The design of intracellular oscillators that interact with metabolism

Biological oscillations such as circadian rhythms are ubiquitous in nature and have attracted significant attention because of their intriguing dynamics and important biological roles. Understanding of such sophisticated and robust oscillators requires more than the traditional reductionist approach. Recently, a synthetic approach similar to the design of engineering machinery has provided a valuable alternative for testing hypothetical operating principles. These man-made genetic circuits and gene-metabolic circuits are designed based on physical concepts, guided by mathematical models, and constrained by biological and chemical reality. While still primitive compared with the natural circuits, the designed gene-metabolic oscillator has begun to show hallmarks of circadian rhythms such as temperature compensation and close interaction with metabolism. Received 29 December 2005; received after revision 12 February 2006; accepted 16 March 2006     

Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes

Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers.     

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.     

Selenocystine induces apoptosis of A375 human melanoma cells by activating ROS-mediated mitochondrial pathway and p53 phosphorylation

Selenocystine (SeC), a naturally occurring selenoamino acid, has been shown to be a novel compound with broad-spectrum anticancer activity. In this study, we showed that SeC triggered time- and dose-dependent apoptosis in A375 human melanoma cells by activating the mitochondria-mediated and death receptor-mediated apoptosis pathways. Pretreatment of cells with a general caspase inhibitor z-VAD-fmk significantly prevented SeC-induced apoptosis. A375 cells exposed to SeC showed an increase in levels of total p53 and phosphorylated p53 (serine-15). Silencing of p53 expression with RNA interference significantly suppressed SeC-induced p53 phosphorylation, caspase activation and apoptotic cell death. Moreover, generation of reactive oxygen species and subsequent induction of DNA strand breaks were found to be upstream mediators of p53 activation induced by SeC. In a nude mice xenograft experiment, SeC significantly inhibited the tumor growth of A375 cells via induction of apoptosis. Taken together, these results suggest the potential applications of SeC in cancer chemoprevention.     

支持产品可制造性设计的渐进式CAPP系统研究

分析了并行设计模式下ＣＡＰＰ技术的新特点和目前研究工作中存在的问题。在此基础上，提出了基于原型的渐进式工艺设计新方法，详细地讨论了它的关键性技术和实施策略，总结了这一方法的突出特点。     

SiO_xN_y和SiO_2膜中的高场电子陷阱的温度依赖性和产生机理

研究了温度从１００～４２３Ｋ范围内在薄氮氧化硅膜和薄二氧化硅膜中的高场电子陷阱的温度依赖性。我们发现；在研究的温度范围内，当温度降低时，薄氮氧化硅膜中的有效高场电子陷饼表面浓度增加，相反，在薄二氧化硅膜中的有效高场电子陷阱表面浓度减少；对于二氧化硅膜，有效的高场电子陷阶能级集中在一个非常窄的能量范围，它的产生率是１．２８３×１０１１／ｃｍ２，激活能是０．１９２ｅＶ。根据实验结果，提出了一个在二氧化硅中的高场电子陷阱的产生模型。     

农村治污减排的重点及对策研究

本文介绍了农村地区存在的主要生活污水、生活垃圾、工业污染、养殖污染、化肥农药污染状况,针对农村地区存在的环境问题,从农村水源地保护、生活污水防治、生活垃圾防治、工业污染防治、养殖污染治理、农村土壤污染防治、农业面源污染防治、生态示范工程建设、农村环境管理能力建设等9个方面进行分析,并提出了污染防治对策。     

Adherens junction protein nectin-4 is the epithelial receptor for measles virus

Measles virus is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths. Although it was long believed to replicate in the respiratory epithelium before disseminating, it was recently shown to infect initially macrophages and dendritic cells of the airways using signalling lymphocytic activation molecule family member 1 (SLAMF1; also called CD150) as a receptor. These cells then cross the respiratory epithelium and transport the infection to lymphatic organs where measles virus replicates vigorously. How and where the virus crosses back into the airways has remained unknown. On the basis of functional analyses of surface proteins preferentially expressed on virus-permissive human epithelial cell lines, here we identify nectin-4 (ref. 8; also called poliovirus-receptor-like-4 (PVRL4)) as a candidate host exit receptor. This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. Nectin-4 sustains measles virus entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally. It is downregulated in infected epithelial cells, including those of macaque tracheae. Although other viruses use receptors to enter hosts or transit through their epithelial barriers, we suggest that measles virus targets nectin-4 to emerge in the airways. Nectin-4 is a cellular marker of several types of cancer, which has implications for ongoing measles-virus-based clinical trials of oncolysis.