Passenger deletions generate therapeutic vulnerabilities in cancer

Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events.     

Structural insights into electron transfer in caa3-type cytochrome oxidase

Cytochrome c oxidase is a member of the haem copper oxidase superfamily (HCO). HCOs function as the terminal enzymes in the respiratory chain of mitochondria and aerobic prokaryotes, coupling molecular oxygen reduction to transmembrane proton pumping. Integral to the enzyme's function is the transfer of electrons from cytochrome c to the oxidase via a transient association of the two proteins. Electron entry and exit are proposed to occur from the same site on cytochrome c. Here we report the crystal structure of the caa3-type cytochrome oxidase from Thermus thermophilus, which has a covalently tethered cytochrome c domain. Crystals were grown in a bicontinuous mesophase using a synthetic short-chain monoacylglycerol as the hosting lipid. From the electron density map, at 2.36?? resolution, a novel integral membrane subunit and a native glycoglycerophospholipid embedded in the complex were identified. Contrary to previous electron transfer mechanisms observed for soluble cytochrome c, the structure reveals the architecture of the electron transfer complex for the fused cupredoxin/cytochrome c domain, which implicates different sites on cytochrome c for electron entry and exit. Support for an alternative to the classical proton gate characteristic of this HCO class is presented.     

Accurate whole-genome sequencing and haplotyping from 10 to 20 human cells

Recent advances in whole-genome sequencing have brought the vision of personal genomics and genomic medicine closer to reality. However, current methods lack clinical accuracy and the ability to describe the context (haplotypes) in which genome variants co-occur in a cost-effective manner. Here we describe a low-cost DNA sequencing and haplotyping process, long fragment read (LFR) technology, which is similar to sequencing long single DNA molecules without cloning or separation of metaphase chromosomes. In this study, ten LFR libraries were made using only ～100?picograms of human DNA per sample. Up to 97% of the heterozygous single nucleotide variants were assembled into long haplotype contigs. Removal of false positive single nucleotide variants not phased by multiple LFR haplotypes resulted in a final genome error rate of 1 in 10?megabases. Cost-effective and accurate genome sequencing and haplotyping from 10-20 human cells, as demonstrated here, will enable comprehensive genetic studies and diverse clinical applications.     

Benchmark Forecast and Error Modeling

For a target socioeconomic variable with data from two sources, benchmarking is a process which uses less frequent and more reliable data, called benchmarks, to adjust more frequent and less reliable data. Consequently, forecasts of unknown benchmarks are obtained. The regression method of benchmarking may lead to better results than widely used numerical methods, but the model for the error of the more frequent data is supposed to be known. By properly choosing a first‐order autoregressive model as ‘working model’ for the error, the regression method may work well in reality. We present two new error modeling procedures via inside‐data‐period benchmark forecasts. The performance of several modeling procedures is compared. These results may provide analysts with guidelines for choosing working models for the error in developing and applying benchmarking software. Copyright © 2016 John Wiley & Sons, Ltd.     

消费者TV家庭冲动购物的激励因素

以TV家庭购物和冲动购买为研究基础，分析冲动购物的激励因素，通过检验设定的问题来确定其影响力。分析有一次以上TV家庭购物的303名消费者的调查资料，得出：（1）分析产品激励因素对专卖商品和流行商品的影响，结果表明，激励冲动购物只对流行商品有影响。（2）在促销激励因素中，提供赠品的激励和扩大信用卡打折期限的激励对冲动购物都有一定影响，后者影响更大。（3）价格激励因素中，大幅度降低商品价值的激励比合理的价值激励对冲动购物影响更大。（4）情境激励因素特性表明，引导销售激励比限量销售激励影响更大。（5）消费者TV家庭购物视听关联特性表明，看TV时间长比与有伴看电视对消费者冲动购物影响更大。