NF-κB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK

AbstractConstitutively activated NF-κB occurs in many inflammatory and tumor tissues. Does it interfere with anti-inflammatory or anti-tumor signaling pathway? Here, we report that NF-κB p65 subunit repressed the Nrf2-antioxidant response element (ARE) pathway at transcriptional level. In the cells where NF-κB and Nrf2 were simultaneously activated, p65 unidirectionally antagonized the transcriptional activity of Nrf2. In the p65-overexpressing cells, the ARE-dependent expression of heme oxygenase-1 was strongly suppressed. However, p65 inhibited the ARE-driven gene transcription in a way that was independent of its own transcriptional activity. Two mechanisms were found to coordinate the p65-mediated repression of ARE: (1) p65 selectively deprives CREB binding protein (CBP) from Nrf2 by competitive interaction with the CH1-KIX domain of CBP, which results in inactivation of Nrf2. The inactivation depends on PKA catalytic subunit-mediated phosphorylation of p65 at S276. (2) p65 promotes recruitment of histone deacetylase 3 (HDAC3), the corepressor, to ARE by facilitating the interaction of HDAC3 with either CBP or MafK, leading to local histone hypoacetylation. This investigation revealed the participation of NF-κB p65 in the negative regulation of Nrf2-ARE signaling, and might provide a new insight into a possible role of NF-κB in suppressing the expression of anti-inflammatory or anti-tumor genes

Blockage of transdifferentiation from fibroblast to myofibroblast in experimental ovarian cancer models

<p>Abstract</p> <p>Background</p> <p>Tumour stromal myofibroblasts can promote tumour invasion. As these cells are genetically more stable than cancer cells, there has been enormous interest in developing targeted molecular therapies against them. Chloride intracellular channel 4 (CLIC4) and reactive oxygen species (ROS) have been linked with promoting stromal cell transdifferentiation in various cancers, but little is known of their roles in ovarian cancer. In this study, we examined the functional roles that both CLIC4 and ROS play in the process of ovarian cancer cell-stimulated or TGF-β1 induced fibroblast-to-myofibroblast transdifferentiation. We also examine whether it is possible to reverse such a process, with the aim of developing novel therapies against ovarian cancer by targeting activated transdifferentiated myofibroblasts.</p> <p>Results</p> <p>We demonstrate that TGF-β1 induced or CM^SKOV3activate transdifferentiated myofibroblasts (fibroblasts). These fibroblasts mimic "reactive" stromal myofibroblasts and demonstrate significant up-regulation of CLIC4 expression and increased level of ROS production. Blocking the production of ROS with an antioxidant consequently reduces the expression of CLIC4, and is accompanied by disappearance of <it>α</it>-smooth-muscle actin (α-SMA), a myofibroblast marker, suggesting ROS acts as a signalling molecule that promotes and enhances CLIC4 activities in the myofibroblast transdifferentiaton process. Down-regulation of CLIC4 with a generic agent or specific siRNA both significantly reduces the expression of factors related to the phenotypes and functions of myofibroblasts, such as α-SMA, hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), thus reversing the myofibroblast phenotype back to fibroblasts. These results convincingly show that ROS and CLIC4 are responsible for TGF-β1 induced fibroblast-to-myofibroblast transdifferentiaton and down-regulation of both is sufficient to block transdifferentiated myofibroblasts.</p> <p>Conclusion</p> <p>Molecular targeting of ROS and CLIC4 has the potential to develop novel therapies for ovarian cancer.</p

