新型含芳香核柔性双咪唑配体及其配合物的合成与结构表征

基于含氮杂环配体的金属配位聚合物的独特性能,以取代位置不同的苯二酚、萘二酚、萘醌和蒽醌为起始原料,与1,2-二溴乙烷反应生成芳烃的双溴取代物,然后再与咪唑在碱性条件下发生取代反应,合成得到六种含芳香环的双咪唑类配体(Ⅰ-Ⅵ).结果表明,所有产物的结构均经熔点、IR、1H NMR和元素分析表征,所得数据与结构完全吻合,并对配体Ⅲ与Zn(NO3)2·6H2O形成的配位聚合物晶体结构进行了测定.     

Segregation of receptor and ligand regulates activation of epithelial growth factor receptor

Interactions between ligands and receptors are central to communication between cells and tissues. Human airway epithelia constitutively produce both a ligand, the growth factor heregulin, and its receptors--erbB2, erbB3 and erbB4 (refs 1-3). Although heregulin binding initiates cellular proliferation and differentiation, airway epithelia have a low rate of cell division. This raises the question of how ligand-receptor interactions are controlled in epithelia. Here we show that in differentiated human airway epithelia, heregulin-alpha is present exclusively in the apical membrane and the overlying airway surface liquid, physically separated from erbB2-4, which segregate to the basolateral membrane. This physical arrangement creates a ligand-receptor pair poised for activation whenever epithelial integrity is disrupted. Indeed, immediately following a mechanical injury, heregulin-alpha activates erbB2 in cells at the edge of the wound, and this process hastens restoration of epithelial integrity. Likewise, when epithelial cells are not separated into apical and basolateral membranes ('polarized'), or when tight junctions between adjacent cells are opened, heregulin-alpha activates its receptor. This mechanism of ligand-receptor segregation on either side of epithelial tight junctions may be vital for rapid restoration of integrity following injury, and hence critical for survival. This model also suggests a mechanism for abnormal receptor activation in diseases with increased epithelial permeability.     

Interaction of bride of sevenless membrane-bound ligand and the sevenless tyrosine-kinase receptor

During development of the Drosophila retina, the R8 photoreceptor neuron induces a neighbouring cell to assume an R7 cell fate. Genetic data suggest that the induction is mediated by two transmembrane proteins encoded by bride of sevenless and sevenless. A direct interaction between these two proteins was demonstrated by the heterotypic aggregation of cell lines expressing them. In the developing eye the sevenless-dependent internalization of bride of sevenless by the R7 precursor cell provides evidence for a direct interaction between these two proteins in vivo.     

基于研发型知识经济的内生增长模型

在罗默内生经济增长模型中引入人力资本因素,将技术进步和人力资本同时内生化,得出研发型知识经济增长的最优平衡路径。通过分析最优解以及各因素对经济增长的贡献,进一步说明了技术进步与人力资本在促进经济增长中的主导作用,并给出相应的政策建议。     

A point mutation in the neu oncogene mimics ligand induction of receptor aggregation

The rat neu gene, which encodes a protein closely related to the epidermal growth factor receptor, is a proto-oncogene that can be converted into an oncogene by a point mutation. Both genes encode proteins with a relative molecular mass of 185,000 but the question of why the neu gene product, p185neu, is oncogenic, whereas the product of c-neu, p185c-neu, is not, remains unanswered. The proteins have several features common to the family of tyrosine kinase growth-factor receptors, including cysteine-rich external domains, a hydrophobic transmembrane region and a cytoplasmic tyrosine kinase domain. The oncogenic p185neu differs from p185c-neu by an amino-acid substitution in the transmembrane region of the glycoprotein: this replacement of valine by glutamic acid at position 664 induces increased intrinsic tyrosine kinase activity which is associated with transformation. Many glycoproteins with charged amino acids in the transmembrane region exist as multimeric complexes at the plasma membrane. We have therefore investigated the association state of both products of the neu gene and show that the oncoprotein p185neu is organized at the plasma membrane primarily in an aggregated form, but that p185c-neu is not. Induction of an aggregated state may mimic aspects of ligand-induced receptor aggregation resulting in enzymatic activation that leads to cellular transformation.     

