Correlation of structural elements and infectivity of the HET-s prion

Prions are believed to be infectious, self-propagating polymers of otherwise soluble, host-encoded proteins. This concept is now strongly supported by the recent findings that amyloid fibrils of recombinant prion proteins from yeast, Podospora anserina and mammals can induce prion phenotypes in the corresponding hosts. However, the structural basis of prion infectivity remains largely elusive because acquisition of atomic resolution structural properties of amyloid fibrils represents a largely unsolved technical challenge. HET-s, the prion protein of P. anserina, contains a carboxy-terminal prion domain comprising residues 218-289. Amyloid fibrils of HET-s(218-289) are necessary and sufficient for the induction and propagation of prion infectivity. Here, we have used fluorescence studies, quenched hydrogen exchange NMR and solid-state NMR to determine the sequence-specific positions of amyloid fibril secondary structure elements of HET-s(218-289). This approach revealed four beta-strands constituted by two pseudo-repeat sequences, each forming a beta-strand-turn-beta-strand motif. By using a structure-based mutagenesis approach, we show that this conformation is the functional and infectious entity of the HET-s prion. These results correlate distinct structural elements with prion infectivity.     

Aurora A kinase (AURKA) in normal and pathological cell division

Temporally and spatially controlled activation of the Aurora A kinase (AURKA) regulates centrosome maturation, entry into mitosis, formation and function of the bipolar spindle, and cytokinesis. Genetic amplification and mRNA and protein overexpression of Aurora A are common in many types of solid tumor, and associated with aneuploidy, supernumerary centrosomes, defective mitotic spindles, and resistance to apoptosis. These properties have led Aurora A to be considered a high-value target for development of cancer therapeutics, with multiple agents currently in early-phase clinical trials. More recently, identification of additional, non-mitotic functions and means of activation of Aurora A during interphase neurite elongation and ciliary resorption have significantly expanded our understanding of its function, and may offer insights into the clinical performance of Aurora A inhibitors. Here we review the mitotic and non-mitotic functions of Aurora A, discuss Aurora A regulation in the context of protein structural information, and evaluate progress in understanding and inhibiting Aurora A in cancer.     

雀巢希望更有“中国味”

您上一任工作是担任雀巢的瑞士区总裁，现在是担任大中华区总裁，那么，在商业运作方面，您觉得这两个国家最大的不同在哪里？     

CUSTOMER EQUITY： MAKING MARKETING STRATEGY FINANCIALLY ACCOUNTABLE

1. Introduction The long-term value of a firm is largelydetermined by the value of the company’scustomer relationships, which result in thefirm’s ‘customer equity’ (Blattberg andDeighton 1996), defined by Rust, Lemon andZeithaml (2000, p.4…     

Ecology of flannelmouth sucker in the Lee's Ferry tailwater, Colorado River, Arizona

We investigated ecology of flannelmouth sucker ( Catostomus latipinnis ) from 1992 to 1997 in the 26-km Lee's Ferry reach of the Colorado River immediately below Glen Canyon Dam, Arizona. We captured by electrofishing a total of 212 fish and recaptured 52 previously tagged by others. Flannelmouth sucker were captured throughout the tailwater but tended to aggregate about 5 km of the dam, possibly reflecting blockage of historic migration routes. Catch per hour of electrofishing did not differ among years but was greater from November to February than other periods, suggesting seasonal movements of flannelmouth sucker into the tailwater: Mean lengths and weights of fish did not differ among years or seasons. Length frequency analyses also indicated there were no significantly yearly trends in proportion of catch within size classes of fish. Mean condition differed only among seasons and was greatest in February, lowest in August, coinciding respectively with pre- and post-spawning periods of flannelmouth sucker in tributary just down from Lee's Ferry. Recaptured fish migrated from initial tagging locations 1.4-23.1 km downstream from Lee's Ferry. Fifty-nine percent of recaptured fish with known initial tagging locations increased in length, and fish tagged initially as subadults or adults, respectively, grew an average of 45.9 mm and 5.5 mm per year.     

