Oncogene-induced senescence as an initial barrier in lymphoma development

Acute induction of oncogenic Ras provokes cellular senescence involving the retinoblastoma (Rb) pathway, but the tumour suppressive potential of senescence in vivo remains elusive. Recently, Rb-mediated silencing of growth-promoting genes by heterochromatin formation associated with methylation of histone H3 lysine 9 (H3K9me) was identified as a critical feature of cellular senescence, which may depend on the histone methyltransferase Suv39h1. Here we show that Emicro-N-Ras transgenic mice harbouring targeted heterozygous lesions at the Suv39h1, or the p53 locus for comparison, succumb to invasive T-cell lymphomas that lack expression of Suv39h1 or p53, respectively. By contrast, most N-Ras-transgenic wild-type ('control') animals develop a non-lymphoid neoplasia significantly later. Proliferation of primary lymphocytes is directly stalled by a Suv39h1-dependent, H3K9me-related senescent growth arrest in response to oncogenic Ras, thereby cancelling lymphomagenesis at an initial step. Suv39h1-deficient lymphoma cells grow rapidly but, unlike p53-deficient cells, remain highly susceptible to adriamycin-induced apoptosis. In contrast, only control, but not Suv39h1-deficient or p53-deficient, lymphomas senesce after drug therapy when apoptosis is blocked. These results identify H3K9me-mediated senescence as a novel Suv39h1-dependent tumour suppressor mechanism whose inactivation permits the formation of aggressive but apoptosis-competent lymphomas in response to oncogenic Ras.     

台湾可持续能源发展指标建构与耦合性分析

为应对全球气候变迁之冲击,以及迈向低碳社会,推动可持续能源发展,已成为本世纪各国政府施政的重点.依据国际可持续能源指标架构,建立"台湾可持续能源指标系统",并以Eview计量软件进行指标项目与架构之"单根"(unit root)、"共整合"(integration)、与"因果"(causality)检定,并据此建构的长期稳定关系与各方面耦合性(coupling)的可持续能源发展指标"压力-状态-响应"(Pressure,State,Response,PSR)架构系统.回顾了台湾近18年(1990-2007)来可持续能源发展绩效,获得结论如下:1)台湾能源发展已朝向可持续性,其中以环境保护方面绩效最佳,而能源安全与经济竞争力仍需改善;2)整体指标架构的状态与响应指标耦合度相当高,惟压力指标则呈现脱钩(decoupling)现象;3)权重模拟分析发现,适当调整权重,可以大幅提高经济竞争力与环境保障方面指标耦合性,显示权重具敏感性;惟能源安全指标方面的权重较不具敏感性.     

Extreme damping in composite materials with negative-stiffness inclusions

When a force deforms an elastic object, practical experience suggests that the resulting displacement will be in the same direction as the force. This property is known as positive stiffness. Less familiar is the concept of negative stiffness, where the deforming force and the resulting displacement are in opposite directions. (Negative stiffness is distinct from negative Poisson's ratio, which refers to the occurrence of lateral expansion upon stretching an object.) Negative stiffness can occur, for example, when the deforming object has stored (or is supplied with) energy. This property is usually unstable, but it has been shown theoretically that inclusions of negative stiffness can be stabilized within a positive-stiffness matrix. Here we describe the experimental realization of this composite approach by embedding negative-stiffness inclusions of ferroelastic vanadium dioxide in a pure tin matrix. The resulting composites exhibit extreme mechanical damping and large anomalies in stiffness, as a consequence of the high local strains that result from the inclusions deforming more than the composite as a whole. Moreover, for certain temperature ranges, the negative-stiffness inclusions are more effective than diamond inclusions for increasing the overall composite stiffness. We expect that such composites could be useful as high damping materials, as stiff structural elements or for actuator-type applications.     

Ca2+/calmodulin binds to and modulates P/Q-type calcium channels.

Neurotransmitter release at many central synapses is initiated by an influx of calcium ions through P/Q-type calcium channels, which are densely localized in nerve terminals. Because neurotransmitter release is proportional to the fourth power of calcium concentration, regulation of its entry can profoundly influence neurotransmission. N- and P/Q-type calcium channels are inhibited by G proteins, and recent evidence indicates feedback regulation of P/Q-type channels by calcium. Although calcium-dependent inactivation of L-type channels is well documented, little is known about how calcium modulates P/Q-type channels. Here we report a calcium-dependent interaction between calmodulin and a novel site in the carboxy-terminal domain of the alpha1A subunit of P/Q-type channels. In the presence of low concentrations of intracellular calcium chelators, calcium influx through P/Q-type channels enhances channel inactivation, increases recovery from inactivation and produces a long-lasting facilitation of the calcium current. These effects are prevented by overexpression of a calmodulin-binding inhibitor peptide and by deletion of the calmodulin-binding domain. Our results reveal an unexpected association of Ca2+/calmodulin with P/Q-type calcium channels that may contribute to calcium-dependent synaptic plasticity.     

地下圆形衬砌洞室对SV及Rayleigh波的动应力集中(II):数值结果

为了解决在入射平面SV波和Rayleigh波作用下地下圆形衬砌洞室的动应力集中问题,利用文献[5]的级数解,分析了衬砌刚度、入射波长、入射角度诸因素对动应力集中系数(DSCF)的影响。数值结果表明:(1)衬砌刚度对DSCF有重要影响,柔性衬砌情况DSCF最小,刚性衬砌情况的最大;环向与轴向DSCF最大可分别达到32.31与16.12;(2)入射频率和入射角度对DSCF也有很大影响。     

A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects

Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis.     

TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA

Maintenance of telomeres requires both DNA replication and telomere 'capping' by shelterin. These two processes use two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomeres 1 (POT1). Although RPA and POT1 each have a critical role at telomeres, how they function in concert is not clear. POT1 ablation leads to activation of the ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase at telomeres, suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. Unexpectedly, we found that purified POT1 and its functional partner TPP1 are unable to prevent RPA binding to telomeric ssDNA efficiently. In cell extracts, we identified a novel activity that specifically displaces RPA, but not POT1, from telomeric ssDNA. Using purified protein, here we show that the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) recapitulates the RPA displacing activity. The RPA displacing activity is inhibited by the telomeric repeat-containing RNA (TERRA) in early S phase, but is then unleashed in late S phase when TERRA levels decline at telomeres. Interestingly, TERRA also promotes POT1 binding to telomeric ssDNA by removing hnRNPA1, suggesting that the re-accumulation of TERRA after S phase helps to complete the RPA-to-POT1 switch on telomeric ssDNA. Together, our data suggest that hnRNPA1, TERRA and POT1 act in concert to displace RPA from telomeric ssDNA after DNA replication, and promote telomere capping to preserve genomic integrity.