T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand

The binding of a T-cell antigen receptor (TCR) to peptide antigen presented by major histocompatibility antigens (pMHC) on antigen-presenting cells (APCs) is a central event in adaptive immune responses. The mechanism by which TCR-pMHC ligation initiates signalling, a process termed TCR triggering, remains controversial. It has been proposed that TCR triggering is promoted by segregation at the T cell-APC interface of cell-surface molecules with small ectodomains (such as TCR-pMHC and accessory receptors) from molecules with large ectodomains (such as the receptor protein tyrosine phosphatases CD45 and CD148). Here we show that increasing the dimensions of the TCR-pMHC interaction by elongating the pMHC ectodomain greatly reduces TCR triggering without affecting TCR-pMHC ligation. A similar dependence on receptor-ligand complex dimensions was observed with artificial TCR-ligand systems that span the same dimensions as the TCR-pMHC complex. Interfaces between T cells and APCs expressing elongated pMHC showed an increased intermembrane separation distance and less depletion of CD45. These results show the importance of the small size of the TCR-pMHC complex and support a role for size-based segregation of cell-surface molecules in TCR triggering.     

PPARγ罗格列酮对HT-29的生长抑制作用

PPARγ配体在抗肿瘤中发挥着重要的作用,这些配体具有抗肿瘤、诱导分化和抗血管生成等效果.目的主要是评估PPARγ激动剂罗格列酮对结肠癌细胞株HT-29生长的抑制作用.结果显示,罗格列酮可以有效地抑制体外培养的结肠癌细胞株HT-29的生长及克隆形成,并能抑制HT-29裸鼠移植瘤的生长.与此同时,罗格列酮能够升高PPARγ, p- PPARγ的表达水平.以上结果初步证明罗格列酮在体内外均可抑制结肠癌细胞株HT-29的成长,提示罗格列酮有可能发展成为治疗结肠癌的有效药物.     

Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1.

The underlying causes of obesity are poorly understood but probably involve complex interactions between many neurotransmitter and neuropeptide systems involved in the regulation of food intake and energy balance. Three pieces of evidence indicate that the neuropeptide melanin-concentrating hormone (MCH) is an important component of this system. First, MCH stimulates feeding when injected directly into rat brains; second, the messenger RNA for the MCH precursor is upregulated in the hypothalamus of genetically obese mice and in fasted animals; and third, mice lacking MCH eat less and are lean. MCH antagonists might, therefore, provide a treatment for obesity. However, the development of such molecules has been hampered because the identity of the MCH receptor has been unknown until now. Here we show that the 353-amino-acid human orphan G-protein-coupled receptor SLC-1 expressed in HEK293 cells binds MCH with sub-nanomolar affinity, and is stimulated by MCH to mobilize intracellular Ca2+ and reduce forskolin-elevated cyclic AMP levels. We also show that SLC-1 messenger RNA and protein is expressed in the ventromedial and dorsomedial nuclei of the hypothalamus, consistent with a role for SLC-1 in mediating the effects of MCH on feeding.     

Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand

In a variety of cells, the Ca2+ signalling process is mediated by the endoplasmic-reticulum-membrane-associated Ca2+ release channel, inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R). Being ubiquitous and present in organisms ranging from humans to Caenorhabditis elegans, InsP3R has a vital role in the control of cellular and physiological processes as diverse as cell division, cell proliferation, apoptosis, fertilization, development, behaviour, memory and learning. Mouse type I InsP3R (InsP3R1), found in high abundance in cerebellar Purkinje cells, is a polypeptide with three major functionally distinct regions: the amino-terminal InsP3-binding region, the central modulatory region and the carboxy-terminal channel region. Here we present a 2.2-A crystal structure of the InsP3-binding core of mouse InsP3R1 in complex with InsP3. The asymmetric, boomerang-like structure consists of an N-terminal beta-trefoil domain and a C-terminal alpha-helical domain containing an 'armadillo repeat'-like fold. The cleft formed by the two domains exposes a cluster of arginine and lysine residues that coordinate the three phosphoryl groups of InsP3. Putative Ca2+-binding sites are identified in two separate locations within the InsP3-binding core.     

环境和能源约束下的内生经济增长模型

综合考虑环境和能源这两个制约经济高速发展的因素,建立经济增长和环境质量与能源强度之间的关系。引入人的身体健康指数去衡量环境的质量,并将其引入效用函数,揭示了基于代表性个体的消费和健康的效用函数达到最大化的经济发展需要满足的条件。     

An endogenous annual clock in the toxic marine dinoflagellate Gonyaulax tamarensis

