Tristetraprolin Regulates Interleukin-6 Expression Through p38 MAPK-Dependent Affinity Changes with mRNA 3' Untranslated Region

Tristetraprolin (TTP) is a well-characterized, zinc finger-containing, RNA-binding protein. TTP targets tumor necrosis factor alpha for degradation via the 3- untranslated region (3-UTR). Although AU-rich elements (AREs) in the 3-UTR of interleukin-6 (IL-6) mRNA dictate mRNA degradation, the role of TTP in the post-transcriptional regulation of IL-6 gene expression is unclear. Here we used TTP-deficient mice to test the hypothesis that IL-6 expression is influenced by TTP. Genetic and siRNA-mediated knockdown of TTP resulted in increased IL-6 production and overexpression of TTP had the reverse effect. IL-6 and tumor necrosis factor alpha production were elevated after injection of IL-1- in TTP-deficient mice. Further, embryonic fibroblasts from these mice (mouse embryonic fibroblasts) exhibited greater IL-6 mRNA expression and longer half-life than wild-type mouse embryonic fibroblasts. Overexpression of TTP reduced IL-6 3-UTR luciferase reporter activity in an ARE-dependent manner. Proximal and distal regions of the 3-UTR acted synergistically to produce the full repression of TTP. Mutation-based luciferase assays show that ARE2, ARE3, and ARE4 are required for TTP-mediated repression. The constitutively activated p38-MK2 pathway abrogated TTP-mediated repression of IL-6 3-UTR reporter activity. RNA immunoprecipitation assay indicated that the deficiency of p38alpha resulted in the increased affinity of TTP to IL-6 mRNA. Taken together, we propose that TTP downregulates IL-6 gene expression at the post-transcriptional level by targeting ARE elements in the 3-UTR region.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90500/1/jir-2E2010-2E0154.pd

Type I Interferons Are Associated with Subclinical Markers of Cardiovascular Disease in a Cohort of Systemic Lupus Erythematosus Patients

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94405/1/Somers_2012_Type_I_Interferons_subclinical_markers.pdf165

Dysfunction of endothelial progenitor cells is associated with the type I IFN pathway in patients with polymyositis and dermatomyositis

Objective. Alterations in phenotype and function of endothelial progenitor cells (EPCs) have been associated with poor vascular outcomes and impaired vascular repair in various conditions. Our hypothesis was that patients with PM and DM have dysregulation of EPCs driven by type I IFN and IL-18 similar to other autoimmune diseases. Methods. Quantification of circulating EPCs was performed by flow cytometry in patients with PM/DM and matched healthy controls. The ability of EPCs to differentiate into mature endothelial cells was investigated by light and fluorescence microscopy quantification in the presence or absence of PM/DM or control serum, neutralizing antibodies to type I IFN receptor or IL-18. Serum type I IFN activity was quantified by induction of type I IFN-inducible genes in HeLa cells. Circulating IL-18 concentrations were assessed by ELISA. Results. Circulating EPCs were significantly lower in PM/DM patients compared with controls. PM/DM EPCs displayed a decreased capacity to differentiate into mature endothelial cells and PM/DM serum significantly inhibited differentiation of control EPCs. This effect was reversed in the majority of samples with neutralizing antibodies to IL-18 or to type I IFN receptor or by a combination of these antibodies. Patients with associated impairments in EPC function had higher type I IFN serum activity. Conclusion. PM/DM is associated with dysregulation of EPC phenotype and function that may be attributed, at least in part, to aberrant IL-18 and type I IFN pathways. The implication of these vasculopathic findings for disease prognosis and complications remains to be determined

Type I interferons modulate vascular function, repair, thrombosis, and plaque progression in murine models of lupus and atherosclerosis

