Structural evidence for gene duplication in the evolution of the acid proteases.

X-ray studies of acid proteases indicate a bilobal structure with a well defined active site cleft. An intramolecular twofold symmetry axis relates two topologically similar domains and the active site residues. A possible mechanism for evolution by gene duplication, divergence and gene fusion is presented.     

A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice

Pulmonary adenoma susceptibility 1 (Pas1) is the major mouse lung cancer susceptibility locus on chromosome 6 (ref. 1). Kras2 is a common target of somatic mutation in chemically induced mouse lung tumors and is a candidate Pas1 gene. M. spretus mice (SPRET/Ei) carry a Pas1 resistance haplotype for chemically induced lung tumors. We demonstrate that the SPRET/Ei Pas1 allele is switched from resistance to susceptibility by fixation of the parental origin of the mutant Kras2 allele. This switch correlates with low expression of endogenous Kras2 in SPRET/Ei. We propose that the Pas1 modifier effect is due to Kras2, and that a sensitive balance between the expression levels of wild-type and mutant alleles determines lung tumor susceptibility. These data demonstrate that cancer predisposition should also be considered in the context of somatic events and could have major implications for the design of human association studies to identify cancer susceptibility genes.     

Let-7b is a novel regulator of hepatitis C virus replication

The non-coding microRNA (miRNA) is involved in the regulation of hepatitis C virus (HCV) infection and offers an alternative target for developing anti-HCV agent. In this study, we aim to identify novel cellular miRNAs that directly target the HCV genome with anti-HCV therapeutic potential. Bioinformatic analyses were performed to unveil liver-abundant miRNAs with predicted target sequences on HCV genome. Various cell-based systems confirmed that let-7b plays a negative role in HCV expression. In particular, let-7b suppressed HCV replicon activity and down-regulated HCV accumulation leading to reduced infectivity of HCVcc. Mutational analysis identified let-7b binding sites at the coding sequences of NS5B and 5'-UTR of HCV genome that were conserved among various HCV genotypes. We further demonstrated that the underlying mechanism for let-7b-mediated suppression of HCV RNA accumulation was not dependent on inhibition of HCV translation. Let-7b and IFNα-2a also elicited a synergistic inhibitory effect on HCV infection. Together, let-7b represents a novel cellular miRNA that targets the HCV genome and elicits anti-HCV activity. This study thereby sheds new insight into understanding the role of host miRNAs in HCV pathogenesis and to developing a potential anti-HCV therapeutic strategy.     

Fe—Mn二元系中相能量MEAM研究

应用修正嵌入原子法（ＭＥＡＭ）研究了Ｆｅ－Ｍｎ二元合金中γ相（ｆｃｃ）和α（ｂｃｃ）随Ｍｎ含量变化的不同能量,它们的能量变化趋势与Ｆｅ－Ｍｎ二元相图的推测结果一致,由此表明,用ＭＥＡＭ法研究Ｆｅ－Ｍｎ二元系中两种立方相的能量是有效的。     

Functional genomics reveal that the serine synthesis pathway is essential in breast cancer

Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation. RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes. Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of α-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.     

局外人——评毕可思笔下的主人公廷克勒

毕可思的作品<帝国造就了我>从东方主义视角,追述了主人公廷克勒--一个英国人在殖民地上海(1919-1939)的奋斗历程,进一步展现殖民帝国在中国行使殖民统治权以及现代中国的觉醒过程.廷克勒既是自己社会阶层的局外人,又是上层阶层的局外人;既是英国的局外人,更是上海的局外人.从这个小人物身上,我们可以看到中国社会发展及全球化过程中一类人的身份认同问题.     

有序度和晶粒度及预变形度对CuZnAl合金形状记忆效应的影响

综合研究了母相的有序度ξ、晶粒尺寸d和在马氏体状态的变形度ε对CuZnAl合金中形状记忆效应的影响。从热力学出发,导出了形状回复率η与上述三种参数之间的统一的数学表达式。理论分析与实验测试结果吻合较好。     

Adriamycin-induced chromosome damage: Elevated frequencies of isochromatid aberrations in G2 and S phases

Summary Analysis of chromosomes from cells treated with adriamycin during G₂ and S phases showed a high frequency of isochromatid-type of breaks, in addition to the expected chromatid breaks. These are interpreted as independent breaks on sister chromatids because of preferential effects of the drug in specific chromosome regions. The break points are likely to be different, but morphologically such breaks would be indistinguishable from isochromatid or chromosome breaks.Supported in part by NO1-CM-53773 Division of Cancer Treatment NCI, Bethesda, Maryland, and by Research Grant No. VC-21 from American Cancer Society.