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.     

Tissue-specific and reversible RNA interference in transgenic mice

Genetically engineered mice provide powerful tools for understanding mammalian gene function. These models traditionally rely on gene overexpression from transgenes or targeted, irreversible gene mutation. By adapting the tetracycline (tet)-responsive system previously used for gene overexpression, we have developed a simple transgenic system to reversibly control endogenous gene expression using RNA interference (RNAi) in mice. Transgenic mice harboring a tet-responsive RNA polymerase II promoter driving a microRNA-based short hairpin RNA targeting the tumor suppressor Trp53 reversibly express short hairpin RNA when crossed with existing mouse strains expressing general or tissue-specific 'tet-on' or 'tet-off' transactivators. Reversible Trp53 knockdown can be achieved in several tissues, and restoring Trp53 expression in lymphomas whose development is promoted by Trp53 knockdown leads to tumor regression. By leaving the target gene unaltered, this approach permits tissue-specific, reversible regulation of endogenous gene expression in vivo, with potential broad application in basic biology and drug target validation.     

三维多项式系统焦点量的计算

Fix a collection of polynomial vector fields on R3with a singularity at the origin,for every one of which the linear part at the origin has two pure imaginary and one non-zero eigenvalue. Some such systems admit a local analytic first integral,which then defines a local center manifold of the system. Conditions for existence of a first integral are given by the vanishing certain polynomial or rational functions in the coefficients of the system called focus quantities. In this paper we prove that the focus quantities have a structure analogous to that in the two-dimensional case and use it to formulate an efficient algorithm for computing them.     

Physiological and pathological consequences of cellular senescence

Cellular senescence, a permanent state of cell cycle arrest accompanied by a complex phenotype, is an essential mechanism that limits tumorigenesis and tissue damage. In physiological conditions, senescent cells can be removed by the immune system, facilitating tumor suppression and wound healing. However, as we age, senescent cells accumulate in tissues, either because an aging immune system fails to remove them, the rate of senescent cell formation is elevated, or both. If senescent cells persist in tissues, they have the potential to paradoxically promote pathological conditions. Cellular senescence is associated with an enhanced pro-survival phenotype, which most likely promotes persistence of senescent cells in vivo. This phenotype may have evolved to favor facilitation of a short-term wound healing, followed by the elimination of senescent cells by the immune system. In this review, we provide a perspective on the triggers, mechanisms and physiological as well as pathological consequences of senescent cells.     

利用雅可比椭圆函数计算强非线性杜芬振子的周期响应

应用雅可比椭圆函数及均值方法计算求解受到简谐外激扰的强非线性杜芬振荡系统＋ａυ＋γυ３＝ε（－βυ＋ＦｃｏｓΩＴ）的稳态周期响应。首先利用雅可比椭圆函数给出无扰动系统的周期解。然后，采用对无扰动系统周期解进行扰动的方法，求扰动系统的周期解。在这个过程中，采用均值方法对问题进行了简化。并通过对所得解的讨论与分析，最终得到原问题的稳态周期响应。实例验证的结果表明，我们所介绍的方法是成功的。并可应用于求解其它强非线性系统的周期响应。     

Protective role of phospholipid oxidation products in endotoxin-induced tissue damage

Lipopolysaccharide (LPS), an outer-membrane component of Gram-negative bacteria, interacts with LPS-binding protein and CD14, which present LPS to toll-like receptor 4 (refs 1, 2), which activates inflammatory gene expression through nuclear factor kappa B (NF kappa B) and mitogen-activated protein-kinase signalling. Antibacterial defence involves activation of neutrophils that generate reactive oxygen species capable of killing bacteria; therefore host lipid peroxidation occurs, initiated by enzymes such as NADPH oxidase and myeloperoxidase. Oxidized phospholipids are pro-inflammatory agonists promoting chronic inflammation in atherosclerosis; however, recent data suggest that they can inhibit expression of inflammatory adhesion molecules. Here we show that oxidized phospholipids inhibit LPS-induced but not tumour-necrosis factor-alpha-induced or interleukin-1 beta-induced NF kappa B-mediated upregulation of inflammatory genes, by blocking the interaction of LPS with LPS-binding protein and CD14. Moreover, in LPS-injected mice, oxidized phospholipids inhibited inflammation and protected mice from lethal endotoxin shock. Thus, in severe Gram-negative bacterial infection, endogenously formed oxidized phospholipids may function as a negative feedback to blunt innate immune responses. Furthermore, identified chemical structures capable of inhibiting the effects of endotoxins such as LPS could be used for the development of new drugs for treatment of sepsis.     

Unprecedented Arctic ozone loss in 2011

Chemical ozone destruction occurs over both polar regions in local winter-spring. In the Antarctic, essentially complete removal of lower-stratospheric ozone currently results in an ozone hole every year, whereas in the Arctic, ozone loss is highly variable and has until now been much more limited. Here we demonstrate that chemical ozone destruction over the Arctic in early 2011 was--for the first time in the observational record--comparable to that in the Antarctic ozone hole. Unusually long-lasting cold conditions in the Arctic lower stratosphere led to persistent enhancement in ozone-destroying forms of chlorine and to unprecedented ozone loss, which exceeded 80 per cent over 18-20 kilometres altitude. Our results show that Arctic ozone holes are possible even with temperatures much milder than those in the Antarctic. We cannot at present predict when such severe Arctic ozone depletion may be matched or exceeded.     

Quantum states of neutrons in the Earth's gravitational field.

The discrete quantum properties of matter are manifest in a variety of phenomena. Any particle that is trapped in a sufficiently deep and wide potential well is settled in quantum bound states. For example, the existence of quantum states of electrons in an electromagnetic field is responsible for the structure of atoms, and quantum states of nucleons in a strong nuclear field give rise to the structure of atomic nuclei. In an analogous way, the gravitational field should lead to the formation of quantum states. But the gravitational force is extremely weak compared to the electromagnetic and nuclear force, so the observation of quantum states of matter in a gravitational field is extremely challenging. Because of their charge neutrality and long lifetime, neutrons are promising candidates with which to observe such an effect. Here we report experimental evidence for gravitational quantum bound states of neutrons. The particles are allowed to fall towards a horizontal mirror which, together with the Earth's gravitational field, provides the necessary confining potential well. Under such conditions, the falling neutrons do not move continuously along the vertical direction, but rather jump from one height to another, as predicted by quantum theory.