Innate Immune Response of Human Plasmacytoid Dendritic Cells to Poxvirus Infection Is Subverted by Vaccinia E3 via Its Z-DNA/RNA Binding Domain

Plasmacytoid dendritic cells (pDCs) play important roles in antiviral innate immunity by producing type I interferon (IFN). In this study, we assess the immune responses of primary human pDCs to two poxviruses, vaccinia and myxoma virus. Vaccinia, an orthopoxvirus, was used for immunization against smallpox, a contagious human disease with high mortality. Myxoma virus, a Leporipoxvirus, causes lethal disease in rabbits, but is non-pathogenic in humans. We report that myxoma virus infection of human pDCs induces IFN-α and TNF production, whereas vaccinia infection does not. Co-infection of pDCs with myxoma virus plus vaccinia blocks myxoma induction effects. We find that heat-inactivated vaccinia (Heat-VAC; by incubating the virus at 55°C for 1 h) gains the ability to induce IFN-α and TNF in primary human pDCs. Induction of IFN-α in pDCs by myxoma virus or Heat-VAC is blocked by chloroquine, which inhibits endosomal acidification required for TLR7/9 signaling, and by inhibitors of cellular kinases PI3K and Akt. Using purified pDCs from genetic knockout mice, we demonstrate that Heat-VAC-induced type I IFN production in pDCs requires the endosomal RNA sensor TLR7 and its adaptor MyD88, transcription factor IRF7 and the type I IFN feedback loop mediated by IFNAR1. These results indicate that (i) vaccinia virus, but not myxoma virus, expresses inhibitor(s) of the poxvirus sensing pathway(s) in pDCs; and (ii) Heat-VAC infection fails to produce inhibitor(s) but rather produces novel activator(s), likely viral RNA transcripts that are sensed by the TLR7/MyD88 pathway. Using vaccinia gene deletion mutants, we show that the Z-DNA/RNA binding domain at the N-terminus of the vaccinia immunomodulatory E3 protein is an antagonist of the innate immune response of human pDCs to poxvirus infection and TLR agonists. The myxoma virus ortholog of vaccinia E3 (M029) lacks the N-terminal Z-DNA/RNA binding domain, which might contribute to the immunostimulating properties of myxoma virus

14-3-3ζ Interacts with Stat3 and Regulates Its Constitutive Activation in Multiple Myeloma Cells

The 14-3-3 proteins are a family of regulatory signaling molecules that interact with other proteins in a phosphorylation-dependent manner and function as adapter or scaffold proteins in signal transduction pathways. One family member, 14-3-3ζ, is believed to function in cell signaling, cycle control, and apoptotic death. A systematic proteomic analysis done in our laboratory has identified signal transducers and activators of transcription 3 (Stat3) as a novel 14-3-3ζ interacting protein. Following our initial finding, in this study, we provide evidence that 14-3-3ζ interacts physically with Stat3. We further demonstrate that phosphorylation of Stat3 at Ser727 is vital for 14-3-3ζ interaction and mutation of Ser727 to Alanine abolished 14-3-3ζ/Stat3 association. Inhibition of 14-3-3ζ protein expression in U266 cells inhibited Stat3 Ser727 phosphorylation and nuclear translocation, and decreased both Stat3 DNA binding and transcriptional activity. Moreover, 14-3-3ζ is involved in the regulation of protein kinase C (PKC) activity and 14-3-3ζ binding to Stat3 protects Ser727 dephosphorylation from protein phosphatase 2A (PP2A). Taken together, our findings support the model that multiple signaling events impinge on Stat3 and that 14-3-3ζ serves as an essential coordinator for different pathways to regulate Stat3 activation and function in MM cells

Regional differences and spatial patterns of health status of the member states in the "Belt and Road" Initiative.

The strategy of the "Belt and Road" initiative aims not only to promote the cooperation and the development of economic trade, but also to boost the integration and development in multiple fields-especially in the field of health. This paper explores the health levels of member-states in the Belt and Road initiative from the perspective of regional differences and spatial patterns. Data from the 68 member-states in the Belt and Road initiative were selected from the statistical data on disease and socioeconomics in all countries from the 2015 publication by the World Bank and the World Health Organization. Health indicators that can reflect health levels of member states were selected. Moran's I and Getis-Ord Gi* were used to analyze the spatial clustering and hot/cold spots of the health status. After that a novel spatial statistical method "geographical detector" was used to analysis the spatial stratified heterogeneity of the selected health indicators. The result showed that the health level of the member states fluctuated around the world average and varied greatly within the member states. The health status of the member states showed spatial clustering, and the q-statistics of the geographical detector confirmed that the health status demonstrated statistically significant spatial heterogeneity for different continent the member states reside. In general, member states in Europe and Oceania demonstrated higher health status, while those in South Asia, Southeast Asia, Africa and part of Middle East have lower health status. In particular, special attention should be paid to control communicable diseases in African member states. Different regions and member states face different kinds of health threats in various degrees. Member states should strengthen health cooperation between themselves and work closely with other countries to make the "belt and road" a healthy road

