Comparison of bicyclic phosphorous esters with bicuculline and picrotoxin as antagonists of presynaptic inhibition in the rat cuneate nucleus

Summary The effects of 2 of a series of bicyclic phosphorous esters, the ethyl (EPTBO) and isopropyl (IPTBO) compounds, were compared with those of the GABA antagonists, picrotoxin and bicuculline, on presynaptic inhibition in the rat cuneate nucleus. Both EPTBO and IPTBO were found to be effective, reversible antagonists of presynaptic inhibition, with IPTBO approximately 10 times more potent than EPTBO and equipotent with bicuculline, EPTBO equipotent with picrotoxin.The authors are grateful to Dr J. F. Collins, Department of Chemistry, Sir John Cass School of Science and Technology, 31 Jewry Street, London, for the gift of bicyclic phosphorous esters.     

美国学校数学课程演化的历史观(1900-2006)

通过对100多年来美国学校数学课程演化的分析与思考,旨在提供一种认识美国数学课程的历史观,并从中窥探美国数学课程演化的艰巨性、曲折性和发展性,以启示如何更有效地进行数学课程改革.     

Crystal structure of the β2 adrenergic receptor-Gs protein complex

G protein-coupled receptors (GPCRs) are responsible for the majority of cellular responses to hormones and neurotransmitters as well as the senses of sight, olfaction and taste. The paradigm of GPCR signalling is the activation of a heterotrimeric GTP binding protein (G protein) by an agonist-occupied receptor. The β(2) adrenergic receptor (β(2)AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomeric β(2)AR and nucleotide-free Gs heterotrimer. The principal interactions between the β(2)AR and Gs involve the amino- and carboxy-terminal α-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the β(2)AR include a 14 ? outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an α-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR.     

Tumour evolution inferred by single-cell sequencing

Genomic analysis provides insights into the role of copy number variation in disease, but most methods are not designed to resolve mixed populations of cells. In tumours, where genetic heterogeneity is common, very important information may be lost that would be useful for reconstructing evolutionary history. Here we show that with flow-sorted nuclei, whole genome amplification and next generation sequencing we can accurately quantify genomic copy number within an individual nucleus. We apply single-nucleus sequencing to investigate tumour population structure and evolution in two human breast cancer cases. Analysis of 100 single cells from a polygenomic tumour revealed three distinct clonal subpopulations that probably represent sequential clonal expansions. Additional analysis of 100 single cells from a monogenomic primary tumour and its liver metastasis indicated that a single clonal expansion formed the primary tumour and seeded the metastasis. In both primary tumours, we also identified an unexpectedly abundant subpopulation of genetically diverse 'pseudodiploid' cells that do not travel to the metastatic site. In contrast to gradual models of tumour progression, our data indicate that tumours grow by punctuated clonal expansions with few persistent intermediates.