generated by the purchase of the different services. The CART Classification Tree algorithm. As a result, groups differentiated by probabilities of sales success (migrate from a prepaid to postpaid plan) were found, segments that reflect particular needs and characteristics to design marketing actions focused on the objective of increasing the effectiveness rate, contact information, and sales increase

The generalized Hamiltonian model for the shafting transient analysis of the hydro turbine generating sets.

yesTraditional rotor dynamics mainly focuses on the steady- state behavior of the rotor and shafting. However, for systems such as hydro turbine generating sets (HTGS) where the control and regulation is frequently applied, the shafting safety and stabilization in transient state is then a key factor. The shafting transient state inevitably involves multiparameter domain, multifield coupling, and coupling dynamics. In this paper, the relative value form of the Lagrange function and its equations have been established by defining the base value system of the shafting. Takingthe rotation angle and the angular speed of the shafting as a link, the shafting lateral vibration and generator equations are integrated into the framework of generalized Hamiltonian system. The generalized Hamiltonian control model is thus established. To make the model more general, additional forces of the shafting are taken as the input excitation in proposed model. The control system of the HTGS can be easily connected with the shafting model to form the whole simulation system of the HTGS. It is expected that this study will build a foundation for the coupling dynamics theory using the generalized Hamiltonian theory to investigate coupling dynamic mechanism among the shafting vibration, transient of hydro turbine generating sets, and additional forces of the shafting.National Natural Science Foundation of China under Grant Nos. 51179079 and 5083900

Surface Raman spectroscopic investigation of pyridine adsorption at platinum electrodes - effects of potential and electrolyte

Surface enhanced Raman spectra of pyridine (Py) at Pt electrodes have been investigated as a function of potential and supporting electrolyte. The results show a large difference from those reported for coinage metal electrodes of Ag, Au and Cu, emphasising the effective involvement of chemical enhancement on Pt surfaces. At very negative (or positive) potentials, Raman spectra show the competitive coadsorption of hydrogen (or oxygen-containing species) with Py, and in acidic solutions, PyH+ ions prefer to dissociate into Py adsorbed on Pt surfaces even in the presence of chloride ions. The differences in the surface bonding strength for Py on Pt and coinage metal electrodes are explained in terms of the different electronic configurations of the metals

Electronic properties of metal nanorods probed by surface-enhanced Raman spectroscopy

Applying the probe molecule strategy, surface-enhanced Raman spectroscopy has been used, for the first time, as a diagnostic tool of the electronic properties of metal nanorods; the vibrational frequency of the probe molecule SCN- at Cu nanorods is shown to critically depend on the nanorod's diameter in the range from 50 to 15 nm; the up-shifting of the Fermi level with a decrease of the nanorod's diameter is interpreted based on the change of cohesive energy owing to the high ratio of surface to bulk atoms