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.     

工业设计价值链的全球化管理

尽管工业设计在多数企业里都比其他部门设立得晚,但因企业重视而发展迅速,目前已经成熟到出现了许多分支专业领域的程度。这些分支专业领域不只是刚出现而已,而是发展成几乎独立的专业领域、彼此很难相互取代的地步。尤其是在企业快速全球化的趋势下,其细分化将只会变得愈来愈快。根据所谓价值链的理论,这些分支专业领域虽然因其高独立性而必须由不同人员,甚至是在不同地域执行,但其间仍存有很明确的共同理想与工作目标,那就是必须协力提高设计产品的整体价值,所以其间的良好合作与相互配合就必须透过适当的价值链管理才有可能达成。因此,我们希望探讨应用此项管理概念于工业设计领域的有效方式,以提供企业界的设计管理者参考,并因而有利于其分支专业领域间能够顺利整合,而得以成功提高设计产品的整体价值。由于篇幅限制,将仅限于研究假设之阐述,也就是对如何应用价值链管理之概念于工业设计领域的有效方式进行探讨,至于对其应用效果之验证,则有待后续研究加以完成。     

Study on the Technique of Double-faced Embroidery on Chinese Palace Fans

Double - faced iso - object embroidery is carried out byusing the uneven intercalated stitch crafts of the parallel- lines stitch as a main body, being accompanied by oth-er stitch crafts and miscellaneous stitches, done on thesame textile material. This paper deals with the flower -bird double - faced embroidery fan of the Qing Dynasty,from pattern design, stitching formation and techniqueof color arrangement, describes the possible way of mak-ing double - faced embroidery with iso - object effectboth in the front and in the back.     

CMOS射频集成电路的设计

本书是《10^9赫射频（RF）集成电路设计指南》修订后的第二版。自1998年第一版问世后，RFCMOS的商品化突飞猛进，不少公司用CMOS技术制造RF线路，大学也把CMOS作为教学内容，10^9赫频率上的噪声系数在实际线路中已低于1dB，优良的RF器件模型也相继出现……这些都为本书的适时修订提供了充分条件。     

Regioselective one-pot protection of carbohydrates

Carbohydrates are involved in a wide range of biological processes. These structurally diverse compounds are more complex than other biological polymers, and are often present as heterogeneous mixtures in nature. The chemical synthesis of carbohydrates is one way to obtain pure oligosaccharides, but it is hampered by difficulties associated with the regioselective protection of polyhydroxyls and challenges related to the stereoselective assembly of glycosidic linkages. Here we describe a combinatorial, and highly-regioselective, method that can be used to protect individual hydroxy groups of a monosaccharide. This approach can be used to install an orthogonal protecting group pattern in a single reaction vessel (a 'one-pot' reaction), which removes the need to carry out the time-consuming isolation and purification of intermediates. Hundreds of building blocks have been efficiently prepared starting from d-glucose, and the iterative coupling of these building blocks enabled us to assemble beta-1,6-glucans and a library of oligosaccharides based on the influenza-virus-binding trisaccharide.     

Transvascular delivery of small interfering RNA to the central nervous system

A major impediment in the treatment of neurological diseases is the presence of the blood-brain barrier, which precludes the entry of therapeutic molecules from blood to brain. Here we show that a short peptide derived from rabies virus glycoprotein (RVG) enables the transvascular delivery of small interfering RNA (siRNA) to the brain. This 29-amino-acid peptide specifically binds to the acetylcholine receptor expressed by neuronal cells. To enable siRNA binding, a chimaeric peptide was synthesized by adding nonamer arginine residues at the carboxy terminus of RVG. This RVG-9R peptide was able to bind and transduce siRNA to neuronal cells in vitro, resulting in efficient gene silencing. After intravenous injection into mice, RVG-9R delivered siRNA to the neuronal cells, resulting in specific gene silencing within the brain. Furthermore, intravenous treatment with RVG-9R-bound antiviral siRNA afforded robust protection against fatal viral encephalitis in mice. Repeated administration of RVG-9R-bound siRNA did not induce inflammatory cytokines or anti-peptide antibodies. Thus, RVG-9R provides a safe and noninvasive approach for the delivery of siRNA and potentially other therapeutic molecules across the blood-brain barrier.