Blooms of the toxic dinoflagellate Gonyaulax tamarensis (synonyms Protogonyaulax tamarensis and Alexandrium tamarense) cause outbreaks of paralytic shellfish poisoning (PSP) in coastal waters throughout the world. In the Gulf of Maine, episodes occur between April and November, a seasonality due in part to life-cycle alternations between motile, vegetative cells and resting cysts which overwinter in bottom sediments. Newly formed cysts have a mandatory 2-6 month dormancy period during which germination is not possible, but once mature, the resting state will continue if temperatures are unfavourable or oxygen is unavailable. We now report another factor controlling germination of cysts of G. tamarensis from deep coastal waters--an endogenous annual clock that can override an otherwise favourable environment for germination. Similar annual variability in germination has not been observed for cysts of this species from shallow estuaries. These results represent the first conclusive demonstration of an endogenous circannual rhythm in a marine plant. They are evolutionarily and ecologically significant because an endogenous annual clock can lead to the release of motile cells into deep and relatively invariant bottom waters at those times when temperature and light at the surface are suitable for growth. In shallow waters where seasonal variability is large and extends to bottom sediments, a strategy similar to that of the seeds of terrestrial plants would be more appropriate, namely a direct coupling between germination and the external environment.     

A human homologue of the yeast HDEL receptor

Retention of resident proteins in the lumen of the endoplasmic reticulum is achieved in both yeast and animal cells by their continual retrieval from the cis-Golgi, or a pre-Golgi compartment. Sorting of these proteins is dependent on a C-terminal tetrapeptide signal, usually Lys-Asp-Glu-Leu (KDEL in the single letter code) in animal cells, His-Asp-Glu-Leu (HDEL) in Saccharomyces cerevisiae. There is evidence that the ERD2 gene encodes the sorting receptor that recognizes HDEL in yeast; its product is an integral membrane protein of relative molecular mass 26,000 (26K) that is not glycosylated. In contrast, Vaux et al. suggest that the mammalian KDEL receptor is a 72K glycoprotein that they detected using an anti-idiotypic antibody approach. If this were so, it would indicate a surprising divergence of the retrieval machinery between yeast and animal cells. We report here that human cells express a protein similar in sequence, size and properties to the ERD2 product, and propose that this protein is the human KDEL receptor.     

Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor

Metastasis is a major cause of death in cancer patients and involves a multistep process including detachment of cancer cells from a primary cancer, invasion of surrounding tissue, spread through circulation, re-invasion and proliferation in distant organs. KiSS-1 is a human metastasis suppressor gene, that suppresses metastases of human melanomas and breast carcinomas without affecting tumorigenicity. However, its gene product and functional mechanisms have not been elucidated. Here we show that KiSS-1 (refs 1, 4) encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which we have isolated from human placenta as the endogenous ligand of an orphan G-protein-coupled receptor (hOT7T175) and have named 'metastin'. Metastin inhibits chemotaxis and invasion of hOT7T175-transfected CHO cells in vitro and attenuates pulmonary metastasis of hOT7T175-transfected B16-BL6 melanomas in vivo. The results suggest possible mechanisms of action for KiSS-1 and a potential new therapeutic approach.     

柴达木盆地阿尔金山前带油气勘探方向研究--来自洛杉矶盆地油气勘探实践的启发

柴达木盆地与洛杉矶盆地在构造特征和演化主控因素等方面具有很大的相似性,其中阿尔金断裂带和圣莫尼卡断裂带构造活动特征非常相似,两者山前地区的构造背景也具有可比性.洛杉矶盆地的勘探实践说明断层下盘圈闭有时也能含有很可观的储量.通过对比分析两者之间的相似性,认为柴达木盆地阿尔金山前带构造深部发育的逆冲断裂下盘也应该具有形成油气圈闭的条件.评价和预测此类圈闭的最关键因素是进行走向闭合分析和断层封闭性的评价.     

Mapping of an endogenous retroviral sequence to human chromosome 18

The application of recombinant DNA technologies has allowed the detection of at least three families of moderately repetitive DNA segments in the human genome that are homologous to retroviruses previously isolated from mice and primates. One of these DNA segments has been shown by nucleotide sequence comparisons to be distantly related to both Moloney murine leukaemia virus (MoMuLV) and the endogenous baboon retrovirus and to have the sequence organization characteristic of an integrated retrovirus. Isolation of the homologous locus from chimpanzee DNA indicated that the integration event preceded the evolutionary divergence of chimpanzees and man. Here we have used a panel of rodent x human somatic cell hybrids to assign the chromosomal localization of this segment, called ERV1 (endogenous retrovirus-1), to human chromosome 18 (HSA 18).     

智能化烃类重气泄散过程的数值预测

提出实现烃类重气泄散态势的动态过程数值预测新构想－－基于人工神经网络的“反求源”技术。给出过程系统数学分析模型,根据实际网络预测结果,获取、分析了其动态模拟时域曲线。