Insulin disrupts beta-adrenergic signalling to protein kinase A in adipocytes

Hormones mobilize intracellular second messengers and initiate signalling cascades involving protein kinases and phosphatases, which are often spatially compartmentalized by anchoring proteins to increase signalling specificity. These scaffold proteins may themselves be modulated by hormones. In adipocytes, stimulation of beta-adrenergic receptors increases cyclic AMP levels and activates protein kinase A (PKA), which stimulates lipolysis by phosphorylating hormone-sensitive lipase and perilipin. Acute insulin treatment activates phosphodiesterase 3B, reduces cAMP levels and quenches beta-adrenergic receptor signalling. In contrast, chronic hyperinsulinaemic conditions (typical of type 2 diabetes) enhance beta-adrenergic receptor-mediated cAMP production. This amplification of cAMP signalling is paradoxical because it should enhance lipolysis, the opposite of the known short-term effect of hyperinsulinaemia. Here we show that in adipocytes, chronically high insulin levels inhibit beta-adrenergic receptors (but not other cAMP-elevating stimuli) from activating PKA. We measured this using an improved fluorescent reporter and by phosphorylation of endogenous cAMP-response-element binding protein (CREB). Disruption of PKA scaffolding mimics the interference of insulin with beta-adrenergic receptor signalling. Chronically high insulin levels may disrupt the close apposition of beta-adrenergic receptors and PKA, identifying a new mechanism for crosstalk between heterologous signal transduction pathways.     

Human endothelial senescence can be induced by TNF-α

TNF-α is one of the most important proinfiammatory cytokines in mediating multiple physio-pathological functions during immunological responses. Vascular endothelial cells, when stimulated by TNF-α2 can increase the expression of multiple cytokines and cellular adhesion molecules and, in turn, actively promote the inflammatory responses by recruiting and activating of leukocytes to the inflammatory site. In addition to endothelial death induced by TNF-α2 we found for the first time that TNF-α can also induce the human endothelial cells senescence. The induced senescent endothelial cells will display SA-β-Gal staining and they were arrested in G0-G1 phase. We found that Aψm would always be up-regulated in response to TNF-α stimulation at early time but when the cells become senescent, A ψmshows a tendency to decrease. It may reflect the sthenic function of mitochondria at early time in response to TNF-αstimulation and decay when the endothelial cells were induced senescent. ROS fluctuates at early time and also decreases when the endothelial cells become senescent. Our results show that the change of mitochondrial function may be related to the senescent process.``     

Unresponsiveness to a foreign antigen can be caused by self-tolerance

In mice, two sets of genes govern the immune response to the synthetic antigen GT. One maps to the major histocompatibility complex and behaves like a typical immune response gene. The second is a background gene encoding a cell surface structure found on B cells. Mice which express, and are therefore tolerant of, one form of this structure do not respond to GT. Thus, tolerance of self generates holes in the T-cell repertoire, partially crippling the immune system.     

The cellular oncogene p53 can be activated by mutagenesis

P53 is a cellular phosphoprotein of short half-life (t1/2) which is present at elevated levels in cells transformed by various stimuli including viruses, chemicals and radiation. p53 forms specific stable complexes with simian virus 40 (SV40) large-T antigen and an adenovirus E1b protein of relative molecular mass (Mr) 57,000. A number of reports have associated p53 with cell proliferation, and p53 complementary DNA expression constructs immortalize primary cells in vitro and render them sensitive to transformation by an activated ras oncogene. We have examined the biological properties of a set of p53 expression constructs, and report here that cellular immortalization by a wild-type p53 cDNA gene is conditional upon the promoter/enhancer construction used, but that p53 can extend cellular lifespan by a second distinct mechanism involving rearrangements of the coding sequence which give rise to stable protein products. Cells immortalized by one of these mutants are refractory to subsequent transformation by a ras oncogene, indicating that cellular immortalization and ras cooperation are separate activities.     

葛根素对脂肪细胞糖脂代谢作用研究

探讨葛根素对脂肪细胞糖、脂代谢的影响.建立3T3-L1脂肪细胞IR模型,葡萄糖氧化酶法测定葛根素处理48 h后培养液中葡萄糖残存量、铜试剂显色法测定游离脂肪酸浓度.与模型组比较,葛根素高、低剂量组葡萄糖消耗量显著增加(P<0.05),游离脂肪酸水平呈现降低趋势.葛根素明显增加脂肪细胞的葡萄糖消耗,对TNF-α诱导的脂肪分解无明显作用.     

Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine

Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma and other human tumours are associated with mutations that activate the proto-oncogene Smoothened (SMO) or that inactivate the tumour suppressor Patched (PTCH). Smoothened and Patched mediate the cellular response to the Hedgehog (Hh) secreted protein signal, and oncogenic mutations affecting these proteins cause excess activity of the Hh response pathway. Here we show that the plant-derived teratogen cyclopamine, which inhibits the Hh response, is a potential 'mechanism-based' therapeutic agent for treatment of these tumours. We show that cyclopamine or synthetic derivatives with improved potency block activation of the Hh response pathway and abnormal cell growth associated with both types of oncogenic mutation. Our results also indicate that cyclopamine may act by influencing the balance between active and inactive forms of Smoothened.     

Scalable classification by clustering： Hybrid can be better than Pure

The problem of scalable classification by clustering in large databases was discussed. Clustering based classification method first generates clusters using clustering algorithms. To classify new coming da-ta points, it finds the κ nearest clusters of the data point as neighbors, and assign each data point to the dominant class of these neighbors. Existing algorithms incorporated class information in making clustering decisions and produced pure clusters （each cluster associated with only one class）. We presented hybrid cluster based algorithms, which produce clusters by unsupervised clustering and allow each cluster associ- ated with multiple classes. Experimental results show that hybrid cluster based algorithms outperform pure ones in both classification accuracy and training soeed.     

模拟电路可测性问题分析

为解决含大量不可测节点电路的测试问题及大规模电路测试成本过高的问题,本文分析了电路的可测拓扑结构和可测拓扑条件,提出了模拟电路可测性问题分析。     

Insulin signalling and the regulation of glucose and lipid metabolism.

The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.