Objective Patients with systemic lupus erythematosus (SLE) have a notable increase in atherothrombotic cardiovascular disease (CVD) which is not explained by the Framingham risk equation. In vitro studies indicate that type I interferons (IFNs) may play prominent roles in increased CV risk in SLE. However, the in vivo relevance of these findings, with regard to the development of CVD, has not been characterized. This study was undertaken to examine the role of type I IFNs in endothelial dysfunction, aberrant vascular repair, and atherothrombosis in murine models of lupus and atherosclerosis. Methods Lupus‐prone New Zealand mixed 2328 (NZM) mice and atherosclerosis‐prone apolipoprotein E– knockout (apoE −/− ) mice were compared to mice lacking type I IFN receptor (INZM and apoE −/− IFNAR −/− mice, respectively) with regard to endothelial vasodilatory function, endothelial progenitor cell (EPC) function, in vivo neoangiogenesis, plaque development, and occlusive thrombosis. Similar experiments were performed using NZM and apoE −/− mice exposed to an IFNα‐containing or empty adenovirus. Results Loss of type I IFN receptor signaling improved endothelium‐dependent vasorelaxation, lipoprotein parameters, EPC numbers and function, and neoangiogenesis in lupus‐prone mice, independent of disease activity or sex. Further, acute exposure to IFNα impaired endothelial vasorelaxation and EPC function in lupus‐prone and non–lupus‐prone mice. Decreased atherosclerosis severity and arterial inflammatory infiltrates and increased neoangiogenesis were observed in apoE −/− IFNAR −/− mice, compared to apoE −/− mice, while NZM and apoE −/− mice exposed to IFNα developed accelerated thrombosis and platelet activation. Conclusion These results support the hypothesis that type I IFNs play key roles in the development of premature CVD in SLE and, potentially, in the general population, through pleiotropic deleterious effects on the vasculature.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93543/1/34504_ftp.pd

Effects of Mixing Conditions on Floc Properties in Magnesium Hydroxide Continuous Coagulation Process

Magnesium hydroxide continuous coagulation process was used for treating simulated reactive orange wastewater in this study. Effects of mixing conditions and retention time on the coagulation performance and floc properties of magnesium hydroxide were based on the floc size distribution (FSD), zeta potential, and floc morphology analysis. Floc formation and growth in different reactors were also discussed. The results showed that increasing rapid mixing speed led to a decrease in the final floc size. The floc formation process was mainly carried out in a rapid mixer; a rapid mixing speed of 300 rpm was chosen according to zeta potential and removal efficiency. Reducing retention time caused a relatively small floc size in all reactors. When influent flow was 30 L/h (retention time of 2 min in rapid mixer), the average floc size reached 8.06 μm in a rapid mixer; through breakage and re-growth, the floc size remained stable in the flocculation basin. After growth, the final floc size reached 11.21 μm in a sedimentation tank. The removal efficiency of reactive orange is 89% in the magnesium hydroxide coagulation process

Strain Field Evolution and Constitutive Model of Coal considering the Effect of Beddings

AbstractIn order to study the bedding effect of coal and rock deformation, the surface deformation fields of coal and rock at different bedding angles were obtained by means of digital image correlation (DIC). By optimizing the statistical index describing the nonuniformity of strain field, the initiation and evolution characteristics of deformation localization were analyzed quantitatively. The concepts of equivalent cohesive force and equivalent tensile strength were put forward, and a transverse isotropic constitutive model of coal and rock was established. The results show that the maximum shear deformation field of uniaxial compressed coal and rock in parallel bedding is more likely to show the three-stage characteristics of uniform stage, localization stage, and failure stage. In the vertical and parallel bedding directions, the modified statistical index curve of coal and rock in the process of uniaxial compression shows typical two-stage characteristics. When loading perpendicular to bedding, the starting stress of deformation localization of coal and rock is closer to the peak strength, and when loading parallel to bedding, coal and rock are easier to show localization characteristics

Trench-assisted multi-ring-core fiber for orbital angular momentum modes

Orbital angular momentum (OAM) multiplexing technology has attracted significant interest due to its ability to increase the data transmission capacity in optical communications. By combining OAM-based mode division multiplexing (MDM) and wavelength division multiplexing (WDM) techniques in multi-core fiber (MCF), the transmission rate and spectral efficiency of the optical communication systems can be greatly enhanced. In this paper, we present a design of a multi-ring air-core trench-assisted fiber that supports transmission over the entire C + L (1530–1625 nm) band with low inter-ring crosstalk. The high-contrast ring and trench design can effectively suppress the inter-modal crosstalk. The effects of the ring spacing, wavelength range and doping concentration on the crosstalk suppression are also systematically investigated. Furthermore, the complexity of the MIMO processing system is greatly reduced with a fewer-optical-core structure while keeping low inter-ring crosstalk. The results demonstrate that our designed fiber can support 140 OAM modes at 1550 nm with  5.39 × 10−4. Additionally, our designed fiber can support 224 OAM modes (37.5 mol% Ge-doped) and  5.45 × 10−4) and flat dispersion distribution (chromatic dispersion slope lower than 0.171 ps/nm2/km) across the C + L band