世界地热能发电新进展

 简要回顾了国际地热发电的历史,介绍了过去5年全球地热能开发的理论、技术和设备等方面的巨大变化。2005年开始的高油价以及减少温室气体排放的全球性需求使各国开始把注意力聚焦在可再生能源方面。地热能的开发在全世界范围内发展迅速,既有像新西兰、印度尼西亚和美国这样长久以来热衷于开发地热能的国家,也有像澳大利亚和德国这样过去对地热能不太感兴趣的国家。分析表明,一些新的地热开发项目依旧遵循传统思路在火山活动区域使用常规水热资源,而另一些则选择在非火山活动区采用增强地热系统(EGS)技术开发干热岩地热能。目前,部分国家已经建立一些EGS项目,比如美国,有6个建设中的EGS项目,试图在不同的技术层面进行探索和研究。现代地热开采和发电技术使得人们可以在缺少冷却水以及交通不便的情况下对温度较低的常规地热资源进行开发。根据目前情况来看,预计未来地热工业的发展在发现新的地热田以及提高现有地热田开发程度方面将面临较大的技术挑战,主要可能有以下两个关键问题：(1) 在开发过程中的“生产盲区”问题,这主要针对那些温度不高也不低的地热田,温度不太高但又高到无法下泵,温度不太低但又不能采用闪蒸方法发电;(2) 可靠的EGS开发方案和技术研发,要求可以确保有可持续、足够高的产能(温度与流量),并能向公众,特别是项目附近的居民保证不会诱发地震灾害。     

Deregulated MYC expression induces dependence upon AMPK-related kinase 5

Deregulated expression of the MYC oncoprotein contributes to the genesis of many human tumours, yet strategies to exploit this for a rational tumour therapy are scarce. MYC promotes cell growth and proliferation, and alters cellular metabolism to enhance the provision of precursors for phospholipids and cellular macromolecules. Here we show in human and murine cell lines that oncogenic levels of MYC establish a dependence on AMPK-related kinase 5 (ARK5; also known as NUAK1) for maintaining metabolic homeostasis and for cell survival. ARK5 is an upstream regulator of AMPK and limits protein synthesis via inhibition of the mammalian target of rapamycin 1 (mTORC1) signalling pathway. ARK5 also maintains expression of mitochondrial respiratory chain complexes and respiratory capacity, which is required for efficient glutamine metabolism. Inhibition of ARK5 leads to a collapse of cellular ATP levels in cells expressing deregulated MYC, inducing multiple pro-apoptotic responses as a secondary consequence. Depletion of ARK5 prolongs survival in MYC-driven mouse models of hepatocellular carcinoma, demonstrating that targeting cellular energy homeostasis is a valid therapeutic strategy to eliminate tumour cells that express deregulated MYC.     

Structure of eEF3 and the mechanism of transfer RNA release from the E-site

Elongation factor eEF3 is an ATPase that, in addition to the two canonical factors eEF1A and eEF2, serves an essential function in the translation cycle of fungi. eEF3 is required for the binding of the aminoacyl-tRNA-eEF1A-GTP ternary complex to the ribosomal A-site and has been suggested to facilitate the clearance of deacyl-tRNA from the E-site. Here we present the crystal structure of Saccharomyces cerevisiae eEF3, showing that it consists of an amino-terminal HEAT repeat domain, followed by a four-helix bundle and two ABC-type ATPase domains, with a chromodomain inserted in ABC2. Moreover, we present the cryo-electron microscopy structure of the ATP-bound form of eEF3 in complex with the post-translocational-state 80S ribosome from yeast. eEF3 uses an entirely new factor binding site near the ribosomal E-site, with the chromodomain likely to stabilize the ribosomal L1 stalk in an open conformation, thus allowing tRNA release.