SkyLens: Visual analysis of skyline on multi-dimensional data

Skyline queries have wide-ranging applications in fields that involve multi-criteria decision making, including tourism, retail industry, and human resources. By automatically removing incompetent candidates, skyline queries allow users to focus on a subset of superior data items (i.e., the skyline), thus reducing the decision-making overhead. However, users are still required to interpret and compare these superior items manually before making a successful choice. This task is challenging because of two issues. First, people usually have fuzzy, unstable, and inconsistent preferences when presented with multiple candidates. Second, skyline queries do not reveal the reasons for the superiority of certain skyline points in a multi-dimensional space. To address these issues, we propose SkyLens, a visual analytic system aiming at revealing the superiority of skyline points from different perspectives and at different scales to aid users in their decision making. Two scenarios demonstrate the usefulness of SkyLens on two datasets with a dozen of attributes. A qualitative study is also conducted to show that users can efficiently accomplish skyline understanding and comparison tasks with SkyLens.Comment: 10 pages. Accepted for publication at IEEE VIS 2017 (in proceedings of VAST

Inductance Evaluation and Sensorless Control of a Concentrated Winding PM Vernier Machine

Due to the advantages of high torque density and simple mechanical structure, permanent magnet vernier (PMV) machines have attracted more and more research interests. In this paper, the inductance nonlinearity of an advanced concentrated winding PMV machine is investigated with consideration of both magnetic saturation and cross-coupling saturation under different d-axis and q-axis current loading. Then, the mathematical model with a variable inductance matrix of the PMV machine is established through incorporation of the finite-element analysis and the surface fitting method. Further, a back electromotive force based sensorless control method is developed for this PMV machine model with design of a current-dependent state observer. Based on the sensorless algorithm, the influence of inductance variation on rotor position estimation performance is then quantitatively evaluated. Simulation results show that the PMV machine can be well controlled for steady- and dynamic-state operation, and the position estimation error is effectively decreased. Finally, the proposed sensorless control algorithm is validated through experimental tests of the PMV prototype machine

A phonological history of Amdo Tibetan rhymes

In this study, a reconstruction is offered for the phonetic evolution of rhymes from Old Tibetan to modern-day Amdo Tibetan dialects. The relevant sound changes are proposed, along with their relative chronological precedence and the dating of some specific changes. Most interestingly, although Amdo Tibetan, identically to its ancestor Old Tibetan, does not have phonemic length, this study shows that Amdo Tibetan derives from an intermediate stage which, like many other Tibetan dialects, does make the distinction

<i>Moraxella catarrhalis</i> adhesin UspA1-derived recombinant fragment rD-7 induces monocyte differentiation to CD14+CD206+ phenotype

Circulating monocytes in the bloodstream typically migrate to other tissues and differentiate into tissue resident macrophages, the process being determined by the constituents of the microenvironments encountered. These may include microbes and their products. In this study, we investigated whether Moraxella catarrhalis Ubiquitous Surface Protein A1 (UspA1), known to bind to a widely expressed human cell surface receptor CEACAM1, influences monocyte differentiation as receptor engagement has been shown to have profound effects on monocytes. We used the recombinant molecules corresponding to the regions of UspA1 which either bind (rD-7; UspA1(527–665)) or do not bind (r6–8; UspA1(659–863)) to CEACAM1 and investigated their effects on CD206, CD80 and CD86 expression on freshly isolated human CD14+ monocytes from peripheral blood mononuclear cells (PBMC). Exposure to rD-7, but not r6–8, biased monocyte differentiation towards a CD14+CD206+ phenotype, with reduced CD80 expression. Monocytes treated with rD-7 also secreted high levels of IL-1ra and chemokine IL-8 but not IL-10 or IL-12p70. The effects of rD-7 were independent of any residual endotoxin. Unexpectedly, these effects of rD-7 were also independent of its ability to bind to CEACAM1, as monocyte pre-treatment with the anti-CEACAM antibody A0115 known to inhibit rD-7 binding to the receptor, did not affect rD-7-driven differentiation. Further, another control protein rD-7/D (a mutant form of rD-7, known not to bind to CEACAMs), also behaved as the parent molecule. Our data suggest that specific regions of M. catarrhalis adhesin UspA1 may modulate inflammation during infection through a yet unknown receptor on monocytes