The Accelerated Urbanization Process: A Threat to Soil Resources in Eastern China

The eastern coastal region of China has been experiencing rapid urbanization which has imposed great challenges on soil resources, characterized by soil sealing and fragmented soil landscapes. Taking Zhejiang Province—a fairly economically-developed and highly-urbanized region in eastern China—as a case study, a practical framework that integrates remote sensing, GIS, soil quality assessment and landscape analysis was employed to track and analyze the rapid urbanization process and spatiotemporal dynamics of soil sealing and landscape change from 1990 to 2010. Meanwhile, this paper qualitatively explored the regional inequality and characteristics in soil sealing intensity among cities of different geo-zones in Zhejiang Province. Results showed that total area of 6420 km2 had been sealed during the past two decades for the entire study area, which represents 6.2% of the provincial area. Among these sealed soils, 68.6% are fertile soils located in flat plains, such as Paddy soils. Soil landscapes became more fragmented and dispersed in distribution, more irregular and complex in shape, and less dominant and diverse in soil type, as evidenced by the constant change of various spatial landscape metrics. What is more, different geo-zones exhibited significant differences in dynamics of soil sealing intensity, soil composition and soil landscape patterns. The permanent loss of valuable soil resource and increasing fragmented soil landscape patterns concomitant with rapid urbanization processes may inevitably bring about potential threats to regional soil resources and food security

Additional file 1 of Associations between air pollutants and acute exacerbation of drug-resistant tuberculosis: evidence from a prospective cohort study

Supplementary Material 1: Table S1 RR (95% CIs) for the association between first-time outpatient visits for acute exacerbations of DR-TB and air pollutants concentrations with each IQR increase based on single-pollutant models. Table S2 Single-lag RR (95% CIs) for the association between first-time outpatient visits for acute exacerbations of DR-TB and air pollutants concentrations with each IQR increase based on two-pollutants models. Table S3 Cumulative RR (95% CIs) for the association between first-time outpatient visits for acute exacerbations of DR-TB and air pollutants concentrations with each IQR increase based on two-pollutants models. Figure S1. RR (95% CIs) for the association between first-time outpatient visits for acute exacerbations of DR-TB and air pollutants concentrations with each IQR increase based on single-pollutant models stratified by gender. Figure S2. RR (95% CIs) for the association between first-time outpatient visits for acute exacerbations of DR-TB and air pollutants concentrations with each IQR increase based on single-pollutant models stratified by age. Figure S3. RR (95% CIs) for the association between first-time outpatient visits for acute exacerbations of DR-TB and air pollutants concentrations with each IQR increase based on single-pollutant models stratified by occupation. Figure S4. RR (95% CIs) for the association between first-time outpatient visits for DR-TB and air pollutants concentrations with each IQR increase based on single-pollutant models stratified by high-risk subgroup. Figure S5. RR (95% CIs) for the association between first-time outpatient visits for DR-TB and air pollutants concentrations with each IQR increase based on single-pollutant models stratified by history of treatment. Figure S6. RR (95% CIs) for the association between first-time outpatient visits for DR-TB and air pollutants concentrations with each IQR increase based on single-pollutant models stratified by seaso

Effect of Ecologically Restored Vegetation Roots on the Stability of Shallow Aggregates in Ionic Rare Earth Tailings Piles

Aggregate stability is considered an essential indicator of changes in the physical properties of soils, and vegetation roots play a crucial role in the stability of shallow soil aggregates in ionic rare earth tailings piles during ecological remediation. In this paper, the influence of the law of ecologically restored vegetation roots on the stability of shallow aggregates of ionic rare earth tailing piles was investigated by means of field investigation tests, indoor experiments and mathematical statistics. The influence of different types of root systems on the stability of the shallow depth range aggregates of tailings piles was investigated; the correlation between vegetation root systems and the main physical parameters of rare earth tailings was clarified; and a mathematical correlation model characterizing the characteristic parameters of vegetation root systems was constructed. The evaluation index of the stability of rare earth tailings piles was constructed, and the influence of the law of the ecological restoration of vegetation root systems on the strength of shallow aggregates of ionic rare earth tailings piles was revealed. The results of the study showed that compared with the RD (root density), the root characteristic parameter with the largest response weight to the rare earth tailings pile is the RL (root length density), and the root characteristic parameter with the largest response weight to the water content is the RV (root volume). Suitable vegetation roots can effectively enhance the content of shallow large aggregates of rare ionic earth tailing piles. With the increase of the depth of a tailing pile, the content of large aggregates continues to decrease, and the content of micro aggregates continues increasing. This indicates that the vegetation root system changed the shallow soil of the rare earth tailing pile from disorderly to orderly through its own growth pattern, which effectively improved the stability of the shallow aggregates of the tailing pile and improved the physical properties of the tailing