RNAi-mediated gene silencing in non-human primates

The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.     

“第六代”：后现代文化的符码“仿真”——张元、管虎创作比较研究

张元出生于1963年,1985年进入北京电影学院摄影系学习。他在1990年代初期拍摄完成的《妈妈》被认为是当代国内第一部“独立电影”。张元称得上是中国新生代导演群体中少有的“高产者”。在“浮出地表”之前,电影《北京杂种》《儿子》和《东宫.西宫》为他赢得了众多的国际声誉;而在1998年取得国际广播电影电视总局的“解禁令”之后,他又相继执导了影片《过年回家》《疯狂英语》《我爱你》《绿茶》《江姐》和《看上去很美》,也因此成为较早涉足国内电影商业化运作的一位新生代导演。作为新生代导演群体中的一类代表,张元的典型意义不仅在于他往返游走于“先锋”与“主旋律”之间的那份从容,而且“张元现象”也成为考量中国新生代导演十余年间辗转于电影美学与市场运作之间独特体验的生动样本。别有深意的是,这些细节都在某种特定的“全球化语境”中得到了更进一步的放大和渲染。本期邀约的四篇论文中,孙绍谊博士与李迅研究员提供的导演访谈尽可能地保留了许多现场交流的细节,使我们得以直接了解张元本人对于国内电影市场不无真诚又略显偏激的态度。这不仅是对读者反应式批评的有益补充,而且也正是本栏目所期冀的多元文体与多元研究路向的一次探索实践。刘福泉教授的《张元:在寻找中站立》秉承了传统美学批评的理路,以反叛、寻找、皈依为关键词,梳理张元从“小众”到“大众”乃至“主旋律”创作的心路历程。Adam Lam博士的《“第六代”:后现代文化的符码“仿真”》则通过对张元与另一位新生代导演管虎作品的比较研究,试图说明在“国际化”的巨型“能指”背后隐藏的权力运作机制。关于此问题,钱春莲、邱宝林二位博士合作完成的论文《论新生代电影导演的跨文化传播策略》提供出另外一种思路。论文从传播学的角度入手,探讨在经济全球化和文化全球化的双重维度上,新生代导演如何在直面市场的经济策略与以民族认同为基点的文化策略之间寻求微妙的平衡,并且将两岸三地青年导演的区域性合作纳入新生代电影的产业实践。这无疑开辟出一个新的研究路向,同时也呈现出一种新的合作发展的现实可能性。     

Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema

Integrins are heterodimeric cell-surface proteins that regulate cell growth, migration and survival. We have shown previously that the epithelial-restricted integrin alpha(v)beta6 has another critical function; that is, it binds and activates latent transforming growth factor-beta (TGF-beta). Through a global analysis of pulmonary gene expression in the lungs of mice lacking this integrin (Itgb6 null mice) we have identified a marked induction of macrophage metalloelastase (Mmp12)--a metalloproteinase that preferentially degrades elastin and has been implicated in the chronic lung disease emphysema. Here we report that Itgb6-null mice develop age-related emphysema that is completely abrogated either by transgenic expression of versions of the beta6 integrin subunit that support TGF-beta activation, or by the loss of Mmp12. Furthermore, we show that the effects of Itgb6 deletion are overcome by simultaneous transgenic expression of active TGF-beta1. We have uncovered a pathway in which the loss of integrin-mediated activation of latent TGF-beta causes age-dependent pulmonary emphysema through alterations of macrophage Mmp12 expression. Furthermore, we show that a functional alteration in the TGF-beta activation pathway affects susceptibility to this disease.     

Diurnal change in stature: effects of sleep deprivation in young men and middle-aged men

Sleep deprivation was associated with decreased stature and it blunted the normal 24-h rhythm in young and in middle-aged men. Loss in stature was regained during the first recovery night of sleep. The 24-h rhythm in height is not an endogenous circadian rhythm but depends upon the periods of recumbency over the sleep/wake cycle.     

Fibrillation of tropoelastin induced by proteoglycan

Summary Electrostatic interaction between tropoelastin, the native precursor of elastin, and proteoglycan results in tropoelastin fibrillation. The finding suggests a possible involvement of proteoglycans in elastogenesis.     

Fibrillation of tropoelastin induced by proteoglycan.

Electrostatic interaction between tropoelastin, the native precursor of elastin, and proteoglycan results in tropoelastin fibrillation. The finding suggests a possible involvement of proteoglycans in elastogenesis.     

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity

The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.     

Francis Galton’s regression towards mediocrity and the stability of types

A prevalent narrative locates the discovery of the statistical phenomenon of regression to the mean in the work of Francis Galton. It is claimed that after 1885, Galton came to explain the fact that offspring deviated less from the mean value of the population than their parents did as a population-level statistical phenomenon and not as the result of the processes of inheritance. Arguing against this claim, we show that Galton did not explain regression towards mediocrity statistically, and did not give up on his ideas regarding an inheritance process that caused offspring to revert to the mean. While the common narrative focuses almost exclusively on Galton’s statistics, our arguments emphasize the anthropological and biological questions that Galton addressed. Galton used regression towards mediocrity to support the claim that some biological types were more stable than others and hence were resistant to evolutionary change. This view had implications concerning both natural selection and eugenics. The statistical explanation attributed to Galton appeared later, during the biometrician-mutationist debate in the early 1900s. It was in the context of this debate and specifically by the biometricians, that the development of the statistical explanation was originally attributed to Galton.