Increased ROS Production in Non-Polarized Mammary Epithelial Cells Induces Monocyte Infiltration in 3D Culture

Loss of epithelial cell polarity promotes cell invasion and cancer dissemination. Therefore, identification of factors that disrupt polarized acinar formation is crucial. Reactive oxygen species (ROS) drive cancer progression and promote inflammation. Here, we show that the non-polarized breast cancer cell line T4-2 generates significantly higher ROS levels than polarized S1 and T4R cells in three-dimensional (3D) culture, accompanied by induction of the nuclear factor κB (NF-κB) pathway and cytokine expression. Minimizing ROS in T4-2 cells with antioxidants reestablished basal polarity and inhibited cell proliferation. Introducing constitutively activated RAC1 disrupted cell polarity and increased ROS levels, indicating that RAC1 is a crucial regulator that links cell polarity and ROS generation. We also linked monocyte infiltration with disruption of polarized acinar structure using a 3D co-culture system. Gain- and loss-of-function experiments demonstrated that increased ROS in non-polarized cells is necessary and sufficient to enhance monocyte recruitment. ROS also induced cytokine expression and NF-κB activity. These results suggest that increased ROS production in mammary epithelial cell leads to disruption of cell polarity and promotes monocyte infiltration

Automatic Detection, Validation and Repair of Race Conditions in Interrupt-Driven Embedded Software

Interrupt-driven programs are widely deployed in safety-critical embedded systems to perform hardware and resource dependent data operation tasks. The frequent use of interrupts in these systems can cause race conditions to occur due to interactions between application tasks and interrupt handlers (or two interrupt handlers). Numerous program analysis and testing techniques have been proposed to detect races in multithreaded programs. Little work, however, has addressed race condition problems related to hardware interrupts. In this paper, we present SDRacer, an automated framework that can detect, validate and repair race conditions in interrupt-driven embedded software. It uses a combination of static analysis and symbolic execution to generate input data for exercising the potential races. It then employs virtual platforms to dynamically validate these races by forcing the interrupts to occur at the potential racing points. Finally, it provides repair candidates to eliminate the detected races. We evaluate SDRacer on nine real-world embedded programs written in C language. The results show that SDRacer can precisely detect and successfully fix race conditions.Comment: This is a draft version of the published paper. Ke Wang provides suggestions for improving the paper and README of the GitHub rep

The PLOD2/succinate axis regulates the epithelial–mesenchymal plasticity and cancer cell stemness

Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) was associated with elevation of cytoplasmic succinate during the EMT process. Silencing of PLOD2 expression in breast cancer cells reduced succinate levels and inhibited cancer cell mesenchymal phenotypes and stemness, which was accompanied by elevated 5hmC levels in chromatin. Importantly, exogenous succinate rescued cancer cell stemness and 5hmC levels in PLOD2-silenced cells, suggesting that PLOD2 promotes cancer progression at least partially through succinate. These results reveal the previously unidentified function of succinate in enhancing cancer cell plasticity and stemness

Purine metabolites regulate leukemic cell sensitivity toward cytarabine

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/ An Improved Structure-preserving Doubling Algorithm for a Structured Palindromic Quadratic Eigenvalue Problem

In this paper, we present a numerical method to solve the palindromic quadratic eigenvalue problem (PQEP) (λ 2 A T +λQ+A)z = 0 arising from the vibration analysis of high speed trains, where A, Q ∈ C n×n have special structures: both Q and A are m × m block matrices with each block being k × k, and moreover they are complex symmetric, block tridiagonal and block Toeplitz, and also A has only one nonzero block in the (1, m)th block position. The method is an improved version of Guo’s and Lin’s efficient solvent approach [SIAM J. Matrix Anal. Appl., 31 (2010), 2784-2801] which solves the PQEP by computing the so-called stabilizing solution to the mk×mk nonlinear matrix equation X + A T X −1 A = Q via the doubling algorithm. Here, we exploit the fact that the stabilizing solution X differs from Q only in its (m, m)th block position and which had also been noted and exploited by Guo and Lin there, too. What distinguishes our method from theirs is that we devise a new nonlinear matrix equation ˜X + Ã T ˜ X −1 Ã = ˜ Q of only k × k in size just for computing the differing block. The new and much smaller matrix equation is also solved by the doubling algorithm at the same speed in terms of the number of doubling iterations as but about 4.8 times faster in flops than the doubling algorithm on the larger matrix equation, and its stabilizing solution ˜ X is used to recover the bigger stabilizing solution X. Numerical examples are presented to show the effectiveness of the improved method