Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.     

The God particle et al

The territory of the Large Hadron Collider might be populated not just by the Higgs particle but also by all manner of other exotic apparitions.     

Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis

Intestinal epithelial cells (IECs) provide a primary physical barrier against commensal and pathogenic microorganisms in the gastrointestinal (GI) tract, but the influence of IECs on the development and regulation of immunity to infection is unknown. Here we show that IEC-intrinsic IkappaB kinase (IKK)-beta-dependent gene expression is a critical regulator of responses of dendritic cells and CD4+ T cells in the GI tract. Mice with an IEC-specific deletion of IKK-beta show a reduced expression of the epithelial-cell-restricted cytokine thymic stromal lymphopoietin in the intestine and, after infection with the gut-dwelling parasite Trichuris, fail to develop a pathogen-specific CD4+ T helper type 2 (T(H)2) response and are unable to eradicate infection. Further, these animals show exacerbated production of dendritic-cell-derived interleukin-12/23p40 and tumour necrosis factor-alpha, increased levels of CD4+ T-cell-derived interferon-gamma and interleukin-17, and develop severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKK-beta in IECs to promote CD4+ T(H)2 cell-dependent immunity, identifying an essential function for IECs in tissue-specific conditioning of dendritic cells and limiting type 1 cytokine production in the GI tract. These results indicate that the balance of IKK-beta-dependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis by promoting mucosal immunity and limiting chronic inflammation.     

逆向物流中心动态选址问题的研究

在逆向物流中,集中退货中心(回收中心)管理是企业逆向物流系统高品质运作的基础和前提.随着逆向物流的发展,企业开始关注集中退货中心的选址.针对已有模型没有考虑时间变化对选址决策的影响问题,构建一个双向物流共享运输网络的动态选址模型,提出了应用动态规划的求解思想和方法并结合实例分析了在考虑时间因素时,企业如何做出规划期内选址决策的时间序列;并引入预测确定性因子来解决预测的不确定性.     

An overview of resistive random access memory devices

With recent progress in material science, resistive random access memory (RRAM) devices have attracted interest for nonvolatile, low-power, nondestructive readout, and high-density memories. Relevant performance parameters of RRAM devices include operating voltage, operation speed, resistance ratio, endurance, retention time, device yield, and multilevel storage. Numerous resistive-switching mechanisms, such as conductive filament, space-charge-limited conduction, trap charging and discharging, Schottky Emission, and Pool-Frenkel emission, have been proposed to explain the resistive switching of RRAM devices. In addition to a discussion of these mechanisms, the effects of electrode materials, doped oxide materials, and different configuration devices on the resistive-switching characteristics in nonvolatile memory applications, are reviewed. Finally, suggestions for future research, as well as the challenges awaiting RRAM devices, are given.