The efficacy of a novel compound, (E)-1-(4′-bromo-4-biphenylyl)-1-(4-chlorophenyl)-3-dimethylaminoprop-1-ene againstTrypanosoma cruzi in mice

Summary The biological properties of a novel compound 353C with high activity againstTrypanosoma cruzi, are described. The compound was about 10 times and 20 times more effective than either benznidazole or nifurtimox respectively, in producing radical cure in mice. 353C had a long half-life and showed anti-trypanosomal properties when given to mice at weekly intervals.     

Functions of actin in endocytosis

Endocytosis is a fundamental eukaryotic process required for remodelling plasma-membrane lipids and protein to ensure appropriate membrane composition. Increasing evidence from a number of cell types reveals that actin plays an active, and often essential, role at key endocytic stages. Much of our current mechanistic understanding of the endocytic process has come from studies in budding yeast and has been facilitated by yeast’s genetic amenability and by technological advances in live cell imaging. While endocytosis in metazoans is likely to be subject to a greater array of regulatory signals, recent reports indicate that spatiotemporal aspects of vesicle formation requiring actin are likely to be conserved across eukaryotic evolution. In this review we focus on the ‘modular’ model of endocytosis in yeast before highlighting comparisons with other cell types. Our discussion is limited to endocytosis involving clathrin as other types of endocytosis have not been demonstrated in yeast.     

抗癌新武器--培养病毒攻击肿瘤

世界各地的科学家们都在努力探索治疗癌症的各种方法,现在已有10多个研究小组正在尝试用病毒治疗肿瘤.他们培养对正常组织无害的病毒,或者改变致病性病毒的遗传特征,然后把它们投放到肿瘤内,期望这些病毒能够杀死癌细胞,同时又不损伤正常的组织.     

基因组怎样为进化作准备

插入基因组一些DNA序列的，是那些能促发迅疾而广泛的遗传改变的区段。著名作家和癌学家刘易斯·托马斯（LewisThomas）曾经写道：“DNA对稍稍出错的包容，真是奇妙的事。没有这个特性，我们会仍是厌氧细菌，更不会有音乐。”像许多其他学者──诺贝尔奖金获得者巴巴拉·麦克琳托克（BarbaraMcClintock）是著名的例外──托马斯认为，遗传的改变，也即新物种的进化，源于一些基因的个别、微小、随机的突变。但是，大量增长的论据──多数发表于今年六月纽约科学院主持召开的《生物进化的分子策略》研讨会──表明，生物学家之主流必须…     

Species diversity and habitat of grassland passerines during grazing of a prescribe-burned, mixed-grass prairie

No published data exist on responses of grassland passerines and their habitat to combined grazing and burning treatments in northern mixed-grass prairie. At Lostwood National Wildlife Refuge (LNWR) in northwestern North Dakota, we monitored breeding bird occurrence, abundance, and habitat during successive annual grazing treatments (1998-2000) on 5 prescribe-burned, mixed-grass prairie management units (range = 50-534 ha, each burned 3-6 times in the previous 10-20 years). All breeding passerine species characteristic of upland, northern mixed-grass prairie were common (> 10% occurrence) during at least 1 of 3 years on burned and grazed units, except Chestnut-collared Longspur ( Calcarius ornatus ), which was uncommon. Vegetation was generally shorter and sparser than that found on 4 nearby units treated by fire only (1999; density, visual obstruction, and height, all P Molothrus ater ) occurred 2.4 times more frequently on burned and grazed units studied. Our data suggest that species diversity of breeding grassland passerines changes little during initial years of rotation grazing at moderate stocking rates in fire-managed, northern mixed-grass prairie at LNWR.     

Structure of the insulin receptor ectodomain reveals a folded-over conformation

The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14 (ref. 4), grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding.     

Structure of mammalian AMPK and its regulation by ADP

The heterotrimeric AMP-activated protein kinase (AMPK) has a key role in regulating cellular energy metabolism; in response to a fall in intracellular ATP levels it activates energy-producing pathways and inhibits energy-consuming processes. AMPK has been implicated in a number of diseases related to energy metabolism including type 2 diabetes, obesity and, most recently, cancer. AMPK is converted from an inactive form to a catalytically competent form by phosphorylation of the activation loop within the kinase domain: AMP binding to the γ-regulatory domain promotes phosphorylation by the upstream kinase, protects the enzyme against dephosphorylation, as well as causing allosteric activation. Here we show that ADP binding to just one of the two exchangeable AXP (AMP/ADP/ATP) binding sites on the regulatory domain protects the enzyme from dephosphorylation, although it does not lead to allosteric activation. Our studies show that active mammalian AMPK displays significantly tighter binding to ADP than to Mg-ATP, explaining how the enzyme is regulated under physiological conditions where the concentration of Mg-ATP is higher than that of ADP and much higher than that of AMP. We have determined the crystal structure of an active AMPK complex. The structure shows how the activation loop of the kinase domain is stabilized by the regulatory domain and how the kinase linker region interacts with the regulatory nucleotide-binding site that mediates protection against dephosphorylation. From our biochemical and structural data we develop a model for how the energy status of a cell regulates AMPK activity.